The 2 cardinal properties of stem cells are the ability to self-renew and the ability to differentiate into distinctive end-stage cell types. The work of Caplan¹ captured our early attention, with cells cultured from bone marrow differentiating into a number of different cell types of orthopedic interest. Our latest attention has been captured by the additional abilities of these cells to mobilize, monitor, and interact with their surrounding environment.^2-4 In response to their environment, stem cells are able to release a broad spectrum of macromolecules with trophic, chemotactic, and immunomodulatory potential, which allows them to participate in injury response, tissue healing, and tissue regeneration.⁴ These cells are innate to the body’s monitoring, maintenance, repair, and stress response systems.^2,4-11 Basic science and animal studies have illustrated the potential of cells with stem potential regardless of their environment/source of harvest.

Where Can We Get Stem Cells?

Cells with stem properties are present in many environmental niches, including the bone marrow, peripheral circulatory system, adipose tissue, synovial tissue, muscle tissue, and tendon tissue.^12-15 A number of cell types with stem properties populate the bone marrow niche, including hematopoietic stem/progenitor cells (HSPC), perivascular stromal cells (PSC), endothelial stem cells (ESC), and immature cells with qualities like embryonal stem cells termed very small embryonal-like stem cells (VESL).^12,15-19 All of these cells have stem properties and have been shown to differentiate to tissues of orthopedic interest.The interplay, interaction, and potential of these cell types is complex and incompletely understood.^12,15-19 When bone marrow is aspirated for culturing purposes, it is unclear which cell line produces the plastic-adherent multipotent cells grown in culture, which are often referred to as mesenchymal stem cells (MSCs). Researches propose that HSPC and/or VESL circulate peripherally in small numbers but leave the bone marrow in certain mobilization instances and are important for the monitoring and maintenance of the majority of tissues in our bodies.^5,16 Current clinical utilization of these cell types by the orthopedic community primarily utilizes point-of-care bone marrow aspiration and concentration, while the hematology oncology community mobilizes cells from the bone marrow to the blood stream with pharmaceutical agents and harvests cells via apheresis. Bone marrow aspiration produces variable numbers of stem cells, with studies ranging from 1 stem cell per mL of tissue collected to 300,000 stem cells per mL of tissue collected.20Mobilization and apheresis can produce large volumes of peripheral blood-derived cells with 600,000 HSPC per mL and 2.32 million PSC per mL of tissue collected.²¹

In adipose tissue, cells adherent to the abluminal side of blood vessels known as pericytes also carry stem qualities. Aspiration and processing of adipose tissue can access these stem cells, producing a product often referred to as stromal vascular fraction (SVF). Processing of lipoaspirate to create stromal vascular fraction requires mechanical or enzymatic processing. This also produces variable numbers of stem cells, with quantitative studies ranging from 5000 to 1.5 million stem cells per mL of tissue collected.²⁰ Similar to adipose-derived stem cells, synovial-derived and muscle-derived stem cells also require mechanical or enzymatic processing. For applications where it is believed that a large number of cells is necessary, investigators often utilize culturing techniques for all sources with the exception of mobilization and apheresis harvest. As clinicians, 3 challenges have proven more important than which cell type to utilize: 1) patient-care logistics regarding collection and application; 2) the undefined dose-response curve regarding stem cell treatments; and 3) evolving government/community regulation.

Regulation of Stem Cell Therapies

The regulation of stem cell technologies is a double-edged sword for development. While loose regulation encourages clinical application and experimentation, patient safety and efficacy concerns are raised, and a technology’s worth is not proven before clinical application. Tight regulation temporarily hampers progress, yet ensures the proof of safety and efficacy prior to widespread implementation. Within the United States, the Food and Drug Administration (FDA) has tightened regulation, established precedent, and intervened in the ability of clinicians to utilize stem cell therapies in humans, through “warning letters,” “untitled letters,” and industry guidance documents.^22-30

The FDA categorizes stem cell therapies as human cells, tissues, and cellular- and tissue-based products (HCT/Ps). Section 361 of the Public Health Safety (PHS) Act established and outlined the authority of the FDA to regulate low-risk HCT/Ps in order to prevent the introduction, transmission, and spread of communicable disease. Section 361 provided standards for safety without requiring preclinical development. The FDA established 4 principles to determine the risk of HCT/Ps: the extent of manipulation involved in manufacture, the metabolic activity/autologous nature of the product, whether the product represents a tissue combined with another product, and whether the product is utilized in a fashion homologous with its original function (Figure 1). If a product/therapy meets requirements around all 4 of these principles, then it is deemed a low-risk product and regulated under Section 361 alone. If a product/therapy does not meet requirements around all 4 of these principles, then the FDA regulates the product/therapy under additional codes including Section 351 of the PHS Act. Section 351 outlines a developmental process including preclinical animal trials, phased clinical study, and premarket review by the FDA prior to offering the product/treatment in clinical practice. The developmental process requires investigators and/or industry developers to initiate an Investigational New Drug (IND) program whose end goal is to present data from all developmental study and obtain a Biologic License Application (BLA) approval to market the product.^22-23 To establish safety and efficacy, the traditional IND program involves a preclinical animal study, a small pilot human study (Phase I), a small initial randomized controlled trial (Phase II), followed by a large multicenter randomized controlled trial (Phase III) (Figure 2). The FDA has recognized little to no stem cell treatments as products regulated by Section 361 alone. Additionally, the FDA has established precedent regarding allograft stem cells, cells obtained from fat harvest, amniotic/placental products, and cultured cells, suggesting that these products are not low risk and require an IND pathway outlined in Section 351.^24-30

Bone Marrow Aspiration

Surprisingly, the FDA has not moved to regulate the point-of-care use of bone marrow aspirate or platelet-rich plasma and has labeled these as “not HCTPs.” The stem cell concentration of bone marrow aspirate is technique-dependent, declines with age, and has been found to be an important factor for clinical benefit.³¹ While it is possible to aspirate from multiple sites, posterior iliac crest harvest produces the highest stem cell yield.^32-34 Hernigou and colleagues^35-36 have outlined safe zones for trocar placement and illustrated that strong aspiration with small-volume syringes, 10-mL syringes, optimizes stem cell harvest. Additionally, studies by Hernigou and colleagues^31,37-38 involving tibial nonunion, avascular necrosis of the femur, and augmentation of rotator cuff repair are guideposts to clinicians utilizing bone marrow aspirate.

Amniotic Stem Cell Technologies and Adipose-Derived Stem Cells

While some argue that there is regulatory confusion around amniotic/placental-derived tissues and adipose-derived products, the FDA has clearly established precedent establishing these as products requiring Section 351 development.^26-29 Companies are marketing products derived from perinatal byproducts, yet there are multiple FDA letters suggesting that these are not products regulated solely under PHS Act 361 because they do not meet the criteria of homologous use and are not autologous.^28-29 Use of these products places risk upon the clinician and the patient. Some argue that adipose-derived stem cell products are 361 products. While the FDA has approved devices for the mechanical processing of lipoaspirate, they have established precedent suggesting that they consider orthopedic applications nonhomologous and any processing that “alters the original relevant characteristics of adipose tissue relating to the tissue’s utility for reconstruction, repair, or replacement” as more than minimal manipulation.^26,27 The FDA originally planned an open forum for discussion with clinicians and industry for April 2016. This open forum was delayed due to the volume of interest, and a workshop has been planned for Fall 2016.

Future Regulation of Stem Cell Technologies

While many countries have mirrored the FDA with tight regulatory mechanisms, a few countries have established modern regulatory mechanisms aimed at the promotion of conscientious development, including South Korea, Japan, and England. For example, in 2014 Japan labeled stem cell technologies as “regenerative medicine products,” setting them apart from pharmaceuticals, and implemented a new approval system allowing early observed commercialization with reimbursement after less stringent safety and efficacy milestones.²²The observed commercialization lowers time and financial hurdles for development while still requiring the proof of the technology’s worth. Countries that have effected change have positioned themselves to be pioneers in this emerging field.

