Daily oral treatment with venetoclax induced substantial responses with manageable adverse effects in patients with relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma in a first-in-human phase I dose-escalation study.

The promising effects of the highly selective investigational inhibitor of BCL2 – a protein central to the survival of CLL cells – were noted even in patients with poor prognostic features, who comprised 89% of the cohort, reported Dr. Andrew W. Roberts of Royal Melbourne Hospital, Australia, and his colleagues. The study was published online Jan. 28 in The New England Journal of Medicine.

In the dose escalation phase of the study, 56 patients received active treatment at doses raging from 150 to 1,200 mg daily, and 60 additional patients received weekly stepwise ramp-up with doses beginning at 20 mg daily with weekly increases to 50 mg, 100 mg, and 200 mg daily up to the target dose of 400 mg daily. The patients had received a median of 3 previous therapies (range, 1-11).

Of 116 treated patients, 92 (79%) had a response, and 20% achieved complete remission, including 5% with no minimal residual disease on flow cytometry, the investigators said (N Engl J Med. 2016;374:311-22).

Venetoclax was active at all doses used in the study, and no maximum tolerated dose was identified.

Tumor lysis syndrome occurred in 10 patients, but clinically important sequelae occurred in only 3 of those patients, 2 of whom had severe sequelae. After adjustments were made to dosing schedule, no further cases occurred.

Other side effects included mild diarrhea, upper respiratory tract infection, nausea, and grade 3 or 4 neutropenia, which occurred in 41%-52% of patients. Serious adverse events included febrile neutropenia in 6% of patients, pneumonia in 4%, upper respiratory tract infection in 3%, and immune thrombocytopenia in 3%.

Among the patients with an adverse prognosis, treatment response rates ranged from 71% to 79%, depending on the subgroup. For example, the response rate was 79% in 70 patients with resistance to fludarabine, and 71% in 31 patients with chromosome 17p deletions.

New treatments, including ibrutinib monotherapy and idelalisib in combination with rituximab, have improved outcomes for patients with relapsed CLL, but despite these advances, complete remissions remain uncommon, the authors said.

“This first trial of venetoclax showed the potential of BCL2 antagonism as an additional therapeutic avenue for patients with relapsed CLL,” they wrote, adding that the 79% overall response rate in this study – including deep responses and complete responses without minimal residual disease in patients up to age 86 years and patients with poor prognostic factors – “provides support for further development of venetoclax as a treatment option for patients with heavily pretreated relapsed or refractory CLL or SLL.”

Of note, the Food and Drug Administration on Jan. 28 – the date this study was released – granted venetoclax Breakthrough Therapy Designation for use in combination with hypomethylating agents for the treatment of acute myeloid leukemia patients who aren’t eligible for standard induction chemotherapy. The designation – the third for the agent – is supported by data from a single study of untreated patients aged 65 years or older with AML. Prior venetoclax Breakthrough Therapy Designations were granted in April 2015 for its use as monotherapy in patients with refractory CLL who have the 17p deletion genetic mutation, and in January for its use with rituximab for the treatment of relapsed/refractory CLL.

AbbVie and Genentech supported the study. Dr. Roberts reported receiving grant support and study drugs form AbbVie, serving as an investigator in trials sponsored by Genentech, AbbVie, Janssen, and Beigene, and receiving institutional research funding from Genentech for the development of venetoclax. His coauthors reported ties to various pharmaceutical companies.

[email protected]

Daily oral treatment with venetoclax induced substantial responses with manageable adverse effects in patients with relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma in a first-in-human phase I dose-escalation study.

The promising effects of the highly selective investigational inhibitor of BCL2 – a protein central to the survival of CLL cells – were noted even in patients with poor prognostic features, who comprised 89% of the cohort, reported Dr. Andrew W. Roberts of Royal Melbourne Hospital, Australia, and his colleagues. The study was published online Jan. 28 in The New England Journal of Medicine.

In the dose escalation phase of the study, 56 patients received active treatment at doses raging from 150 to 1,200 mg daily, and 60 additional patients received weekly stepwise ramp-up with doses beginning at 20 mg daily with weekly increases to 50 mg, 100 mg, and 200 mg daily up to the target dose of 400 mg daily. The patients had received a median of 3 previous therapies (range, 1-11).

Of 116 treated patients, 92 (79%) had a response, and 20% achieved complete remission, including 5% with no minimal residual disease on flow cytometry, the investigators said (N Engl J Med. 2016;374:311-22).

Venetoclax was active at all doses used in the study, and no maximum tolerated dose was identified.

Tumor lysis syndrome occurred in 10 patients, but clinically important sequelae occurred in only 3 of those patients, 2 of whom had severe sequelae. After adjustments were made to dosing schedule, no further cases occurred.

Other side effects included mild diarrhea, upper respiratory tract infection, nausea, and grade 3 or 4 neutropenia, which occurred in 41%-52% of patients. Serious adverse events included febrile neutropenia in 6% of patients, pneumonia in 4%, upper respiratory tract infection in 3%, and immune thrombocytopenia in 3%.

Among the patients with an adverse prognosis, treatment response rates ranged from 71% to 79%, depending on the subgroup. For example, the response rate was 79% in 70 patients with resistance to fludarabine, and 71% in 31 patients with chromosome 17p deletions.

New treatments, including ibrutinib monotherapy and idelalisib in combination with rituximab, have improved outcomes for patients with relapsed CLL, but despite these advances, complete remissions remain uncommon, the authors said.

“This first trial of venetoclax showed the potential of BCL2 antagonism as an additional therapeutic avenue for patients with relapsed CLL,” they wrote, adding that the 79% overall response rate in this study – including deep responses and complete responses without minimal residual disease in patients up to age 86 years and patients with poor prognostic factors – “provides support for further development of venetoclax as a treatment option for patients with heavily pretreated relapsed or refractory CLL or SLL.”

Of note, the Food and Drug Administration on Jan. 28 – the date this study was released – granted venetoclax Breakthrough Therapy Designation for use in combination with hypomethylating agents for the treatment of acute myeloid leukemia patients who aren’t eligible for standard induction chemotherapy. The designation – the third for the agent – is supported by data from a single study of untreated patients aged 65 years or older with AML. Prior venetoclax Breakthrough Therapy Designations were granted in April 2015 for its use as monotherapy in patients with refractory CLL who have the 17p deletion genetic mutation, and in January for its use with rituximab for the treatment of relapsed/refractory CLL.

AbbVie and Genentech supported the study. Dr. Roberts reported receiving grant support and study drugs form AbbVie, serving as an investigator in trials sponsored by Genentech, AbbVie, Janssen, and Beigene, and receiving institutional research funding from Genentech for the development of venetoclax. His coauthors reported ties to various pharmaceutical companies.

[email protected]

Daily oral treatment with venetoclax induced substantial responses with manageable adverse effects in patients with relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma in a first-in-human phase I dose-escalation study.

The promising effects of the highly selective investigational inhibitor of BCL2 – a protein central to the survival of CLL cells – were noted even in patients with poor prognostic features, who comprised 89% of the cohort, reported Dr. Andrew W. Roberts of Royal Melbourne Hospital, Australia, and his colleagues. The study was published online Jan. 28 in The New England Journal of Medicine.

In the dose escalation phase of the study, 56 patients received active treatment at doses raging from 150 to 1,200 mg daily, and 60 additional patients received weekly stepwise ramp-up with doses beginning at 20 mg daily with weekly increases to 50 mg, 100 mg, and 200 mg daily up to the target dose of 400 mg daily. The patients had received a median of 3 previous therapies (range, 1-11).

Of 116 treated patients, 92 (79%) had a response, and 20% achieved complete remission, including 5% with no minimal residual disease on flow cytometry, the investigators said (N Engl J Med. 2016;374:311-22).

Venetoclax was active at all doses used in the study, and no maximum tolerated dose was identified.

Tumor lysis syndrome occurred in 10 patients, but clinically important sequelae occurred in only 3 of those patients, 2 of whom had severe sequelae. After adjustments were made to dosing schedule, no further cases occurred.

Other side effects included mild diarrhea, upper respiratory tract infection, nausea, and grade 3 or 4 neutropenia, which occurred in 41%-52% of patients. Serious adverse events included febrile neutropenia in 6% of patients, pneumonia in 4%, upper respiratory tract infection in 3%, and immune thrombocytopenia in 3%.

Among the patients with an adverse prognosis, treatment response rates ranged from 71% to 79%, depending on the subgroup. For example, the response rate was 79% in 70 patients with resistance to fludarabine, and 71% in 31 patients with chromosome 17p deletions.

New treatments, including ibrutinib monotherapy and idelalisib in combination with rituximab, have improved outcomes for patients with relapsed CLL, but despite these advances, complete remissions remain uncommon, the authors said.

“This first trial of venetoclax showed the potential of BCL2 antagonism as an additional therapeutic avenue for patients with relapsed CLL,” they wrote, adding that the 79% overall response rate in this study – including deep responses and complete responses without minimal residual disease in patients up to age 86 years and patients with poor prognostic factors – “provides support for further development of venetoclax as a treatment option for patients with heavily pretreated relapsed or refractory CLL or SLL.”

Of note, the Food and Drug Administration on Jan. 28 – the date this study was released – granted venetoclax Breakthrough Therapy Designation for use in combination with hypomethylating agents for the treatment of acute myeloid leukemia patients who aren’t eligible for standard induction chemotherapy. The designation – the third for the agent – is supported by data from a single study of untreated patients aged 65 years or older with AML. Prior venetoclax Breakthrough Therapy Designations were granted in April 2015 for its use as monotherapy in patients with refractory CLL who have the 17p deletion genetic mutation, and in January for its use with rituximab for the treatment of relapsed/refractory CLL.

AbbVie and Genentech supported the study. Dr. Roberts reported receiving grant support and study drugs form AbbVie, serving as an investigator in trials sponsored by Genentech, AbbVie, Janssen, and Beigene, and receiving institutional research funding from Genentech for the development of venetoclax. His coauthors reported ties to various pharmaceutical companies.

[email protected]

SAN ANTONIO – Tourniquets are being overemphasized in preparations for mass shootings in the United States, according to a review by the Committee for Tactical Emergency Casualty Care of wounding patterns in 12 mass shootings.

Since the 2012 shootings in Newtown, Conn., efforts to improve survival have tended to emphasize tourniquets to stop bleeding from wounded limbs. The recently-launched federal “Stop the Bleed” campaign promotes public awareness of compression and tourniquets, and the American College of Surgeons and other groups recently called for public education and use of tourniquets as one of many responses to mass-casualty and active-shooter events, stating that “the most significant preventable cause of death in the prehospital environment is external hemorrhage.” There are thoughts of making tourniquets at least as common as automated external defibrillators in public settings.

The efforts are driven by combat experience in Afghanistan and Iraq, where about half of wounds were to arms and legs, and tourniquets saved many lives.

Wikimedia Creative Commons License/INDNAM

Tourniquets are important especially for civilian bombings, but fatalities in civilian mass shootings – shootings with at least four deaths in which killing is the primary aim – are from head and chest wounds, not extremity wounds. The emphasis on bleeding control overshadows public education about other simple interventions that could be more useful in shootings, according to emergency physician Dr. Reed Smith, medical director of the Arlington County (Va.) Fire Department and cofounder and cochairman of the Committee for Tactical Emergency Casualty Care (C-TECC).

“We need a civilian perspective on civilian incidents, not a military perspective,” he said at the Eastern Association for the Surgery of Trauma scientific assembly.

Dr. Smith and other C-TECC investigators reviewed autopsy reports from 12 U.S. civilian mass shootings from the period of 1996-2012. They tried to get data for more, but ran into significant resistance from authorities.

There were 371 bullet wounds and 139 deaths, an average of 2.7 wounds per victim but a range of 1-10. About 40% of deaths were from shots to the head; another 40% from shots to the chest or upper back; and the rest from shots to the face/neck, abdomen/lower back, or multiple regions.

“We looked at every one of these events, and with the exception of the Gabby Giffords Tucson shooting, no tourniquets were used. There were no cases of major peripheral vascular injury, and no fatalities from extremity exsanguination,” Dr. Smith said.

The investigators estimated that nine fatalities were potentially survivable, without injuries to the heart, brain, or major blood vessels, and definitive care available within 60 minutes. The victims died from face and torso wounds, not wounds to the limbs.

“Wounding in active-shooter events differs from combat and may require different therapeutic emphasis. Although tourniquets and external hemorrhage control techniques hold value, their role in active-shooter events may be overemphasized as a means to decrease fatality. The focus on external hemorrhage is important, but it’s not enough,” Dr. Smith said.

Additional interventions could be taught for every step in the chain of contact, from citizen to trauma surgeon, that could have greater benefit. Teachers, for instance, could be taught to roll victims on their sides and clear out their mouths to keep airways open, and to keep them warm to prevent hypothermia until help arrives. Police could learn to insert nasal airways, and occlude sucking chest wounds. Fire/EMS could start initial damage control. “Everything builds,” Dr. Smith said.

C-TECC made many recommendations for enhanced mass-causality response its 2015 Tactical Emergency Casualty Care Guidelines.

Dr. Smith had no disclosures.

[email protected]

SAN ANTONIO – Tourniquets are being overemphasized in preparations for mass shootings in the United States, according to a review by the Committee for Tactical Emergency Casualty Care of wounding patterns in 12 mass shootings.

Since the 2012 shootings in Newtown, Conn., efforts to improve survival have tended to emphasize tourniquets to stop bleeding from wounded limbs. The recently-launched federal “Stop the Bleed” campaign promotes public awareness of compression and tourniquets, and the American College of Surgeons and other groups recently called for public education and use of tourniquets as one of many responses to mass-casualty and active-shooter events, stating that “the most significant preventable cause of death in the prehospital environment is external hemorrhage.” There are thoughts of making tourniquets at least as common as automated external defibrillators in public settings.

The efforts are driven by combat experience in Afghanistan and Iraq, where about half of wounds were to arms and legs, and tourniquets saved many lives.

Wikimedia Creative Commons License/INDNAM

Tourniquets are important especially for civilian bombings, but fatalities in civilian mass shootings – shootings with at least four deaths in which killing is the primary aim – are from head and chest wounds, not extremity wounds. The emphasis on bleeding control overshadows public education about other simple interventions that could be more useful in shootings, according to emergency physician Dr. Reed Smith, medical director of the Arlington County (Va.) Fire Department and cofounder and cochairman of the Committee for Tactical Emergency Casualty Care (C-TECC).

“We need a civilian perspective on civilian incidents, not a military perspective,” he said at the Eastern Association for the Surgery of Trauma scientific assembly.

Dr. Smith and other C-TECC investigators reviewed autopsy reports from 12 U.S. civilian mass shootings from the period of 1996-2012. They tried to get data for more, but ran into significant resistance from authorities.

There were 371 bullet wounds and 139 deaths, an average of 2.7 wounds per victim but a range of 1-10. About 40% of deaths were from shots to the head; another 40% from shots to the chest or upper back; and the rest from shots to the face/neck, abdomen/lower back, or multiple regions.

“We looked at every one of these events, and with the exception of the Gabby Giffords Tucson shooting, no tourniquets were used. There were no cases of major peripheral vascular injury, and no fatalities from extremity exsanguination,” Dr. Smith said.

The investigators estimated that nine fatalities were potentially survivable, without injuries to the heart, brain, or major blood vessels, and definitive care available within 60 minutes. The victims died from face and torso wounds, not wounds to the limbs.

“Wounding in active-shooter events differs from combat and may require different therapeutic emphasis. Although tourniquets and external hemorrhage control techniques hold value, their role in active-shooter events may be overemphasized as a means to decrease fatality. The focus on external hemorrhage is important, but it’s not enough,” Dr. Smith said.

