Doctor and patient

Photo by Logan Tuttle

VIENNA—Despite progress made in recent years, there are “major problems” in pediatric oncology care in Europe, according to a report from the European Society for Paediatric Oncology (SIOPE).

Cancer is still the first cause of death by disease in children age 1 and older in Europe, and more than 300,000 European citizens are pediatric cancer survivors.

These individuals have a higher risk of death at 5 years after diagnosis than that of the general population.

“This is a serious problem for patients, their families, and for health services, with major inequalities existing across Europe,” said SIOPE President Gilles Vassal, MD, PhD, of the Institut Gustave Roussy in Villejuif, France.

“Add to this the fact that 35% of such cancers normally occur before the child is 5 years old and that many pediatric cancers are difficult to treat, and you will understand why we thought it essential to try to tackle this problem in a practical way.”

The resulting report, “The SIOPE Strategic Plan: A European Cancer Plan for Children and Adolescents,” was recently presented at the 2015 European Cancer Congress.

Problem-solving

The report was drawn up after widespread consultation, including discussions with parents, patients, and survivors. It sets out existing problems and proposes solutions to tackle them.

Among these problems are poor access to new drugs for pediatric patients; lack of funding; disparities across Europe in access to treatment and, hence, survival; and the fact that pediatric oncology has been relatively isolated from the adult oncology community.

With the goal of fixing these problems, the report sets out a number of goals and lists the key factors that will be necessary in order to achieve them.

These include a commitment of all funding bodies to finance projects and structures of relevance to pediatric oncology; a strong partnership with patients, parents, and survivors, including better communication and dissemination of information; better collaboration with adult oncology; and transparent partnerships with industry.

Understanding biology

“One of the most important objectives focuses on increasing our knowledge of the biology of pediatric tumors,” said SIOPE President-Elect Martin Schrappe, MD, of the University of Kiel, Germany.

“Cancers in adults result from a multistep process, usually after exposure to external carcinogens such as tobacco, alcohol, and diet, and often progress over many years. Pediatric malignancies develop early in life and over a much shorter time period. This suggests that fewer and stronger events are required for them to progress. Compared with adult cancers, most of them show fewer genetic defects and have a lower genetic complexity.”

“Major progress has been made in understanding pediatric tumor biology, and this has led to the discovery of some unique cancer hallmarks. Now, we need to use modern, innovative technologies to further decipher the mechanisms of pediatric tumor development, progression, and relapse, and speed up its translation to the clinic.”

To do this effectively and fairly, according to the report, interactions need to be strengthened at several levels—between networks of basic research teams, between basic scientists and clinical researchers, and by increasing the involvement of patients and parents in the search for personalized treatments. SIOPE plans to monitor progress through research into outcomes.

Improving quality of life

Another important issue for SIOPE is improving the quality of life for survivors.

“We believe that, in 2020, there will be nearly half a million European pediatric cancer survivors, and many of them will have side effects that are severe enough to affect their daily lives,” Dr Schrappe said. “While the fact that so many survive is a cause for rejoicing, we have a duty to provide them with optimal long-term care so that the rest of their lives may be as normal as possible.”

“One way of doing this would be the creation of a ‘survivorship passport’ for each child and adolescent cured of a cancer. This would contain a history of their disease and treatment, together with relevant follow-up measures aimed at improving their quality of life and a database for storing the clinical data [that would] facilitate monitoring and research.”

Doctor and patient

Photo by Logan Tuttle

VIENNA—Despite progress made in recent years, there are “major problems” in pediatric oncology care in Europe, according to a report from the European Society for Paediatric Oncology (SIOPE).

Cancer is still the first cause of death by disease in children age 1 and older in Europe, and more than 300,000 European citizens are pediatric cancer survivors.

These individuals have a higher risk of death at 5 years after diagnosis than that of the general population.

“This is a serious problem for patients, their families, and for health services, with major inequalities existing across Europe,” said SIOPE President Gilles Vassal, MD, PhD, of the Institut Gustave Roussy in Villejuif, France.

“Add to this the fact that 35% of such cancers normally occur before the child is 5 years old and that many pediatric cancers are difficult to treat, and you will understand why we thought it essential to try to tackle this problem in a practical way.”

The resulting report, “The SIOPE Strategic Plan: A European Cancer Plan for Children and Adolescents,” was recently presented at the 2015 European Cancer Congress.

Problem-solving

The report was drawn up after widespread consultation, including discussions with parents, patients, and survivors. It sets out existing problems and proposes solutions to tackle them.

Among these problems are poor access to new drugs for pediatric patients; lack of funding; disparities across Europe in access to treatment and, hence, survival; and the fact that pediatric oncology has been relatively isolated from the adult oncology community.

With the goal of fixing these problems, the report sets out a number of goals and lists the key factors that will be necessary in order to achieve them.

These include a commitment of all funding bodies to finance projects and structures of relevance to pediatric oncology; a strong partnership with patients, parents, and survivors, including better communication and dissemination of information; better collaboration with adult oncology; and transparent partnerships with industry.

Understanding biology

“One of the most important objectives focuses on increasing our knowledge of the biology of pediatric tumors,” said SIOPE President-Elect Martin Schrappe, MD, of the University of Kiel, Germany.

“Cancers in adults result from a multistep process, usually after exposure to external carcinogens such as tobacco, alcohol, and diet, and often progress over many years. Pediatric malignancies develop early in life and over a much shorter time period. This suggests that fewer and stronger events are required for them to progress. Compared with adult cancers, most of them show fewer genetic defects and have a lower genetic complexity.”

“Major progress has been made in understanding pediatric tumor biology, and this has led to the discovery of some unique cancer hallmarks. Now, we need to use modern, innovative technologies to further decipher the mechanisms of pediatric tumor development, progression, and relapse, and speed up its translation to the clinic.”

To do this effectively and fairly, according to the report, interactions need to be strengthened at several levels—between networks of basic research teams, between basic scientists and clinical researchers, and by increasing the involvement of patients and parents in the search for personalized treatments. SIOPE plans to monitor progress through research into outcomes.

Improving quality of life

Another important issue for SIOPE is improving the quality of life for survivors.

“We believe that, in 2020, there will be nearly half a million European pediatric cancer survivors, and many of them will have side effects that are severe enough to affect their daily lives,” Dr Schrappe said. “While the fact that so many survive is a cause for rejoicing, we have a duty to provide them with optimal long-term care so that the rest of their lives may be as normal as possible.”

“One way of doing this would be the creation of a ‘survivorship passport’ for each child and adolescent cured of a cancer. This would contain a history of their disease and treatment, together with relevant follow-up measures aimed at improving their quality of life and a database for storing the clinical data [that would] facilitate monitoring and research.”

Doctor and patient

Photo by Logan Tuttle

VIENNA—Despite progress made in recent years, there are “major problems” in pediatric oncology care in Europe, according to a report from the European Society for Paediatric Oncology (SIOPE).

Cancer is still the first cause of death by disease in children age 1 and older in Europe, and more than 300,000 European citizens are pediatric cancer survivors.

These individuals have a higher risk of death at 5 years after diagnosis than that of the general population.

“This is a serious problem for patients, their families, and for health services, with major inequalities existing across Europe,” said SIOPE President Gilles Vassal, MD, PhD, of the Institut Gustave Roussy in Villejuif, France.

“Add to this the fact that 35% of such cancers normally occur before the child is 5 years old and that many pediatric cancers are difficult to treat, and you will understand why we thought it essential to try to tackle this problem in a practical way.”

The resulting report, “The SIOPE Strategic Plan: A European Cancer Plan for Children and Adolescents,” was recently presented at the 2015 European Cancer Congress.

Problem-solving

The report was drawn up after widespread consultation, including discussions with parents, patients, and survivors. It sets out existing problems and proposes solutions to tackle them.

Among these problems are poor access to new drugs for pediatric patients; lack of funding; disparities across Europe in access to treatment and, hence, survival; and the fact that pediatric oncology has been relatively isolated from the adult oncology community.

With the goal of fixing these problems, the report sets out a number of goals and lists the key factors that will be necessary in order to achieve them.

These include a commitment of all funding bodies to finance projects and structures of relevance to pediatric oncology; a strong partnership with patients, parents, and survivors, including better communication and dissemination of information; better collaboration with adult oncology; and transparent partnerships with industry.

Understanding biology

“One of the most important objectives focuses on increasing our knowledge of the biology of pediatric tumors,” said SIOPE President-Elect Martin Schrappe, MD, of the University of Kiel, Germany.

“Cancers in adults result from a multistep process, usually after exposure to external carcinogens such as tobacco, alcohol, and diet, and often progress over many years. Pediatric malignancies develop early in life and over a much shorter time period. This suggests that fewer and stronger events are required for them to progress. Compared with adult cancers, most of them show fewer genetic defects and have a lower genetic complexity.”

“Major progress has been made in understanding pediatric tumor biology, and this has led to the discovery of some unique cancer hallmarks. Now, we need to use modern, innovative technologies to further decipher the mechanisms of pediatric tumor development, progression, and relapse, and speed up its translation to the clinic.”

To do this effectively and fairly, according to the report, interactions need to be strengthened at several levels—between networks of basic research teams, between basic scientists and clinical researchers, and by increasing the involvement of patients and parents in the search for personalized treatments. SIOPE plans to monitor progress through research into outcomes.

Improving quality of life

Another important issue for SIOPE is improving the quality of life for survivors.

“We believe that, in 2020, there will be nearly half a million European pediatric cancer survivors, and many of them will have side effects that are severe enough to affect their daily lives,” Dr Schrappe said. “While the fact that so many survive is a cause for rejoicing, we have a duty to provide them with optimal long-term care so that the rest of their lives may be as normal as possible.”

“One way of doing this would be the creation of a ‘survivorship passport’ for each child and adolescent cured of a cancer. This would contain a history of their disease and treatment, together with relevant follow-up measures aimed at improving their quality of life and a database for storing the clinical data [that would] facilitate monitoring and research.”

Micrograph showing AML

Image by Lance Liotta

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for azacitidine for injection (Vidaza).

The CHMP is recommending that azacitidine be approved to treat adults age 65 and older with acute myeloid leukemia (AML) who are not eligible for hematopoietic stem cell transplant (HSCT) and have more than 30% blasts according to the WHO classification.

The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision in 2 months.

The CHMP said this new indication for azacitidine would bring significant clinical benefit in comparison with existing therapies. If the EC follows the CHMP’s recommendation, azacitidine will receive extended market protection in all its indications for an additional year throughout the European Economic Area.

Azacitidine is already approved in the European Economic Area for the treatment of HSCT-ineligible adults diagnosed with intermediate-2- and high-risk myelodysplastic syndromes; chronic myelomonocytic leukemia with 10%-29% marrow blasts without myeloproliferative disorder; or AML with 20%-30% blasts and multi-lineage dysplasia.

AML-001 trial

The CHMP’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.

Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle) or best supportive care only.

Patients were then randomized to receive either azacitidine (75 mg/m²/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).

Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).

One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.

Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.

Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33%, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively. 

Micrograph showing AML

Image by Lance Liotta

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for azacitidine for injection (Vidaza).

The CHMP is recommending that azacitidine be approved to treat adults age 65 and older with acute myeloid leukemia (AML) who are not eligible for hematopoietic stem cell transplant (HSCT) and have more than 30% blasts according to the WHO classification.

The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision in 2 months.

The CHMP said this new indication for azacitidine would bring significant clinical benefit in comparison with existing therapies. If the EC follows the CHMP’s recommendation, azacitidine will receive extended market protection in all its indications for an additional year throughout the European Economic Area.

Azacitidine is already approved in the European Economic Area for the treatment of HSCT-ineligible adults diagnosed with intermediate-2- and high-risk myelodysplastic syndromes; chronic myelomonocytic leukemia with 10%-29% marrow blasts without myeloproliferative disorder; or AML with 20%-30% blasts and multi-lineage dysplasia.

AML-001 trial

The CHMP’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.

Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle) or best supportive care only.

Patients were then randomized to receive either azacitidine (75 mg/m²/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).

Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).

One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.

Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.

Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33%, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively. 

Micrograph showing AML

Image by Lance Liotta

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for azacitidine for injection (Vidaza).

The CHMP is recommending that azacitidine be approved to treat adults age 65 and older with acute myeloid leukemia (AML) who are not eligible for hematopoietic stem cell transplant (HSCT) and have more than 30% blasts according to the WHO classification.

The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision in 2 months.

The CHMP said this new indication for azacitidine would bring significant clinical benefit in comparison with existing therapies. If the EC follows the CHMP’s recommendation, azacitidine will receive extended market protection in all its indications for an additional year throughout the European Economic Area.

Azacitidine is already approved in the European Economic Area for the treatment of HSCT-ineligible adults diagnosed with intermediate-2- and high-risk myelodysplastic syndromes; chronic myelomonocytic leukemia with 10%-29% marrow blasts without myeloproliferative disorder; or AML with 20%-30% blasts and multi-lineage dysplasia.

AML-001 trial

The CHMP’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.

Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle) or best supportive care only.