In March 2016, the Reliable and Effective Growth for Regenerative Health Options that Improve Wellness (REGROW) Act of 2016 (S. 2689 / H.R. 4762) was introduced into the United States Congress. This bipartisan, bicameral legislation was introduced, read twice, and referred to subcommittee. Its goal is to reduce barriers and accelerate development of biologic therapies while keeping the frame work set forth under Sections 351 and 361 of the PHS Act.³⁹ Similar to the pathway in Japan, the REGROW Act would establish a conditional approval pathway that would ensure products are safe and effective while also evolving the regulatory pathway towards progress (Figure 3). Development would still require an IND application after preclinical animal study. However, after safety was established with human Phase I data and preliminary evidence of efficacy with Phase II data, patients could be treated with the investigational therapies and reimbursement collected for a limited period of time (5 years) prior to a large Phase III human clinical trial. Patients treated with the new therapy would be monitored closely. All results would be reported to the FDA in a BLA. This change in legislation would lower but not remove regulatory hurdles necessary for development.

Conclusion

The future of stem cell treatments hinges upon the creation of new favorable regulatory mechanisms that will promote clinical application while ensuring that safety and efficacy milestones are reached. Clinical researchers require freedom to develop these technologies while protecting patients and ensuring the validity of treatments. The coordination of research and regulatory affairs on a global level is necessary focusing on the harmonization of guidelines, regulations, and mechanisms for simultaneous adoption in different countries. The global orthopedic community has made strides regarding the science of stem cell technologies; it is time for us to initiate progressive change regarding regulation so that we can determine what is effective clinically.

The 2 cardinal properties of stem cells are the ability to self-renew and the ability to differentiate into distinctive end-stage cell types. The work of Caplan¹ captured our early attention, with cells cultured from bone marrow differentiating into a number of different cell types of orthopedic interest. Our latest attention has been captured by the additional abilities of these cells to mobilize, monitor, and interact with their surrounding environment.^2-4 In response to their environment, stem cells are able to release a broad spectrum of macromolecules with trophic, chemotactic, and immunomodulatory potential, which allows them to participate in injury response, tissue healing, and tissue regeneration.⁴ These cells are innate to the body’s monitoring, maintenance, repair, and stress response systems.^2,4-11 Basic science and animal studies have illustrated the potential of cells with stem potential regardless of their environment/source of harvest.

Where Can We Get Stem Cells?

Cells with stem properties are present in many environmental niches, including the bone marrow, peripheral circulatory system, adipose tissue, synovial tissue, muscle tissue, and tendon tissue.^12-15 A number of cell types with stem properties populate the bone marrow niche, including hematopoietic stem/progenitor cells (HSPC), perivascular stromal cells (PSC), endothelial stem cells (ESC), and immature cells with qualities like embryonal stem cells termed very small embryonal-like stem cells (VESL).^12,15-19 All of these cells have stem properties and have been shown to differentiate to tissues of orthopedic interest.The interplay, interaction, and potential of these cell types is complex and incompletely understood.^12,15-19 When bone marrow is aspirated for culturing purposes, it is unclear which cell line produces the plastic-adherent multipotent cells grown in culture, which are often referred to as mesenchymal stem cells (MSCs). Researches propose that HSPC and/or VESL circulate peripherally in small numbers but leave the bone marrow in certain mobilization instances and are important for the monitoring and maintenance of the majority of tissues in our bodies.^5,16 Current clinical utilization of these cell types by the orthopedic community primarily utilizes point-of-care bone marrow aspiration and concentration, while the hematology oncology community mobilizes cells from the bone marrow to the blood stream with pharmaceutical agents and harvests cells via apheresis. Bone marrow aspiration produces variable numbers of stem cells, with studies ranging from 1 stem cell per mL of tissue collected to 300,000 stem cells per mL of tissue collected.20Mobilization and apheresis can produce large volumes of peripheral blood-derived cells with 600,000 HSPC per mL and 2.32 million PSC per mL of tissue collected.²¹

In adipose tissue, cells adherent to the abluminal side of blood vessels known as pericytes also carry stem qualities. Aspiration and processing of adipose tissue can access these stem cells, producing a product often referred to as stromal vascular fraction (SVF). Processing of lipoaspirate to create stromal vascular fraction requires mechanical or enzymatic processing. This also produces variable numbers of stem cells, with quantitative studies ranging from 5000 to 1.5 million stem cells per mL of tissue collected.²⁰ Similar to adipose-derived stem cells, synovial-derived and muscle-derived stem cells also require mechanical or enzymatic processing. For applications where it is believed that a large number of cells is necessary, investigators often utilize culturing techniques for all sources with the exception of mobilization and apheresis harvest. As clinicians, 3 challenges have proven more important than which cell type to utilize: 1) patient-care logistics regarding collection and application; 2) the undefined dose-response curve regarding stem cell treatments; and 3) evolving government/community regulation.

Regulation of Stem Cell Therapies

The regulation of stem cell technologies is a double-edged sword for development. While loose regulation encourages clinical application and experimentation, patient safety and efficacy concerns are raised, and a technology’s worth is not proven before clinical application. Tight regulation temporarily hampers progress, yet ensures the proof of safety and efficacy prior to widespread implementation. Within the United States, the Food and Drug Administration (FDA) has tightened regulation, established precedent, and intervened in the ability of clinicians to utilize stem cell therapies in humans, through “warning letters,” “untitled letters,” and industry guidance documents.^22-30

The FDA categorizes stem cell therapies as human cells, tissues, and cellular- and tissue-based products (HCT/Ps). Section 361 of the Public Health Safety (PHS) Act established and outlined the authority of the FDA to regulate low-risk HCT/Ps in order to prevent the introduction, transmission, and spread of communicable disease. Section 361 provided standards for safety without requiring preclinical development. The FDA established 4 principles to determine the risk of HCT/Ps: the extent of manipulation involved in manufacture, the metabolic activity/autologous nature of the product, whether the product represents a tissue combined with another product, and whether the product is utilized in a fashion homologous with its original function (Figure 1). If a product/therapy meets requirements around all 4 of these principles, then it is deemed a low-risk product and regulated under Section 361 alone. If a product/therapy does not meet requirements around all 4 of these principles, then the FDA regulates the product/therapy under additional codes including Section 351 of the PHS Act. Section 351 outlines a developmental process including preclinical animal trials, phased clinical study, and premarket review by the FDA prior to offering the product/treatment in clinical practice. The developmental process requires investigators and/or industry developers to initiate an Investigational New Drug (IND) program whose end goal is to present data from all developmental study and obtain a Biologic License Application (BLA) approval to market the product.^22-23 To establish safety and efficacy, the traditional IND program involves a preclinical animal study, a small pilot human study (Phase I), a small initial randomized controlled trial (Phase II), followed by a large multicenter randomized controlled trial (Phase III) (Figure 2). The FDA has recognized little to no stem cell treatments as products regulated by Section 361 alone. Additionally, the FDA has established precedent regarding allograft stem cells, cells obtained from fat harvest, amniotic/placental products, and cultured cells, suggesting that these products are not low risk and require an IND pathway outlined in Section 351.^24-30

Bone Marrow Aspiration

Surprisingly, the FDA has not moved to regulate the point-of-care use of bone marrow aspirate or platelet-rich plasma and has labeled these as “not HCTPs.” The stem cell concentration of bone marrow aspirate is technique-dependent, declines with age, and has been found to be an important factor for clinical benefit.³¹ While it is possible to aspirate from multiple sites, posterior iliac crest harvest produces the highest stem cell yield.^32-34 Hernigou and colleagues^35-36 have outlined safe zones for trocar placement and illustrated that strong aspiration with small-volume syringes, 10-mL syringes, optimizes stem cell harvest. Additionally, studies by Hernigou and colleagues^31,37-38 involving tibial nonunion, avascular necrosis of the femur, and augmentation of rotator cuff repair are guideposts to clinicians utilizing bone marrow aspirate.