Additional interventions could be taught for every step in the chain of contact, from citizen to trauma surgeon, that could have greater benefit. Teachers, for instance, could be taught to roll victims on their sides and clear out their mouths to keep airways open, and to keep them warm to prevent hypothermia until help arrives. Police could learn to insert nasal airways, and occlude sucking chest wounds. Fire/EMS could start initial damage control. “Everything builds,” Dr. Smith said.

C-TECC made many recommendations for enhanced mass-causality response its 2015 Tactical Emergency Casualty Care Guidelines.

Dr. Smith had no disclosures.

[email protected]

SAN ANTONIO – Tourniquets are being overemphasized in preparations for mass shootings in the United States, according to a review by the Committee for Tactical Emergency Casualty Care of wounding patterns in 12 mass shootings.

Since the 2012 shootings in Newtown, Conn., efforts to improve survival have tended to emphasize tourniquets to stop bleeding from wounded limbs. The recently-launched federal “Stop the Bleed” campaign promotes public awareness of compression and tourniquets, and the American College of Surgeons and other groups recently called for public education and use of tourniquets as one of many responses to mass-casualty and active-shooter events, stating that “the most significant preventable cause of death in the prehospital environment is external hemorrhage.” There are thoughts of making tourniquets at least as common as automated external defibrillators in public settings.

The efforts are driven by combat experience in Afghanistan and Iraq, where about half of wounds were to arms and legs, and tourniquets saved many lives.

Wikimedia Creative Commons License/INDNAM

Tourniquets are important especially for civilian bombings, but fatalities in civilian mass shootings – shootings with at least four deaths in which killing is the primary aim – are from head and chest wounds, not extremity wounds. The emphasis on bleeding control overshadows public education about other simple interventions that could be more useful in shootings, according to emergency physician Dr. Reed Smith, medical director of the Arlington County (Va.) Fire Department and cofounder and cochairman of the Committee for Tactical Emergency Casualty Care (C-TECC).

“We need a civilian perspective on civilian incidents, not a military perspective,” he said at the Eastern Association for the Surgery of Trauma scientific assembly.

Dr. Smith and other C-TECC investigators reviewed autopsy reports from 12 U.S. civilian mass shootings from the period of 1996-2012. They tried to get data for more, but ran into significant resistance from authorities.

There were 371 bullet wounds and 139 deaths, an average of 2.7 wounds per victim but a range of 1-10. About 40% of deaths were from shots to the head; another 40% from shots to the chest or upper back; and the rest from shots to the face/neck, abdomen/lower back, or multiple regions.

“We looked at every one of these events, and with the exception of the Gabby Giffords Tucson shooting, no tourniquets were used. There were no cases of major peripheral vascular injury, and no fatalities from extremity exsanguination,” Dr. Smith said.

The investigators estimated that nine fatalities were potentially survivable, without injuries to the heart, brain, or major blood vessels, and definitive care available within 60 minutes. The victims died from face and torso wounds, not wounds to the limbs.

“Wounding in active-shooter events differs from combat and may require different therapeutic emphasis. Although tourniquets and external hemorrhage control techniques hold value, their role in active-shooter events may be overemphasized as a means to decrease fatality. The focus on external hemorrhage is important, but it’s not enough,” Dr. Smith said.

Additional interventions could be taught for every step in the chain of contact, from citizen to trauma surgeon, that could have greater benefit. Teachers, for instance, could be taught to roll victims on their sides and clear out their mouths to keep airways open, and to keep them warm to prevent hypothermia until help arrives. Police could learn to insert nasal airways, and occlude sucking chest wounds. Fire/EMS could start initial damage control. “Everything builds,” Dr. Smith said.

C-TECC made many recommendations for enhanced mass-causality response its 2015 Tactical Emergency Casualty Care Guidelines.

Dr. Smith had no disclosures.

[email protected]

Less than half of children aged 6-23 months are vaccinated for influenza in the United States, according to an analysis of data obtained via the 2003-2013 National Immunization Survey.

The researchers analyzed providers’ reports of influenza vaccinations, received as one or two doses by children aged 6-23 months. The age group studied is at highest risk of influenza-related complications and was the first group of children for which the Advisory Committee on Immunization Practices recommended influenza vaccination, regardless of an individual’s medical condition.

© Sean Locke/iStockphoto.com

A child’s age was defined by his or her age on Nov. 1 of each influenza season under study. Two full calendar years of data files were combined to enable analysis of full influenza seasons, which cover parts of 2 consecutive calendar years. The percentages of children requiring two doses to be considered fully vaccinated were based on the dosage recommendations for each flu season.

Overall, flu vaccination coverage increased, reaching 45% in the 2011-2012 flu season, up from 5% during the 2002-2003 flu season. Within each racial/ethnic group examined, influenza vaccination coverage also grew; however, lower percentages of non-Hispanic black children and Hispanic children were vaccinated than of non-Hispanic white children during all 10 of the flu seasons studied. Coverage ranged from 24% in Mississippi to 72% in Massachusetts.

“Despite the increase, the majority of children 6-23 months in the United States were not fully vaccinated against influenza,” said Tammy A. Santibanez, Ph.D., of the Centers for Disease Control and Prevention, and her colleagues.

Among other findings consistent throughout each flu season examined was that full influenza vaccination coverage was higher among children requiring only one dose of a flu vaccine, compared with those requiring two doses of a flu vaccine.

“Prevention of influenza among infants and young children is a public health priority because of their high risk for influenza-related complications,” wrote Dr. Santibanez and her colleagues. “Appropriate implementation of evidence-based strategies is needed to increase the percentage of children who are fully vaccinated.”

Read the study in Pediatrics (doi: 10.1542/peds.2015.3280).

[email protected]

Less than half of children aged 6-23 months are vaccinated for influenza in the United States, according to an analysis of data obtained via the 2003-2013 National Immunization Survey.

The researchers analyzed providers’ reports of influenza vaccinations, received as one or two doses by children aged 6-23 months. The age group studied is at highest risk of influenza-related complications and was the first group of children for which the Advisory Committee on Immunization Practices recommended influenza vaccination, regardless of an individual’s medical condition.

© Sean Locke/iStockphoto.com

A child’s age was defined by his or her age on Nov. 1 of each influenza season under study. Two full calendar years of data files were combined to enable analysis of full influenza seasons, which cover parts of 2 consecutive calendar years. The percentages of children requiring two doses to be considered fully vaccinated were based on the dosage recommendations for each flu season.

Overall, flu vaccination coverage increased, reaching 45% in the 2011-2012 flu season, up from 5% during the 2002-2003 flu season. Within each racial/ethnic group examined, influenza vaccination coverage also grew; however, lower percentages of non-Hispanic black children and Hispanic children were vaccinated than of non-Hispanic white children during all 10 of the flu seasons studied. Coverage ranged from 24% in Mississippi to 72% in Massachusetts.

“Despite the increase, the majority of children 6-23 months in the United States were not fully vaccinated against influenza,” said Tammy A. Santibanez, Ph.D., of the Centers for Disease Control and Prevention, and her colleagues.

Among other findings consistent throughout each flu season examined was that full influenza vaccination coverage was higher among children requiring only one dose of a flu vaccine, compared with those requiring two doses of a flu vaccine.

“Prevention of influenza among infants and young children is a public health priority because of their high risk for influenza-related complications,” wrote Dr. Santibanez and her colleagues. “Appropriate implementation of evidence-based strategies is needed to increase the percentage of children who are fully vaccinated.”

Read the study in Pediatrics (doi: 10.1542/peds.2015.3280).

[email protected]

Less than half of children aged 6-23 months are vaccinated for influenza in the United States, according to an analysis of data obtained via the 2003-2013 National Immunization Survey.

The researchers analyzed providers’ reports of influenza vaccinations, received as one or two doses by children aged 6-23 months. The age group studied is at highest risk of influenza-related complications and was the first group of children for which the Advisory Committee on Immunization Practices recommended influenza vaccination, regardless of an individual’s medical condition.

© Sean Locke/iStockphoto.com

A child’s age was defined by his or her age on Nov. 1 of each influenza season under study. Two full calendar years of data files were combined to enable analysis of full influenza seasons, which cover parts of 2 consecutive calendar years. The percentages of children requiring two doses to be considered fully vaccinated were based on the dosage recommendations for each flu season.

Overall, flu vaccination coverage increased, reaching 45% in the 2011-2012 flu season, up from 5% during the 2002-2003 flu season. Within each racial/ethnic group examined, influenza vaccination coverage also grew; however, lower percentages of non-Hispanic black children and Hispanic children were vaccinated than of non-Hispanic white children during all 10 of the flu seasons studied. Coverage ranged from 24% in Mississippi to 72% in Massachusetts.

“Despite the increase, the majority of children 6-23 months in the United States were not fully vaccinated against influenza,” said Tammy A. Santibanez, Ph.D., of the Centers for Disease Control and Prevention, and her colleagues.

Among other findings consistent throughout each flu season examined was that full influenza vaccination coverage was higher among children requiring only one dose of a flu vaccine, compared with those requiring two doses of a flu vaccine.

“Prevention of influenza among infants and young children is a public health priority because of their high risk for influenza-related complications,” wrote Dr. Santibanez and her colleagues. “Appropriate implementation of evidence-based strategies is needed to increase the percentage of children who are fully vaccinated.”

Read the study in Pediatrics (doi: 10.1542/peds.2015.3280).

[email protected]

As the practice of medicine continues to transition to performance-based payment systems, the number of mergers of hospitalists and specialists has surged. Payment models that focus on clinical outcomes and best practices link payment to the ability of physicians to provide efficient, quality healthcare and improve patient outcomes. These payment systems are changing the way healthcare services are delivered by demanding better patient care at a lower cost. The result is increasing pressure on physicians to meet operational and quality goals, or receive less reimbursement for their services.

Studies have shown that the effective use of hospitalists can improve standardized patient care for surgical patients. Hospitalists also provide value to specialists by freeing up time so they can focus on their area of expertise. As a result, co-management arrangements between hospitalists and specialists have become a popular tool to define working relationships and improve the quality of care patients receive.

Hospitalist Evolution

When hospitalists first debuted, they were seen as a threat to primary care physicians and specialists. Over time, they were criticized for performing routine work for specialized physicians. To overcome these negative connotations and prove their worth, hospitalists began co-managing patients for surgical specialists, who soon realized the significant value hospitalist services provided. Not only do they share in the responsibility of care provided to patients, but they also reduce readmissions and costs associated with providing healthcare.

Now there are even specialty hospitalists who specialize in a particular field, such as orthopedics or obstetrics.

Why Co-Management?

Hospitalists add value by helping to alleviate the burden on specialists—providing ED coverage, assisting in the operating room, and rounding on patients. They evaluate surgical patients for medical issues, reconcile medications across the spectrum of a patient’s care, and standardize the patient discharge and communication processes.

Providing these services frees specialists from rounding and allows them to concentrate on their specialty. Hospitalists do not have office-based practices, which allows them to spend their time in the hospital caring for admitted, pre-operative, and post-operative patients.

It is in the pre-operative and post-operative environments where hospitalists have established their extreme value to specialists. Under co-management arrangements, hospitalists are able to ensure that all pre-operative tests are conducted, reports are dictated, and the patient’s medical history is available. Pre-operative evaluations allow the hospitalist to develop a post-operative plan of care and proactively address many medical concerns. Also, the hospitalist is available to see patients immediately after surgery, allowing immediate evaluation and treatment for high blood pressure, diabetic issues, or other medical issues.

In sum, the hospitalist is responsible for the medical care of the specialist’s patients, and the specialist is able to focus on the specialty services he or she provides. Providing these services gives hospitalists the opportunity to anticipate problems and overcome issues, which results in more efficient care, shorter lengths of stay in the hospital, and improved patient satisfaction. Such results make hospitalists critical to success in performance-based payment systems.

Successful Co-Management Arrangements

A key to success in establishing a co-management arrangement between a hospitalist and a specialist is setting forth the parameters of the relationship in a written agreement. It is particularly important that the relationship foster equality among the parties, regardless of who is the attending physician of record. The parties should be jointly responsible for patient care, with the hospitalist treating the patient’s general medical concerns and the specialist focusing on techniques within his specialty to improve the patient’s issues.

The agreement should clearly state the responsibilities of each party, including delineating the party responsible for decisions such as admission and discharge. It should address resources and set forth the standardized processes and protocols to be used when treating patients.

Specialists can vary in their treatment of patients, so it is best to document their expectations at the onset of the relationship. Also, successful co-management is contingent upon regular communication between the hospitalist and the specialist. It is important to establish those boundaries in advance to prevent miscommunication down the road.

In particular, the agreement should explicitly describe the lines of authority and how conflicts will be addressed.

Final Thoughts

Co-management is a growing trend that can provide an opportunity for hospitalists to expand their practice and reinforce their value to both specialists and the hospital. The improved quality of care and patient satisfaction that is associated with hospitalist services can be crucial to maximizing reimbursement under a value-based reimbursement system. TH

As the practice of medicine continues to transition to performance-based payment systems, the number of mergers of hospitalists and specialists has surged. Payment models that focus on clinical outcomes and best practices link payment to the ability of physicians to provide efficient, quality healthcare and improve patient outcomes. These payment systems are changing the way healthcare services are delivered by demanding better patient care at a lower cost. The result is increasing pressure on physicians to meet operational and quality goals, or receive less reimbursement for their services.

Studies have shown that the effective use of hospitalists can improve standardized patient care for surgical patients. Hospitalists also provide value to specialists by freeing up time so they can focus on their area of expertise. As a result, co-management arrangements between hospitalists and specialists have become a popular tool to define working relationships and improve the quality of care patients receive.

Hospitalist Evolution

When hospitalists first debuted, they were seen as a threat to primary care physicians and specialists. Over time, they were criticized for performing routine work for specialized physicians. To overcome these negative connotations and prove their worth, hospitalists began co-managing patients for surgical specialists, who soon realized the significant value hospitalist services provided. Not only do they share in the responsibility of care provided to patients, but they also reduce readmissions and costs associated with providing healthcare.

Now there are even specialty hospitalists who specialize in a particular field, such as orthopedics or obstetrics.

Why Co-Management?

Hospitalists add value by helping to alleviate the burden on specialists—providing ED coverage, assisting in the operating room, and rounding on patients. They evaluate surgical patients for medical issues, reconcile medications across the spectrum of a patient’s care, and standardize the patient discharge and communication processes.

Providing these services frees specialists from rounding and allows them to concentrate on their specialty. Hospitalists do not have office-based practices, which allows them to spend their time in the hospital caring for admitted, pre-operative, and post-operative patients.

It is in the pre-operative and post-operative environments where hospitalists have established their extreme value to specialists. Under co-management arrangements, hospitalists are able to ensure that all pre-operative tests are conducted, reports are dictated, and the patient’s medical history is available. Pre-operative evaluations allow the hospitalist to develop a post-operative plan of care and proactively address many medical concerns. Also, the hospitalist is available to see patients immediately after surgery, allowing immediate evaluation and treatment for high blood pressure, diabetic issues, or other medical issues.

In sum, the hospitalist is responsible for the medical care of the specialist’s patients, and the specialist is able to focus on the specialty services he or she provides. Providing these services gives hospitalists the opportunity to anticipate problems and overcome issues, which results in more efficient care, shorter lengths of stay in the hospital, and improved patient satisfaction. Such results make hospitalists critical to success in performance-based payment systems.

Successful Co-Management Arrangements

A key to success in establishing a co-management arrangement between a hospitalist and a specialist is setting forth the parameters of the relationship in a written agreement. It is particularly important that the relationship foster equality among the parties, regardless of who is the attending physician of record. The parties should be jointly responsible for patient care, with the hospitalist treating the patient’s general medical concerns and the specialist focusing on techniques within his specialty to improve the patient’s issues.