Patients were then randomized to receive either azacitidine (75 mg/m²/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).

Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).

One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.

Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.

Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33%, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively. 

An OBG Management reader recently requested assistance finding an app or Web site that would be helpful for International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10) coding, particularly for practicing ObGyns. It is not surprising that I have received this question, as we already are seeing a ton of smartphone apps that promise to search through the code descriptions quickly. None of these apps are ObGyn-specific but, given the vast amount, deciding which one is the best option to purchase and download can be a challenge.

Purchase considerations

Before you buy, decide what features you are looking for and make sure the app you have chosen can deliver what you need. Pay special attention to any reviews to learn the app’s pros and the cons. For instance, some apps offer code conversion from ICD-9 to ICD-10. Keep in mind, however, that not all conversions are accurate, and your search may just lead you to another unspecified code. Some apps will offer a decision tree, which is ideal. What you would like to avoid is an app that generates a list of 200 codes from a single search term.

A useful resource that I have found is this Buyers Guide to Mobile ICD-10 Apps from mHealthNews.¹ This guide compares and contrasts the available apps (as of March 2014) for Android and Apple products. Some, you will note, are free; others are not. Try out a few before choosing. While several companies have developed products geared for ICD-10, many are not geared for mobile use and may have a substantial purchase price. Many of them also seem to be geared toward coders, not toward physician users.

My picks

ICD-10 Search was developed by e-MDs.² It appears that this search program is part of a more extensive product that e-MDs sells, but for the time being, is free. This app deserves a look, especially because the decision tree format quickly gets you to the most specific code.

ICD-10 Code Lookup is the official offering from the Centers for Medicare & Medicaid Services (CMS).³ After you type in the term you are looking for, you get the search results in code order. The more specific your search terms, the closer you will get to the needed code. One caveat: the search mode is not set up to accept all clinical terms. For instance, I typed in "menorrhagia" and got 0 results; I typed in “menstruation, frequent” and I received 2 codes.

I hope this information is helpful, and I wish you an easy transition from ICD-9 to ICD-10.

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected]

An OBG Management reader recently requested assistance finding an app or Web site that would be helpful for International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10) coding, particularly for practicing ObGyns. It is not surprising that I have received this question, as we already are seeing a ton of smartphone apps that promise to search through the code descriptions quickly. None of these apps are ObGyn-specific but, given the vast amount, deciding which one is the best option to purchase and download can be a challenge.

Purchase considerations

Before you buy, decide what features you are looking for and make sure the app you have chosen can deliver what you need. Pay special attention to any reviews to learn the app’s pros and the cons. For instance, some apps offer code conversion from ICD-9 to ICD-10. Keep in mind, however, that not all conversions are accurate, and your search may just lead you to another unspecified code. Some apps will offer a decision tree, which is ideal. What you would like to avoid is an app that generates a list of 200 codes from a single search term.

A useful resource that I have found is this Buyers Guide to Mobile ICD-10 Apps from mHealthNews.¹ This guide compares and contrasts the available apps (as of March 2014) for Android and Apple products. Some, you will note, are free; others are not. Try out a few before choosing. While several companies have developed products geared for ICD-10, many are not geared for mobile use and may have a substantial purchase price. Many of them also seem to be geared toward coders, not toward physician users.

My picks

ICD-10 Search was developed by e-MDs.² It appears that this search program is part of a more extensive product that e-MDs sells, but for the time being, is free. This app deserves a look, especially because the decision tree format quickly gets you to the most specific code.

ICD-10 Code Lookup is the official offering from the Centers for Medicare & Medicaid Services (CMS).³ After you type in the term you are looking for, you get the search results in code order. The more specific your search terms, the closer you will get to the needed code. One caveat: the search mode is not set up to accept all clinical terms. For instance, I typed in "menorrhagia" and got 0 results; I typed in “menstruation, frequent” and I received 2 codes.

I hope this information is helpful, and I wish you an easy transition from ICD-9 to ICD-10.

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected]

An OBG Management reader recently requested assistance finding an app or Web site that would be helpful for International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10) coding, particularly for practicing ObGyns. It is not surprising that I have received this question, as we already are seeing a ton of smartphone apps that promise to search through the code descriptions quickly. None of these apps are ObGyn-specific but, given the vast amount, deciding which one is the best option to purchase and download can be a challenge.

Purchase considerations

Before you buy, decide what features you are looking for and make sure the app you have chosen can deliver what you need. Pay special attention to any reviews to learn the app’s pros and the cons. For instance, some apps offer code conversion from ICD-9 to ICD-10. Keep in mind, however, that not all conversions are accurate, and your search may just lead you to another unspecified code. Some apps will offer a decision tree, which is ideal. What you would like to avoid is an app that generates a list of 200 codes from a single search term.

A useful resource that I have found is this Buyers Guide to Mobile ICD-10 Apps from mHealthNews.¹ This guide compares and contrasts the available apps (as of March 2014) for Android and Apple products. Some, you will note, are free; others are not. Try out a few before choosing. While several companies have developed products geared for ICD-10, many are not geared for mobile use and may have a substantial purchase price. Many of them also seem to be geared toward coders, not toward physician users.

My picks

ICD-10 Search was developed by e-MDs.² It appears that this search program is part of a more extensive product that e-MDs sells, but for the time being, is free. This app deserves a look, especially because the decision tree format quickly gets you to the most specific code.

ICD-10 Code Lookup is the official offering from the Centers for Medicare & Medicaid Services (CMS).³ After you type in the term you are looking for, you get the search results in code order. The more specific your search terms, the closer you will get to the needed code. One caveat: the search mode is not set up to accept all clinical terms. For instance, I typed in "menorrhagia" and got 0 results; I typed in “menstruation, frequent” and I received 2 codes.

I hope this information is helpful, and I wish you an easy transition from ICD-9 to ICD-10.

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected]

A new composite measure that incorporates both time in therapeutic range and international normalized ratio variability appears to be more accurate than either of these tests alone at monitoring warfarin anticoagulation, according to a report published online Sept. 29 in Circulation: Cardiovascular Quality and Outcomes.

Time in therapeutic range (TTR) and international normalized ratio (INR) variability track two different aspects of anticoagulation control. TTR measures the percentage of time that patients spend within the therapeutic range while taking warfarin, which reflects the amount of time that treatment intensity was appropriate. INR variability measures variations in the stability of warfarin’s anticoagulation effects over time. Most clinicians monitor their patients using one or the other of these measures, usually TTR. A composite measure that combines the two “would encourage providers to focus on all components of anticoagulation control, not just those measured by the current standard of care, TTR,” said Dr. Zayd Razouki of the Center for Health Services Research in Primary Care, Durham (N.C.) Veterans Affairs Medical Center, and his associates.

Copyright American Stroke Association

It is important to note that a substantial number of patients taking warfarin could be classified as having poor control of anticoagulation by one of these measures, but good control by the other. Combining TTR with INR variability would ensure that both appropriate intensity and appropriate stability of warfarin therapy were being used to judge each patient’s anticoagulation control, they noted.

The investigators devised such a measure, a summary score they called WCM (warfarin composite measure). They then compared the performance of all three measures at predicting major warfarin-related complications, using as a sample population 40,404 participants in the Veterans Affairs Study to Improve Anticoagulation (VARIA). These study subjects were aged 65 years or older (mean age 76), had been taking warfarin for at least 6 months to treat atrial fibrillation, and were followed for an average of 14 months for the development of ischemic stroke, major bleeding, and fatal bleeding.

A total of 3.1% of these patients developed ischemic stroke, 6.4% developed major bleeding, and 0.9% developed fatal bleeding while taking warfarin. After the data were adjusted to account for numerous potential confounding factors, WCM correlated most closely with risk for adverse warfarin-related clinical events, Dr. Razouki and his associates wrote (Circ Cardiovasc Qual Outcomes. 2015 Sep 29. doi:10.1161/circoutcomes.115.001789).

Their findings also indicate that WCM may be a more accurate measure of a clinic’s or a medical system’s performance at monitoring anticoagulation than either their average TTR or INR variability alone.

The study results may not be generalizable to all populations, because this VA sample was overwhelmingly male (98%), the investigators added.

A new composite measure that incorporates both time in therapeutic range and international normalized ratio variability appears to be more accurate than either of these tests alone at monitoring warfarin anticoagulation, according to a report published online Sept. 29 in Circulation: Cardiovascular Quality and Outcomes.

Time in therapeutic range (TTR) and international normalized ratio (INR) variability track two different aspects of anticoagulation control. TTR measures the percentage of time that patients spend within the therapeutic range while taking warfarin, which reflects the amount of time that treatment intensity was appropriate. INR variability measures variations in the stability of warfarin’s anticoagulation effects over time. Most clinicians monitor their patients using one or the other of these measures, usually TTR. A composite measure that combines the two “would encourage providers to focus on all components of anticoagulation control, not just those measured by the current standard of care, TTR,” said Dr. Zayd Razouki of the Center for Health Services Research in Primary Care, Durham (N.C.) Veterans Affairs Medical Center, and his associates.

Copyright American Stroke Association

It is important to note that a substantial number of patients taking warfarin could be classified as having poor control of anticoagulation by one of these measures, but good control by the other. Combining TTR with INR variability would ensure that both appropriate intensity and appropriate stability of warfarin therapy were being used to judge each patient’s anticoagulation control, they noted.

The investigators devised such a measure, a summary score they called WCM (warfarin composite measure). They then compared the performance of all three measures at predicting major warfarin-related complications, using as a sample population 40,404 participants in the Veterans Affairs Study to Improve Anticoagulation (VARIA). These study subjects were aged 65 years or older (mean age 76), had been taking warfarin for at least 6 months to treat atrial fibrillation, and were followed for an average of 14 months for the development of ischemic stroke, major bleeding, and fatal bleeding.

A total of 3.1% of these patients developed ischemic stroke, 6.4% developed major bleeding, and 0.9% developed fatal bleeding while taking warfarin. After the data were adjusted to account for numerous potential confounding factors, WCM correlated most closely with risk for adverse warfarin-related clinical events, Dr. Razouki and his associates wrote (Circ Cardiovasc Qual Outcomes. 2015 Sep 29. doi:10.1161/circoutcomes.115.001789).

Their findings also indicate that WCM may be a more accurate measure of a clinic’s or a medical system’s performance at monitoring anticoagulation than either their average TTR or INR variability alone.

The study results may not be generalizable to all populations, because this VA sample was overwhelmingly male (98%), the investigators added.

A new composite measure that incorporates both time in therapeutic range and international normalized ratio variability appears to be more accurate than either of these tests alone at monitoring warfarin anticoagulation, according to a report published online Sept. 29 in Circulation: Cardiovascular Quality and Outcomes.

Time in therapeutic range (TTR) and international normalized ratio (INR) variability track two different aspects of anticoagulation control. TTR measures the percentage of time that patients spend within the therapeutic range while taking warfarin, which reflects the amount of time that treatment intensity was appropriate. INR variability measures variations in the stability of warfarin’s anticoagulation effects over time. Most clinicians monitor their patients using one or the other of these measures, usually TTR. A composite measure that combines the two “would encourage providers to focus on all components of anticoagulation control, not just those measured by the current standard of care, TTR,” said Dr. Zayd Razouki of the Center for Health Services Research in Primary Care, Durham (N.C.) Veterans Affairs Medical Center, and his associates.

Copyright American Stroke Association

It is important to note that a substantial number of patients taking warfarin could be classified as having poor control of anticoagulation by one of these measures, but good control by the other. Combining TTR with INR variability would ensure that both appropriate intensity and appropriate stability of warfarin therapy were being used to judge each patient’s anticoagulation control, they noted.

The investigators devised such a measure, a summary score they called WCM (warfarin composite measure). They then compared the performance of all three measures at predicting major warfarin-related complications, using as a sample population 40,404 participants in the Veterans Affairs Study to Improve Anticoagulation (VARIA). These study subjects were aged 65 years or older (mean age 76), had been taking warfarin for at least 6 months to treat atrial fibrillation, and were followed for an average of 14 months for the development of ischemic stroke, major bleeding, and fatal bleeding.

A total of 3.1% of these patients developed ischemic stroke, 6.4% developed major bleeding, and 0.9% developed fatal bleeding while taking warfarin. After the data were adjusted to account for numerous potential confounding factors, WCM correlated most closely with risk for adverse warfarin-related clinical events, Dr. Razouki and his associates wrote (Circ Cardiovasc Qual Outcomes. 2015 Sep 29. doi:10.1161/circoutcomes.115.001789).

Their findings also indicate that WCM may be a more accurate measure of a clinic’s or a medical system’s performance at monitoring anticoagulation than either their average TTR or INR variability alone.

The study results may not be generalizable to all populations, because this VA sample was overwhelmingly male (98%), the investigators added.

 Much has been written about “the difficult patient” in the medical literature.^1,2 Also labeled as a “heartsink patient,” “hateful patient,” and “black hole,” they possess charac­teristics that evoke powerful, often nega­tive, emotional responses in providers that can be counter-therapeutic. “The difficult provider” also is thought to contribute to the failure of the patient encounter,³ and providers may have lim­ited awareness of these patient–provider characteristics that can lead to such inter­actions. Early identification of these char­acteristics is essential to implementing effective interventions for the care of a difficult patient.