Amniotic Stem Cell Technologies and Adipose-Derived Stem Cells

While some argue that there is regulatory confusion around amniotic/placental-derived tissues and adipose-derived products, the FDA has clearly established precedent establishing these as products requiring Section 351 development.^26-29 Companies are marketing products derived from perinatal byproducts, yet there are multiple FDA letters suggesting that these are not products regulated solely under PHS Act 361 because they do not meet the criteria of homologous use and are not autologous.^28-29 Use of these products places risk upon the clinician and the patient. Some argue that adipose-derived stem cell products are 361 products. While the FDA has approved devices for the mechanical processing of lipoaspirate, they have established precedent suggesting that they consider orthopedic applications nonhomologous and any processing that “alters the original relevant characteristics of adipose tissue relating to the tissue’s utility for reconstruction, repair, or replacement” as more than minimal manipulation.^26,27 The FDA originally planned an open forum for discussion with clinicians and industry for April 2016. This open forum was delayed due to the volume of interest, and a workshop has been planned for Fall 2016.

Future Regulation of Stem Cell Technologies

While many countries have mirrored the FDA with tight regulatory mechanisms, a few countries have established modern regulatory mechanisms aimed at the promotion of conscientious development, including South Korea, Japan, and England. For example, in 2014 Japan labeled stem cell technologies as “regenerative medicine products,” setting them apart from pharmaceuticals, and implemented a new approval system allowing early observed commercialization with reimbursement after less stringent safety and efficacy milestones.²²The observed commercialization lowers time and financial hurdles for development while still requiring the proof of the technology’s worth. Countries that have effected change have positioned themselves to be pioneers in this emerging field.

In March 2016, the Reliable and Effective Growth for Regenerative Health Options that Improve Wellness (REGROW) Act of 2016 (S. 2689 / H.R. 4762) was introduced into the United States Congress. This bipartisan, bicameral legislation was introduced, read twice, and referred to subcommittee. Its goal is to reduce barriers and accelerate development of biologic therapies while keeping the frame work set forth under Sections 351 and 361 of the PHS Act.³⁹ Similar to the pathway in Japan, the REGROW Act would establish a conditional approval pathway that would ensure products are safe and effective while also evolving the regulatory pathway towards progress (Figure 3). Development would still require an IND application after preclinical animal study. However, after safety was established with human Phase I data and preliminary evidence of efficacy with Phase II data, patients could be treated with the investigational therapies and reimbursement collected for a limited period of time (5 years) prior to a large Phase III human clinical trial. Patients treated with the new therapy would be monitored closely. All results would be reported to the FDA in a BLA. This change in legislation would lower but not remove regulatory hurdles necessary for development.

Conclusion

The future of stem cell treatments hinges upon the creation of new favorable regulatory mechanisms that will promote clinical application while ensuring that safety and efficacy milestones are reached. Clinical researchers require freedom to develop these technologies while protecting patients and ensuring the validity of treatments. The coordination of research and regulatory affairs on a global level is necessary focusing on the harmonization of guidelines, regulations, and mechanisms for simultaneous adoption in different countries. The global orthopedic community has made strides regarding the science of stem cell technologies; it is time for us to initiate progressive change regarding regulation so that we can determine what is effective clinically.

The 2 cardinal properties of stem cells are the ability to self-renew and the ability to differentiate into distinctive end-stage cell types. The work of Caplan¹ captured our early attention, with cells cultured from bone marrow differentiating into a number of different cell types of orthopedic interest. Our latest attention has been captured by the additional abilities of these cells to mobilize, monitor, and interact with their surrounding environment.^2-4 In response to their environment, stem cells are able to release a broad spectrum of macromolecules with trophic, chemotactic, and immunomodulatory potential, which allows them to participate in injury response, tissue healing, and tissue regeneration.⁴ These cells are innate to the body’s monitoring, maintenance, repair, and stress response systems.^2,4-11 Basic science and animal studies have illustrated the potential of cells with stem potential regardless of their environment/source of harvest.

Where Can We Get Stem Cells?

Cells with stem properties are present in many environmental niches, including the bone marrow, peripheral circulatory system, adipose tissue, synovial tissue, muscle tissue, and tendon tissue.^12-15 A number of cell types with stem properties populate the bone marrow niche, including hematopoietic stem/progenitor cells (HSPC), perivascular stromal cells (PSC), endothelial stem cells (ESC), and immature cells with qualities like embryonal stem cells termed very small embryonal-like stem cells (VESL).^12,15-19 All of these cells have stem properties and have been shown to differentiate to tissues of orthopedic interest.The interplay, interaction, and potential of these cell types is complex and incompletely understood.^12,15-19 When bone marrow is aspirated for culturing purposes, it is unclear which cell line produces the plastic-adherent multipotent cells grown in culture, which are often referred to as mesenchymal stem cells (MSCs). Researches propose that HSPC and/or VESL circulate peripherally in small numbers but leave the bone marrow in certain mobilization instances and are important for the monitoring and maintenance of the majority of tissues in our bodies.^5,16 Current clinical utilization of these cell types by the orthopedic community primarily utilizes point-of-care bone marrow aspiration and concentration, while the hematology oncology community mobilizes cells from the bone marrow to the blood stream with pharmaceutical agents and harvests cells via apheresis. Bone marrow aspiration produces variable numbers of stem cells, with studies ranging from 1 stem cell per mL of tissue collected to 300,000 stem cells per mL of tissue collected.20Mobilization and apheresis can produce large volumes of peripheral blood-derived cells with 600,000 HSPC per mL and 2.32 million PSC per mL of tissue collected.²¹

In adipose tissue, cells adherent to the abluminal side of blood vessels known as pericytes also carry stem qualities. Aspiration and processing of adipose tissue can access these stem cells, producing a product often referred to as stromal vascular fraction (SVF). Processing of lipoaspirate to create stromal vascular fraction requires mechanical or enzymatic processing. This also produces variable numbers of stem cells, with quantitative studies ranging from 5000 to 1.5 million stem cells per mL of tissue collected.²⁰ Similar to adipose-derived stem cells, synovial-derived and muscle-derived stem cells also require mechanical or enzymatic processing. For applications where it is believed that a large number of cells is necessary, investigators often utilize culturing techniques for all sources with the exception of mobilization and apheresis harvest. As clinicians, 3 challenges have proven more important than which cell type to utilize: 1) patient-care logistics regarding collection and application; 2) the undefined dose-response curve regarding stem cell treatments; and 3) evolving government/community regulation.

Regulation of Stem Cell Therapies

The regulation of stem cell technologies is a double-edged sword for development. While loose regulation encourages clinical application and experimentation, patient safety and efficacy concerns are raised, and a technology’s worth is not proven before clinical application. Tight regulation temporarily hampers progress, yet ensures the proof of safety and efficacy prior to widespread implementation. Within the United States, the Food and Drug Administration (FDA) has tightened regulation, established precedent, and intervened in the ability of clinicians to utilize stem cell therapies in humans, through “warning letters,” “untitled letters,” and industry guidance documents.^22-30

The FDA categorizes stem cell therapies as human cells, tissues, and cellular- and tissue-based products (HCT/Ps). Section 361 of the Public Health Safety (PHS) Act established and outlined the authority of the FDA to regulate low-risk HCT/Ps in order to prevent the introduction, transmission, and spread of communicable disease. Section 361 provided standards for safety without requiring preclinical development. The FDA established 4 principles to determine the risk of HCT/Ps: the extent of manipulation involved in manufacture, the metabolic activity/autologous nature of the product, whether the product represents a tissue combined with another product, and whether the product is utilized in a fashion homologous with its original function (Figure 1). If a product/therapy meets requirements around all 4 of these principles, then it is deemed a low-risk product and regulated under Section 361 alone. If a product/therapy does not meet requirements around all 4 of these principles, then the FDA regulates the product/therapy under additional codes including Section 351 of the PHS Act. Section 351 outlines a developmental process including preclinical animal trials, phased clinical study, and premarket review by the FDA prior to offering the product/treatment in clinical practice. The developmental process requires investigators and/or industry developers to initiate an Investigational New Drug (IND) program whose end goal is to present data from all developmental study and obtain a Biologic License Application (BLA) approval to market the product.^22-23 To establish safety and efficacy, the traditional IND program involves a preclinical animal study, a small pilot human study (Phase I), a small initial randomized controlled trial (Phase II), followed by a large multicenter randomized controlled trial (Phase III) (Figure 2). The FDA has recognized little to no stem cell treatments as products regulated by Section 361 alone. Additionally, the FDA has established precedent regarding allograft stem cells, cells obtained from fat harvest, amniotic/placental products, and cultured cells, suggesting that these products are not low risk and require an IND pathway outlined in Section 351.^24-30