The agreement should clearly state the responsibilities of each party, including delineating the party responsible for decisions such as admission and discharge. It should address resources and set forth the standardized processes and protocols to be used when treating patients.

Specialists can vary in their treatment of patients, so it is best to document their expectations at the onset of the relationship. Also, successful co-management is contingent upon regular communication between the hospitalist and the specialist. It is important to establish those boundaries in advance to prevent miscommunication down the road.

In particular, the agreement should explicitly describe the lines of authority and how conflicts will be addressed.

Final Thoughts

Co-management is a growing trend that can provide an opportunity for hospitalists to expand their practice and reinforce their value to both specialists and the hospital. The improved quality of care and patient satisfaction that is associated with hospitalist services can be crucial to maximizing reimbursement under a value-based reimbursement system. TH

As the practice of medicine continues to transition to performance-based payment systems, the number of mergers of hospitalists and specialists has surged. Payment models that focus on clinical outcomes and best practices link payment to the ability of physicians to provide efficient, quality healthcare and improve patient outcomes. These payment systems are changing the way healthcare services are delivered by demanding better patient care at a lower cost. The result is increasing pressure on physicians to meet operational and quality goals, or receive less reimbursement for their services.

Studies have shown that the effective use of hospitalists can improve standardized patient care for surgical patients. Hospitalists also provide value to specialists by freeing up time so they can focus on their area of expertise. As a result, co-management arrangements between hospitalists and specialists have become a popular tool to define working relationships and improve the quality of care patients receive.

Hospitalist Evolution

When hospitalists first debuted, they were seen as a threat to primary care physicians and specialists. Over time, they were criticized for performing routine work for specialized physicians. To overcome these negative connotations and prove their worth, hospitalists began co-managing patients for surgical specialists, who soon realized the significant value hospitalist services provided. Not only do they share in the responsibility of care provided to patients, but they also reduce readmissions and costs associated with providing healthcare.

Now there are even specialty hospitalists who specialize in a particular field, such as orthopedics or obstetrics.

Why Co-Management?

Hospitalists add value by helping to alleviate the burden on specialists—providing ED coverage, assisting in the operating room, and rounding on patients. They evaluate surgical patients for medical issues, reconcile medications across the spectrum of a patient’s care, and standardize the patient discharge and communication processes.

Providing these services frees specialists from rounding and allows them to concentrate on their specialty. Hospitalists do not have office-based practices, which allows them to spend their time in the hospital caring for admitted, pre-operative, and post-operative patients.

It is in the pre-operative and post-operative environments where hospitalists have established their extreme value to specialists. Under co-management arrangements, hospitalists are able to ensure that all pre-operative tests are conducted, reports are dictated, and the patient’s medical history is available. Pre-operative evaluations allow the hospitalist to develop a post-operative plan of care and proactively address many medical concerns. Also, the hospitalist is available to see patients immediately after surgery, allowing immediate evaluation and treatment for high blood pressure, diabetic issues, or other medical issues.

In sum, the hospitalist is responsible for the medical care of the specialist’s patients, and the specialist is able to focus on the specialty services he or she provides. Providing these services gives hospitalists the opportunity to anticipate problems and overcome issues, which results in more efficient care, shorter lengths of stay in the hospital, and improved patient satisfaction. Such results make hospitalists critical to success in performance-based payment systems.

Successful Co-Management Arrangements

A key to success in establishing a co-management arrangement between a hospitalist and a specialist is setting forth the parameters of the relationship in a written agreement. It is particularly important that the relationship foster equality among the parties, regardless of who is the attending physician of record. The parties should be jointly responsible for patient care, with the hospitalist treating the patient’s general medical concerns and the specialist focusing on techniques within his specialty to improve the patient’s issues.

The agreement should clearly state the responsibilities of each party, including delineating the party responsible for decisions such as admission and discharge. It should address resources and set forth the standardized processes and protocols to be used when treating patients.

Specialists can vary in their treatment of patients, so it is best to document their expectations at the onset of the relationship. Also, successful co-management is contingent upon regular communication between the hospitalist and the specialist. It is important to establish those boundaries in advance to prevent miscommunication down the road.

In particular, the agreement should explicitly describe the lines of authority and how conflicts will be addressed.

Final Thoughts

Co-management is a growing trend that can provide an opportunity for hospitalists to expand their practice and reinforce their value to both specialists and the hospital. The improved quality of care and patient satisfaction that is associated with hospitalist services can be crucial to maximizing reimbursement under a value-based reimbursement system. TH

NEW YORK (Reuters Health)—Women with heart failure (HF) derive as much benefit from implantable cardiac defibrillators (ICDs) for primary prevention as men, according to a comparative effectiveness study.

"Randomized clinical trials demonstrated that the ICD confers survival benefit to many patients with heart failure; however, data on ICDs in women were inadequate due to the relatively small number of women enrolled in those trials," study investigator Dr. Sana Al-Khatib, heart rhythm specialist from Duke Clinical Research Institute in Durham, North Carolina, told Reuters Health by email.

This analysis, online January 12 in Circulation: Heart Failure, showed that women with heart failure and an ICD had "significantly better survival than women with no ICD," Dr. Al-Khatib said.

"Our findings support the gender-neutral guideline recommendations regarding the use of primary prevention ICDs in eligible patients. As a result, women with heart failure should be equally considered for a primary prevention ICD as men," she added.

For the analysis, researchers linked data from 264 hospitals participating in the Get With The Guidelines Heart Failure registry with data from the Centers for Medicare and Medicaid

Services.

Using propensity score matching, they created a cohort of 430 women with heart failure and a preventive ICD and 430 similar women with heart failure but no ICD. For comparison, they propensity score matched 859 men with heart failure and an ICD to 859 men without an ICD.

After three years, 40.2% of women with an ICD had died, compared with 48.7% of women without an ICD. The corresponding mortality rates in men were 42.9% and 52.9%.

In the matched cohorts, an ICD was associated with "similarly better survival" in women and men (hazard ratios, 0.78 and 0.76, respectively). There was no interaction between sex and presence of an ICD with regard to survival (p=0.79).

"Despite the survival benefits of primary prevention ICDs in patients with HF demonstrated in randomized clinical trials, benefit in the subgroup of women from these trials has not been

definitively proved. This uncertainty on survival benefit may be one of several contributing factors to the lower rates of ICD referral and implantation in eligible women," the investigators note in their article.

The current data, they conclude, "support current guideline recommendations" for the implantation of a primary prevention ICD in eligible women and men with HF and reduced left ventricular ejection fraction.

The Agency for Healthcare Research and Quality funded the study. One author reported consulting for Medtronic.

NEW YORK (Reuters Health)—Women with heart failure (HF) derive as much benefit from implantable cardiac defibrillators (ICDs) for primary prevention as men, according to a comparative effectiveness study.

"Randomized clinical trials demonstrated that the ICD confers survival benefit to many patients with heart failure; however, data on ICDs in women were inadequate due to the relatively small number of women enrolled in those trials," study investigator Dr. Sana Al-Khatib, heart rhythm specialist from Duke Clinical Research Institute in Durham, North Carolina, told Reuters Health by email.

This analysis, online January 12 in Circulation: Heart Failure, showed that women with heart failure and an ICD had "significantly better survival than women with no ICD," Dr. Al-Khatib said.

"Our findings support the gender-neutral guideline recommendations regarding the use of primary prevention ICDs in eligible patients. As a result, women with heart failure should be equally considered for a primary prevention ICD as men," she added.

For the analysis, researchers linked data from 264 hospitals participating in the Get With The Guidelines Heart Failure registry with data from the Centers for Medicare and Medicaid

Services.

Using propensity score matching, they created a cohort of 430 women with heart failure and a preventive ICD and 430 similar women with heart failure but no ICD. For comparison, they propensity score matched 859 men with heart failure and an ICD to 859 men without an ICD.

After three years, 40.2% of women with an ICD had died, compared with 48.7% of women without an ICD. The corresponding mortality rates in men were 42.9% and 52.9%.

In the matched cohorts, an ICD was associated with "similarly better survival" in women and men (hazard ratios, 0.78 and 0.76, respectively). There was no interaction between sex and presence of an ICD with regard to survival (p=0.79).

"Despite the survival benefits of primary prevention ICDs in patients with HF demonstrated in randomized clinical trials, benefit in the subgroup of women from these trials has not been

definitively proved. This uncertainty on survival benefit may be one of several contributing factors to the lower rates of ICD referral and implantation in eligible women," the investigators note in their article.

The current data, they conclude, "support current guideline recommendations" for the implantation of a primary prevention ICD in eligible women and men with HF and reduced left ventricular ejection fraction.

The Agency for Healthcare Research and Quality funded the study. One author reported consulting for Medtronic.

NEW YORK (Reuters Health)—Women with heart failure (HF) derive as much benefit from implantable cardiac defibrillators (ICDs) for primary prevention as men, according to a comparative effectiveness study.

"Randomized clinical trials demonstrated that the ICD confers survival benefit to many patients with heart failure; however, data on ICDs in women were inadequate due to the relatively small number of women enrolled in those trials," study investigator Dr. Sana Al-Khatib, heart rhythm specialist from Duke Clinical Research Institute in Durham, North Carolina, told Reuters Health by email.

This analysis, online January 12 in Circulation: Heart Failure, showed that women with heart failure and an ICD had "significantly better survival than women with no ICD," Dr. Al-Khatib said.

"Our findings support the gender-neutral guideline recommendations regarding the use of primary prevention ICDs in eligible patients. As a result, women with heart failure should be equally considered for a primary prevention ICD as men," she added.

For the analysis, researchers linked data from 264 hospitals participating in the Get With The Guidelines Heart Failure registry with data from the Centers for Medicare and Medicaid

Services.

Using propensity score matching, they created a cohort of 430 women with heart failure and a preventive ICD and 430 similar women with heart failure but no ICD. For comparison, they propensity score matched 859 men with heart failure and an ICD to 859 men without an ICD.

After three years, 40.2% of women with an ICD had died, compared with 48.7% of women without an ICD. The corresponding mortality rates in men were 42.9% and 52.9%.

In the matched cohorts, an ICD was associated with "similarly better survival" in women and men (hazard ratios, 0.78 and 0.76, respectively). There was no interaction between sex and presence of an ICD with regard to survival (p=0.79).

"Despite the survival benefits of primary prevention ICDs in patients with HF demonstrated in randomized clinical trials, benefit in the subgroup of women from these trials has not been

definitively proved. This uncertainty on survival benefit may be one of several contributing factors to the lower rates of ICD referral and implantation in eligible women," the investigators note in their article.

The current data, they conclude, "support current guideline recommendations" for the implantation of a primary prevention ICD in eligible women and men with HF and reduced left ventricular ejection fraction.

The Agency for Healthcare Research and Quality funded the study. One author reported consulting for Medtronic.

Meng-Meng Ji, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Preclinical research has revealed mutations that may affect the performance of histone deacetylase inhibitors (HDACis) in patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

The researchers identified histone-modifying gene mutations in patients with PTCL-NOS and found evidence to suggest these mutations confer shorter survival.

The team also conducted experiments in Jurkat cells showing that certain HDACis could counteract loss-of-function mutations, while others could not.

Meng-Meng Ji, MD, PhD, of the Shanghai Institute of Hematology in China, presented this research at the 8th Annual T-cell Lymphoma Forum.

Dr Ji and her colleagues first performed targeted sequencing in tumor samples from 105 patients newly diagnosed with PTCL-NOS.

The team discovered 62 mutations of “important” lymphoma-associated histone-modifying genes in 31 patients. They found mutations in MLL2 (n=21), TET2 (n=17), EP300 (n=8), CREBBP (n=8), and SETD2 (n=6).

Clinical data revealed a significant difference in overall survival between patients who had these mutations and those who did not (P=0.0038).

Because most of the mutations they identified are loss-of-function mutations, Dr Ji and her colleagues wanted to determine whether HDACis could restore the expression of the mutated genes. So they tested 4 HDACis—valproic acid, vorinostat, romidepsin, and chidamide—in Jurkat cells.

All 4 HDACis upregulated expression of EP300 and CREBBP. However, only romidepsin and chidamide upregulated MLL2, and only valproic acid and vorinostat upregulated SETD2. Dr Ji said there was no obvious change in TET2 expression with any of the HDACis.

The researchers then took a closer look at the EP300, MLL2, and SETD2 mutations. They found that most EP300 mutations were located on the HAT domain. MLL2 mutations could be found in a variety of locations, but some were located on the SET domain. And most SETD2 mutations were located on the SET domain.

Based on the crystal structure of each gene, the team found that EP300 mutations on the HAT domain and both MLL2 mutations and SETD2 mutations located on the SET domain induce loss of function.

So the researchers constructed a mutant for EP300 (p.H1377R), MLL2 (p.V5389M), and SETD2 (p.R1598_) and transfected Jurkat cells with each mutant.

The mutants reduced gene expression significantly when compared to wild-type cells.

Like in the previous experiments, all 4 HDACis could restore the expression of EP300. But only romidepsin and chidamide could restore MLL2 expression, and only valproic acid and vorinostat could restore SETD2 expression.

In addition, all 4 HDACis restored H3K18 hypoacetylation, which was inhibited in Jurkat cells transfected with the EP300 mutant.

Romidepsin and chidamide restored H3K4me3 expression, which was inhibited by the MLL2 mutant. And valproic acid and vorinostat restored H3K36me3 expression, which was inhibited by the SETD2 mutant.

“HDACis targeted differently histone H3 acetylation or methylation modulated by the mutations, suggesting their distinct therapeutic efficiency in PTCL-NOS,” Dr Ji noted.

She said she and her colleagues are continuing this research in samples from patients with PTCL-NOS.

Meng-Meng Ji, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Preclinical research has revealed mutations that may affect the performance of histone deacetylase inhibitors (HDACis) in patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

The researchers identified histone-modifying gene mutations in patients with PTCL-NOS and found evidence to suggest these mutations confer shorter survival.

The team also conducted experiments in Jurkat cells showing that certain HDACis could counteract loss-of-function mutations, while others could not.

Meng-Meng Ji, MD, PhD, of the Shanghai Institute of Hematology in China, presented this research at the 8th Annual T-cell Lymphoma Forum.

Dr Ji and her colleagues first performed targeted sequencing in tumor samples from 105 patients newly diagnosed with PTCL-NOS.

The team discovered 62 mutations of “important” lymphoma-associated histone-modifying genes in 31 patients. They found mutations in MLL2 (n=21), TET2 (n=17), EP300 (n=8), CREBBP (n=8), and SETD2 (n=6).

Clinical data revealed a significant difference in overall survival between patients who had these mutations and those who did not (P=0.0038).

Because most of the mutations they identified are loss-of-function mutations, Dr Ji and her colleagues wanted to determine whether HDACis could restore the expression of the mutated genes. So they tested 4 HDACis—valproic acid, vorinostat, romidepsin, and chidamide—in Jurkat cells.

All 4 HDACis upregulated expression of EP300 and CREBBP. However, only romidepsin and chidamide upregulated MLL2, and only valproic acid and vorinostat upregulated SETD2. Dr Ji said there was no obvious change in TET2 expression with any of the HDACis.

The researchers then took a closer look at the EP300, MLL2, and SETD2 mutations. They found that most EP300 mutations were located on the HAT domain. MLL2 mutations could be found in a variety of locations, but some were located on the SET domain. And most SETD2 mutations were located on the SET domain.

Based on the crystal structure of each gene, the team found that EP300 mutations on the HAT domain and both MLL2 mutations and SETD2 mutations located on the SET domain induce loss of function.

So the researchers constructed a mutant for EP300 (p.H1377R), MLL2 (p.V5389M), and SETD2 (p.R1598_) and transfected Jurkat cells with each mutant.

The mutants reduced gene expression significantly when compared to wild-type cells.