The mnemonic ABCD highlights patient characteristics that suggest you are dealing with a difficult patient (Table).

7 Negatives that affect the provider–patient relationship
The 7 Es highlight negative provider-related variables that contribute to per­ceived and actual difficulty providing care. As a psychiatrist doing consultation-liaison work, this memory device also can be a tool to educate physician–colleagues, nursing staff, and other members of the treatment team.

Expertise. Lack of basic knowledge or experience with your patient’s condi­tion and circumstances, or not being familiar with available resources, could limit your confidence, be counter-productive, and lead to inappropriate care.

Experiences. Current and past life experiences could negatively color a provider’s feelings, thoughts, and inter­actions with the patient. Negative inter­personal experiences could manifest as countertransference.

Empathy. The inability to empathize makes it difficult to understand the patient, creating distance between you and the patient.

Engagement level. A lack of rapport and ineffective communication leads to a patient feeling misunderstood and unsat­isfied with the clinical interaction.

Emotions. Feeling tired, angry, or resentful harms the provider–patient interaction.

Environment. A stressful, loud, pres­sured environment filled with distrac­tions can undermine the provider–patient relationship.

Extra help. Limited access to, and the unavailability of, social services, hous­ing, and similar resources could make an already difficult situation seem impossible to solve. Working without such help can lead to feelings of helplessness and hope­lessness for you and your patient.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. The views expressed in this publication/presentation are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.

 Much has been written about “the difficult patient” in the medical literature.^1,2 Also labeled as a “heartsink patient,” “hateful patient,” and “black hole,” they possess charac­teristics that evoke powerful, often nega­tive, emotional responses in providers that can be counter-therapeutic. “The difficult provider” also is thought to contribute to the failure of the patient encounter,³ and providers may have lim­ited awareness of these patient–provider characteristics that can lead to such inter­actions. Early identification of these char­acteristics is essential to implementing effective interventions for the care of a difficult patient.

The mnemonic ABCD highlights patient characteristics that suggest you are dealing with a difficult patient (Table).

7 Negatives that affect the provider–patient relationship
The 7 Es highlight negative provider-related variables that contribute to per­ceived and actual difficulty providing care. As a psychiatrist doing consultation-liaison work, this memory device also can be a tool to educate physician–colleagues, nursing staff, and other members of the treatment team.

Expertise. Lack of basic knowledge or experience with your patient’s condi­tion and circumstances, or not being familiar with available resources, could limit your confidence, be counter-productive, and lead to inappropriate care.

Experiences. Current and past life experiences could negatively color a provider’s feelings, thoughts, and inter­actions with the patient. Negative inter­personal experiences could manifest as countertransference.

Empathy. The inability to empathize makes it difficult to understand the patient, creating distance between you and the patient.

Engagement level. A lack of rapport and ineffective communication leads to a patient feeling misunderstood and unsat­isfied with the clinical interaction.

Emotions. Feeling tired, angry, or resentful harms the provider–patient interaction.

Environment. A stressful, loud, pres­sured environment filled with distrac­tions can undermine the provider–patient relationship.

Extra help. Limited access to, and the unavailability of, social services, hous­ing, and similar resources could make an already difficult situation seem impossible to solve. Working without such help can lead to feelings of helplessness and hope­lessness for you and your patient.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. The views expressed in this publication/presentation are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.

 Much has been written about “the difficult patient” in the medical literature.^1,2 Also labeled as a “heartsink patient,” “hateful patient,” and “black hole,” they possess charac­teristics that evoke powerful, often nega­tive, emotional responses in providers that can be counter-therapeutic. “The difficult provider” also is thought to contribute to the failure of the patient encounter,³ and providers may have lim­ited awareness of these patient–provider characteristics that can lead to such inter­actions. Early identification of these char­acteristics is essential to implementing effective interventions for the care of a difficult patient.

The mnemonic ABCD highlights patient characteristics that suggest you are dealing with a difficult patient (Table).

7 Negatives that affect the provider–patient relationship
The 7 Es highlight negative provider-related variables that contribute to per­ceived and actual difficulty providing care. As a psychiatrist doing consultation-liaison work, this memory device also can be a tool to educate physician–colleagues, nursing staff, and other members of the treatment team.

Expertise. Lack of basic knowledge or experience with your patient’s condi­tion and circumstances, or not being familiar with available resources, could limit your confidence, be counter-productive, and lead to inappropriate care.

Experiences. Current and past life experiences could negatively color a provider’s feelings, thoughts, and inter­actions with the patient. Negative inter­personal experiences could manifest as countertransference.

Empathy. The inability to empathize makes it difficult to understand the patient, creating distance between you and the patient.

Engagement level. A lack of rapport and ineffective communication leads to a patient feeling misunderstood and unsat­isfied with the clinical interaction.

Emotions. Feeling tired, angry, or resentful harms the provider–patient interaction.

Environment. A stressful, loud, pres­sured environment filled with distrac­tions can undermine the provider–patient relationship.

Extra help. Limited access to, and the unavailability of, social services, hous­ing, and similar resources could make an already difficult situation seem impossible to solve. Working without such help can lead to feelings of helplessness and hope­lessness for you and your patient.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. The views expressed in this publication/presentation are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.

Postpartum preeclampsia, mother dies: $6.9M settlement
Four days after delivery of a healthy child, a 31-year-old mother went to the emergency department (ED) reporting tightness in her chest, difficulty breathing, and swelling in her lower extremities. Pulmonary embolism was ruled out and she was discharged. When she returned 3 days later, her legs were more swollen than before and her systolic blood pressure was 160 mm Hg. She was sent home again. Four days later, she suffered a seizure at home, in the ambulance during transport, and at the hospital. She was transferred to another facility a few days later where she died a week after transfer.

Estate’s Claim The ED physicians and hospital staff were negligent in not diagnosing and treating postpartum preeclampsia. This led to seizures, brain damage, and death. Antihypertensive and antiseizure medications would have prevented her death.

Defendant’s defense The actions taken were reasonable because she had no symptoms of preeclampsia during pregnancy or delivery.

Verdict A $6.9 million Illinois settlement was reached.

Ovary not removed; cyst develops
A 38-year-old woman underwent what was planned as total hysterectomy with bilateral salpingo-oophorectomy. The procedure was prophylactic: she had been treated for stage 3 breast cancer and her family history put her at high risk for developing ovarian cancer. Two days after surgery, the pathology report noted only 1 ovary.

Two months later, the patient went to the ED with right lower quadrant pain. It was determined that she had an ovarian cyst. She underwent additional surgery to remove the right ovary.

Patient’s claim The gynecologist was negligent in failing to remove the patient’s right ovary.

Physician’s defense Failure to remove the ovary was due to the patient’s abnormal anatomy.

Verdict A $250,000 Missouri verdict was returned.

Microcephaly not detected before birth
At 19 weeks’ gestation, an ultrasonographic anatomy scan showed that both hands of the fetus were clenched tightly. Amniocentesis results were reported as normal. No further fetal testing was ordered.

At birth, the baby was found to have Dandy Walker Variant, a severe brain malformation. The child has difficulty moving, is cognitively impaired, and requires a feeding tube and 24-hour care.

Parents’ claim Seen on ultrasonography, the fetus’ clenched fists were a sign of possible fetal abnormality. The maternal-fetal medicine (MFM) specialist who evaluated the ultrasound and amniocentesis and the ObGyn should have recommended fetal magnetic resonance imaging, which would have shown the microcephaly. If the parents had known of the abnormality, they would have terminated the pregnancy.

Defendant’s defense The case was settled during trial.

Verdict A $6 million New Jersey settlement was reached, including 
$5 million from the MFM and 
$1 million from the ObGyn.

Injury during hydrothermal ablation
When a 41-year-old woman underwent hydrothermal ablation to treat menorrhagia, her uterus was perforated and hot saline solution injured her intestines. During repair surgery, 21 inches of bowel were resected and a colostomy was created, which was reversed 8 months later.

Patient’s claim The gynecologist was negligent in performing the ablation. The manufacturer produced a poorly designed device.

Defendant’s defense The rupture was spontaneous. The procedure was properly performed. The device is safe.

Verdict A $2 million Kansas verdict was returned. The gynecologist was found 60% at fault and the manufacturer was 40% at fault. The patient’s net recovery was $322,300 due to the state cap.
 

Postpartum preeclampsia, mother dies: $6.9M settlement
Four days after delivery of a healthy child, a 31-year-old mother went to the emergency department (ED) reporting tightness in her chest, difficulty breathing, and swelling in her lower extremities. Pulmonary embolism was ruled out and she was discharged. When she returned 3 days later, her legs were more swollen than before and her systolic blood pressure was 160 mm Hg. She was sent home again. Four days later, she suffered a seizure at home, in the ambulance during transport, and at the hospital. She was transferred to another facility a few days later where she died a week after transfer.

Estate’s Claim The ED physicians and hospital staff were negligent in not diagnosing and treating postpartum preeclampsia. This led to seizures, brain damage, and death. Antihypertensive and antiseizure medications would have prevented her death.

Defendant’s defense The actions taken were reasonable because she had no symptoms of preeclampsia during pregnancy or delivery.

Verdict A $6.9 million Illinois settlement was reached.

Ovary not removed; cyst develops
A 38-year-old woman underwent what was planned as total hysterectomy with bilateral salpingo-oophorectomy. The procedure was prophylactic: she had been treated for stage 3 breast cancer and her family history put her at high risk for developing ovarian cancer. Two days after surgery, the pathology report noted only 1 ovary.

Two months later, the patient went to the ED with right lower quadrant pain. It was determined that she had an ovarian cyst. She underwent additional surgery to remove the right ovary.

Patient’s claim The gynecologist was negligent in failing to remove the patient’s right ovary.

Physician’s defense Failure to remove the ovary was due to the patient’s abnormal anatomy.

Verdict A $250,000 Missouri verdict was returned.

Microcephaly not detected before birth
At 19 weeks’ gestation, an ultrasonographic anatomy scan showed that both hands of the fetus were clenched tightly. Amniocentesis results were reported as normal. No further fetal testing was ordered.

At birth, the baby was found to have Dandy Walker Variant, a severe brain malformation. The child has difficulty moving, is cognitively impaired, and requires a feeding tube and 24-hour care.

Parents’ claim Seen on ultrasonography, the fetus’ clenched fists were a sign of possible fetal abnormality. The maternal-fetal medicine (MFM) specialist who evaluated the ultrasound and amniocentesis and the ObGyn should have recommended fetal magnetic resonance imaging, which would have shown the microcephaly. If the parents had known of the abnormality, they would have terminated the pregnancy.

Defendant’s defense The case was settled during trial.

Verdict A $6 million New Jersey settlement was reached, including 
$5 million from the MFM and 
$1 million from the ObGyn.

Injury during hydrothermal ablation
When a 41-year-old woman underwent hydrothermal ablation to treat menorrhagia, her uterus was perforated and hot saline solution injured her intestines. During repair surgery, 21 inches of bowel were resected and a colostomy was created, which was reversed 8 months later.

Patient’s claim The gynecologist was negligent in performing the ablation. The manufacturer produced a poorly designed device.

Defendant’s defense The rupture was spontaneous. The procedure was properly performed. The device is safe.

Verdict A $2 million Kansas verdict was returned. The gynecologist was found 60% at fault and the manufacturer was 40% at fault. The patient’s net recovery was $322,300 due to the state cap.
 

Postpartum preeclampsia, mother dies: $6.9M settlement
Four days after delivery of a healthy child, a 31-year-old mother went to the emergency department (ED) reporting tightness in her chest, difficulty breathing, and swelling in her lower extremities. Pulmonary embolism was ruled out and she was discharged. When she returned 3 days later, her legs were more swollen than before and her systolic blood pressure was 160 mm Hg. She was sent home again. Four days later, she suffered a seizure at home, in the ambulance during transport, and at the hospital. She was transferred to another facility a few days later where she died a week after transfer.

Estate’s Claim The ED physicians and hospital staff were negligent in not diagnosing and treating postpartum preeclampsia. This led to seizures, brain damage, and death. Antihypertensive and antiseizure medications would have prevented her death.

Defendant’s defense The actions taken were reasonable because she had no symptoms of preeclampsia during pregnancy or delivery.

Verdict A $6.9 million Illinois settlement was reached.

Ovary not removed; cyst develops
A 38-year-old woman underwent what was planned as total hysterectomy with bilateral salpingo-oophorectomy. The procedure was prophylactic: she had been treated for stage 3 breast cancer and her family history put her at high risk for developing ovarian cancer. Two days after surgery, the pathology report noted only 1 ovary.

Two months later, the patient went to the ED with right lower quadrant pain. It was determined that she had an ovarian cyst. She underwent additional surgery to remove the right ovary.

Patient’s claim The gynecologist was negligent in failing to remove the patient’s right ovary.