Bone Marrow Aspiration

Surprisingly, the FDA has not moved to regulate the point-of-care use of bone marrow aspirate or platelet-rich plasma and has labeled these as “not HCTPs.” The stem cell concentration of bone marrow aspirate is technique-dependent, declines with age, and has been found to be an important factor for clinical benefit.³¹ While it is possible to aspirate from multiple sites, posterior iliac crest harvest produces the highest stem cell yield.^32-34 Hernigou and colleagues^35-36 have outlined safe zones for trocar placement and illustrated that strong aspiration with small-volume syringes, 10-mL syringes, optimizes stem cell harvest. Additionally, studies by Hernigou and colleagues^31,37-38 involving tibial nonunion, avascular necrosis of the femur, and augmentation of rotator cuff repair are guideposts to clinicians utilizing bone marrow aspirate.

Amniotic Stem Cell Technologies and Adipose-Derived Stem Cells

While some argue that there is regulatory confusion around amniotic/placental-derived tissues and adipose-derived products, the FDA has clearly established precedent establishing these as products requiring Section 351 development.^26-29 Companies are marketing products derived from perinatal byproducts, yet there are multiple FDA letters suggesting that these are not products regulated solely under PHS Act 361 because they do not meet the criteria of homologous use and are not autologous.^28-29 Use of these products places risk upon the clinician and the patient. Some argue that adipose-derived stem cell products are 361 products. While the FDA has approved devices for the mechanical processing of lipoaspirate, they have established precedent suggesting that they consider orthopedic applications nonhomologous and any processing that “alters the original relevant characteristics of adipose tissue relating to the tissue’s utility for reconstruction, repair, or replacement” as more than minimal manipulation.^26,27 The FDA originally planned an open forum for discussion with clinicians and industry for April 2016. This open forum was delayed due to the volume of interest, and a workshop has been planned for Fall 2016.

Future Regulation of Stem Cell Technologies

While many countries have mirrored the FDA with tight regulatory mechanisms, a few countries have established modern regulatory mechanisms aimed at the promotion of conscientious development, including South Korea, Japan, and England. For example, in 2014 Japan labeled stem cell technologies as “regenerative medicine products,” setting them apart from pharmaceuticals, and implemented a new approval system allowing early observed commercialization with reimbursement after less stringent safety and efficacy milestones.²²The observed commercialization lowers time and financial hurdles for development while still requiring the proof of the technology’s worth. Countries that have effected change have positioned themselves to be pioneers in this emerging field.

In March 2016, the Reliable and Effective Growth for Regenerative Health Options that Improve Wellness (REGROW) Act of 2016 (S. 2689 / H.R. 4762) was introduced into the United States Congress. This bipartisan, bicameral legislation was introduced, read twice, and referred to subcommittee. Its goal is to reduce barriers and accelerate development of biologic therapies while keeping the frame work set forth under Sections 351 and 361 of the PHS Act.³⁹ Similar to the pathway in Japan, the REGROW Act would establish a conditional approval pathway that would ensure products are safe and effective while also evolving the regulatory pathway towards progress (Figure 3). Development would still require an IND application after preclinical animal study. However, after safety was established with human Phase I data and preliminary evidence of efficacy with Phase II data, patients could be treated with the investigational therapies and reimbursement collected for a limited period of time (5 years) prior to a large Phase III human clinical trial. Patients treated with the new therapy would be monitored closely. All results would be reported to the FDA in a BLA. This change in legislation would lower but not remove regulatory hurdles necessary for development.

Conclusion

The future of stem cell treatments hinges upon the creation of new favorable regulatory mechanisms that will promote clinical application while ensuring that safety and efficacy milestones are reached. Clinical researchers require freedom to develop these technologies while protecting patients and ensuring the validity of treatments. The coordination of research and regulatory affairs on a global level is necessary focusing on the harmonization of guidelines, regulations, and mechanisms for simultaneous adoption in different countries. The global orthopedic community has made strides regarding the science of stem cell technologies; it is time for us to initiate progressive change regarding regulation so that we can determine what is effective clinically.

Yes. Physicians taking care of patients who have hypertension and resistant hypertension should be aware of the possible diagnosis of obstructive sleep apnea (OSA) and offer in-laboratory polysomnography or home sleep testing if appropriate. Large, long-term observational studies have shown higher incidence rates of hypertension in people with untreated OSA than in those who underwent treatment for it with continuous positive airway pressure (CPAP). Read more on how OSA and hypertension are linked in this article from Cleveland Clinic Journal of Medicine, available at: http://www.ccjm.org/current-issue/issue-single-view/should-i-suspect-obstructive-sleep-apnea-if-a-patient-has-hard-to-control-hypertension/b8ddb92518fe3517d3e073b1eacb89c2.html.

Yes. Physicians taking care of patients who have hypertension and resistant hypertension should be aware of the possible diagnosis of obstructive sleep apnea (OSA) and offer in-laboratory polysomnography or home sleep testing if appropriate. Large, long-term observational studies have shown higher incidence rates of hypertension in people with untreated OSA than in those who underwent treatment for it with continuous positive airway pressure (CPAP). Read more on how OSA and hypertension are linked in this article from Cleveland Clinic Journal of Medicine, available at: http://www.ccjm.org/current-issue/issue-single-view/should-i-suspect-obstructive-sleep-apnea-if-a-patient-has-hard-to-control-hypertension/b8ddb92518fe3517d3e073b1eacb89c2.html.

Yes. Physicians taking care of patients who have hypertension and resistant hypertension should be aware of the possible diagnosis of obstructive sleep apnea (OSA) and offer in-laboratory polysomnography or home sleep testing if appropriate. Large, long-term observational studies have shown higher incidence rates of hypertension in people with untreated OSA than in those who underwent treatment for it with continuous positive airway pressure (CPAP). Read more on how OSA and hypertension are linked in this article from Cleveland Clinic Journal of Medicine, available at: http://www.ccjm.org/current-issue/issue-single-view/should-i-suspect-obstructive-sleep-apnea-if-a-patient-has-hard-to-control-hypertension/b8ddb92518fe3517d3e073b1eacb89c2.html.

Substituting a less-expensive hepatitis C core antigen test into the standard 2-step process for diagnosing active hepatitis C virus (HCV) infection could streamline and cut the cost of HCV detection, according to the results of a study published in Annals of Internal Medicine. Dr. J. Morgan Freiman, of the Boston Medical Center, and her colleagues, performed a meta-analysis to determine the sensitivity and specificity associated with each of the 5 HCV core antigen tests. To find out which tests performed best, go to Family Practice News: http://www.familypracticenews.com/specialty-focus/infectious-diseases/single-article-page/new-hcv-test-approach-could-cut-costs-streamline-diagnosis/8d117e35547c3068dfb553f396ff7ed7.html.

Substituting a less-expensive hepatitis C core antigen test into the standard 2-step process for diagnosing active hepatitis C virus (HCV) infection could streamline and cut the cost of HCV detection, according to the results of a study published in Annals of Internal Medicine. Dr. J. Morgan Freiman, of the Boston Medical Center, and her colleagues, performed a meta-analysis to determine the sensitivity and specificity associated with each of the 5 HCV core antigen tests. To find out which tests performed best, go to Family Practice News: http://www.familypracticenews.com/specialty-focus/infectious-diseases/single-article-page/new-hcv-test-approach-could-cut-costs-streamline-diagnosis/8d117e35547c3068dfb553f396ff7ed7.html.