Like in the previous experiments, all 4 HDACis could restore the expression of EP300. But only romidepsin and chidamide could restore MLL2 expression, and only valproic acid and vorinostat could restore SETD2 expression.

In addition, all 4 HDACis restored H3K18 hypoacetylation, which was inhibited in Jurkat cells transfected with the EP300 mutant.

Romidepsin and chidamide restored H3K4me3 expression, which was inhibited by the MLL2 mutant. And valproic acid and vorinostat restored H3K36me3 expression, which was inhibited by the SETD2 mutant.

“HDACis targeted differently histone H3 acetylation or methylation modulated by the mutations, suggesting their distinct therapeutic efficiency in PTCL-NOS,” Dr Ji noted.

She said she and her colleagues are continuing this research in samples from patients with PTCL-NOS.

Meng-Meng Ji, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Preclinical research has revealed mutations that may affect the performance of histone deacetylase inhibitors (HDACis) in patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

The researchers identified histone-modifying gene mutations in patients with PTCL-NOS and found evidence to suggest these mutations confer shorter survival.

The team also conducted experiments in Jurkat cells showing that certain HDACis could counteract loss-of-function mutations, while others could not.

Meng-Meng Ji, MD, PhD, of the Shanghai Institute of Hematology in China, presented this research at the 8th Annual T-cell Lymphoma Forum.

Dr Ji and her colleagues first performed targeted sequencing in tumor samples from 105 patients newly diagnosed with PTCL-NOS.

The team discovered 62 mutations of “important” lymphoma-associated histone-modifying genes in 31 patients. They found mutations in MLL2 (n=21), TET2 (n=17), EP300 (n=8), CREBBP (n=8), and SETD2 (n=6).

Clinical data revealed a significant difference in overall survival between patients who had these mutations and those who did not (P=0.0038).

Because most of the mutations they identified are loss-of-function mutations, Dr Ji and her colleagues wanted to determine whether HDACis could restore the expression of the mutated genes. So they tested 4 HDACis—valproic acid, vorinostat, romidepsin, and chidamide—in Jurkat cells.

All 4 HDACis upregulated expression of EP300 and CREBBP. However, only romidepsin and chidamide upregulated MLL2, and only valproic acid and vorinostat upregulated SETD2. Dr Ji said there was no obvious change in TET2 expression with any of the HDACis.

The researchers then took a closer look at the EP300, MLL2, and SETD2 mutations. They found that most EP300 mutations were located on the HAT domain. MLL2 mutations could be found in a variety of locations, but some were located on the SET domain. And most SETD2 mutations were located on the SET domain.

Based on the crystal structure of each gene, the team found that EP300 mutations on the HAT domain and both MLL2 mutations and SETD2 mutations located on the SET domain induce loss of function.

So the researchers constructed a mutant for EP300 (p.H1377R), MLL2 (p.V5389M), and SETD2 (p.R1598_) and transfected Jurkat cells with each mutant.

The mutants reduced gene expression significantly when compared to wild-type cells.

Like in the previous experiments, all 4 HDACis could restore the expression of EP300. But only romidepsin and chidamide could restore MLL2 expression, and only valproic acid and vorinostat could restore SETD2 expression.

In addition, all 4 HDACis restored H3K18 hypoacetylation, which was inhibited in Jurkat cells transfected with the EP300 mutant.

Romidepsin and chidamide restored H3K4me3 expression, which was inhibited by the MLL2 mutant. And valproic acid and vorinostat restored H3K36me3 expression, which was inhibited by the SETD2 mutant.

“HDACis targeted differently histone H3 acetylation or methylation modulated by the mutations, suggesting their distinct therapeutic efficiency in PTCL-NOS,” Dr Ji noted.

She said she and her colleagues are continuing this research in samples from patients with PTCL-NOS.

Patient consults pharmacist

Photo by Rhoda Baer

Sun Pharma has announced the US launch of imatinib mesylate tablets, which are a generic version of Novartis’s Gleevec, for indications approved by the US Food and Drug Administration (FDA).

As part of this launch, Sun Pharma has rolled out a savings card program. The goal is to provide greater access to imatinib mesylate tablets for patients who have commercial insurance, but their out-of-pocket cost may exceed an affordable amount.

Sun Pharma’s Imatinib Mesylate Savings Card will reduce patient’s co-payment to $10. The card will also offer patients an additional savings benefit of up to $700 for a 30-day fill to offset any additional out-of-pocket cost should they be required to meet their deductible or co-insurance.

Participating pharmacies across the US can use the patient’s card as part of this program.

Eligible patients can participate in Sun Pharma’s Imatinib Mesylate Savings Card program by registering at www.imatinibrx.com or by requesting a savings card from their oncologist. Sun Pharma will be supplying its Imatinib Mesylate Savings Cards to more than 4500 oncologists.

Sun Pharma has established a Hub service so patients can call and speak with a trained healthcare professional about imatinib mesylate. The number is 1-844-502-5950.

In addition, qualifying patients can receive Sun Pharma’s imatinib mesylate at no cost. Based on qualifications for applying and including a doctor’s prescription, the Hub service will determine if a patient is qualified to receive imatinib mesylate for free. Upon acceptance, the prescription will be processed and delivered to the qualifying patient at no cost.

Sun Pharma’s imatinib mesylate was approved by the FDA in December 2015 and was granted 180 days of marketing exclusivity from the time of its launch. The drug is available in 100 mg and 400 mg tablets.

It is approved to treat:

• Newly diagnosed adult and pediatric patients with Philadelphia-chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adults with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adults with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
• Adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia, including those who have the FIP1L1-PDGFRα fusion kinase
• Adult patients with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.

Sun Pharma’s imatinib mesylate is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Patient consults pharmacist

Photo by Rhoda Baer

Sun Pharma has announced the US launch of imatinib mesylate tablets, which are a generic version of Novartis’s Gleevec, for indications approved by the US Food and Drug Administration (FDA).

As part of this launch, Sun Pharma has rolled out a savings card program. The goal is to provide greater access to imatinib mesylate tablets for patients who have commercial insurance, but their out-of-pocket cost may exceed an affordable amount.

Sun Pharma’s Imatinib Mesylate Savings Card will reduce patient’s co-payment to $10. The card will also offer patients an additional savings benefit of up to $700 for a 30-day fill to offset any additional out-of-pocket cost should they be required to meet their deductible or co-insurance.

Participating pharmacies across the US can use the patient’s card as part of this program.

Eligible patients can participate in Sun Pharma’s Imatinib Mesylate Savings Card program by registering at www.imatinibrx.com or by requesting a savings card from their oncologist. Sun Pharma will be supplying its Imatinib Mesylate Savings Cards to more than 4500 oncologists.

Sun Pharma has established a Hub service so patients can call and speak with a trained healthcare professional about imatinib mesylate. The number is 1-844-502-5950.

In addition, qualifying patients can receive Sun Pharma’s imatinib mesylate at no cost. Based on qualifications for applying and including a doctor’s prescription, the Hub service will determine if a patient is qualified to receive imatinib mesylate for free. Upon acceptance, the prescription will be processed and delivered to the qualifying patient at no cost.

Sun Pharma’s imatinib mesylate was approved by the FDA in December 2015 and was granted 180 days of marketing exclusivity from the time of its launch. The drug is available in 100 mg and 400 mg tablets.

It is approved to treat:

• Newly diagnosed adult and pediatric patients with Philadelphia-chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adults with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adults with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
• Adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia, including those who have the FIP1L1-PDGFRα fusion kinase
• Adult patients with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.

Sun Pharma’s imatinib mesylate is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Patient consults pharmacist

Photo by Rhoda Baer

Sun Pharma has announced the US launch of imatinib mesylate tablets, which are a generic version of Novartis’s Gleevec, for indications approved by the US Food and Drug Administration (FDA).

As part of this launch, Sun Pharma has rolled out a savings card program. The goal is to provide greater access to imatinib mesylate tablets for patients who have commercial insurance, but their out-of-pocket cost may exceed an affordable amount.

Sun Pharma’s Imatinib Mesylate Savings Card will reduce patient’s co-payment to $10. The card will also offer patients an additional savings benefit of up to $700 for a 30-day fill to offset any additional out-of-pocket cost should they be required to meet their deductible or co-insurance.

Participating pharmacies across the US can use the patient’s card as part of this program.

Eligible patients can participate in Sun Pharma’s Imatinib Mesylate Savings Card program by registering at www.imatinibrx.com or by requesting a savings card from their oncologist. Sun Pharma will be supplying its Imatinib Mesylate Savings Cards to more than 4500 oncologists.

Sun Pharma has established a Hub service so patients can call and speak with a trained healthcare professional about imatinib mesylate. The number is 1-844-502-5950.

In addition, qualifying patients can receive Sun Pharma’s imatinib mesylate at no cost. Based on qualifications for applying and including a doctor’s prescription, the Hub service will determine if a patient is qualified to receive imatinib mesylate for free. Upon acceptance, the prescription will be processed and delivered to the qualifying patient at no cost.

Sun Pharma’s imatinib mesylate was approved by the FDA in December 2015 and was granted 180 days of marketing exclusivity from the time of its launch. The drug is available in 100 mg and 400 mg tablets.

It is approved to treat:

• Newly diagnosed adult and pediatric patients with Philadelphia-chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adults with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adults with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
• Adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia, including those who have the FIP1L1-PDGFRα fusion kinase
• Adult patients with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.

Sun Pharma’s imatinib mesylate is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

HSCT preparation

Photo by Chad McNeeley

Results of a phase 3 trial suggest defibrotide may improve survival in patients who develop hepatic veno-occlusive disease (VOD) and multi-organ failure (MOF) after hematopoietic stem cell transplant (HSCT).

The patients in this trial had a significant improvement in complete response (CR) rate and survival at day 100 after HSCT, when compared with historical controls.

The researchers said defibrotide was generally well-tolerated, and toxicity was manageable.

However, nearly all defibrotide-treated patients had at least 1 adverse event (AE), as did all historical controls. And a majority of patients in both groups had a fatal AE.

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Blood. The trial was sponsored by Jazz Pharmaceuticals, makers of defibrotide.

“Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need,” Dr Richardson said.

“Although HSCT has improved substantially over the last decade, hepatic [VOD] with MOF remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

Dr Richardson and his colleagues investigated the safety and efficacy of defibrotide in 102 adult and pediatric HSCT patients with established hepatic VOD with MOF.

The patients received defibrotide intravenously at 25 mg/kg/day for a minimum of 21 days. Treatment was scheduled to continue beyond 21 days until the resolution of VOD or the patient’s discharge from the hospital.

The researchers compared the 102 patients who received defibrotide with 32 historical controls who were treated at the same institutions. The controls were identified via a review of medical charts of HSCT patients by an independent medical review committee, which was blinded to outcomes.

Baseline characteristics

Baseline characteristics between the groups were largely well balanced. This includes underlying disease, graft source, conditioning regimen, myeloablative regimen, and VOD and MOF parameters.

However, 15% of defibrotide-treated patients received tacrolimus plus sirolimus as graft-versus-host disease prophylaxis, compared with none of the historical controls. Most patients discontinued this regimen upon diagnosis of VOD.

All patients had hyperbilirubinemia. Ascites, weight gain, and hepatomegaly were present in 72% of patients in the defibrotide group and 59% of historical controls.

Renal dysfunction was present in 78% of patients in the defibrotide group (20% dialysis-dependent) and 75% of historical controls (6% dialysis-dependent). Pulmonary dysfunction was present in 85% (26% ventilator-dependent) and 97% (19% ventilator-dependent), respectively.

Sixty-four percent of patients in the defibrotide group and 72% of historical controls had both renal and pulmonary dysfunction.

Response and survival

The primary endpoint was survival at day 100 post-HSCT, which was 38.2% in the defibrotide group and 25% in the historical control group. The estimated between-group difference, using a propensity-adjusted analysis, was 23% (P=0.0109).

The CR rate was 25.5% in the defibrotide group and 12.5% in the historical control group. The estimated difference, adjusted for propensity score, was 19% (P=0.0160).

The median time to CR was 34.5 days in the defibrotide group and 39.5 days in the control group. CR was durable for 22 of 26 patients in the defibrotide group, who still had a CR at last observation. Four patients in the defibrotide group had CR end dates before day 180. All 4 patients died of sepsis or leukemia.

In the historical control group, 1 patient had a durable CR (162 days), 2 patients had a limited CR duration (9 and 10 days, respectively), and 1 patient could not be assessed.

Safety

The median duration of defibrotide treatment was 21.5 days. Eleven patients discontinued treatment prematurely due to possible drug-related toxicity (10.7%).

All but 1 of the defibrotide-treated patients and all historical controls had at least 1 AE. Hypotension was the most common AE in both groups—39.2% with defibrotide and 50.0% for historical controls. Diarrhea was also common—23.5% and 37.5%, respectively.

Sixty-four percent of patients in the defibrotide group (n=65) and 69% of historical controls (n=22) had a fatal AE.

Fifteen patients (14.7%) in the defibrotide group and 2 (6.3%) in the historical control group had 1 or more hemorrhagic AEs leading to death.

For the defibrotide group, these were gastrointestinal hemorrhage (n=1), cerebral hemorrhage (n=2), intracranial hemorrhage (n=1), subarachnoid hemorrhage (n=1), pulmonary alveolar hemorrhage (n=7), pulmonary hemorrhage (n=2), and vascular disorders hemorrhage (n=1).

Both hemorrhagic AEs leading to death in historical controls were pulmonary alveolar hemorrhage.

HSCT preparation

Photo by Chad McNeeley

Results of a phase 3 trial suggest defibrotide may improve survival in patients who develop hepatic veno-occlusive disease (VOD) and multi-organ failure (MOF) after hematopoietic stem cell transplant (HSCT).

The patients in this trial had a significant improvement in complete response (CR) rate and survival at day 100 after HSCT, when compared with historical controls.

The researchers said defibrotide was generally well-tolerated, and toxicity was manageable.

However, nearly all defibrotide-treated patients had at least 1 adverse event (AE), as did all historical controls. And a majority of patients in both groups had a fatal AE.

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Blood. The trial was sponsored by Jazz Pharmaceuticals, makers of defibrotide.

“Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need,” Dr Richardson said.

“Although HSCT has improved substantially over the last decade, hepatic [VOD] with MOF remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

Dr Richardson and his colleagues investigated the safety and efficacy of defibrotide in 102 adult and pediatric HSCT patients with established hepatic VOD with MOF.

The patients received defibrotide intravenously at 25 mg/kg/day for a minimum of 21 days. Treatment was scheduled to continue beyond 21 days until the resolution of VOD or the patient’s discharge from the hospital.

The researchers compared the 102 patients who received defibrotide with 32 historical controls who were treated at the same institutions. The controls were identified via a review of medical charts of HSCT patients by an independent medical review committee, which was blinded to outcomes.

Baseline characteristics

Baseline characteristics between the groups were largely well balanced. This includes underlying disease, graft source, conditioning regimen, myeloablative regimen, and VOD and MOF parameters.

However, 15% of defibrotide-treated patients received tacrolimus plus sirolimus as graft-versus-host disease prophylaxis, compared with none of the historical controls. Most patients discontinued this regimen upon diagnosis of VOD.

All patients had hyperbilirubinemia. Ascites, weight gain, and hepatomegaly were present in 72% of patients in the defibrotide group and 59% of historical controls.

Renal dysfunction was present in 78% of patients in the defibrotide group (20% dialysis-dependent) and 75% of historical controls (6% dialysis-dependent). Pulmonary dysfunction was present in 85% (26% ventilator-dependent) and 97% (19% ventilator-dependent), respectively.

Sixty-four percent of patients in the defibrotide group and 72% of historical controls had both renal and pulmonary dysfunction.