Physician’s defense Failure to remove the ovary was due to the patient’s abnormal anatomy.

Verdict A $250,000 Missouri verdict was returned.

Microcephaly not detected before birth
At 19 weeks’ gestation, an ultrasonographic anatomy scan showed that both hands of the fetus were clenched tightly. Amniocentesis results were reported as normal. No further fetal testing was ordered.

At birth, the baby was found to have Dandy Walker Variant, a severe brain malformation. The child has difficulty moving, is cognitively impaired, and requires a feeding tube and 24-hour care.

Parents’ claim Seen on ultrasonography, the fetus’ clenched fists were a sign of possible fetal abnormality. The maternal-fetal medicine (MFM) specialist who evaluated the ultrasound and amniocentesis and the ObGyn should have recommended fetal magnetic resonance imaging, which would have shown the microcephaly. If the parents had known of the abnormality, they would have terminated the pregnancy.

Defendant’s defense The case was settled during trial.

Verdict A $6 million New Jersey settlement was reached, including 
$5 million from the MFM and 
$1 million from the ObGyn.

Injury during hydrothermal ablation
When a 41-year-old woman underwent hydrothermal ablation to treat menorrhagia, her uterus was perforated and hot saline solution injured her intestines. During repair surgery, 21 inches of bowel were resected and a colostomy was created, which was reversed 8 months later.

Patient’s claim The gynecologist was negligent in performing the ablation. The manufacturer produced a poorly designed device.

Defendant’s defense The rupture was spontaneous. The procedure was properly performed. The device is safe.

Verdict A $2 million Kansas verdict was returned. The gynecologist was found 60% at fault and the manufacturer was 40% at fault. The patient’s net recovery was $322,300 due to the state cap.
 

Being a caring, knowledgeable clinician is vital for patient care, but having such skill does not necessarily mean that running a medical practice comes easy— especially if you do not have a basic back­ground in business. Financial fundamentals are rarely taught in residency and, with administrative burdens increasingly placed on physicians in solo and small practices, it isn’t surprising that many practitioners feel underprepared.

Fortunately, it doesn’t take a master’s degree in business administration to con­quer these challenges. You just need some understanding of key operating principles.

Accounting basics
It isn’t personal; it’s only business. Delineate the point at which personal finances stop and business finances begin. Make sure that you have a business checking account and credit card, and run all your business expenses through those accounts—never through your personal accounts. That policy will save you time if your practice is audited and, more important, will help you be effi­cient by guiding your focus to the right set of numbers by which to manage the practice.

Set up a system to track transactions. Many businesses use the accounting soft­ware QuickBooks; the program can gener­ate sophisticated reports, and many banks can export data to it automatically. But QuickBooks might be more complicated than what you need to get started; a simple spreadsheet program, such as Excel, might suffice. By working through the numbers yourself, you gain a more intimate knowl­edge of the state of your finances.

Assemble a team of experts to assist you, at least in the beginning, with building a core knowledge base and good habits. Don’t think that this absolves you of responsibility, however: Ultimately, you sign off on what your advisors recommend. For example, an accountant can prepare your tax return, but you review and approve it, and a financial advisor might recommend certain invest­ments, but only you can authorize them. You might work with a banker for a business loan or a bookkeeper to help you with your day-to-day record-keeping, but no one can give you the critical thinking you need to maximize your financial success.

The devil is in those details
Delve into your practice’s profit/loss statement, or create one if it doesn’t exist. Understanding these data is critical for maintaining financial health. Without know­ing how much money you are taking in and where it is going, you cannot be confident that your business model is viable.

Revenue is easier to digest because it typi­cally derives from only a few sources: pro­fessional fees and interest and, perhaps, speaking engagements, consultation to trainees, teaching, and rental income.

Expenses. Getting a grasp of where the money goes is more challenging. Common examples of costs of running a practice include, but aren’t limited to, the list in the Table.

Other financial reports, such as a balance sheet and a statement of cash flow, are useful for giving you a sense of your practice’s long-term financial health. Typically, however, they are unnecessary during early stages of establishing a practice—and the work they require can be overwhelming.

After you’re done with the math
Based on your financial analysis of the prac­tice, you will be able to pay yourself a salary based on the profit (that is, revenue minus expenses). Before you take your salary, however:
   • Consider keeping enough in your busi­ness checking account to pay next month’s bills.
   • Remember to adjust your monthly compensation downward by 20% to 50% to withhold for payroll and estimated federal and state taxes.
   • Look into tax-advantaged business benefit plans. A retirement account, cer­tain savings plans (eg, flexible spending accounts for dependent care or health care), a commuter plan, and life insurance paid for by the business can make your income go further. Some of these benefits are available only to employees of corporations; crunch the numbers, however, and discuss with your accountant whether the cost of incor­porating is worthwhile.
   • Determine whether hiring an assistant, or adding an additional one, will increase your bottom line. You incur significant expenses by hiring an employee—salary, payroll taxes, and time spent training, to name a few—but doing so might be worth it if the time that he (she) saves you opens up billable hours for seeing patients.

Good care requires a solid foundation
Caring for people who are suffering, while being financially successful, are not con­tradictory goals. Although you deal with a person’s private, intense feelings when you provide care, you also have an obliga­tion to ensure the financial health of your practice.

Disclosure
Dr. Braslow is the founder of Luminello.com.

Being a caring, knowledgeable clinician is vital for patient care, but having such skill does not necessarily mean that running a medical practice comes easy— especially if you do not have a basic back­ground in business. Financial fundamentals are rarely taught in residency and, with administrative burdens increasingly placed on physicians in solo and small practices, it isn’t surprising that many practitioners feel underprepared.

Fortunately, it doesn’t take a master’s degree in business administration to con­quer these challenges. You just need some understanding of key operating principles.

Accounting basics
It isn’t personal; it’s only business. Delineate the point at which personal finances stop and business finances begin. Make sure that you have a business checking account and credit card, and run all your business expenses through those accounts—never through your personal accounts. That policy will save you time if your practice is audited and, more important, will help you be effi­cient by guiding your focus to the right set of numbers by which to manage the practice.

Set up a system to track transactions. Many businesses use the accounting soft­ware QuickBooks; the program can gener­ate sophisticated reports, and many banks can export data to it automatically. But QuickBooks might be more complicated than what you need to get started; a simple spreadsheet program, such as Excel, might suffice. By working through the numbers yourself, you gain a more intimate knowl­edge of the state of your finances.

Assemble a team of experts to assist you, at least in the beginning, with building a core knowledge base and good habits. Don’t think that this absolves you of responsibility, however: Ultimately, you sign off on what your advisors recommend. For example, an accountant can prepare your tax return, but you review and approve it, and a financial advisor might recommend certain invest­ments, but only you can authorize them. You might work with a banker for a business loan or a bookkeeper to help you with your day-to-day record-keeping, but no one can give you the critical thinking you need to maximize your financial success.

The devil is in those details
Delve into your practice’s profit/loss statement, or create one if it doesn’t exist. Understanding these data is critical for maintaining financial health. Without know­ing how much money you are taking in and where it is going, you cannot be confident that your business model is viable.

Revenue is easier to digest because it typi­cally derives from only a few sources: pro­fessional fees and interest and, perhaps, speaking engagements, consultation to trainees, teaching, and rental income.

Expenses. Getting a grasp of where the money goes is more challenging. Common examples of costs of running a practice include, but aren’t limited to, the list in the Table.

Other financial reports, such as a balance sheet and a statement of cash flow, are useful for giving you a sense of your practice’s long-term financial health. Typically, however, they are unnecessary during early stages of establishing a practice—and the work they require can be overwhelming.

After you’re done with the math
Based on your financial analysis of the prac­tice, you will be able to pay yourself a salary based on the profit (that is, revenue minus expenses). Before you take your salary, however:
   • Consider keeping enough in your busi­ness checking account to pay next month’s bills.
   • Remember to adjust your monthly compensation downward by 20% to 50% to withhold for payroll and estimated federal and state taxes.
   • Look into tax-advantaged business benefit plans. A retirement account, cer­tain savings plans (eg, flexible spending accounts for dependent care or health care), a commuter plan, and life insurance paid for by the business can make your income go further. Some of these benefits are available only to employees of corporations; crunch the numbers, however, and discuss with your accountant whether the cost of incor­porating is worthwhile.
   • Determine whether hiring an assistant, or adding an additional one, will increase your bottom line. You incur significant expenses by hiring an employee—salary, payroll taxes, and time spent training, to name a few—but doing so might be worth it if the time that he (she) saves you opens up billable hours for seeing patients.

Good care requires a solid foundation
Caring for people who are suffering, while being financially successful, are not con­tradictory goals. Although you deal with a person’s private, intense feelings when you provide care, you also have an obliga­tion to ensure the financial health of your practice.

Disclosure
Dr. Braslow is the founder of Luminello.com.

Being a caring, knowledgeable clinician is vital for patient care, but having such skill does not necessarily mean that running a medical practice comes easy— especially if you do not have a basic back­ground in business. Financial fundamentals are rarely taught in residency and, with administrative burdens increasingly placed on physicians in solo and small practices, it isn’t surprising that many practitioners feel underprepared.

Fortunately, it doesn’t take a master’s degree in business administration to con­quer these challenges. You just need some understanding of key operating principles.

Accounting basics
It isn’t personal; it’s only business. Delineate the point at which personal finances stop and business finances begin. Make sure that you have a business checking account and credit card, and run all your business expenses through those accounts—never through your personal accounts. That policy will save you time if your practice is audited and, more important, will help you be effi­cient by guiding your focus to the right set of numbers by which to manage the practice.

Set up a system to track transactions. Many businesses use the accounting soft­ware QuickBooks; the program can gener­ate sophisticated reports, and many banks can export data to it automatically. But QuickBooks might be more complicated than what you need to get started; a simple spreadsheet program, such as Excel, might suffice. By working through the numbers yourself, you gain a more intimate knowl­edge of the state of your finances.

Assemble a team of experts to assist you, at least in the beginning, with building a core knowledge base and good habits. Don’t think that this absolves you of responsibility, however: Ultimately, you sign off on what your advisors recommend. For example, an accountant can prepare your tax return, but you review and approve it, and a financial advisor might recommend certain invest­ments, but only you can authorize them. You might work with a banker for a business loan or a bookkeeper to help you with your day-to-day record-keeping, but no one can give you the critical thinking you need to maximize your financial success.

The devil is in those details
Delve into your practice’s profit/loss statement, or create one if it doesn’t exist. Understanding these data is critical for maintaining financial health. Without know­ing how much money you are taking in and where it is going, you cannot be confident that your business model is viable.

Revenue is easier to digest because it typi­cally derives from only a few sources: pro­fessional fees and interest and, perhaps, speaking engagements, consultation to trainees, teaching, and rental income.

Expenses. Getting a grasp of where the money goes is more challenging. Common examples of costs of running a practice include, but aren’t limited to, the list in the Table.

Other financial reports, such as a balance sheet and a statement of cash flow, are useful for giving you a sense of your practice’s long-term financial health. Typically, however, they are unnecessary during early stages of establishing a practice—and the work they require can be overwhelming.

After you’re done with the math
Based on your financial analysis of the prac­tice, you will be able to pay yourself a salary based on the profit (that is, revenue minus expenses). Before you take your salary, however:
   • Consider keeping enough in your busi­ness checking account to pay next month’s bills.
   • Remember to adjust your monthly compensation downward by 20% to 50% to withhold for payroll and estimated federal and state taxes.
   • Look into tax-advantaged business benefit plans. A retirement account, cer­tain savings plans (eg, flexible spending accounts for dependent care or health care), a commuter plan, and life insurance paid for by the business can make your income go further. Some of these benefits are available only to employees of corporations; crunch the numbers, however, and discuss with your accountant whether the cost of incor­porating is worthwhile.
   • Determine whether hiring an assistant, or adding an additional one, will increase your bottom line. You incur significant expenses by hiring an employee—salary, payroll taxes, and time spent training, to name a few—but doing so might be worth it if the time that he (she) saves you opens up billable hours for seeing patients.

Good care requires a solid foundation
Caring for people who are suffering, while being financially successful, are not con­tradictory goals. Although you deal with a person’s private, intense feelings when you provide care, you also have an obliga­tion to ensure the financial health of your practice.

Disclosure
Dr. Braslow is the founder of Luminello.com.

When a patient who smokes enters a tobacco-free medical facility and has access to caffeinated beverages, he (she) might experience toxicity to many pharmaceuticals and caffeine. Similarly, if a patient is discharged from a smoke-free envi­ronment with a newly adjusted medication regimen and resumes smoking or caffeine consumption, alterations in enzyme activ­ity might reduce therapeutic efficacy of pre­scribed medicines. These effects are a result of alterations in the hepatic cytochrome P450 (CYP) enzyme system.

Taking a careful history of tobacco and caffeine use, and knowing the effects that these substances will have on specific medi­cations, will help guide treatment and man­agement decisions.