Substituting a less-expensive hepatitis C core antigen test into the standard 2-step process for diagnosing active hepatitis C virus (HCV) infection could streamline and cut the cost of HCV detection, according to the results of a study published in Annals of Internal Medicine. Dr. J. Morgan Freiman, of the Boston Medical Center, and her colleagues, performed a meta-analysis to determine the sensitivity and specificity associated with each of the 5 HCV core antigen tests. To find out which tests performed best, go to Family Practice News: http://www.familypracticenews.com/specialty-focus/infectious-diseases/single-article-page/new-hcv-test-approach-could-cut-costs-streamline-diagnosis/8d117e35547c3068dfb553f396ff7ed7.html.

A meta-analysis of 20 randomized controlled studies involving more than 4000 heart failure patients confirmed that an exercise training intervention run for at least 3 weeks produces a statistically significant relative reduction in all-cause mortality of 18%, according to Oriana Ciani, PhD, a health technology researcher at the University of Exeter (England). The individual patient data meta-analysis also showed a statistically significant 11% relative reduction in the incidence of all-cause hospitalization during at least 6 months of follow-up to the exercise programs. Learn more about the findings at Cardiology News, available at: http://www.ecardiologynews.com/specialty-focus/heart-failure/single-article-page/exercise-training-cuts-heart-failure-mortality/c94d2f9c4abf4eea8381de3290883eea.html.

A meta-analysis of 20 randomized controlled studies involving more than 4000 heart failure patients confirmed that an exercise training intervention run for at least 3 weeks produces a statistically significant relative reduction in all-cause mortality of 18%, according to Oriana Ciani, PhD, a health technology researcher at the University of Exeter (England). The individual patient data meta-analysis also showed a statistically significant 11% relative reduction in the incidence of all-cause hospitalization during at least 6 months of follow-up to the exercise programs. Learn more about the findings at Cardiology News, available at: http://www.ecardiologynews.com/specialty-focus/heart-failure/single-article-page/exercise-training-cuts-heart-failure-mortality/c94d2f9c4abf4eea8381de3290883eea.html.

A meta-analysis of 20 randomized controlled studies involving more than 4000 heart failure patients confirmed that an exercise training intervention run for at least 3 weeks produces a statistically significant relative reduction in all-cause mortality of 18%, according to Oriana Ciani, PhD, a health technology researcher at the University of Exeter (England). The individual patient data meta-analysis also showed a statistically significant 11% relative reduction in the incidence of all-cause hospitalization during at least 6 months of follow-up to the exercise programs. Learn more about the findings at Cardiology News, available at: http://www.ecardiologynews.com/specialty-focus/heart-failure/single-article-page/exercise-training-cuts-heart-failure-mortality/c94d2f9c4abf4eea8381de3290883eea.html.

Glucose self-monitoring not only yields valuable information on which to base diabetes treatment, it also helps motivate patients and keeps them engaged in and adherent to their care. However, choosing the most appropriate meters and supplies from the plethora available can be challenging. Working together, healthcare providers and certified diabetes educators can ensure that people with diabetes are getting the most out of self-monitoring process. To find out who should monitor blood glucose and how often, and the advances in and limitations of current devices, go to Cleveland Clinic Journal of Medicine: http://www.ccjm.org/past-issues/past-issue-single-view/self-monitoring-of-blood-glucose-advice-for-providers-and-patients/a077c938c36233cb5bb87ccf89270041.html.

Glucose self-monitoring not only yields valuable information on which to base diabetes treatment, it also helps motivate patients and keeps them engaged in and adherent to their care. However, choosing the most appropriate meters and supplies from the plethora available can be challenging. Working together, healthcare providers and certified diabetes educators can ensure that people with diabetes are getting the most out of self-monitoring process. To find out who should monitor blood glucose and how often, and the advances in and limitations of current devices, go to Cleveland Clinic Journal of Medicine: http://www.ccjm.org/past-issues/past-issue-single-view/self-monitoring-of-blood-glucose-advice-for-providers-and-patients/a077c938c36233cb5bb87ccf89270041.html.

Glucose self-monitoring not only yields valuable information on which to base diabetes treatment, it also helps motivate patients and keeps them engaged in and adherent to their care. However, choosing the most appropriate meters and supplies from the plethora available can be challenging. Working together, healthcare providers and certified diabetes educators can ensure that people with diabetes are getting the most out of self-monitoring process. To find out who should monitor blood glucose and how often, and the advances in and limitations of current devices, go to Cleveland Clinic Journal of Medicine: http://www.ccjm.org/past-issues/past-issue-single-view/self-monitoring-of-blood-glucose-advice-for-providers-and-patients/a077c938c36233cb5bb87ccf89270041.html.

The sun has finally set on Kobe Bryant’s magnificent career. After all the tributes and tearful goodbyes, he has finally played his last game and become a part of basketball history. Ever since his field trip to Germany for interleukin-1 receptor antagonist protein (IRAP) treatments to his knee, and his subsequent return to high-level play, I’ve been under siege in the office by patients who “want what Kobe had.” I’ve had to explain, time and time again, that IRAP treatment is not available in the United States and that platelet-rich plasma (PRP) is the closest alternative treatment, convince them that PRP may be even better, and then let them know that it’s considered experimental and not covered by insurance.

In the last issue, we discussed the future of orthopedics, which in my opinion will rely heavily on the biologic therapies now considered experimental. In this issue, we will look into our crystal balls and imagine what that future might look like. To do so, we should first consider what we hope to accomplish through the incorporation of biologic therapies.

The regeneration of articular cartilage, acceleration of fracture and tissue healing, and faster incorporation of tendon grafts to bone have long been considered the Holy Grail of Orthopedics. In his best seller, The Da Vinci Code, Dan Brown makes a compelling argument that the Holy Grail, the chalice thought to have held the blood of Christ, was in fact a mistranslated reference to his living descendants. Whenever I have a visitor or student in the operating room, I focus the scope on the synovial capillaries so they can see the individual red blood cells passing single-file through the vessels on their way to supply cells with the nutrients they need.

Perhaps, like in The Da Vinci Code, the solution to our greatest biologic challenges lies in the blood, already there, just waiting to be unlocked.

PRP has been utilized for everything from tendinopathy to arthropathy, with varied results in the literature. The lack of standardization of PRP preparations, which vary in inclusion of white cells and absolute platelet count, confounds these results even further. In this issue, we review its use in sports medicine and knee arthritis, taking a closer look at partial ulnar collateral ligament tears in baseball players.

In “Tips of the Trade,” we present a technique for “superior capsular reconstruction” that provides a novel solution for patients with pseudoparalysis from massive rotator cuff tears with little other options beside reverse total shoulder arthroplasty.

The one absolute statement I can make regarding biologics is that we currently have more questions than answers, and every hypothesis we prove simply begets more questions. More randomized controlled studies are needed in virtually every aspect of biologics, and we should all consider taking part. While the solutions our patients crave may not arrive during our careers, or even our lifetimes, the groundwork we do now will set the stage for future generations to enjoy biologically enhanced outcomes.

The sun has finally set on Kobe Bryant’s magnificent career. After all the tributes and tearful goodbyes, he has finally played his last game and become a part of basketball history. Ever since his field trip to Germany for interleukin-1 receptor antagonist protein (IRAP) treatments to his knee, and his subsequent return to high-level play, I’ve been under siege in the office by patients who “want what Kobe had.” I’ve had to explain, time and time again, that IRAP treatment is not available in the United States and that platelet-rich plasma (PRP) is the closest alternative treatment, convince them that PRP may be even better, and then let them know that it’s considered experimental and not covered by insurance.

In the last issue, we discussed the future of orthopedics, which in my opinion will rely heavily on the biologic therapies now considered experimental. In this issue, we will look into our crystal balls and imagine what that future might look like. To do so, we should first consider what we hope to accomplish through the incorporation of biologic therapies.