Response and survival

The primary endpoint was survival at day 100 post-HSCT, which was 38.2% in the defibrotide group and 25% in the historical control group. The estimated between-group difference, using a propensity-adjusted analysis, was 23% (P=0.0109).

The CR rate was 25.5% in the defibrotide group and 12.5% in the historical control group. The estimated difference, adjusted for propensity score, was 19% (P=0.0160).

The median time to CR was 34.5 days in the defibrotide group and 39.5 days in the control group. CR was durable for 22 of 26 patients in the defibrotide group, who still had a CR at last observation. Four patients in the defibrotide group had CR end dates before day 180. All 4 patients died of sepsis or leukemia.

In the historical control group, 1 patient had a durable CR (162 days), 2 patients had a limited CR duration (9 and 10 days, respectively), and 1 patient could not be assessed.

Safety

The median duration of defibrotide treatment was 21.5 days. Eleven patients discontinued treatment prematurely due to possible drug-related toxicity (10.7%).

All but 1 of the defibrotide-treated patients and all historical controls had at least 1 AE. Hypotension was the most common AE in both groups—39.2% with defibrotide and 50.0% for historical controls. Diarrhea was also common—23.5% and 37.5%, respectively.

Sixty-four percent of patients in the defibrotide group (n=65) and 69% of historical controls (n=22) had a fatal AE.

Fifteen patients (14.7%) in the defibrotide group and 2 (6.3%) in the historical control group had 1 or more hemorrhagic AEs leading to death.

For the defibrotide group, these were gastrointestinal hemorrhage (n=1), cerebral hemorrhage (n=2), intracranial hemorrhage (n=1), subarachnoid hemorrhage (n=1), pulmonary alveolar hemorrhage (n=7), pulmonary hemorrhage (n=2), and vascular disorders hemorrhage (n=1).

Both hemorrhagic AEs leading to death in historical controls were pulmonary alveolar hemorrhage.

HSCT preparation

Photo by Chad McNeeley

Results of a phase 3 trial suggest defibrotide may improve survival in patients who develop hepatic veno-occlusive disease (VOD) and multi-organ failure (MOF) after hematopoietic stem cell transplant (HSCT).

The patients in this trial had a significant improvement in complete response (CR) rate and survival at day 100 after HSCT, when compared with historical controls.

The researchers said defibrotide was generally well-tolerated, and toxicity was manageable.

However, nearly all defibrotide-treated patients had at least 1 adverse event (AE), as did all historical controls. And a majority of patients in both groups had a fatal AE.

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Blood. The trial was sponsored by Jazz Pharmaceuticals, makers of defibrotide.

“Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need,” Dr Richardson said.

“Although HSCT has improved substantially over the last decade, hepatic [VOD] with MOF remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

Dr Richardson and his colleagues investigated the safety and efficacy of defibrotide in 102 adult and pediatric HSCT patients with established hepatic VOD with MOF.

The patients received defibrotide intravenously at 25 mg/kg/day for a minimum of 21 days. Treatment was scheduled to continue beyond 21 days until the resolution of VOD or the patient’s discharge from the hospital.

The researchers compared the 102 patients who received defibrotide with 32 historical controls who were treated at the same institutions. The controls were identified via a review of medical charts of HSCT patients by an independent medical review committee, which was blinded to outcomes.

Baseline characteristics

Baseline characteristics between the groups were largely well balanced. This includes underlying disease, graft source, conditioning regimen, myeloablative regimen, and VOD and MOF parameters.

However, 15% of defibrotide-treated patients received tacrolimus plus sirolimus as graft-versus-host disease prophylaxis, compared with none of the historical controls. Most patients discontinued this regimen upon diagnosis of VOD.

All patients had hyperbilirubinemia. Ascites, weight gain, and hepatomegaly were present in 72% of patients in the defibrotide group and 59% of historical controls.

Renal dysfunction was present in 78% of patients in the defibrotide group (20% dialysis-dependent) and 75% of historical controls (6% dialysis-dependent). Pulmonary dysfunction was present in 85% (26% ventilator-dependent) and 97% (19% ventilator-dependent), respectively.

Sixty-four percent of patients in the defibrotide group and 72% of historical controls had both renal and pulmonary dysfunction.

Response and survival

The primary endpoint was survival at day 100 post-HSCT, which was 38.2% in the defibrotide group and 25% in the historical control group. The estimated between-group difference, using a propensity-adjusted analysis, was 23% (P=0.0109).

The CR rate was 25.5% in the defibrotide group and 12.5% in the historical control group. The estimated difference, adjusted for propensity score, was 19% (P=0.0160).

The median time to CR was 34.5 days in the defibrotide group and 39.5 days in the control group. CR was durable for 22 of 26 patients in the defibrotide group, who still had a CR at last observation. Four patients in the defibrotide group had CR end dates before day 180. All 4 patients died of sepsis or leukemia.

In the historical control group, 1 patient had a durable CR (162 days), 2 patients had a limited CR duration (9 and 10 days, respectively), and 1 patient could not be assessed.

Safety

The median duration of defibrotide treatment was 21.5 days. Eleven patients discontinued treatment prematurely due to possible drug-related toxicity (10.7%).

All but 1 of the defibrotide-treated patients and all historical controls had at least 1 AE. Hypotension was the most common AE in both groups—39.2% with defibrotide and 50.0% for historical controls. Diarrhea was also common—23.5% and 37.5%, respectively.

Sixty-four percent of patients in the defibrotide group (n=65) and 69% of historical controls (n=22) had a fatal AE.

Fifteen patients (14.7%) in the defibrotide group and 2 (6.3%) in the historical control group had 1 or more hemorrhagic AEs leading to death.

For the defibrotide group, these were gastrointestinal hemorrhage (n=1), cerebral hemorrhage (n=2), intracranial hemorrhage (n=1), subarachnoid hemorrhage (n=1), pulmonary alveolar hemorrhage (n=7), pulmonary hemorrhage (n=2), and vascular disorders hemorrhage (n=1).

Both hemorrhagic AEs leading to death in historical controls were pulmonary alveolar hemorrhage.

Rivaroxaban (Xarelto)

An investigation by The BMJ has called into question the validity of the ROCKET AF trial, which was used to support approval for the direct oral anticoagulant rivaroxaban (Xarelto) in the US and European Union (EU).

For this trial, which was published in NEJM in 2011, researchers compared rivaroxaban to warfarin in patients with nonvalvular atrial fibrillation.

Results suggested rivaroxaban was noninferior to warfarin for preventing stroke or systemic embolism.

And there was no significant difference between the treatment arms with regard to major or nonmajor clinically relevant bleeding.

However, The BMJ article questions these results because the Alere INRatio Monitor System (INRatio Monitor or INRatio2 Monitor and INRatio Test Strips), which was used to measure patients’ international

normalized ratios (INRs) during the trial, was recalled in December 2014 after giving falsely low test results.

“In terms of the trial results, [the defect with the system] could make rivaroxaban seem safer than it was with respect to the risk of bleeding and throws doubt onto outcomes used to support the use of the world’s best-selling new oral anticoagulant,” said Deborah Cohen, The BMJ’s associate editor and author of the article.

In November 2015, the European Medicines Agency told The BMJ they were investigating the potential implications of the issue with the INRatio system. And the US Food and Drug Administration (FDA) said they were “aware of concerns regarding the INRatio device and its use in the ROCKET AF trial and [were] reviewing relevant data.”

The makers of the INRatio system (Alere) confirmed that the fault dates back to 2002. However, neither they nor the FDA responded to questions about why nothing had been done about the problem earlier.

In the meantime, Harlan Krumholz, MD, of Yale University in New Haven, Connecticut, said NEJM should place an “immediate Expression of Concern” on the paper describing ROCKET AF to notify the medical community, and there should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction.”

In December, Duke University’s Clinical Research Institute, which carried out the trial on behalf of Johnson and Johnson and Bayer Healthcare, said analyses conducted after the ROCKET AF trial was first published  “are consistent with the results from the original trial and do not alter the conclusions of ROCKET AF.”

But former FDA reviewer Thomas Marciniak, MD, told The BMJ he would not rely on any re-analyses done by Duke, Johnson and Johnson, or the FDA. He added that public release of the data is “the only solution that would lead to unbiased analyses.”

However, Bayer told The BMJ the company has only signed up to share information on “study reports for new medicines approved in the US and the EU after January 1, 2014.”

According to former FDA clinical pharmacologist Bob Powell, PharmD, once a drug is on the market, the regulators lack a mandate to act without a safety signal.

“It is this lack of safety signal that appears to be hindering the FDA in their desire to pursue tailored dosing for [direct oral anticoagulants],” he said. “If it turns out that the issue with the INRatio device changes the safety profile of rivaroxaban, this very well may constitute the safety signal necessary for the FDA to act in this regard.”

Rivaroxaban (Xarelto)

An investigation by The BMJ has called into question the validity of the ROCKET AF trial, which was used to support approval for the direct oral anticoagulant rivaroxaban (Xarelto) in the US and European Union (EU).

For this trial, which was published in NEJM in 2011, researchers compared rivaroxaban to warfarin in patients with nonvalvular atrial fibrillation.

Results suggested rivaroxaban was noninferior to warfarin for preventing stroke or systemic embolism.

And there was no significant difference between the treatment arms with regard to major or nonmajor clinically relevant bleeding.

However, The BMJ article questions these results because the Alere INRatio Monitor System (INRatio Monitor or INRatio2 Monitor and INRatio Test Strips), which was used to measure patients’ international

normalized ratios (INRs) during the trial, was recalled in December 2014 after giving falsely low test results.

“In terms of the trial results, [the defect with the system] could make rivaroxaban seem safer than it was with respect to the risk of bleeding and throws doubt onto outcomes used to support the use of the world’s best-selling new oral anticoagulant,” said Deborah Cohen, The BMJ’s associate editor and author of the article.

In November 2015, the European Medicines Agency told The BMJ they were investigating the potential implications of the issue with the INRatio system. And the US Food and Drug Administration (FDA) said they were “aware of concerns regarding the INRatio device and its use in the ROCKET AF trial and [were] reviewing relevant data.”

The makers of the INRatio system (Alere) confirmed that the fault dates back to 2002. However, neither they nor the FDA responded to questions about why nothing had been done about the problem earlier.

In the meantime, Harlan Krumholz, MD, of Yale University in New Haven, Connecticut, said NEJM should place an “immediate Expression of Concern” on the paper describing ROCKET AF to notify the medical community, and there should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction.”

In December, Duke University’s Clinical Research Institute, which carried out the trial on behalf of Johnson and Johnson and Bayer Healthcare, said analyses conducted after the ROCKET AF trial was first published  “are consistent with the results from the original trial and do not alter the conclusions of ROCKET AF.”

But former FDA reviewer Thomas Marciniak, MD, told The BMJ he would not rely on any re-analyses done by Duke, Johnson and Johnson, or the FDA. He added that public release of the data is “the only solution that would lead to unbiased analyses.”

However, Bayer told The BMJ the company has only signed up to share information on “study reports for new medicines approved in the US and the EU after January 1, 2014.”

According to former FDA clinical pharmacologist Bob Powell, PharmD, once a drug is on the market, the regulators lack a mandate to act without a safety signal.

“It is this lack of safety signal that appears to be hindering the FDA in their desire to pursue tailored dosing for [direct oral anticoagulants],” he said. “If it turns out that the issue with the INRatio device changes the safety profile of rivaroxaban, this very well may constitute the safety signal necessary for the FDA to act in this regard.”

Rivaroxaban (Xarelto)

An investigation by The BMJ has called into question the validity of the ROCKET AF trial, which was used to support approval for the direct oral anticoagulant rivaroxaban (Xarelto) in the US and European Union (EU).

For this trial, which was published in NEJM in 2011, researchers compared rivaroxaban to warfarin in patients with nonvalvular atrial fibrillation.

Results suggested rivaroxaban was noninferior to warfarin for preventing stroke or systemic embolism.

And there was no significant difference between the treatment arms with regard to major or nonmajor clinically relevant bleeding.

However, The BMJ article questions these results because the Alere INRatio Monitor System (INRatio Monitor or INRatio2 Monitor and INRatio Test Strips), which was used to measure patients’ international

normalized ratios (INRs) during the trial, was recalled in December 2014 after giving falsely low test results.

“In terms of the trial results, [the defect with the system] could make rivaroxaban seem safer than it was with respect to the risk of bleeding and throws doubt onto outcomes used to support the use of the world’s best-selling new oral anticoagulant,” said Deborah Cohen, The BMJ’s associate editor and author of the article.

In November 2015, the European Medicines Agency told The BMJ they were investigating the potential implications of the issue with the INRatio system. And the US Food and Drug Administration (FDA) said they were “aware of concerns regarding the INRatio device and its use in the ROCKET AF trial and [were] reviewing relevant data.”

The makers of the INRatio system (Alere) confirmed that the fault dates back to 2002. However, neither they nor the FDA responded to questions about why nothing had been done about the problem earlier.

In the meantime, Harlan Krumholz, MD, of Yale University in New Haven, Connecticut, said NEJM should place an “immediate Expression of Concern” on the paper describing ROCKET AF to notify the medical community, and there should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction.”

In December, Duke University’s Clinical Research Institute, which carried out the trial on behalf of Johnson and Johnson and Bayer Healthcare, said analyses conducted after the ROCKET AF trial was first published  “are consistent with the results from the original trial and do not alter the conclusions of ROCKET AF.”

But former FDA reviewer Thomas Marciniak, MD, told The BMJ he would not rely on any re-analyses done by Duke, Johnson and Johnson, or the FDA. He added that public release of the data is “the only solution that would lead to unbiased analyses.”

However, Bayer told The BMJ the company has only signed up to share information on “study reports for new medicines approved in the US and the EU after January 1, 2014.”

According to former FDA clinical pharmacologist Bob Powell, PharmD, once a drug is on the market, the regulators lack a mandate to act without a safety signal.

“It is this lack of safety signal that appears to be hindering the FDA in their desire to pursue tailored dosing for [direct oral anticoagulants],” he said. “If it turns out that the issue with the INRatio device changes the safety profile of rivaroxaban, this very well may constitute the safety signal necessary for the FDA to act in this regard.”

Heart failure management has become increasingly complex over the past couple of decades, with new drugs and drug combinations, new uses for potentially life-saving implanted devices, and a more sophisticated appreciation of the ways that various comorbidities complicate a heart failure patient’s clinical status. These expanded dimensions of heart failure care resulted in the establishment in 2008 of a new secondary subspecialty, Advanced Heart Failure and Transplant Cardiology, aimed at training and certifying physicians in all the nuances of complex heart failure diagnostics and care.

But as the 2009 manifesto announcing this new heart failure subspecialty detailed, care for the vast majority of U.S. patients with heart failure remains in the hands of internal medicine primary care physicians (PCPs) and general cardiologists (J Am Coll Cardiol. 2009 Mar 10;53[10]:834-6). To some extent this is a manpower issue. The estimated number of Americans living with heart failure exceeds 5 million, a figure that dwarfs the very modest number of U.S. physicians and clinicians who are certified or self-identified heart failure specialists.

As of today, fewer than 1,000 U.S. physicians have received formal certification as heart failure subspecialists through the examination administered in 2010, 2012, and 2014, said Michele Blair, chief executive officer of the Heart Failure Society of America. A more liberal definition of a heart failure specialist might include the roughly 3,000 unique physicians (mostly cardiologists, but also some hospitalists and emergency physicians) who have recently attended an annual meeting of the HFSA, as well as the roughly 2,300 physician assistants and nurse practitioners who have shown a heart failure interest by coming to a recent HFSA meeting. But even these expanded estimates calculate out to about 1 clinician with a special interest in heart failure for each 1,000 heart failure patients, not a very reassuring ratio.