The role of CYP enzymes
CYP hepatic enzymes detoxify a variety of environmental agents into water-soluble compounds that are excreted in urine. CYP1A2 metabolizes 20% of drugs handled by the CYP system and comprises 13% of all the CYP enzymes expressed in the liver. The wide interindividual variation in CYP1A2 enzyme activity is influenced by a combina­tion of genetic, epigenetic, ethnic, and envi­ronmental variables.¹

Influence of tobacco on CYP
The polycyclic aromatic hydrocarbons in tobacco smoke induce CYP1A2 and CYP2B6 hepatic enzymes.² Smokers exhibit increased activity of these enzymes, which results in faster clearance of many drugs, lower con­centrations in blood, and diminished clinical response. The Table lists psycho­tropic medicines that are metabolized by CYP1A2 and CYP2B6. Co-administration of these substrates could decrease the elimina­tion rate of other drugs also metabolized by CYP1A2. Nicotine in tobacco or in nicotine replacement therapies does not play a role in inducing CYP enzymes.

The turnover time for CYP1A2 is rapid— approximately 3 days—and a new CYP1A2 steady state activity is reached after approxi­mately 1 week,⁴ which is important to remember when managing inpatients in a smoke-free facility. During acute hospitaliza­tion, patients could experience drug toxic­ity if the outpatient dosage is maintained.⁵

When they resume smoking after being discharged on a stabilized dosage of any of the medications listed in the Table, previous enzyme activity rebounds and might reduce the drug level, potentially leading to inad­equate clinical response.

Caffeine and other substances
Asking about the patient’s caffeine intake is necessary because consumption of coffee is prevalent among smokers, and caffeine is metabolized by CYP1A2. Smokers need to consume as much as 4 times the amount of caffeine as non-smokers to achieve a similar caffeine serum concentration.² Caffeine can form an insoluble precipitate with antipsychotic medication in the gut, which decreases absorption. The interac­tion between smoking-related induction of CYP1A2 enzymes and forced smoking ces­sation during hospitalization, with ongo­ing caffeine consumption, could lead to caffeine toxicity.^4,5

Other common inducers of CYP1A2 are insulin, cabbage, cauliflower, broccoli, and charcoal-grilled meat. Also, cumin and tur­meric inhibit CYP1A2 activity, which might explain an ethnic difference in drug toler­ance across population groups. Additionally, certain genetic polymorphisms, in specific ethnic distributions, alter the potential for tobacco smoke to induce CYP1A2.⁶

Some of these polymorphisms can be genotyped for clinical application.³

Asking about a patient’s tobacco and caffeine use and understanding their inter­actions with specific medications provides guidance when prescribing antipsychotic medications and adjusting dosage for inpatients and during clinical follow-up care.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

When a patient who smokes enters a tobacco-free medical facility and has access to caffeinated beverages, he (she) might experience toxicity to many pharmaceuticals and caffeine. Similarly, if a patient is discharged from a smoke-free envi­ronment with a newly adjusted medication regimen and resumes smoking or caffeine consumption, alterations in enzyme activ­ity might reduce therapeutic efficacy of pre­scribed medicines. These effects are a result of alterations in the hepatic cytochrome P450 (CYP) enzyme system.

Taking a careful history of tobacco and caffeine use, and knowing the effects that these substances will have on specific medi­cations, will help guide treatment and man­agement decisions.

The role of CYP enzymes
CYP hepatic enzymes detoxify a variety of environmental agents into water-soluble compounds that are excreted in urine. CYP1A2 metabolizes 20% of drugs handled by the CYP system and comprises 13% of all the CYP enzymes expressed in the liver. The wide interindividual variation in CYP1A2 enzyme activity is influenced by a combina­tion of genetic, epigenetic, ethnic, and envi­ronmental variables.¹

Influence of tobacco on CYP
The polycyclic aromatic hydrocarbons in tobacco smoke induce CYP1A2 and CYP2B6 hepatic enzymes.² Smokers exhibit increased activity of these enzymes, which results in faster clearance of many drugs, lower con­centrations in blood, and diminished clinical response. The Table lists psycho­tropic medicines that are metabolized by CYP1A2 and CYP2B6. Co-administration of these substrates could decrease the elimina­tion rate of other drugs also metabolized by CYP1A2. Nicotine in tobacco or in nicotine replacement therapies does not play a role in inducing CYP enzymes.

The turnover time for CYP1A2 is rapid— approximately 3 days—and a new CYP1A2 steady state activity is reached after approxi­mately 1 week,⁴ which is important to remember when managing inpatients in a smoke-free facility. During acute hospitaliza­tion, patients could experience drug toxic­ity if the outpatient dosage is maintained.⁵

When they resume smoking after being discharged on a stabilized dosage of any of the medications listed in the Table, previous enzyme activity rebounds and might reduce the drug level, potentially leading to inad­equate clinical response.

Caffeine and other substances
Asking about the patient’s caffeine intake is necessary because consumption of coffee is prevalent among smokers, and caffeine is metabolized by CYP1A2. Smokers need to consume as much as 4 times the amount of caffeine as non-smokers to achieve a similar caffeine serum concentration.² Caffeine can form an insoluble precipitate with antipsychotic medication in the gut, which decreases absorption. The interac­tion between smoking-related induction of CYP1A2 enzymes and forced smoking ces­sation during hospitalization, with ongo­ing caffeine consumption, could lead to caffeine toxicity.^4,5

Other common inducers of CYP1A2 are insulin, cabbage, cauliflower, broccoli, and charcoal-grilled meat. Also, cumin and tur­meric inhibit CYP1A2 activity, which might explain an ethnic difference in drug toler­ance across population groups. Additionally, certain genetic polymorphisms, in specific ethnic distributions, alter the potential for tobacco smoke to induce CYP1A2.⁶

Some of these polymorphisms can be genotyped for clinical application.³

Asking about a patient’s tobacco and caffeine use and understanding their inter­actions with specific medications provides guidance when prescribing antipsychotic medications and adjusting dosage for inpatients and during clinical follow-up care.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

When a patient who smokes enters a tobacco-free medical facility and has access to caffeinated beverages, he (she) might experience toxicity to many pharmaceuticals and caffeine. Similarly, if a patient is discharged from a smoke-free envi­ronment with a newly adjusted medication regimen and resumes smoking or caffeine consumption, alterations in enzyme activ­ity might reduce therapeutic efficacy of pre­scribed medicines. These effects are a result of alterations in the hepatic cytochrome P450 (CYP) enzyme system.

Taking a careful history of tobacco and caffeine use, and knowing the effects that these substances will have on specific medi­cations, will help guide treatment and man­agement decisions.

The role of CYP enzymes
CYP hepatic enzymes detoxify a variety of environmental agents into water-soluble compounds that are excreted in urine. CYP1A2 metabolizes 20% of drugs handled by the CYP system and comprises 13% of all the CYP enzymes expressed in the liver. The wide interindividual variation in CYP1A2 enzyme activity is influenced by a combina­tion of genetic, epigenetic, ethnic, and envi­ronmental variables.¹

Influence of tobacco on CYP
The polycyclic aromatic hydrocarbons in tobacco smoke induce CYP1A2 and CYP2B6 hepatic enzymes.² Smokers exhibit increased activity of these enzymes, which results in faster clearance of many drugs, lower con­centrations in blood, and diminished clinical response. The Table lists psycho­tropic medicines that are metabolized by CYP1A2 and CYP2B6. Co-administration of these substrates could decrease the elimina­tion rate of other drugs also metabolized by CYP1A2. Nicotine in tobacco or in nicotine replacement therapies does not play a role in inducing CYP enzymes.

The turnover time for CYP1A2 is rapid— approximately 3 days—and a new CYP1A2 steady state activity is reached after approxi­mately 1 week,⁴ which is important to remember when managing inpatients in a smoke-free facility. During acute hospitaliza­tion, patients could experience drug toxic­ity if the outpatient dosage is maintained.⁵

When they resume smoking after being discharged on a stabilized dosage of any of the medications listed in the Table, previous enzyme activity rebounds and might reduce the drug level, potentially leading to inad­equate clinical response.

Caffeine and other substances
Asking about the patient’s caffeine intake is necessary because consumption of coffee is prevalent among smokers, and caffeine is metabolized by CYP1A2. Smokers need to consume as much as 4 times the amount of caffeine as non-smokers to achieve a similar caffeine serum concentration.² Caffeine can form an insoluble precipitate with antipsychotic medication in the gut, which decreases absorption. The interac­tion between smoking-related induction of CYP1A2 enzymes and forced smoking ces­sation during hospitalization, with ongo­ing caffeine consumption, could lead to caffeine toxicity.^4,5

Other common inducers of CYP1A2 are insulin, cabbage, cauliflower, broccoli, and charcoal-grilled meat. Also, cumin and tur­meric inhibit CYP1A2 activity, which might explain an ethnic difference in drug toler­ance across population groups. Additionally, certain genetic polymorphisms, in specific ethnic distributions, alter the potential for tobacco smoke to induce CYP1A2.⁶

Some of these polymorphisms can be genotyped for clinical application.³

Asking about a patient’s tobacco and caffeine use and understanding their inter­actions with specific medications provides guidance when prescribing antipsychotic medications and adjusting dosage for inpatients and during clinical follow-up care.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

LAS VEGAS – A higher-than-expected proportion of trauma-related deaths occur in the months and years after hospital discharge, according to findings from a prospective cohort study.

In 908 trauma patients followed for up to 9.8 years (median, 1.7 years), overall mortality was 27%, and in 509 patients followed for at least 2 years, overall mortality was 38%. Mortality was highest among those who were severely injured (43% at 5 years), Dr. Rachael A. Callcut reported at the annual meeting of the American Association for the Surgery of Trauma.

Spotmatik/ThinkStock

The median Injury Severity Scale score was 18, but for all ISS groups, survival was significantly worse than predicted actuarial survival for that group – even after exclusion of deaths that occurred within 30 days, she said.

For example, at 5 years, predicted actuarial survival was greater than 95%, but actual survival was about 90% for those with ISS less than 15, about 85% for those with ISS of 15-24, and about 57% for those with ISS greater than 24. This dose-response–like relationship between injury severity and mortality demonstrates that the deaths are not just occurring in “patients who are old and would have died from a heart attack anyway” she explained.

The 30-day mortality in the cohort was 22%, and in-hospital mortality was 22.9%, as eight patients who died after the first 30 days did so in the hospital. Forty-five of the 245 deaths (18%) occurred after 30 days, and 36 of those (80%) occurred after hospital discharge, meaning the out-of-hospital mortality rate was 5.3% overall, and 10% for the most severely injured (hazard ratio, 2.7 for the most severe vs. the least severe injuries).

“I personally found this quite striking given that when a patient leaves the hospital, we feel, to some degree, that we won – only to find out that at least 5% of these patients will go on to subsequently die,” said Dr. Callcut of the University of California San Francisco, adding that “if you look at it slightly differently, which is even more concerning, 37 of the out-of-hospital deaths of the total of 245 deaths, mean that out-of-hospital deaths account for 15% of the total mortality following trauma.”

Further, of the deaths that occurred after 30 days, 53% occurred between 31 days and 1 year after trauma, and trauma was the leading cause of postdischarge death, accounting for 41% of the late deaths, she said.

The patients included in this analysis were all highest level trauma activation patients enrolled in the ongoing study between 2005 and 2012. Comprehensive prospective data were collected, and patients were followed throughout their hospitalization and after discharge. Institutional medical records or death certificates were used to determine timing and cause of death, and survival status was determined based on the last date of care in the institution or by query of the National Death Index for 2013.

These findings provide a rare glimpse of trauma-related outcomes among patients discharged from the hospital. Most prior studies focused on 30-day outcomes, with a few extended out to 90 days, but very few studies have looked at long-term outcomes, Dr. Callcut noted.

“You could say that despite having survived to leave the hospital alive, long-term survival is actually worse than predicted actuarial survival, and this suggests to us that successful hospital discharge does not mean success for your patient,” she concluded.

Dr. Callcut was supported in part by a National Institutes of Health award.

[email protected]

LAS VEGAS – A higher-than-expected proportion of trauma-related deaths occur in the months and years after hospital discharge, according to findings from a prospective cohort study.

In 908 trauma patients followed for up to 9.8 years (median, 1.7 years), overall mortality was 27%, and in 509 patients followed for at least 2 years, overall mortality was 38%. Mortality was highest among those who were severely injured (43% at 5 years), Dr. Rachael A. Callcut reported at the annual meeting of the American Association for the Surgery of Trauma.

Spotmatik/ThinkStock

The median Injury Severity Scale score was 18, but for all ISS groups, survival was significantly worse than predicted actuarial survival for that group – even after exclusion of deaths that occurred within 30 days, she said.

For example, at 5 years, predicted actuarial survival was greater than 95%, but actual survival was about 90% for those with ISS less than 15, about 85% for those with ISS of 15-24, and about 57% for those with ISS greater than 24. This dose-response–like relationship between injury severity and mortality demonstrates that the deaths are not just occurring in “patients who are old and would have died from a heart attack anyway” she explained.