The regeneration of articular cartilage, acceleration of fracture and tissue healing, and faster incorporation of tendon grafts to bone have long been considered the Holy Grail of Orthopedics. In his best seller, The Da Vinci Code, Dan Brown makes a compelling argument that the Holy Grail, the chalice thought to have held the blood of Christ, was in fact a mistranslated reference to his living descendants. Whenever I have a visitor or student in the operating room, I focus the scope on the synovial capillaries so they can see the individual red blood cells passing single-file through the vessels on their way to supply cells with the nutrients they need.

Perhaps, like in The Da Vinci Code, the solution to our greatest biologic challenges lies in the blood, already there, just waiting to be unlocked.

PRP has been utilized for everything from tendinopathy to arthropathy, with varied results in the literature. The lack of standardization of PRP preparations, which vary in inclusion of white cells and absolute platelet count, confounds these results even further. In this issue, we review its use in sports medicine and knee arthritis, taking a closer look at partial ulnar collateral ligament tears in baseball players.

In “Tips of the Trade,” we present a technique for “superior capsular reconstruction” that provides a novel solution for patients with pseudoparalysis from massive rotator cuff tears with little other options beside reverse total shoulder arthroplasty.

The one absolute statement I can make regarding biologics is that we currently have more questions than answers, and every hypothesis we prove simply begets more questions. More randomized controlled studies are needed in virtually every aspect of biologics, and we should all consider taking part. While the solutions our patients crave may not arrive during our careers, or even our lifetimes, the groundwork we do now will set the stage for future generations to enjoy biologically enhanced outcomes.

The sun has finally set on Kobe Bryant’s magnificent career. After all the tributes and tearful goodbyes, he has finally played his last game and become a part of basketball history. Ever since his field trip to Germany for interleukin-1 receptor antagonist protein (IRAP) treatments to his knee, and his subsequent return to high-level play, I’ve been under siege in the office by patients who “want what Kobe had.” I’ve had to explain, time and time again, that IRAP treatment is not available in the United States and that platelet-rich plasma (PRP) is the closest alternative treatment, convince them that PRP may be even better, and then let them know that it’s considered experimental and not covered by insurance.

In the last issue, we discussed the future of orthopedics, which in my opinion will rely heavily on the biologic therapies now considered experimental. In this issue, we will look into our crystal balls and imagine what that future might look like. To do so, we should first consider what we hope to accomplish through the incorporation of biologic therapies.

The regeneration of articular cartilage, acceleration of fracture and tissue healing, and faster incorporation of tendon grafts to bone have long been considered the Holy Grail of Orthopedics. In his best seller, The Da Vinci Code, Dan Brown makes a compelling argument that the Holy Grail, the chalice thought to have held the blood of Christ, was in fact a mistranslated reference to his living descendants. Whenever I have a visitor or student in the operating room, I focus the scope on the synovial capillaries so they can see the individual red blood cells passing single-file through the vessels on their way to supply cells with the nutrients they need.

Perhaps, like in The Da Vinci Code, the solution to our greatest biologic challenges lies in the blood, already there, just waiting to be unlocked.

PRP has been utilized for everything from tendinopathy to arthropathy, with varied results in the literature. The lack of standardization of PRP preparations, which vary in inclusion of white cells and absolute platelet count, confounds these results even further. In this issue, we review its use in sports medicine and knee arthritis, taking a closer look at partial ulnar collateral ligament tears in baseball players.

In “Tips of the Trade,” we present a technique for “superior capsular reconstruction” that provides a novel solution for patients with pseudoparalysis from massive rotator cuff tears with little other options beside reverse total shoulder arthroplasty.

The one absolute statement I can make regarding biologics is that we currently have more questions than answers, and every hypothesis we prove simply begets more questions. More randomized controlled studies are needed in virtually every aspect of biologics, and we should all consider taking part. While the solutions our patients crave may not arrive during our careers, or even our lifetimes, the groundwork we do now will set the stage for future generations to enjoy biologically enhanced outcomes.

In contrast to stable chronic obstructive pulmonary disease (COPD), acute exacerbations of COPD pose special management challenges and can significantly increase the risks of morbidity and death as well as the cost of care. This review from Cleveland Clinic Journal of Medicine, available at http://www.ccjm.org/topics/pulmonary/single-article-page/treating-and-preventing-acute-exacerbations-of-copd/8265d5ff355c3a17c96fa34564ea7465.html, provides the latest information on the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.

In contrast to stable chronic obstructive pulmonary disease (COPD), acute exacerbations of COPD pose special management challenges and can significantly increase the risks of morbidity and death as well as the cost of care. This review from Cleveland Clinic Journal of Medicine, available at http://www.ccjm.org/topics/pulmonary/single-article-page/treating-and-preventing-acute-exacerbations-of-copd/8265d5ff355c3a17c96fa34564ea7465.html, provides the latest information on the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.

In contrast to stable chronic obstructive pulmonary disease (COPD), acute exacerbations of COPD pose special management challenges and can significantly increase the risks of morbidity and death as well as the cost of care. This review from Cleveland Clinic Journal of Medicine, available at http://www.ccjm.org/topics/pulmonary/single-article-page/treating-and-preventing-acute-exacerbations-of-copd/8265d5ff355c3a17c96fa34564ea7465.html, provides the latest information on the definition and diagnosis of COPD exacerbations, disease burden and costs, etiology and pathogenesis, and management and prevention strategies.

SAN DIEGO – New research suggests histamine-2 receptor antagonists aren’t a viable alternative to proton pump inhibitors to prevent recurrence of bleeding peptic ulcers in clopidogrel users.

U.S. and European agencies have warned of interactions between proton pump inhibitors (PPIs) and clopidogrel. But a study presented at the annual Digestive Disease Week finds significant upper GI events were much more common in patients who took famotidine (Protonix), a histamine-2 receptor antagonist (H₂RA), compared with those who took pantoprazole (Pepcid), a PPI, as a preventive treatment.

“The findings will change the practice of some physicians who prescribe H₂RA to prevent UGI [upper GI] events in clopidogrel users,” said study lead author Dr. Ping-I Hsu, chief of gastroenterology at Kaohsiung Veterans General Hospital and professor of medicine at National Yang-Ming University, both in Taiwan.

Currently, Dr. Hsu said, “physicians often use PPIs to prevent ulcer complications in clopidogrel users because it is the only drug proven useful in the prevention of peptic ulcers and ulcer complications in clopidogrel users.”

But “both the U.S. Food & Drug Administration and the European Medicines Agency have posted safety warnings and discourage the use of PPIs with clopidogrel unless absolutely necessary,” he said.

Enter the prospect of H₂RA medications as an alternative. The new study, Dr. Hsu said, is the first to explore the GI protection effect and safety of H₂RAs in patients on clopidogrel monotherapy.

The randomized prospective study followed 120 patients with a history of peptic ulcer bleeding (but not at initial endoscopy) and atherosclerosis. All long-term users of ADP receptor antagonists, they were assigned to pantoprazole (40 mg daily) or famotidine (40 mg daily) for 48 weeks.

Patients were examined via endoscopy when they experienced events like severe epigastric discomfort.

The famotidine group had more significant upper GI events (13.3%) than the pantoprazole group (1.7%). Diarrhea was equal in both groups (1.7%). Pneumonia was comparable (0% and 1.7% for pantoprazole and famotidine, respectively), as was fracture (1.7% and 0%).

Wider differences were found in acute myocardial infarction (1.5% and 4.5%), and cerebral vascular accident (0% and 3.4%) for pantoprazole and famotidine, respectively.

According to Dr. Hsu, three earlier studies linked concurrent use of PPIs and clopidogrel to significant increases in cardiovascular events. But this study linked a higher cardiac risk to the H₂RA medication.

The researchers found no differences between the drugs in sequential changes of serum magnesium levels and bone mineral densities.

Dr. Hsu made this recommendation to physicians: “Please don’t use H₂RAs to prevent peptic ulcer or ulcer complications in clopidogrel users. It is ineffective to prevent UGI [upper GI] events in clopidogrel users who have a history of ulcer bleeding. PPIs can effectively prevent UGI events in clopidogrel users with a history of ulcer bleeding.”

In addition, he said, the risk of thrombotic events is lower on a PPI.