The burgeoning numbers of heart failure patients, compared with the relative scarcity of both heart failure experts and general cardiologists, raises issues of how primary-care internists best share this management responsibility. Recent interviews with several heart failure subspecialists and primary care internists provide some insight into how this division of labor is now playing out in routine U.S. practice. What often occurs is that primary care internists take exclusive responsibility for caring for heart failure patients until they feel they are getting in over their heads, at which time they’ll consult with a cardiology colleague or refer the patient to a cardiologist. That moment of recognition by the generalist – that the demands and complexity of the case exceed their comfort level – varies widely, with some PCPs referring patients as soon as heart failure symptoms appear while others stay comfortable as the primary care giver even as a patient’s disease deteriorates to a more advanced stage.

Heart failure specialists highlighted their reliance on PCPs to take an ongoing, active role even for patients with significantly advanced heart failure, as generalists are well suited to coordinating the multispecialty care that such patients usually require, with attention to their need for lifestyle modifications as well as management of their diabetes, sleep apnea, chronic obstructive pulmonary disease, renal failure, and other comorbidities.

Mitchel L. Zoler/Frontline Medical News

As Dr. Michael K. Ong, a primary care internist at the University of California, Los Angeles, said in an interview, his heart failure specialist colleague manages patients’ heart failure; “I manage [or refer] everything else not directly related to the heart failure.”

The most successful U.S. care models seem to be some variation on a team-care approach, in which physicians collaborate with pharmacists, nurses, rehabilitation specialists, and social workers as well as specialists, a team that would include and perhaps be led by either a primary care internist, a cardiologist, or a heart failure specialist but would also broadly include physicians able to deal with all the morbidity facets of heart failure. It’s a model that remains unavailable in many U.S. settings or is just starting to emerge, as fee-for-service coverage of patients gets replaced by population-management models that better accommodate the upfront financial demands of coordinated team care. It makes financial sense a few years down the road when improved patient outcomes result in cost savings.

Primary care and patients with symptomatic heart failure

The heart failure definitions and staging system established in 2001 by a guidelines panel of the American College of Cardiology and American Heart Association defined stage A heart failure as starting before a patient exhibits any heart failure symptoms (the classic ones include dyspnea, rales, and peripheral edema). The panel designated symptomatic heart failure patients as stage C. Patients without heart failure symptoms but with one or more risk factors (such as hypertension, diabetes, obesity, and cardiovascular disease) plus structural heart disease (such as cardiomyopathy or other forms of heart remodeling) were designated stage B. The panel said that people at stage A had one or more risk factors but no structural heart changes and no heart failure symptoms.

Although stage-A heart failure patients are clearly the types of people most often seen and cared for by PCPs, many of these physicians, as well as many heart failure specialists, don’t consider patients who have only hypertension or only diabetes or only obesity as yet having heart failure. That paradox deserves more discussion, but the best way to begin talking about PCPs and heart failure patients is when patients are symptomatic and have what everyone would agree is heart failure.

Even though the ACC/AHA staging system places stage C patients well down the heart failure road, stage C is usually when patients are first diagnosed with heart failure. Although the diagnosis is often first made by a hospitalist or emergency-department physician when severe and sudden-onset heart failure symptoms drive the patient to a hospital, or the diagnosis originates with a cardiologist or heart failure specialist when the patient’s presentation and differential diagnosis isn’t straightforward, most commonly the diagnosis starts with a PCP in an office encounter with a patient who is symptomatic but not acutely ill.

“Patients with shortness of breath or other forms of effort intolerance most often seek care from PCPs. The differential diagnosis of dyspnea is long and complex. Recognition that a patient with dyspnea may have HF is crucial” for timely management and treatment, said Dr. Mary Norine Walsh, medical director of Heart Failure and Cardiac Transplantation at St. Vincent Heart Center in Indianapolis.

At the Mayo Clinic in Rochester, Minn., “most of the heart failure diagnoses are done by PCPs, usually first identified at stage C when a patient comes in with symptoms. Stage B heart failure is usually only identified as an incidental finding when echocardiography is done for some other reason,” said Dr. Paul M. McKie, a heart failure cardiologist who works closely with the primary-care staff at Mayo as an embedded consultant cardiologist.

Mitchel L. Zoler/Frontline Medical News

According to Dr. Mariell L. Jessup, a heart failure physician and professor at the University of Pennsylvania in Philadelphia, a key to PCPs promptly identifying patients with recent-onset, stage C heart failure is to keep the disease as well as its prominent risk factors at the top of their differential-diagnosis list for at-risk patients. “Heart failure is a common disorder,” Dr. Jessup said, and must be considered for patients with shortness of breath. “The leading causes of heart failure are hypertension, obesity, and diabetes. So keep heart failure in mind, especially for patients with one or more of these risk factors.”

Although PCPs might order an echocardiography examination or a lab test like measurement of brain natriuretic protein (BNP) to help nail down the diagnosis, they often leave reading the echocardiography results to a cardiologist colleague. “When a PCP orders an echo it’s automatically read by a cardiologist, and then we get the cardiologist’s report. I don’t read echos myself,” said Dr. Rebecca J. Cunningham, an internal medicine PCP at Brigham and Women’s Hospital in Boston who frequently sees patients with heart failure as medical director of the hospital’s Integrated Care Management Program. “I had one PCP colleague who undertook additional training to learn to read echos himself, but that’s unusual.”

Dr. Mary Ann Bauman, an internal medicine PCP and medical director for Women’s Health and Community Relations at INTEGRIS Health in Oklahoma City, noted a similar division of labor. “If a patient has shortness of breath, maybe some edema, and I hear a few rales, but is totally functional, I always order an echo but I don’t read it. I refer the echo to a cardiologist who then sends me a report,” Dr. Bauman said in an interview. “If I think the patient may have heart failure I’ll also order a BNP or NT-proBNP test. If I suspect heart failure and the BNP is high, it’s a red flag. BNP is another tool for getting the diagnosis right.”

The next step seems much more variable. Some PCPs retain primary control of heart failure management for many of their patients, especially when stage C patients remain stable and functional on simple, straightforward treatment and particularly when they have heart failure with preserved ejection fraction (HFpEF), usually defined as a left ventricular ejection fraction that is at least 40%-45%. Consultation or referral to a cardiologist or heart-failure physician seems much more common for patients with frequent decompensations and hospitalizations or patients with heart failure with reduced ejection fraction (HFrEF). But the main thread reported by both PCPs and cardiologists is that it all depends and varies for each patient and for each PCP depending on what patient responsibilities a PCP feels comfortable taking on.

Dr. Bauman sits at one end of the spectrum: “If it looks like a patient has heart failure, I refer them right away; I don’t wait for decompensation to occur. I want to be sure that there are no nuances in the patient that need something before I recognize it. Most of my PCP partners do the same. You don’t know what it is you don’t know. For me, it’s better to refer the patient right away so the patient has a cardiologist who already knows them who can be called if they start to decompensate.”

Dr. Bauman cited the increasing complexity of heart failure management as the main driver of her current approach, which she contrasted to how she dealt with heart failure patients 20 years ago. “It’s become so complicated that, as a PCP, I don’t feel that I can keep up” with the optimal ways to manage every heart failure patient. “I might not give my heart failure patients the best care they could receive.” The aspects of care that Dr. Bauman said she can provide to heart failure patients she has referred include “dealing with lifestyle changes, making sure patients are taking their medications and getting to their appointments, adjusting their heart-failure medication dosages as needed once they start on the drugs, and seeing that their diabetes and hypertension are well controlled. That is the role of the PCP. But when it comes to deciding which HF medications to use, that’s when I like to have a cardiologist involved.”

But the PCPs at Mayo Clinic often take a different tack, said Dr. McKie. “If the patient is a simple case of heart failure with no red flags and the patient is doing relatively well on treatment with simple diuretic treatment, then initiation of heart failure medications and ongoing management is often directed by the PCP with some cardiology backup as needed,” he said. But Dr. McKie conceded that a spectrum of PCP approaches exists at Mayo as well. “A lot depends on the patient and on the specific provider. Some patients we never get calls about; their PCPs are excellent at managing diuretics and uptitrating beta-blockers and ACE inhibitors. We may only get called if the patient decompensates, But other PCPs are very uncomfortable and they request that we get involved as soon as the diagnosis of stage C heart failure is made. So there is a wide range.” Dr. McKie noted that he thinks it is appropriate for himself or one of his cardiology colleagues to get more active when the HFrEF patient’s ejection fraction drops below 40% and certainly below 35%. That’s because at this stage, patients also need treatment with an aldosterone receptor antagonist such as spironolactone, and they undergo consideration for receiving an implantable cardioverter defibrillator or a cardiac resynchronization therapy device.

Mitchel L. Zoler/Frontline Medical News

“There is nothing magic about heart failure management; it is very well proscribed by guidelines. Nothing precludes a PCP from taking ownership” of heart failure patients, said Dr. Akshay S. Desai, a heart failure cardiologist at Brigham and Women’s Hospital. “I think there is some fear among PCPs that they intrude” by managing heart failure patients. But for patients with structural heart disease or even left ventricular dysfunction, “PCPs should feel empowered to start standard heart failure treatments, including ACE inhibitors and beta-blockers, especially because half of heart failure patients have HFpEF, and PCPs often don’t refer HFpEF patients to cardiologists. It’s the patients with left ventricular dysfunction who end up in heart failure clinics,” Dr. Desai said.

On the other hand, Dr. Desai cautioned PCPs against waiting too long to bring more complex, sicker, and harder-to-manage patients to the attention of a heart failure specialist.

“What we worry about are late referrals, when patients are profoundly decompensated,” he said. “By the time they show up [at a heart failure clinic or emergency department] they have end-organ dysfunction,” which makes them much harder to treat and maybe irreversible. “Recognizing heart failure early is the key, and early referral is an obligation” when a heart failure patient is deteriorating or becomes too complex for a PCP to properly manage, Dr. Desai advised.

But even when heart failure patients develop more severe disease, with significantly depressed left ventricular function or frequent decompensations, PCPs continue to play a valuable role in coordinating the wide range of treatments patients need for their various comorbidities.

“Once a cardiologist or heart failure physician is involved there is still a role for PCPs” said Dr. Monica R. Shah, deputy chief of the Heart Failure and Arrhythmia Branch of the National Heart, Lung, and Blood Institute in Bethesda, Md. “Heart failure patients are complex, it’s not just one organ system that’s affected, and you need a partnership between cardiologists and PCPs to coordinate all of a patient’s care. A heart failure physician needs to work with a PCP to be sure that the patient’s health is optimal. Collaboration between cardiologists and PCPs is key to ensure that optimal care is effectively delivered to patients,” Dr. Shah said in an interview.

“Keeping the PCP at the center of the care team is critical, especially with the multiple comorbidities that HF patients can have, including chronic obstructive pulmonary disease, diabetes, renal failure, sleep apnea, atrial fibrillation, and degenerative joint disease. Before you know it you have a half-dozen subspecialists involved in care and it can become uncoordinated. Keeping the PCP at the center of the team and providing the PCP with support from specialists as needed is critical,” said Dr. McKie.

Even for the most severe heart failure patients, PCPs can still play an important role by providing palliative care and dealing with end-of-life issues, specialists said.

Primary care and heart failure’s antecedents

The other, obvious time in heart failure’s severity spectrum for PCPs to take a very active role is with presymptomatic, stage A patients. Perhaps the only controversial element of this is whether such patients really have a form of heart failure and whether is it important to conceptualize heart failure this way.

The notion of stage A heart failure dates back to the 2001 edition of heart failure diagnosis and management recommendations issued by a panel organized by the ACC and AHA (J Am Coll Cardiol. 2001 Dec;38[7]:2101-13). The 2001 writing committee members said that they “decided to take a new approach to the classification of heart failure that emphasized both the evolution and progression of the disease.” They defined stage A patients as presymptomatic and without structural heart disease but with “conditions strongly associated with the development of heart failure,” specifically systemic hypertension, coronary artery disease, diabetes, a history of cardiotoxic drug therapy or alcohol abuse, a history of rheumatic fever, or a family history of cardiomyopathy.

When the ACC and AHA panel members next updated the heart failure recommendations in 2005, they seemed to take a rhetorical step back, saying that stage A and B “are clearly not heart failure but are an attempt to help healthcare providers identify patients early who are at risk for developing heart failure. Stage A and B patients are best defined as those with risk factors that clearly predispose toward the development of HF.” (J Am Coll Cardiol. 2005 Sept. 46[6]:1116-43) In 2005, the panel also streamlined the list of risk factors that identify stage A heart failure patients: hypertension, atherosclerotic disease, diabetes, obesity, metabolic syndrome, patients who have taken cardiotoxins, or patients with a family history of cardiomyopathy. The 2009 recommendation update left this definition of stage A heart failure unchanged, but in 2013 the most recent update devoted less attention to explaining the significance of the stage-A heart failure, although it clearly highlighted the importance of controlling hypertension, diabetes, and obesity as ways to prevent patients from developing symptomatic heart failure (J Am Coll Cardiol. 2013 Oct 15;62[16]:e147-e239).

The subtle, official tweaking of the stage A (and B) heart failure concept during 2001-2013, as well establishment of stage A in the first place, seems to have left both PCPs and heart failure specialists unsure on exactly how to think about presymptomatic people with one or more of the prominent heart failure risk factors of hypertension, diabetes, and obesity. While they uniformly agree that identifying these risk factors and then treating them according to contemporary guidelines is hugely important for stopping or deferring the onset of heart failure, and they also agree that this aspect of patient care is clearly a core responsibility for PCPs, many also say that they don’t think of presymptomatic patients as having heart failure of any type despite the stage A designation on the books.

One exception is St. Vincent’s Dr. Walsh. “I think the writers of the 2001 heart failure guidelines had an inspired approach. Identifying patients with hypertension, diabetes, coronary artery disease, etc., as patients with heart failure has helped drive home the point that treatment and control of these diseases is crucial,” she said in an interview. “But I am not sure all physicians have adopted the concept. “Uncontrolled hypertension is prevalent, and not viewed by all as resulting in heart failure down the road. Diabetes and hypertension are very important risk factors for the development of heart failure in women,” she added. “I’m especially diligent in ensuring that women with one or both of these diseases get treated aggressively.”

Highlighting specifically the fundamental role that uncontrolled hypertension plays in causing heart failure, the University of Pennsylvania’s Dr. Jessup estimated that controlling hypertension throughout the U.S. population could probably cut heart failure incidence in half.

Others draw a sharper contrast between the risk factor stage and the symptomatic stages of heart failure, though they all agree on the importance of risk factor management by PCPs. “Hypertension does not mean that a patient has heart failure; it means they have a risk factor for heart failure and the patient is in the prevention stage,” said the NHLBI’s Dr. Shah. ”The most important role for PCPs is to identify the risk factors and prevent development of [symptomatic] heart failure. This is where PCPs are critically important because patients present to them at the early stages.”

Dr. Bauman, the PCP with INTEGRIS in Oklahoma City, generally doesn’t conflate risk factors with stage A heart failure. “I look at every patient with hypertension or diabetes as a person at risk for cardiovascular disease. I push them to get their blood pressure and glycemia under control. But I don’t think of them as stage A heart failure patients. I think of them as patients at risk for heart failure, but also at risk for atrial fibrillation, MI, and stroke. I think about their risk, but I don’t label them in my mind as having stage A heart failure. I think that this is a patient at risk for cardiovascular disease and that I must do what I should to manage their risk factors.”