The 30-day mortality in the cohort was 22%, and in-hospital mortality was 22.9%, as eight patients who died after the first 30 days did so in the hospital. Forty-five of the 245 deaths (18%) occurred after 30 days, and 36 of those (80%) occurred after hospital discharge, meaning the out-of-hospital mortality rate was 5.3% overall, and 10% for the most severely injured (hazard ratio, 2.7 for the most severe vs. the least severe injuries).

“I personally found this quite striking given that when a patient leaves the hospital, we feel, to some degree, that we won – only to find out that at least 5% of these patients will go on to subsequently die,” said Dr. Callcut of the University of California San Francisco, adding that “if you look at it slightly differently, which is even more concerning, 37 of the out-of-hospital deaths of the total of 245 deaths, mean that out-of-hospital deaths account for 15% of the total mortality following trauma.”

Further, of the deaths that occurred after 30 days, 53% occurred between 31 days and 1 year after trauma, and trauma was the leading cause of postdischarge death, accounting for 41% of the late deaths, she said.

The patients included in this analysis were all highest level trauma activation patients enrolled in the ongoing study between 2005 and 2012. Comprehensive prospective data were collected, and patients were followed throughout their hospitalization and after discharge. Institutional medical records or death certificates were used to determine timing and cause of death, and survival status was determined based on the last date of care in the institution or by query of the National Death Index for 2013.

These findings provide a rare glimpse of trauma-related outcomes among patients discharged from the hospital. Most prior studies focused on 30-day outcomes, with a few extended out to 90 days, but very few studies have looked at long-term outcomes, Dr. Callcut noted.

“You could say that despite having survived to leave the hospital alive, long-term survival is actually worse than predicted actuarial survival, and this suggests to us that successful hospital discharge does not mean success for your patient,” she concluded.

Dr. Callcut was supported in part by a National Institutes of Health award.

[email protected]

LAS VEGAS – A higher-than-expected proportion of trauma-related deaths occur in the months and years after hospital discharge, according to findings from a prospective cohort study.

In 908 trauma patients followed for up to 9.8 years (median, 1.7 years), overall mortality was 27%, and in 509 patients followed for at least 2 years, overall mortality was 38%. Mortality was highest among those who were severely injured (43% at 5 years), Dr. Rachael A. Callcut reported at the annual meeting of the American Association for the Surgery of Trauma.

Spotmatik/ThinkStock

The median Injury Severity Scale score was 18, but for all ISS groups, survival was significantly worse than predicted actuarial survival for that group – even after exclusion of deaths that occurred within 30 days, she said.

For example, at 5 years, predicted actuarial survival was greater than 95%, but actual survival was about 90% for those with ISS less than 15, about 85% for those with ISS of 15-24, and about 57% for those with ISS greater than 24. This dose-response–like relationship between injury severity and mortality demonstrates that the deaths are not just occurring in “patients who are old and would have died from a heart attack anyway” she explained.

The 30-day mortality in the cohort was 22%, and in-hospital mortality was 22.9%, as eight patients who died after the first 30 days did so in the hospital. Forty-five of the 245 deaths (18%) occurred after 30 days, and 36 of those (80%) occurred after hospital discharge, meaning the out-of-hospital mortality rate was 5.3% overall, and 10% for the most severely injured (hazard ratio, 2.7 for the most severe vs. the least severe injuries).

“I personally found this quite striking given that when a patient leaves the hospital, we feel, to some degree, that we won – only to find out that at least 5% of these patients will go on to subsequently die,” said Dr. Callcut of the University of California San Francisco, adding that “if you look at it slightly differently, which is even more concerning, 37 of the out-of-hospital deaths of the total of 245 deaths, mean that out-of-hospital deaths account for 15% of the total mortality following trauma.”

Further, of the deaths that occurred after 30 days, 53% occurred between 31 days and 1 year after trauma, and trauma was the leading cause of postdischarge death, accounting for 41% of the late deaths, she said.

The patients included in this analysis were all highest level trauma activation patients enrolled in the ongoing study between 2005 and 2012. Comprehensive prospective data were collected, and patients were followed throughout their hospitalization and after discharge. Institutional medical records or death certificates were used to determine timing and cause of death, and survival status was determined based on the last date of care in the institution or by query of the National Death Index for 2013.

These findings provide a rare glimpse of trauma-related outcomes among patients discharged from the hospital. Most prior studies focused on 30-day outcomes, with a few extended out to 90 days, but very few studies have looked at long-term outcomes, Dr. Callcut noted.

“You could say that despite having survived to leave the hospital alive, long-term survival is actually worse than predicted actuarial survival, and this suggests to us that successful hospital discharge does not mean success for your patient,” she concluded.

Dr. Callcut was supported in part by a National Institutes of Health award.

[email protected]

Brexpiprazole, FDA-approved in July 2015 to treat schizophrenia and as an adjunct for major depressive disorder (MDD) (Table 1), has shown effi­cacy in 2 phase-III acute trials for each indication.^1-6 Although brexpiprazole is a dopamine D2 partial agonist, it differs from aripiprazole, the other available D2 partial agonist, because it is more potent at serotonin 5-HT1A and 5-HT2A recep­tors and displays less intrinsic activity at D2 receptors,⁷ which could mean better tolerability.

Clinical implications
Schizophrenia is heterogeneous, and indi­vidual response and tolerability to anti­psychotics vary greatly⁸; therefore, new drug options are useful. For MDD, before the availability of brexpiprazole, only 3 antipsychotics were FDA-approved for adjunctive use with antidepressant ther­apy⁹; brexpiprazole represents another agent for patients whose depressive symp­toms persist after standard antidepressant treatment.

Variables that limit the use of antipsy­chotics include extrapyramidal symptoms (EPS), akathisia, sedation/somnolence, weight gain, metabolic abnormalities, and hyperprolactinemia. If post-marketing studies and clinical experience confirm that brexpiprazole has an overall favor­able side-effect profile regarding these tolerability obstacles, brexpiprazole would potentially have advantages over some other available agents, including aripiprazole.

How it works
In addition to a subnanomolar binding affin­ity (Ki < 1 nM) to dopamine D2 receptors as a partial agonist, brexpiprazole also exhib­its similar binding affinities for serotonin 5-HT1A (partial agonist), 5-HT2A (antago­nist), and adrenergic α1B (antagonist) and α2C (antagonist) receptors.⁷

Brexpiprazole also has high affinity (Ki < 5 nM) for dopamine D3 (partial ago­ nist), serotonin 5-HT2B (antagonist), and 5-HT7 (antagonist), and at adrenergic α1A (antagonist) and α1D (antagonist) recep­tors. Brexpiprazole has moderate affinity for histamine H1 receptors (Ki = 19 nM, antago­nist), and low affinity for muscarinic M1 receptors (Ki > 1000 nM, antagonist).

Brexpiprazole’s pharmacodynamic pro­file differs from other available antipsy­chotics, including aripiprazole. Whether this translates to meaningful differences in efficacy and tolerability will depend on the outcomes of specifically designed clinical trials as well as “real-world” experience. Animal models have suggested amelio­ration of schizophrenia-like behavior, depression-like behavior, and anxiety-like behavior with brexipiprazole.⁶

Pharmacokinetics
At 91 hours, brexpiprazole’s half-life is rel­atively long; a steady-state concentration therefore is attained in approximately 2 weeks.1 In the phase-III clinical trials, brex­piprazole was titrated to target dosages, and therefore the product label recommends the same. Brexpiprazole can be administered with or without food.

In a study of brexpiprazole excretion, after a single oral dose of [14C]-labeled brexpip­razole, approximately 25% and 46% of the administered radioactivity was recovered in urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine, and approximately 14% of the oral dose was recovered unchanged in the feces.

Exposure, as measured by maximum con­centration and area under the concentration curve, is dose proportional.

Metabolism of brexpiprazole is mediated principally by cytochrome P450 (CYP) 3A4 and CYP2D6. Based on in vitro data, brex­piprazole shows little or no inhibition of CYP450 isozymes.

Efficacy
FDA approval for brexpiprazole for schizo­phrenia and for adjunctive use in MDD was based on 4 phase-III pivotal acute clinical trials conducted in adults, 2 studies each for each disorder.^1-6 These studies are described in Table 2.^2-5

Although not described in product label­ing, a phase-III 52-week maintenance study demonstrated brexpiprazole’s efficacy in preventing exacerbation of psychotic symp­toms and impending relapse in patients with schizophrenia.10 Time from randomiza­tion to exacerbation of psychotic symptoms or impending relapse showed a beneficial effect with brexpiprazole compared with placebo (log-rank test: hazard ratio = 0.292, P < .0001). Significantly fewer patients in the brexpiprazole group relapsed compared with placebo (13.5% vs 38.5%, P < .0001), resulting in a NNT of 4 (95% CI, 3-8).

Major depressive disorder. The primary outcome measure for the acute MDD stud­ies was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to 6-week endpoint of the ran­domized treatment phase. All patients were required to have a history of inadequate response to 1 to 3 treatment trials of standard antidepressants for their current depressive episode. In addition, patients entered the randomized phase only if they had an inad­equate response to antidepressant therapy during an 8-week prospective treatment trial of standard antidepressant treatment plus single-blind placebo.

Participants who responded adequately to the antidepressant in the prospective single-blind phase were not randomized, but instead continued on antidepressant treat­ment plus single-blind placebo for 6 weeks.

The phase-III studies showed positive results for brexpiprazole, 2 mg/d and 3 mg/d, with change in MADRS from baseline to endpoint superior to that observed with placebo.^4,5

When examining treatment response, defined as a reduction of ≥50% in MADRS total score from baseline, NNT vs placebo for response were 12 at all dosages tested, however, NNT vs placebo for remission (defined as MADRS total score ≤10 and ≥50% improvement from baseline) ranged from 17 to 31 and were not statistically significant.⁶ When the results for brexpiprazole, 1 mg/d, 2 mg/d, and 3 mg/d, from the 2 phase-III tri­als are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI, 8-26); 14.4% of the brexpiprazole-treated patients met remission criteria, vs 9.6% for placebo, resulting in a NNT of 21 (95% CI, 12-138).⁶

Tolerability
Overall tolerability can be evaluated by examining the percentage of patients who discontinued the clinical trials because of an adverse event (AE). In the acute schizo­phrenia double-blind trials for the recom­mended dosage range of 2 to 4 mg, the discontinuation rates were lower overall for patients receiving brexpiprazole com­pared with placebo.^2,3 In the acute MDD trials, 32.6% of brexpiprazole-treated patients and 10.7% of placebo-treated patients discontinued because of AEs,^4,5 yielding a number needed to harm (NNH) of 53 (95% CI, 30-235).⁶

The most commonly encountered AEs for MDD (incidence ≥5% and at least twice the rate for placebo) were akathisia (8.6% vs 1.7% for brexpiprazole vs placebo, and dose-related) and weight gain (6.7% vs 1.9%),¹ with NNH values of 15 (95% CI, 11-23), and 22 (95% CI, 15-42), respectively.⁶ The most commonly encountered AE for schizophre­nia (incidence ≥4% and at least twice the rate for placebo) was weight gain (4% vs 2%),¹ with a NNH of 50 (95% CI, 26-1773).⁶

Of note, rates of akathisia in the schizo­phrenia trials were 5.5% for brexpiprazole and 4.6% for placebo,¹ yielding a non-statistically significant NNH of 112.6 In a 6-week exploratory study,¹¹ the incidence of EPS-related AEs including akathisia was lower for brexpiprazole-treated patients (14.1%) compared with those receiving aripiprazole (30.3%), for a NNT advan­tage for brexpiprazole of 7 (not statistically significant).

Short-term weight gain appears modest; however, outliers with an increase of ≥7% of body weight were evident in open-label long-term safety studies.^1,6 Effects on glucose and lipids were small. Minimal effects on prolac­tin were observed, and no clinically relevant effects on the QT interval were evident.

Contraindications
The only absolute contraindication for brexpiprazole is known hypersensitivity to brexpiprazole or any of its components. Reactions have included rash, facial swell­ing, urticaria, and anaphylaxis.¹

As with all antipsychotics and antipsy­chotics with an indication for a depressive disorder:
   • there is a bolded boxed warning in the product label regarding increased mortality in geriatric patients with dementia-related psychosis. Brexpiprazole is not approved for treating patients with dementia-related psychosis
   • there is a bolded boxed warning in the product label about suicidal thoughts and behaviors in patients age ≤24. The safety and efficacy of brexpiprazole have not been estab­lished in pediatric patients.
 

Dosing
Schizophrenia. The recommended starting dosage for brexpiprazole for schizophrenia is 1 mg/d on Days 1 to 4. Brexpiprazole can be titrated to 2 mg/d on Day 5 through Day 7, then to 4 mg/d on Day 8 based on the patient’s response and ability to tolerate the medication. The recommended target dos­age is 2 to 4 mg/d with a maximum recom­mended daily dosage of 4 mg.

Major depressive disorder. The recom­mended starting dosage for brexpiprazole as adjunctive treatment for MDD is 0.5 mg or 1 mg/d. Brexpiprazole can be titrated to 1 mg/d, then up to the target dosage of 2 mg/d, with dosage increases occurring at weekly intervals based on the patient’s clinical response and ability to tolerate the agent, with a maximum recommended dos­age of 3 mg/d.