SAN DIEGO – New research suggests histamine-2 receptor antagonists aren’t a viable alternative to proton pump inhibitors to prevent recurrence of bleeding peptic ulcers in clopidogrel users.

U.S. and European agencies have warned of interactions between proton pump inhibitors (PPIs) and clopidogrel. But a study presented at the annual Digestive Disease Week finds significant upper GI events were much more common in patients who took famotidine (Protonix), a histamine-2 receptor antagonist (H₂RA), compared with those who took pantoprazole (Pepcid), a PPI, as a preventive treatment.

“The findings will change the practice of some physicians who prescribe H₂RA to prevent UGI [upper GI] events in clopidogrel users,” said study lead author Dr. Ping-I Hsu, chief of gastroenterology at Kaohsiung Veterans General Hospital and professor of medicine at National Yang-Ming University, both in Taiwan.

Currently, Dr. Hsu said, “physicians often use PPIs to prevent ulcer complications in clopidogrel users because it is the only drug proven useful in the prevention of peptic ulcers and ulcer complications in clopidogrel users.”

But “both the U.S. Food & Drug Administration and the European Medicines Agency have posted safety warnings and discourage the use of PPIs with clopidogrel unless absolutely necessary,” he said.

Enter the prospect of H₂RA medications as an alternative. The new study, Dr. Hsu said, is the first to explore the GI protection effect and safety of H₂RAs in patients on clopidogrel monotherapy.

The randomized prospective study followed 120 patients with a history of peptic ulcer bleeding (but not at initial endoscopy) and atherosclerosis. All long-term users of ADP receptor antagonists, they were assigned to pantoprazole (40 mg daily) or famotidine (40 mg daily) for 48 weeks.

Patients were examined via endoscopy when they experienced events like severe epigastric discomfort.

The famotidine group had more significant upper GI events (13.3%) than the pantoprazole group (1.7%). Diarrhea was equal in both groups (1.7%). Pneumonia was comparable (0% and 1.7% for pantoprazole and famotidine, respectively), as was fracture (1.7% and 0%).

Wider differences were found in acute myocardial infarction (1.5% and 4.5%), and cerebral vascular accident (0% and 3.4%) for pantoprazole and famotidine, respectively.

According to Dr. Hsu, three earlier studies linked concurrent use of PPIs and clopidogrel to significant increases in cardiovascular events. But this study linked a higher cardiac risk to the H₂RA medication.

The researchers found no differences between the drugs in sequential changes of serum magnesium levels and bone mineral densities.

Dr. Hsu made this recommendation to physicians: “Please don’t use H₂RAs to prevent peptic ulcer or ulcer complications in clopidogrel users. It is ineffective to prevent UGI [upper GI] events in clopidogrel users who have a history of ulcer bleeding. PPIs can effectively prevent UGI events in clopidogrel users with a history of ulcer bleeding.”

In addition, he said, the risk of thrombotic events is lower on a PPI.

SAN DIEGO – New research suggests histamine-2 receptor antagonists aren’t a viable alternative to proton pump inhibitors to prevent recurrence of bleeding peptic ulcers in clopidogrel users.

U.S. and European agencies have warned of interactions between proton pump inhibitors (PPIs) and clopidogrel. But a study presented at the annual Digestive Disease Week finds significant upper GI events were much more common in patients who took famotidine (Protonix), a histamine-2 receptor antagonist (H₂RA), compared with those who took pantoprazole (Pepcid), a PPI, as a preventive treatment.

“The findings will change the practice of some physicians who prescribe H₂RA to prevent UGI [upper GI] events in clopidogrel users,” said study lead author Dr. Ping-I Hsu, chief of gastroenterology at Kaohsiung Veterans General Hospital and professor of medicine at National Yang-Ming University, both in Taiwan.

Currently, Dr. Hsu said, “physicians often use PPIs to prevent ulcer complications in clopidogrel users because it is the only drug proven useful in the prevention of peptic ulcers and ulcer complications in clopidogrel users.”

But “both the U.S. Food & Drug Administration and the European Medicines Agency have posted safety warnings and discourage the use of PPIs with clopidogrel unless absolutely necessary,” he said.

Enter the prospect of H₂RA medications as an alternative. The new study, Dr. Hsu said, is the first to explore the GI protection effect and safety of H₂RAs in patients on clopidogrel monotherapy.

The randomized prospective study followed 120 patients with a history of peptic ulcer bleeding (but not at initial endoscopy) and atherosclerosis. All long-term users of ADP receptor antagonists, they were assigned to pantoprazole (40 mg daily) or famotidine (40 mg daily) for 48 weeks.

Patients were examined via endoscopy when they experienced events like severe epigastric discomfort.

The famotidine group had more significant upper GI events (13.3%) than the pantoprazole group (1.7%). Diarrhea was equal in both groups (1.7%). Pneumonia was comparable (0% and 1.7% for pantoprazole and famotidine, respectively), as was fracture (1.7% and 0%).

Wider differences were found in acute myocardial infarction (1.5% and 4.5%), and cerebral vascular accident (0% and 3.4%) for pantoprazole and famotidine, respectively.

According to Dr. Hsu, three earlier studies linked concurrent use of PPIs and clopidogrel to significant increases in cardiovascular events. But this study linked a higher cardiac risk to the H₂RA medication.

The researchers found no differences between the drugs in sequential changes of serum magnesium levels and bone mineral densities.

Dr. Hsu made this recommendation to physicians: “Please don’t use H₂RAs to prevent peptic ulcer or ulcer complications in clopidogrel users. It is ineffective to prevent UGI [upper GI] events in clopidogrel users who have a history of ulcer bleeding. PPIs can effectively prevent UGI events in clopidogrel users with a history of ulcer bleeding.”

In addition, he said, the risk of thrombotic events is lower on a PPI.

SAN FRANCISCO – Hospitalized patients who have a change in the medical residents responsible for their care are more likely to die, finds a retrospective cohort study of roughly a quarter million discharges from Veterans Affairs medical centers.

A monthly change in resident care was associated with 9%-20% higher adjusted odds of death during the hospital stay and after discharge, investigators reported in a poster discussion session and press briefing at an international conference of the American Thoracic Society. Analyses suggested that such transitions accounted for 718 additional deaths in the hospital alone during the 6-year study period.

“These are very strong findings,” said Dr. Joshua L. Denson, a fellow in the divisions of pulmonary sciences and critical care medicine at the University of Colorado, Aurora.

The study results represent an important initial step in bringing the problem to light, he said. “Handoffs shift to shift have been looked at, but not this end-of-month, more permanent switching, which I think is a much more substantial transition in care.”

The factors driving the increased mortality are unclear, according to Dr. Denson; however, “when you go on to a new service [as a resident] ... you are now responsible for 20 new people all of a sudden that night.” Therefore, these transitions can be a hectic time characterized by reduced communication and inefficient discharges. In addition, the incoming residents lack familiarity with their new patients’ particulars.

“The handoffs are definitely not preventable, so this is something that has to be dealt with,” he maintained. The study’s findings hint at several possible areas for improvement.

None of the 10 residency programs surveyed provided formal education for monthly resident handoffs, focusing instead on handoffs at shift changes, and most programs lacked a standard procedure, with just one requiring that the handoff be done in person. The programs also varied greatly in their staggering of handoffs – separating transitions of interns (first-year residents) and higher-level residents by at least a few days – to minimize impact.

Despite the absence of outcomes data in this area, some hospitals are forging ahead with their own interventions intended to smooth care transitions, Dr. Denson reported. “In at least two hospitals that I’ve worked in, they are implementing what is called a warm handoff,” he explained. “Basically, a resident from the prior rotation comes the next day and rounds with the new team so he can tell them, ‘Oh, this guy looks a little worse today, you may want to watch him,’ or ‘He looks a little better.’ ”

In the study, conducted while Dr. Denson was chief resident at the NYU School of Medicine, he and his colleagues analyzed data from 10 university-affiliated Veterans Affairs hospitals and internal medicine residency programs that provided their residents’ schedules. Analyses were based on a total of 230,701 discharges of adult medical patients between July 2008 and June 2014.