“I don’t personally think about patients having stage A heart failure,” agreed Dr. Cunningham, a PCP at Brigham and Women’s Hospital. “When I see patients with hypertension, I counsel them about what matters to them so that they will take their medications, because if they currently feel fine they may not understand the long-term risk they face. So I invest time in making the patient understand why their hypertension is important and the risks it poses, so that in the long-run they won’t have a stroke or MI or develop heart failure. But I don’t think that the stage A definition has changed my approach; I already think of hypertension as a precursor to a variety of bad downstream consequences. I don’t think of someone as a heart failure patient just because they have hypertension, and I don’t think that every patient with hypertension will develop heart failure.” Speaking of her colleagues, Dr. Cunningham added, “I don’t have a sense that the stages of heart failure have made much of an impact on how other PCPs talk with patients or plan their care.”

“The heart failure staging system is useful from the standpoint of emphasizing that the disease begins with primordial risk and progresses through a period of structural injury during which patients may not be symptomatic,” summed up Dr. Desai. “But practically, most of us confront the diagnosis of heart failure when patients become symptomatic and reach stage C.”

Can an intensified approach better slow stage A progression?

One of the inherent limitations right now in referring to patients as having stage A heart failure is that it adds little to how heart failure risk factors are managed. A patient with hypertension undergoing appropriate care will receive treatment to lower blood pressure to recommended goal levels. The antihypertensive treatment remains the same regardless of whether the patient is considered to have only hypertension or whether the treating physician also thinks of the patient as having stage A heart failure. The same applies to patients diagnosed with diabetes; their hyperglycemia-controlling treatment remains unchanged whether or not their physician labels them as stage A heart failure patients.

But what if an evidence-based way existed to not only identify patients with hypertension or diabetes, but to identify within those patients the subset who faced a particularly increased risk for developing heart failure? And what if an evidence-based intervention existed that could be added to standard blood pressure–lowering or hyperglycemia-controlling interventions and had proved to slow or stop progression of patients to heart failure?

Preliminary evidence that screening for stage A heart failure patients can successfully identify a subset at elevated risk for developing symptomatic heart failure and that intensified risk-factor control helped mitigate this risk appeared in two reports published in 2013. But both studies were relatively small, they ran in Europe, and neither has undergone replication in a U.S. study in the 2.5 years since their publication.

The larger study, STOP-HF (St. Vincent’s Screening to Prevent Heart Failure), included patients at 39 primary care practices in Ireland, a study organized by researchers at St. Vincent’s University Hospital in Dublin. They enrolled people without symptoms of heart failure who were at least 41 years old and had at least one of these risk factors: hypertension, hypercholesterolemia, obesity, vascular disease, diabetes, an arrhythmia, or valvular disease: In short, primarily stage A heart failure patients.

The researchers then tested 1,374 of these people for their baseline blood level of BNP and randomized them into two intervention arms. For those randomized to the active arm, the PCPs for these people received an unblinded report of the BNP results, and those with a level of 50 pg/mL or higher underwent further assessment by screening echocardiography and intensified risk-factor control, including risk-factor coaching by a nurse. Those randomized to this arm who had a lower BNP level at baseline underwent annual follow-up BNP screening, and if their level reached the 50 pg/ML threshold they switched to the more intensified protocol. Those randomized to the control arm received a more standard program of risk-factor modification and their BNP levels were never unblinded.

After an average follow-up of 4.2 years, people in the active intervention arm of STOP-HF had a 5% cumulative incidence of left ventricular dysfunction or heart failure, while those in the control arm had a 9% rate, a 45% relative risk reduction from the active intervention that was statistically significant for the study’s primary endpoint (JAMA. 2013 July 3;310[1]:66-74).

The second study, PONTIAC (NT-proBNP Selected Prevention of Cardiac Events in a Population of Diabetic Patients Without a History of Cardiac Disease), ran in Austria and Germany and involved 300 patients who had type 2 diabetes and were free from cardiac disease at baseline. At baseline, all people considered for the study underwent a screening measure of their blood level of NT-proBNP (a physiologic precursor to BNP) and those with a level above 125 pg/mL were randomized to either a usual-care group or an arm that underwent more intensified up-titration treatment with a renin-angiotensin system antagonist drug and with a beta-blocker. The primary endpoint was the incidence of hospitalization or death due to cardiac disease after 2 years, which was a relative 65% lower in the intensified intervention group, a statistically significant difference (J Am Coll Cardiol. 2013 Oct 8;62[15]:1365-72).

Both studies focused on people with common risk factors seen in primary care practices and used BNP or a BNP-like blood marker to identify people with an elevated risk for developing heart failure or other cardiac disease, and both studies showed that application of a more aggressive risk-factor intervention program resulted in a significant reduction in heart failure or heart failure–related outcomes after 2-4 years. Both studies appeared to offer models for improving risk-factor management by PCPs for people with stage A heart failure, but at the end of 2015 neither model had undergone U.S. testing.

“The STOP-HF and PONTIAC studies were proofs of concept for using biomarkers to gain a better sense of cardiac health,” said Dr. Tariq Ahmad, a heart failure physician at Yale University in New Haven, Conn., who is interested in developing biomarkers for guiding heart failure management. “Metrics like blood pressure and heart rate are relatively crude measures of cardiac health. We need to see in a large trial if we can use these more objective measures of cardiac health to decide how to treat patients,” In addition to BNP and NT-proBNP, Dr. Ahmad cited ST2 and galectin-3 as other promising biomarkers in the blood that may better gauge a person’s risk for developing heart failure and the need for intensified risk-factor control. The current inability of PCPs to better risk stratify people who meet the stage A heart failure definition so that those at highest risk could undergo more intensified interventions constitutes a missed opportunity for heart failure prevention, he said.

“The STOP-HF trial is really important and desperately needs replication,” said Dr. Margaret M. Redfield, professor of medicine and a heart failure physician at Mayo Clinic in Rochester, Minn.

She, and her Mayo associates, including Dr. McKie, are planning to launch a research protocol this year to finally test a STOP-HF type of program in a U.S. setting. They are planning to measure NT-proBNP levels in patients with stage A heart failure and then randomize some to an intervention arm with intensified risk reduction treatments.

“The problem with stage A today is, if we apply it according to the ACC and AHA definition, it would include quite a large number of patients, and not all of them – in fact a minority – would go on to develop symptomatic heart failure,” said Dr. McKie. “How you can further risk stratify the stage A population with simple testing is an issue for ongoing research,” he said. “The STOP-HF and PONTIAC strategies need more testing. Both studies were done in Europe, and we haven’t studied this approach in the U.S. Their approach makes sense and is appealing but it needs more testing.”

The economic barrier to intensified stage-A management

Even if a U.S. based study could replicate the STOP-HF results and provide an evidence base for improved prevention of symptomatic heart failure by interventions instituted by PCPs, it’s not clear whether the U.S. health care system as it currently is structured provides a framework that is able to invest in intensified upfront management of risk factors to achieve a reduced incidence of symptomatic heart failure several years later.

“One of the interesting aspects of STOP-HF was its use of a nurse-based intervention. We don’t have the resources for that in our practices right now,” noted Dr. Cunningham, the PCP at Brigham and Women’s Hospital who is medical director of the hospital’s Integrated Care Management Program for medically complex patients. While that program uses nurse care coordinators to pull together the disparate elements of care for heart failure patients and others with more severe, chronic illnesses, the program currently serves only patients with advanced disease, not presymptomatic patients who face a potentially elevated risk for bad outcomes that would happen many years in the future.

“This speaks to the need for more population-based preventive management, which PCPs are trying to start to do, but currently we are nowhere near fulfilling that potential,” said Dr. Cunningham. The barrier is having clinical resources for help in managing lower-risk patients, to make sure they receive all the interventions they should. We’re now trying to start using care teams for patients with diabetes or other conditions. The biggest gap is that we don’t have the resources; we don’t have enough nurses on our staff to intervene” for all the patients who could potentially benefit. “Right now, we can only afford to use nurses for selected, high-risk patients.” The challenge is to have a care model that allows a lot of upfront costs to generate savings over a long-term time horizon, he said. “It’s very important for improving population health, but it’s hard to make it happen in our current health care system.”

Dr. Ahmad noted the enormous downside of a health system that is not proactive and often waits for heart failure patients to declare themselves with severe illness.

“The majority of heart failure patients I see drifted through the health care system” without recognition of their accumulating morbidity. “By the time they show heart failure symptoms, their disease is pretty advanced and we have real difficulty managing it. A lot of patients do not have their heart failure managed until they fall off the edge and their condition is much less modifiable. If we could identify these patients sooner, it would help both them and the health care system. It would be great to have objective measures that could help PCPs identify early abnormal patients who need more aggressive management. In much of U.S. practice, heart failure management is more specialty driven. It might be different in closed systems, but in many heart failure practices there is no PCP coordination. The health care system is not set up to allow PCPs to take care of these issues.”

Dr. Bauman said she sees some reason for optimism in looming reimbursement changes, where population management might help drive a shift toward more team care for heart failure and a focus on earlier identification of patients at risk and intervention at early stages of their disease.

“As we move toward population management it becomes more obvious that you need a team approach to managing heart failure, involving not just physicians but also pharmacists, nurses, social workers, and care coordinators. In my system, INTEGRIS, the whole-team management approach is beginning to happen. It’s new to primary care to apply a large team of clinicians; it takes a lot of resources. Being able to afford a team was a problem when we were paid by fee-for-service, it wasn’t practical. Population management will make it possible.”

Dr. Desai has been a consultant to Novartis, Merck, St. Jude, and Relypsa and has received research funding from Novartis and AtCor Medical. Dr. Redfield has been a consultant to Merck and Eli Lilly. Dr. Ahmad has been a consultant to Roche. Dr. Ong, Dr. Walsh, Dr. Jessup, Dr. McKie, Dr. Bauman, Dr. Shah, and Dr. Cunningham had no disclosures.

[email protected]

On Twitter @mitchelzoler

Heart failure management has become increasingly complex over the past couple of decades, with new drugs and drug combinations, new uses for potentially life-saving implanted devices, and a more sophisticated appreciation of the ways that various comorbidities complicate a heart failure patient’s clinical status. These expanded dimensions of heart failure care resulted in the establishment in 2008 of a new secondary subspecialty, Advanced Heart Failure and Transplant Cardiology, aimed at training and certifying physicians in all the nuances of complex heart failure diagnostics and care.

But as the 2009 manifesto announcing this new heart failure subspecialty detailed, care for the vast majority of U.S. patients with heart failure remains in the hands of internal medicine primary care physicians (PCPs) and general cardiologists (J Am Coll Cardiol. 2009 Mar 10;53[10]:834-6). To some extent this is a manpower issue. The estimated number of Americans living with heart failure exceeds 5 million, a figure that dwarfs the very modest number of U.S. physicians and clinicians who are certified or self-identified heart failure specialists.

As of today, fewer than 1,000 U.S. physicians have received formal certification as heart failure subspecialists through the examination administered in 2010, 2012, and 2014, said Michele Blair, chief executive officer of the Heart Failure Society of America. A more liberal definition of a heart failure specialist might include the roughly 3,000 unique physicians (mostly cardiologists, but also some hospitalists and emergency physicians) who have recently attended an annual meeting of the HFSA, as well as the roughly 2,300 physician assistants and nurse practitioners who have shown a heart failure interest by coming to a recent HFSA meeting. But even these expanded estimates calculate out to about 1 clinician with a special interest in heart failure for each 1,000 heart failure patients, not a very reassuring ratio.

The burgeoning numbers of heart failure patients, compared with the relative scarcity of both heart failure experts and general cardiologists, raises issues of how primary-care internists best share this management responsibility. Recent interviews with several heart failure subspecialists and primary care internists provide some insight into how this division of labor is now playing out in routine U.S. practice. What often occurs is that primary care internists take exclusive responsibility for caring for heart failure patients until they feel they are getting in over their heads, at which time they’ll consult with a cardiology colleague or refer the patient to a cardiologist. That moment of recognition by the generalist – that the demands and complexity of the case exceed their comfort level – varies widely, with some PCPs referring patients as soon as heart failure symptoms appear while others stay comfortable as the primary care giver even as a patient’s disease deteriorates to a more advanced stage.

Heart failure specialists highlighted their reliance on PCPs to take an ongoing, active role even for patients with significantly advanced heart failure, as generalists are well suited to coordinating the multispecialty care that such patients usually require, with attention to their need for lifestyle modifications as well as management of their diabetes, sleep apnea, chronic obstructive pulmonary disease, renal failure, and other comorbidities.

Mitchel L. Zoler/Frontline Medical News

As Dr. Michael K. Ong, a primary care internist at the University of California, Los Angeles, said in an interview, his heart failure specialist colleague manages patients’ heart failure; “I manage [or refer] everything else not directly related to the heart failure.”

The most successful U.S. care models seem to be some variation on a team-care approach, in which physicians collaborate with pharmacists, nurses, rehabilitation specialists, and social workers as well as specialists, a team that would include and perhaps be led by either a primary care internist, a cardiologist, or a heart failure specialist but would also broadly include physicians able to deal with all the morbidity facets of heart failure. It’s a model that remains unavailable in many U.S. settings or is just starting to emerge, as fee-for-service coverage of patients gets replaced by population-management models that better accommodate the upfront financial demands of coordinated team care. It makes financial sense a few years down the road when improved patient outcomes result in cost savings.

Primary care and patients with symptomatic heart failure

The heart failure definitions and staging system established in 2001 by a guidelines panel of the American College of Cardiology and American Heart Association defined stage A heart failure as starting before a patient exhibits any heart failure symptoms (the classic ones include dyspnea, rales, and peripheral edema). The panel designated symptomatic heart failure patients as stage C. Patients without heart failure symptoms but with one or more risk factors (such as hypertension, diabetes, obesity, and cardiovascular disease) plus structural heart disease (such as cardiomyopathy or other forms of heart remodeling) were designated stage B. The panel said that people at stage A had one or more risk factors but no structural heart changes and no heart failure symptoms.

Although stage-A heart failure patients are clearly the types of people most often seen and cared for by PCPs, many of these physicians, as well as many heart failure specialists, don’t consider patients who have only hypertension or only diabetes or only obesity as yet having heart failure. That paradox deserves more discussion, but the best way to begin talking about PCPs and heart failure patients is when patients are symptomatic and have what everyone would agree is heart failure.

Even though the ACC/AHA staging system places stage C patients well down the heart failure road, stage C is usually when patients are first diagnosed with heart failure. Although the diagnosis is often first made by a hospitalist or emergency-department physician when severe and sudden-onset heart failure symptoms drive the patient to a hospital, or the diagnosis originates with a cardiologist or heart failure specialist when the patient’s presentation and differential diagnosis isn’t straightforward, most commonly the diagnosis starts with a PCP in an office encounter with a patient who is symptomatic but not acutely ill.

“Patients with shortness of breath or other forms of effort intolerance most often seek care from PCPs. The differential diagnosis of dyspnea is long and complex. Recognition that a patient with dyspnea may have HF is crucial” for timely management and treatment, said Dr. Mary Norine Walsh, medical director of Heart Failure and Cardiac Transplantation at St. Vincent Heart Center in Indianapolis.

At the Mayo Clinic in Rochester, Minn., “most of the heart failure diagnoses are done by PCPs, usually first identified at stage C when a patient comes in with symptoms. Stage B heart failure is usually only identified as an incidental finding when echocardiography is done for some other reason,” said Dr. Paul M. McKie, a heart failure cardiologist who works closely with the primary-care staff at Mayo as an embedded consultant cardiologist.

Mitchel L. Zoler/Frontline Medical News

According to Dr. Mariell L. Jessup, a heart failure physician and professor at the University of Pennsylvania in Philadelphia, a key to PCPs promptly identifying patients with recent-onset, stage C heart failure is to keep the disease as well as its prominent risk factors at the top of their differential-diagnosis list for at-risk patients. “Heart failure is a common disorder,” Dr. Jessup said, and must be considered for patients with shortness of breath. “The leading causes of heart failure are hypertension, obesity, and diabetes. So keep heart failure in mind, especially for patients with one or more of these risk factors.”