Other considerations. For patients with moderate to severe hepatic impairment, or moderate, severe, or end-stage renal impair­ment, the maximum recommended dosage is 3 mg/d for patients with schizophrenia, and 2 mg/d for patients with MDD.

In general, dosage adjustments are rec­ommended in patients who are known CYP2D6 poor metabolizers and in those taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers¹:
   • for strong CYP2D6 or CYP3A4 inhibi­tors, administer one-half the usual dosage
   • for strong/moderate CYP2D6 with strong/moderate CYP3A4 inhibitors, administer a one-quarter of the usual dosage
   • for known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors, also administer a one-quarter of the usual dosage
   • for strong CYP3A4 inducers, double the usual dosage and further adjust based on clinical response.

In clinical trials for MDD, brexpiprazole dosage was not adjusted for strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine). Therefore, CYP considerations are already factored into general dosing recommenda­tions and brexpiprazole could be adminis­tered without dosage adjustment in patients with MDD; however, under these circum­stances, it would be prudent to start brexpip­razole at 0.5 mg, which, although “on-label,” represents a low starting dosage. (Whenever 2 drugs are co-administered and 1 agent has the ability to disturb the metabolism of the other, using smaller increments to the target dosage and possibly waiting longer between dosage adjustments could help avoid poten­tial drug–drug interactions.)

No dosage adjustment for brexpiprazole is required on the basis of sex, race or eth­nicity, or smoking status. Although clinical studies did not include patients age ≥65, the product label recommends that in general, dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.
 

Bottom Line
Brexpiprazole, an atypical antipsychotic, is FDA-approved for schizophrenia and as an adjunct to antidepressants in major depressive disorder. For both indications, brexpiprazole demonstrated positive results compared with placebo in phase-III trials. Brexpiprazole is more potent at serotonin 5-HT1A and 5-HT2A receptors and displays less intrinsic activity at D2 receptors than aripiprazole, which could mean that the drug may be better-tolerated.

Related Resources
• Citrome L. Brexpiprazole: a new dopamine D2 receptor par­tial agonist for the treatment of schizophrenia and major de­pressive disorder. Drugs Today (Barc). 2015;51(7):397-414.
• Citrome L, Stensbøl TB, Maeda K. The preclinical profile of brexpiprazole: what is its clinical relevance for the treat­ment of psychiatric disorders? Expert Rev Neurother. In press.

Drug Brand Names
Aripiprazole • Abilify
Brexpiprazole • Rexulti
Fluoxetine • Prozac
Paroxetine • Paxil

Disclosure
Dr. Citrome is a consultant to Alexza Pharmaceuticals, Alkermes, Allergan, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Forum Pharmaceuticals, Genentech, Janssen, Jazz Pharmaceuticals, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, and Valeant Pharmaceuticals; and is a speaker for Allergan, AstraZeneca, Janssen, Jazz Pharmaceuticals, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda, and Teva.

Brexpiprazole, FDA-approved in July 2015 to treat schizophrenia and as an adjunct for major depressive disorder (MDD) (Table 1), has shown effi­cacy in 2 phase-III acute trials for each indication.^1-6 Although brexpiprazole is a dopamine D2 partial agonist, it differs from aripiprazole, the other available D2 partial agonist, because it is more potent at serotonin 5-HT1A and 5-HT2A recep­tors and displays less intrinsic activity at D2 receptors,⁷ which could mean better tolerability.

Clinical implications
Schizophrenia is heterogeneous, and indi­vidual response and tolerability to anti­psychotics vary greatly⁸; therefore, new drug options are useful. For MDD, before the availability of brexpiprazole, only 3 antipsychotics were FDA-approved for adjunctive use with antidepressant ther­apy⁹; brexpiprazole represents another agent for patients whose depressive symp­toms persist after standard antidepressant treatment.

Variables that limit the use of antipsy­chotics include extrapyramidal symptoms (EPS), akathisia, sedation/somnolence, weight gain, metabolic abnormalities, and hyperprolactinemia. If post-marketing studies and clinical experience confirm that brexpiprazole has an overall favor­able side-effect profile regarding these tolerability obstacles, brexpiprazole would potentially have advantages over some other available agents, including aripiprazole.

How it works
In addition to a subnanomolar binding affin­ity (Ki < 1 nM) to dopamine D2 receptors as a partial agonist, brexpiprazole also exhib­its similar binding affinities for serotonin 5-HT1A (partial agonist), 5-HT2A (antago­nist), and adrenergic α1B (antagonist) and α2C (antagonist) receptors.⁷

Brexpiprazole also has high affinity (Ki < 5 nM) for dopamine D3 (partial ago­ nist), serotonin 5-HT2B (antagonist), and 5-HT7 (antagonist), and at adrenergic α1A (antagonist) and α1D (antagonist) recep­tors. Brexpiprazole has moderate affinity for histamine H1 receptors (Ki = 19 nM, antago­nist), and low affinity for muscarinic M1 receptors (Ki > 1000 nM, antagonist).

Brexpiprazole’s pharmacodynamic pro­file differs from other available antipsy­chotics, including aripiprazole. Whether this translates to meaningful differences in efficacy and tolerability will depend on the outcomes of specifically designed clinical trials as well as “real-world” experience. Animal models have suggested amelio­ration of schizophrenia-like behavior, depression-like behavior, and anxiety-like behavior with brexipiprazole.⁶

Pharmacokinetics
At 91 hours, brexpiprazole’s half-life is rel­atively long; a steady-state concentration therefore is attained in approximately 2 weeks.1 In the phase-III clinical trials, brex­piprazole was titrated to target dosages, and therefore the product label recommends the same. Brexpiprazole can be administered with or without food.

In a study of brexpiprazole excretion, after a single oral dose of [14C]-labeled brexpip­razole, approximately 25% and 46% of the administered radioactivity was recovered in urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine, and approximately 14% of the oral dose was recovered unchanged in the feces.

Exposure, as measured by maximum con­centration and area under the concentration curve, is dose proportional.

Metabolism of brexpiprazole is mediated principally by cytochrome P450 (CYP) 3A4 and CYP2D6. Based on in vitro data, brex­piprazole shows little or no inhibition of CYP450 isozymes.

Efficacy
FDA approval for brexpiprazole for schizo­phrenia and for adjunctive use in MDD was based on 4 phase-III pivotal acute clinical trials conducted in adults, 2 studies each for each disorder.^1-6 These studies are described in Table 2.^2-5

Although not described in product label­ing, a phase-III 52-week maintenance study demonstrated brexpiprazole’s efficacy in preventing exacerbation of psychotic symp­toms and impending relapse in patients with schizophrenia.10 Time from randomiza­tion to exacerbation of psychotic symptoms or impending relapse showed a beneficial effect with brexpiprazole compared with placebo (log-rank test: hazard ratio = 0.292, P < .0001). Significantly fewer patients in the brexpiprazole group relapsed compared with placebo (13.5% vs 38.5%, P < .0001), resulting in a NNT of 4 (95% CI, 3-8).

Major depressive disorder. The primary outcome measure for the acute MDD stud­ies was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to 6-week endpoint of the ran­domized treatment phase. All patients were required to have a history of inadequate response to 1 to 3 treatment trials of standard antidepressants for their current depressive episode. In addition, patients entered the randomized phase only if they had an inad­equate response to antidepressant therapy during an 8-week prospective treatment trial of standard antidepressant treatment plus single-blind placebo.

Participants who responded adequately to the antidepressant in the prospective single-blind phase were not randomized, but instead continued on antidepressant treat­ment plus single-blind placebo for 6 weeks.

The phase-III studies showed positive results for brexpiprazole, 2 mg/d and 3 mg/d, with change in MADRS from baseline to endpoint superior to that observed with placebo.^4,5

When examining treatment response, defined as a reduction of ≥50% in MADRS total score from baseline, NNT vs placebo for response were 12 at all dosages tested, however, NNT vs placebo for remission (defined as MADRS total score ≤10 and ≥50% improvement from baseline) ranged from 17 to 31 and were not statistically significant.⁶ When the results for brexpiprazole, 1 mg/d, 2 mg/d, and 3 mg/d, from the 2 phase-III tri­als are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI, 8-26); 14.4% of the brexpiprazole-treated patients met remission criteria, vs 9.6% for placebo, resulting in a NNT of 21 (95% CI, 12-138).⁶

Tolerability
Overall tolerability can be evaluated by examining the percentage of patients who discontinued the clinical trials because of an adverse event (AE). In the acute schizo­phrenia double-blind trials for the recom­mended dosage range of 2 to 4 mg, the discontinuation rates were lower overall for patients receiving brexpiprazole com­pared with placebo.^2,3 In the acute MDD trials, 32.6% of brexpiprazole-treated patients and 10.7% of placebo-treated patients discontinued because of AEs,^4,5 yielding a number needed to harm (NNH) of 53 (95% CI, 30-235).⁶

The most commonly encountered AEs for MDD (incidence ≥5% and at least twice the rate for placebo) were akathisia (8.6% vs 1.7% for brexpiprazole vs placebo, and dose-related) and weight gain (6.7% vs 1.9%),¹ with NNH values of 15 (95% CI, 11-23), and 22 (95% CI, 15-42), respectively.⁶ The most commonly encountered AE for schizophre­nia (incidence ≥4% and at least twice the rate for placebo) was weight gain (4% vs 2%),¹ with a NNH of 50 (95% CI, 26-1773).⁶

Of note, rates of akathisia in the schizo­phrenia trials were 5.5% for brexpiprazole and 4.6% for placebo,¹ yielding a non-statistically significant NNH of 112.6 In a 6-week exploratory study,¹¹ the incidence of EPS-related AEs including akathisia was lower for brexpiprazole-treated patients (14.1%) compared with those receiving aripiprazole (30.3%), for a NNT advan­tage for brexpiprazole of 7 (not statistically significant).

Short-term weight gain appears modest; however, outliers with an increase of ≥7% of body weight were evident in open-label long-term safety studies.^1,6 Effects on glucose and lipids were small. Minimal effects on prolac­tin were observed, and no clinically relevant effects on the QT interval were evident.

Contraindications
The only absolute contraindication for brexpiprazole is known hypersensitivity to brexpiprazole or any of its components. Reactions have included rash, facial swell­ing, urticaria, and anaphylaxis.¹

As with all antipsychotics and antipsy­chotics with an indication for a depressive disorder:
   • there is a bolded boxed warning in the product label regarding increased mortality in geriatric patients with dementia-related psychosis. Brexpiprazole is not approved for treating patients with dementia-related psychosis
   • there is a bolded boxed warning in the product label about suicidal thoughts and behaviors in patients age ≤24. The safety and efficacy of brexpiprazole have not been estab­lished in pediatric patients.
 

Dosing
Schizophrenia. The recommended starting dosage for brexpiprazole for schizophrenia is 1 mg/d on Days 1 to 4. Brexpiprazole can be titrated to 2 mg/d on Day 5 through Day 7, then to 4 mg/d on Day 8 based on the patient’s response and ability to tolerate the medication. The recommended target dos­age is 2 to 4 mg/d with a maximum recom­mended daily dosage of 4 mg.

Major depressive disorder. The recom­mended starting dosage for brexpiprazole as adjunctive treatment for MDD is 0.5 mg or 1 mg/d. Brexpiprazole can be titrated to 1 mg/d, then up to the target dosage of 2 mg/d, with dosage increases occurring at weekly intervals based on the patient’s clinical response and ability to tolerate the agent, with a maximum recommended dos­age of 3 mg/d.

Other considerations. For patients with moderate to severe hepatic impairment, or moderate, severe, or end-stage renal impair­ment, the maximum recommended dosage is 3 mg/d for patients with schizophrenia, and 2 mg/d for patients with MDD.

In general, dosage adjustments are rec­ommended in patients who are known CYP2D6 poor metabolizers and in those taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers¹:
   • for strong CYP2D6 or CYP3A4 inhibi­tors, administer one-half the usual dosage
   • for strong/moderate CYP2D6 with strong/moderate CYP3A4 inhibitors, administer a one-quarter of the usual dosage
   • for known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors, also administer a one-quarter of the usual dosage
   • for strong CYP3A4 inducers, double the usual dosage and further adjust based on clinical response.

In clinical trials for MDD, brexpiprazole dosage was not adjusted for strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine). Therefore, CYP considerations are already factored into general dosing recommenda­tions and brexpiprazole could be adminis­tered without dosage adjustment in patients with MDD; however, under these circum­stances, it would be prudent to start brexpip­razole at 0.5 mg, which, although “on-label,” represents a low starting dosage. (Whenever 2 drugs are co-administered and 1 agent has the ability to disturb the metabolism of the other, using smaller increments to the target dosage and possibly waiting longer between dosage adjustments could help avoid poten­tial drug–drug interactions.)

No dosage adjustment for brexpiprazole is required on the basis of sex, race or eth­nicity, or smoking status. Although clinical studies did not include patients age ≥65, the product label recommends that in general, dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.
 