Hospitalized patients were categorized as having a transition in resident care if they were admitted before the date of an end-of-month house staff transition in care and were discharged in the week after it.

In unadjusted analyses, patients who had a transition of care – whether of intern only, resident only, or both – had significantly higher odds of inpatient mortality and of 30-day mortality and 90-day postdischarge mortality, compared with counterparts who did not have the corresponding transition of care.

In adjusted analyses, patients who had an intern transition still had higher odds of in-hospital mortality (odds ratio, 1.14). In addition, patients had persistently elevated odds of 30-day mortality and 90-day postdischarge mortality if they had an intern transition (odds ratios, 1.20 and 1.17, respectively), a resident transition (1.15 and 1.14), or both (1.10 and 1.09).

The findings “suggest possibly a level-of-training effect to these transitions, as it’s the most inexperienced people that have the higher rate of mortality,” noted Dr. Denson, who disclosed that he had no relevant conflicts of interest. “Interns, being the first-years, tend to carry the bulk of the work in most hospitals, which is an interesting paradigm in our organization. And that may be a good explanation for why we are seeing this.”

SAN FRANCISCO – Hospitalized patients who have a change in the medical residents responsible for their care are more likely to die, finds a retrospective cohort study of roughly a quarter million discharges from Veterans Affairs medical centers.

A monthly change in resident care was associated with 9%-20% higher adjusted odds of death during the hospital stay and after discharge, investigators reported in a poster discussion session and press briefing at an international conference of the American Thoracic Society. Analyses suggested that such transitions accounted for 718 additional deaths in the hospital alone during the 6-year study period.

“These are very strong findings,” said Dr. Joshua L. Denson, a fellow in the divisions of pulmonary sciences and critical care medicine at the University of Colorado, Aurora.

The study results represent an important initial step in bringing the problem to light, he said. “Handoffs shift to shift have been looked at, but not this end-of-month, more permanent switching, which I think is a much more substantial transition in care.”

The factors driving the increased mortality are unclear, according to Dr. Denson; however, “when you go on to a new service [as a resident] ... you are now responsible for 20 new people all of a sudden that night.” Therefore, these transitions can be a hectic time characterized by reduced communication and inefficient discharges. In addition, the incoming residents lack familiarity with their new patients’ particulars.

“The handoffs are definitely not preventable, so this is something that has to be dealt with,” he maintained. The study’s findings hint at several possible areas for improvement.

None of the 10 residency programs surveyed provided formal education for monthly resident handoffs, focusing instead on handoffs at shift changes, and most programs lacked a standard procedure, with just one requiring that the handoff be done in person. The programs also varied greatly in their staggering of handoffs – separating transitions of interns (first-year residents) and higher-level residents by at least a few days – to minimize impact.

Despite the absence of outcomes data in this area, some hospitals are forging ahead with their own interventions intended to smooth care transitions, Dr. Denson reported. “In at least two hospitals that I’ve worked in, they are implementing what is called a warm handoff,” he explained. “Basically, a resident from the prior rotation comes the next day and rounds with the new team so he can tell them, ‘Oh, this guy looks a little worse today, you may want to watch him,’ or ‘He looks a little better.’ ”

In the study, conducted while Dr. Denson was chief resident at the NYU School of Medicine, he and his colleagues analyzed data from 10 university-affiliated Veterans Affairs hospitals and internal medicine residency programs that provided their residents’ schedules. Analyses were based on a total of 230,701 discharges of adult medical patients between July 2008 and June 2014.

Hospitalized patients were categorized as having a transition in resident care if they were admitted before the date of an end-of-month house staff transition in care and were discharged in the week after it.

In unadjusted analyses, patients who had a transition of care – whether of intern only, resident only, or both – had significantly higher odds of inpatient mortality and of 30-day mortality and 90-day postdischarge mortality, compared with counterparts who did not have the corresponding transition of care.

In adjusted analyses, patients who had an intern transition still had higher odds of in-hospital mortality (odds ratio, 1.14). In addition, patients had persistently elevated odds of 30-day mortality and 90-day postdischarge mortality if they had an intern transition (odds ratios, 1.20 and 1.17, respectively), a resident transition (1.15 and 1.14), or both (1.10 and 1.09).

The findings “suggest possibly a level-of-training effect to these transitions, as it’s the most inexperienced people that have the higher rate of mortality,” noted Dr. Denson, who disclosed that he had no relevant conflicts of interest. “Interns, being the first-years, tend to carry the bulk of the work in most hospitals, which is an interesting paradigm in our organization. And that may be a good explanation for why we are seeing this.”

SAN FRANCISCO – Hospitalized patients who have a change in the medical residents responsible for their care are more likely to die, finds a retrospective cohort study of roughly a quarter million discharges from Veterans Affairs medical centers.

A monthly change in resident care was associated with 9%-20% higher adjusted odds of death during the hospital stay and after discharge, investigators reported in a poster discussion session and press briefing at an international conference of the American Thoracic Society. Analyses suggested that such transitions accounted for 718 additional deaths in the hospital alone during the 6-year study period.

“These are very strong findings,” said Dr. Joshua L. Denson, a fellow in the divisions of pulmonary sciences and critical care medicine at the University of Colorado, Aurora.

The study results represent an important initial step in bringing the problem to light, he said. “Handoffs shift to shift have been looked at, but not this end-of-month, more permanent switching, which I think is a much more substantial transition in care.”

The factors driving the increased mortality are unclear, according to Dr. Denson; however, “when you go on to a new service [as a resident] ... you are now responsible for 20 new people all of a sudden that night.” Therefore, these transitions can be a hectic time characterized by reduced communication and inefficient discharges. In addition, the incoming residents lack familiarity with their new patients’ particulars.

“The handoffs are definitely not preventable, so this is something that has to be dealt with,” he maintained. The study’s findings hint at several possible areas for improvement.

None of the 10 residency programs surveyed provided formal education for monthly resident handoffs, focusing instead on handoffs at shift changes, and most programs lacked a standard procedure, with just one requiring that the handoff be done in person. The programs also varied greatly in their staggering of handoffs – separating transitions of interns (first-year residents) and higher-level residents by at least a few days – to minimize impact.

Despite the absence of outcomes data in this area, some hospitals are forging ahead with their own interventions intended to smooth care transitions, Dr. Denson reported. “In at least two hospitals that I’ve worked in, they are implementing what is called a warm handoff,” he explained. “Basically, a resident from the prior rotation comes the next day and rounds with the new team so he can tell them, ‘Oh, this guy looks a little worse today, you may want to watch him,’ or ‘He looks a little better.’ ”

In the study, conducted while Dr. Denson was chief resident at the NYU School of Medicine, he and his colleagues analyzed data from 10 university-affiliated Veterans Affairs hospitals and internal medicine residency programs that provided their residents’ schedules. Analyses were based on a total of 230,701 discharges of adult medical patients between July 2008 and June 2014.

Hospitalized patients were categorized as having a transition in resident care if they were admitted before the date of an end-of-month house staff transition in care and were discharged in the week after it.

In unadjusted analyses, patients who had a transition of care – whether of intern only, resident only, or both – had significantly higher odds of inpatient mortality and of 30-day mortality and 90-day postdischarge mortality, compared with counterparts who did not have the corresponding transition of care.

In adjusted analyses, patients who had an intern transition still had higher odds of in-hospital mortality (odds ratio, 1.14). In addition, patients had persistently elevated odds of 30-day mortality and 90-day postdischarge mortality if they had an intern transition (odds ratios, 1.20 and 1.17, respectively), a resident transition (1.15 and 1.14), or both (1.10 and 1.09).

The findings “suggest possibly a level-of-training effect to these transitions, as it’s the most inexperienced people that have the higher rate of mortality,” noted Dr. Denson, who disclosed that he had no relevant conflicts of interest. “Interns, being the first-years, tend to carry the bulk of the work in most hospitals, which is an interesting paradigm in our organization. And that may be a good explanation for why we are seeing this.”