Bottom Line
Brexpiprazole, an atypical antipsychotic, is FDA-approved for schizophrenia and as an adjunct to antidepressants in major depressive disorder. For both indications, brexpiprazole demonstrated positive results compared with placebo in phase-III trials. Brexpiprazole is more potent at serotonin 5-HT1A and 5-HT2A receptors and displays less intrinsic activity at D2 receptors than aripiprazole, which could mean that the drug may be better-tolerated.

Related Resources
• Citrome L. Brexpiprazole: a new dopamine D2 receptor par­tial agonist for the treatment of schizophrenia and major de­pressive disorder. Drugs Today (Barc). 2015;51(7):397-414.
• Citrome L, Stensbøl TB, Maeda K. The preclinical profile of brexpiprazole: what is its clinical relevance for the treat­ment of psychiatric disorders? Expert Rev Neurother. In press.

Drug Brand Names
Aripiprazole • Abilify
Brexpiprazole • Rexulti
Fluoxetine • Prozac
Paroxetine • Paxil

Disclosure
Dr. Citrome is a consultant to Alexza Pharmaceuticals, Alkermes, Allergan, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Forum Pharmaceuticals, Genentech, Janssen, Jazz Pharmaceuticals, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, and Valeant Pharmaceuticals; and is a speaker for Allergan, AstraZeneca, Janssen, Jazz Pharmaceuticals, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda, and Teva.

Brexpiprazole, FDA-approved in July 2015 to treat schizophrenia and as an adjunct for major depressive disorder (MDD) (Table 1), has shown effi­cacy in 2 phase-III acute trials for each indication.^1-6 Although brexpiprazole is a dopamine D2 partial agonist, it differs from aripiprazole, the other available D2 partial agonist, because it is more potent at serotonin 5-HT1A and 5-HT2A recep­tors and displays less intrinsic activity at D2 receptors,⁷ which could mean better tolerability.

Clinical implications
Schizophrenia is heterogeneous, and indi­vidual response and tolerability to anti­psychotics vary greatly⁸; therefore, new drug options are useful. For MDD, before the availability of brexpiprazole, only 3 antipsychotics were FDA-approved for adjunctive use with antidepressant ther­apy⁹; brexpiprazole represents another agent for patients whose depressive symp­toms persist after standard antidepressant treatment.

Variables that limit the use of antipsy­chotics include extrapyramidal symptoms (EPS), akathisia, sedation/somnolence, weight gain, metabolic abnormalities, and hyperprolactinemia. If post-marketing studies and clinical experience confirm that brexpiprazole has an overall favor­able side-effect profile regarding these tolerability obstacles, brexpiprazole would potentially have advantages over some other available agents, including aripiprazole.

How it works
In addition to a subnanomolar binding affin­ity (Ki < 1 nM) to dopamine D2 receptors as a partial agonist, brexpiprazole also exhib­its similar binding affinities for serotonin 5-HT1A (partial agonist), 5-HT2A (antago­nist), and adrenergic α1B (antagonist) and α2C (antagonist) receptors.⁷

Brexpiprazole also has high affinity (Ki < 5 nM) for dopamine D3 (partial ago­ nist), serotonin 5-HT2B (antagonist), and 5-HT7 (antagonist), and at adrenergic α1A (antagonist) and α1D (antagonist) recep­tors. Brexpiprazole has moderate affinity for histamine H1 receptors (Ki = 19 nM, antago­nist), and low affinity for muscarinic M1 receptors (Ki > 1000 nM, antagonist).

Brexpiprazole’s pharmacodynamic pro­file differs from other available antipsy­chotics, including aripiprazole. Whether this translates to meaningful differences in efficacy and tolerability will depend on the outcomes of specifically designed clinical trials as well as “real-world” experience. Animal models have suggested amelio­ration of schizophrenia-like behavior, depression-like behavior, and anxiety-like behavior with brexipiprazole.⁶

Pharmacokinetics
At 91 hours, brexpiprazole’s half-life is rel­atively long; a steady-state concentration therefore is attained in approximately 2 weeks.1 In the phase-III clinical trials, brex­piprazole was titrated to target dosages, and therefore the product label recommends the same. Brexpiprazole can be administered with or without food.

In a study of brexpiprazole excretion, after a single oral dose of [14C]-labeled brexpip­razole, approximately 25% and 46% of the administered radioactivity was recovered in urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine, and approximately 14% of the oral dose was recovered unchanged in the feces.

Exposure, as measured by maximum con­centration and area under the concentration curve, is dose proportional.

Metabolism of brexpiprazole is mediated principally by cytochrome P450 (CYP) 3A4 and CYP2D6. Based on in vitro data, brex­piprazole shows little or no inhibition of CYP450 isozymes.

Efficacy
FDA approval for brexpiprazole for schizo­phrenia and for adjunctive use in MDD was based on 4 phase-III pivotal acute clinical trials conducted in adults, 2 studies each for each disorder.^1-6 These studies are described in Table 2.^2-5

Although not described in product label­ing, a phase-III 52-week maintenance study demonstrated brexpiprazole’s efficacy in preventing exacerbation of psychotic symp­toms and impending relapse in patients with schizophrenia.10 Time from randomiza­tion to exacerbation of psychotic symptoms or impending relapse showed a beneficial effect with brexpiprazole compared with placebo (log-rank test: hazard ratio = 0.292, P < .0001). Significantly fewer patients in the brexpiprazole group relapsed compared with placebo (13.5% vs 38.5%, P < .0001), resulting in a NNT of 4 (95% CI, 3-8).

Major depressive disorder. The primary outcome measure for the acute MDD stud­ies was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to 6-week endpoint of the ran­domized treatment phase. All patients were required to have a history of inadequate response to 1 to 3 treatment trials of standard antidepressants for their current depressive episode. In addition, patients entered the randomized phase only if they had an inad­equate response to antidepressant therapy during an 8-week prospective treatment trial of standard antidepressant treatment plus single-blind placebo.

Participants who responded adequately to the antidepressant in the prospective single-blind phase were not randomized, but instead continued on antidepressant treat­ment plus single-blind placebo for 6 weeks.

The phase-III studies showed positive results for brexpiprazole, 2 mg/d and 3 mg/d, with change in MADRS from baseline to endpoint superior to that observed with placebo.^4,5

When examining treatment response, defined as a reduction of ≥50% in MADRS total score from baseline, NNT vs placebo for response were 12 at all dosages tested, however, NNT vs placebo for remission (defined as MADRS total score ≤10 and ≥50% improvement from baseline) ranged from 17 to 31 and were not statistically significant.⁶ When the results for brexpiprazole, 1 mg/d, 2 mg/d, and 3 mg/d, from the 2 phase-III tri­als are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs 14.5% for placebo, yielding a NNT of 12 (95% CI, 8-26); 14.4% of the brexpiprazole-treated patients met remission criteria, vs 9.6% for placebo, resulting in a NNT of 21 (95% CI, 12-138).⁶

Tolerability
Overall tolerability can be evaluated by examining the percentage of patients who discontinued the clinical trials because of an adverse event (AE). In the acute schizo­phrenia double-blind trials for the recom­mended dosage range of 2 to 4 mg, the discontinuation rates were lower overall for patients receiving brexpiprazole com­pared with placebo.^2,3 In the acute MDD trials, 32.6% of brexpiprazole-treated patients and 10.7% of placebo-treated patients discontinued because of AEs,^4,5 yielding a number needed to harm (NNH) of 53 (95% CI, 30-235).⁶

The most commonly encountered AEs for MDD (incidence ≥5% and at least twice the rate for placebo) were akathisia (8.6% vs 1.7% for brexpiprazole vs placebo, and dose-related) and weight gain (6.7% vs 1.9%),¹ with NNH values of 15 (95% CI, 11-23), and 22 (95% CI, 15-42), respectively.⁶ The most commonly encountered AE for schizophre­nia (incidence ≥4% and at least twice the rate for placebo) was weight gain (4% vs 2%),¹ with a NNH of 50 (95% CI, 26-1773).⁶

Of note, rates of akathisia in the schizo­phrenia trials were 5.5% for brexpiprazole and 4.6% for placebo,¹ yielding a non-statistically significant NNH of 112.6 In a 6-week exploratory study,¹¹ the incidence of EPS-related AEs including akathisia was lower for brexpiprazole-treated patients (14.1%) compared with those receiving aripiprazole (30.3%), for a NNT advan­tage for brexpiprazole of 7 (not statistically significant).

Short-term weight gain appears modest; however, outliers with an increase of ≥7% of body weight were evident in open-label long-term safety studies.^1,6 Effects on glucose and lipids were small. Minimal effects on prolac­tin were observed, and no clinically relevant effects on the QT interval were evident.

Contraindications
The only absolute contraindication for brexpiprazole is known hypersensitivity to brexpiprazole or any of its components. Reactions have included rash, facial swell­ing, urticaria, and anaphylaxis.¹

As with all antipsychotics and antipsy­chotics with an indication for a depressive disorder:
   • there is a bolded boxed warning in the product label regarding increased mortality in geriatric patients with dementia-related psychosis. Brexpiprazole is not approved for treating patients with dementia-related psychosis
   • there is a bolded boxed warning in the product label about suicidal thoughts and behaviors in patients age ≤24. The safety and efficacy of brexpiprazole have not been estab­lished in pediatric patients.
 

Dosing
Schizophrenia. The recommended starting dosage for brexpiprazole for schizophrenia is 1 mg/d on Days 1 to 4. Brexpiprazole can be titrated to 2 mg/d on Day 5 through Day 7, then to 4 mg/d on Day 8 based on the patient’s response and ability to tolerate the medication. The recommended target dos­age is 2 to 4 mg/d with a maximum recom­mended daily dosage of 4 mg.

Major depressive disorder. The recom­mended starting dosage for brexpiprazole as adjunctive treatment for MDD is 0.5 mg or 1 mg/d. Brexpiprazole can be titrated to 1 mg/d, then up to the target dosage of 2 mg/d, with dosage increases occurring at weekly intervals based on the patient’s clinical response and ability to tolerate the agent, with a maximum recommended dos­age of 3 mg/d.

Other considerations. For patients with moderate to severe hepatic impairment, or moderate, severe, or end-stage renal impair­ment, the maximum recommended dosage is 3 mg/d for patients with schizophrenia, and 2 mg/d for patients with MDD.

In general, dosage adjustments are rec­ommended in patients who are known CYP2D6 poor metabolizers and in those taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers¹:
   • for strong CYP2D6 or CYP3A4 inhibi­tors, administer one-half the usual dosage
   • for strong/moderate CYP2D6 with strong/moderate CYP3A4 inhibitors, administer a one-quarter of the usual dosage
   • for known CYP2D6 poor metabolizers taking strong/moderate CYP3A4 inhibitors, also administer a one-quarter of the usual dosage
   • for strong CYP3A4 inducers, double the usual dosage and further adjust based on clinical response.

In clinical trials for MDD, brexpiprazole dosage was not adjusted for strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine). Therefore, CYP considerations are already factored into general dosing recommenda­tions and brexpiprazole could be adminis­tered without dosage adjustment in patients with MDD; however, under these circum­stances, it would be prudent to start brexpip­razole at 0.5 mg, which, although “on-label,” represents a low starting dosage. (Whenever 2 drugs are co-administered and 1 agent has the ability to disturb the metabolism of the other, using smaller increments to the target dosage and possibly waiting longer between dosage adjustments could help avoid poten­tial drug–drug interactions.)

No dosage adjustment for brexpiprazole is required on the basis of sex, race or eth­nicity, or smoking status. Although clinical studies did not include patients age ≥65, the product label recommends that in general, dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.
 

Bottom Line
Brexpiprazole, an atypical antipsychotic, is FDA-approved for schizophrenia and as an adjunct to antidepressants in major depressive disorder. For both indications, brexpiprazole demonstrated positive results compared with placebo in phase-III trials. Brexpiprazole is more potent at serotonin 5-HT1A and 5-HT2A receptors and displays less intrinsic activity at D2 receptors than aripiprazole, which could mean that the drug may be better-tolerated.

Related Resources
• Citrome L. Brexpiprazole: a new dopamine D2 receptor par­tial agonist for the treatment of schizophrenia and major de­pressive disorder. Drugs Today (Barc). 2015;51(7):397-414.
• Citrome L, Stensbøl TB, Maeda K. The preclinical profile of brexpiprazole: what is its clinical relevance for the treat­ment of psychiatric disorders? Expert Rev Neurother. In press.

Drug Brand Names
Aripiprazole • Abilify
Brexpiprazole • Rexulti
Fluoxetine • Prozac
Paroxetine • Paxil

Disclosure
Dr. Citrome is a consultant to Alexza Pharmaceuticals, Alkermes, Allergan, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Forum Pharmaceuticals, Genentech, Janssen, Jazz Pharmaceuticals, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, and Valeant Pharmaceuticals; and is a speaker for Allergan, AstraZeneca, Janssen, Jazz Pharmaceuticals, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda, and Teva.