Although PCPs might order an echocardiography examination or a lab test like measurement of brain natriuretic protein (BNP) to help nail down the diagnosis, they often leave reading the echocardiography results to a cardiologist colleague. “When a PCP orders an echo it’s automatically read by a cardiologist, and then we get the cardiologist’s report. I don’t read echos myself,” said Dr. Rebecca J. Cunningham, an internal medicine PCP at Brigham and Women’s Hospital in Boston who frequently sees patients with heart failure as medical director of the hospital’s Integrated Care Management Program. “I had one PCP colleague who undertook additional training to learn to read echos himself, but that’s unusual.”

Dr. Mary Ann Bauman, an internal medicine PCP and medical director for Women’s Health and Community Relations at INTEGRIS Health in Oklahoma City, noted a similar division of labor. “If a patient has shortness of breath, maybe some edema, and I hear a few rales, but is totally functional, I always order an echo but I don’t read it. I refer the echo to a cardiologist who then sends me a report,” Dr. Bauman said in an interview. “If I think the patient may have heart failure I’ll also order a BNP or NT-proBNP test. If I suspect heart failure and the BNP is high, it’s a red flag. BNP is another tool for getting the diagnosis right.”

The next step seems much more variable. Some PCPs retain primary control of heart failure management for many of their patients, especially when stage C patients remain stable and functional on simple, straightforward treatment and particularly when they have heart failure with preserved ejection fraction (HFpEF), usually defined as a left ventricular ejection fraction that is at least 40%-45%. Consultation or referral to a cardiologist or heart-failure physician seems much more common for patients with frequent decompensations and hospitalizations or patients with heart failure with reduced ejection fraction (HFrEF). But the main thread reported by both PCPs and cardiologists is that it all depends and varies for each patient and for each PCP depending on what patient responsibilities a PCP feels comfortable taking on.

Dr. Bauman sits at one end of the spectrum: “If it looks like a patient has heart failure, I refer them right away; I don’t wait for decompensation to occur. I want to be sure that there are no nuances in the patient that need something before I recognize it. Most of my PCP partners do the same. You don’t know what it is you don’t know. For me, it’s better to refer the patient right away so the patient has a cardiologist who already knows them who can be called if they start to decompensate.”

Dr. Bauman cited the increasing complexity of heart failure management as the main driver of her current approach, which she contrasted to how she dealt with heart failure patients 20 years ago. “It’s become so complicated that, as a PCP, I don’t feel that I can keep up” with the optimal ways to manage every heart failure patient. “I might not give my heart failure patients the best care they could receive.” The aspects of care that Dr. Bauman said she can provide to heart failure patients she has referred include “dealing with lifestyle changes, making sure patients are taking their medications and getting to their appointments, adjusting their heart-failure medication dosages as needed once they start on the drugs, and seeing that their diabetes and hypertension are well controlled. That is the role of the PCP. But when it comes to deciding which HF medications to use, that’s when I like to have a cardiologist involved.”

But the PCPs at Mayo Clinic often take a different tack, said Dr. McKie. “If the patient is a simple case of heart failure with no red flags and the patient is doing relatively well on treatment with simple diuretic treatment, then initiation of heart failure medications and ongoing management is often directed by the PCP with some cardiology backup as needed,” he said. But Dr. McKie conceded that a spectrum of PCP approaches exists at Mayo as well. “A lot depends on the patient and on the specific provider. Some patients we never get calls about; their PCPs are excellent at managing diuretics and uptitrating beta-blockers and ACE inhibitors. We may only get called if the patient decompensates, But other PCPs are very uncomfortable and they request that we get involved as soon as the diagnosis of stage C heart failure is made. So there is a wide range.” Dr. McKie noted that he thinks it is appropriate for himself or one of his cardiology colleagues to get more active when the HFrEF patient’s ejection fraction drops below 40% and certainly below 35%. That’s because at this stage, patients also need treatment with an aldosterone receptor antagonist such as spironolactone, and they undergo consideration for receiving an implantable cardioverter defibrillator or a cardiac resynchronization therapy device.

Mitchel L. Zoler/Frontline Medical News

“There is nothing magic about heart failure management; it is very well proscribed by guidelines. Nothing precludes a PCP from taking ownership” of heart failure patients, said Dr. Akshay S. Desai, a heart failure cardiologist at Brigham and Women’s Hospital. “I think there is some fear among PCPs that they intrude” by managing heart failure patients. But for patients with structural heart disease or even left ventricular dysfunction, “PCPs should feel empowered to start standard heart failure treatments, including ACE inhibitors and beta-blockers, especially because half of heart failure patients have HFpEF, and PCPs often don’t refer HFpEF patients to cardiologists. It’s the patients with left ventricular dysfunction who end up in heart failure clinics,” Dr. Desai said.

On the other hand, Dr. Desai cautioned PCPs against waiting too long to bring more complex, sicker, and harder-to-manage patients to the attention of a heart failure specialist.

“What we worry about are late referrals, when patients are profoundly decompensated,” he said. “By the time they show up [at a heart failure clinic or emergency department] they have end-organ dysfunction,” which makes them much harder to treat and maybe irreversible. “Recognizing heart failure early is the key, and early referral is an obligation” when a heart failure patient is deteriorating or becomes too complex for a PCP to properly manage, Dr. Desai advised.

But even when heart failure patients develop more severe disease, with significantly depressed left ventricular function or frequent decompensations, PCPs continue to play a valuable role in coordinating the wide range of treatments patients need for their various comorbidities.

“Once a cardiologist or heart failure physician is involved there is still a role for PCPs” said Dr. Monica R. Shah, deputy chief of the Heart Failure and Arrhythmia Branch of the National Heart, Lung, and Blood Institute in Bethesda, Md. “Heart failure patients are complex, it’s not just one organ system that’s affected, and you need a partnership between cardiologists and PCPs to coordinate all of a patient’s care. A heart failure physician needs to work with a PCP to be sure that the patient’s health is optimal. Collaboration between cardiologists and PCPs is key to ensure that optimal care is effectively delivered to patients,” Dr. Shah said in an interview.

“Keeping the PCP at the center of the care team is critical, especially with the multiple comorbidities that HF patients can have, including chronic obstructive pulmonary disease, diabetes, renal failure, sleep apnea, atrial fibrillation, and degenerative joint disease. Before you know it you have a half-dozen subspecialists involved in care and it can become uncoordinated. Keeping the PCP at the center of the team and providing the PCP with support from specialists as needed is critical,” said Dr. McKie.

Even for the most severe heart failure patients, PCPs can still play an important role by providing palliative care and dealing with end-of-life issues, specialists said.

Primary care and heart failure’s antecedents

The other, obvious time in heart failure’s severity spectrum for PCPs to take a very active role is with presymptomatic, stage A patients. Perhaps the only controversial element of this is whether such patients really have a form of heart failure and whether is it important to conceptualize heart failure this way.

The notion of stage A heart failure dates back to the 2001 edition of heart failure diagnosis and management recommendations issued by a panel organized by the ACC and AHA (J Am Coll Cardiol. 2001 Dec;38[7]:2101-13). The 2001 writing committee members said that they “decided to take a new approach to the classification of heart failure that emphasized both the evolution and progression of the disease.” They defined stage A patients as presymptomatic and without structural heart disease but with “conditions strongly associated with the development of heart failure,” specifically systemic hypertension, coronary artery disease, diabetes, a history of cardiotoxic drug therapy or alcohol abuse, a history of rheumatic fever, or a family history of cardiomyopathy.

When the ACC and AHA panel members next updated the heart failure recommendations in 2005, they seemed to take a rhetorical step back, saying that stage A and B “are clearly not heart failure but are an attempt to help healthcare providers identify patients early who are at risk for developing heart failure. Stage A and B patients are best defined as those with risk factors that clearly predispose toward the development of HF.” (J Am Coll Cardiol. 2005 Sept. 46[6]:1116-43) In 2005, the panel also streamlined the list of risk factors that identify stage A heart failure patients: hypertension, atherosclerotic disease, diabetes, obesity, metabolic syndrome, patients who have taken cardiotoxins, or patients with a family history of cardiomyopathy. The 2009 recommendation update left this definition of stage A heart failure unchanged, but in 2013 the most recent update devoted less attention to explaining the significance of the stage-A heart failure, although it clearly highlighted the importance of controlling hypertension, diabetes, and obesity as ways to prevent patients from developing symptomatic heart failure (J Am Coll Cardiol. 2013 Oct 15;62[16]:e147-e239).

The subtle, official tweaking of the stage A (and B) heart failure concept during 2001-2013, as well establishment of stage A in the first place, seems to have left both PCPs and heart failure specialists unsure on exactly how to think about presymptomatic people with one or more of the prominent heart failure risk factors of hypertension, diabetes, and obesity. While they uniformly agree that identifying these risk factors and then treating them according to contemporary guidelines is hugely important for stopping or deferring the onset of heart failure, and they also agree that this aspect of patient care is clearly a core responsibility for PCPs, many also say that they don’t think of presymptomatic patients as having heart failure of any type despite the stage A designation on the books.

One exception is St. Vincent’s Dr. Walsh. “I think the writers of the 2001 heart failure guidelines had an inspired approach. Identifying patients with hypertension, diabetes, coronary artery disease, etc., as patients with heart failure has helped drive home the point that treatment and control of these diseases is crucial,” she said in an interview. “But I am not sure all physicians have adopted the concept. “Uncontrolled hypertension is prevalent, and not viewed by all as resulting in heart failure down the road. Diabetes and hypertension are very important risk factors for the development of heart failure in women,” she added. “I’m especially diligent in ensuring that women with one or both of these diseases get treated aggressively.”

Highlighting specifically the fundamental role that uncontrolled hypertension plays in causing heart failure, the University of Pennsylvania’s Dr. Jessup estimated that controlling hypertension throughout the U.S. population could probably cut heart failure incidence in half.

Others draw a sharper contrast between the risk factor stage and the symptomatic stages of heart failure, though they all agree on the importance of risk factor management by PCPs. “Hypertension does not mean that a patient has heart failure; it means they have a risk factor for heart failure and the patient is in the prevention stage,” said the NHLBI’s Dr. Shah. ”The most important role for PCPs is to identify the risk factors and prevent development of [symptomatic] heart failure. This is where PCPs are critically important because patients present to them at the early stages.”

Dr. Bauman, the PCP with INTEGRIS in Oklahoma City, generally doesn’t conflate risk factors with stage A heart failure. “I look at every patient with hypertension or diabetes as a person at risk for cardiovascular disease. I push them to get their blood pressure and glycemia under control. But I don’t think of them as stage A heart failure patients. I think of them as patients at risk for heart failure, but also at risk for atrial fibrillation, MI, and stroke. I think about their risk, but I don’t label them in my mind as having stage A heart failure. I think that this is a patient at risk for cardiovascular disease and that I must do what I should to manage their risk factors.”

“I don’t personally think about patients having stage A heart failure,” agreed Dr. Cunningham, a PCP at Brigham and Women’s Hospital. “When I see patients with hypertension, I counsel them about what matters to them so that they will take their medications, because if they currently feel fine they may not understand the long-term risk they face. So I invest time in making the patient understand why their hypertension is important and the risks it poses, so that in the long-run they won’t have a stroke or MI or develop heart failure. But I don’t think that the stage A definition has changed my approach; I already think of hypertension as a precursor to a variety of bad downstream consequences. I don’t think of someone as a heart failure patient just because they have hypertension, and I don’t think that every patient with hypertension will develop heart failure.” Speaking of her colleagues, Dr. Cunningham added, “I don’t have a sense that the stages of heart failure have made much of an impact on how other PCPs talk with patients or plan their care.”

“The heart failure staging system is useful from the standpoint of emphasizing that the disease begins with primordial risk and progresses through a period of structural injury during which patients may not be symptomatic,” summed up Dr. Desai. “But practically, most of us confront the diagnosis of heart failure when patients become symptomatic and reach stage C.”

Can an intensified approach better slow stage A progression?

One of the inherent limitations right now in referring to patients as having stage A heart failure is that it adds little to how heart failure risk factors are managed. A patient with hypertension undergoing appropriate care will receive treatment to lower blood pressure to recommended goal levels. The antihypertensive treatment remains the same regardless of whether the patient is considered to have only hypertension or whether the treating physician also thinks of the patient as having stage A heart failure. The same applies to patients diagnosed with diabetes; their hyperglycemia-controlling treatment remains unchanged whether or not their physician labels them as stage A heart failure patients.

But what if an evidence-based way existed to not only identify patients with hypertension or diabetes, but to identify within those patients the subset who faced a particularly increased risk for developing heart failure? And what if an evidence-based intervention existed that could be added to standard blood pressure–lowering or hyperglycemia-controlling interventions and had proved to slow or stop progression of patients to heart failure?

Preliminary evidence that screening for stage A heart failure patients can successfully identify a subset at elevated risk for developing symptomatic heart failure and that intensified risk-factor control helped mitigate this risk appeared in two reports published in 2013. But both studies were relatively small, they ran in Europe, and neither has undergone replication in a U.S. study in the 2.5 years since their publication.

The larger study, STOP-HF (St. Vincent’s Screening to Prevent Heart Failure), included patients at 39 primary care practices in Ireland, a study organized by researchers at St. Vincent’s University Hospital in Dublin. They enrolled people without symptoms of heart failure who were at least 41 years old and had at least one of these risk factors: hypertension, hypercholesterolemia, obesity, vascular disease, diabetes, an arrhythmia, or valvular disease: In short, primarily stage A heart failure patients.

The researchers then tested 1,374 of these people for their baseline blood level of BNP and randomized them into two intervention arms. For those randomized to the active arm, the PCPs for these people received an unblinded report of the BNP results, and those with a level of 50 pg/mL or higher underwent further assessment by screening echocardiography and intensified risk-factor control, including risk-factor coaching by a nurse. Those randomized to this arm who had a lower BNP level at baseline underwent annual follow-up BNP screening, and if their level reached the 50 pg/ML threshold they switched to the more intensified protocol. Those randomized to the control arm received a more standard program of risk-factor modification and their BNP levels were never unblinded.

After an average follow-up of 4.2 years, people in the active intervention arm of STOP-HF had a 5% cumulative incidence of left ventricular dysfunction or heart failure, while those in the control arm had a 9% rate, a 45% relative risk reduction from the active intervention that was statistically significant for the study’s primary endpoint (JAMA. 2013 July 3;310[1]:66-74).

The second study, PONTIAC (NT-proBNP Selected Prevention of Cardiac Events in a Population of Diabetic Patients Without a History of Cardiac Disease), ran in Austria and Germany and involved 300 patients who had type 2 diabetes and were free from cardiac disease at baseline. At baseline, all people considered for the study underwent a screening measure of their blood level of NT-proBNP (a physiologic precursor to BNP) and those with a level above 125 pg/mL were randomized to either a usual-care group or an arm that underwent more intensified up-titration treatment with a renin-angiotensin system antagonist drug and with a beta-blocker. The primary endpoint was the incidence of hospitalization or death due to cardiac disease after 2 years, which was a relative 65% lower in the intensified intervention group, a statistically significant difference (J Am Coll Cardiol. 2013 Oct 8;62[15]:1365-72).

Both studies focused on people with common risk factors seen in primary care practices and used BNP or a BNP-like blood marker to identify people with an elevated risk for developing heart failure or other cardiac disease, and both studies showed that application of a more aggressive risk-factor intervention program resulted in a significant reduction in heart failure or heart failure–related outcomes after 2-4 years. Both studies appeared to offer models for improving risk-factor management by PCPs for people with stage A heart failure, but at the end of 2015 neither model had undergone U.S. testing.

“The STOP-HF and PONTIAC studies were proofs of concept for using biomarkers to gain a better sense of cardiac health,” said Dr. Tariq Ahmad, a heart failure physician at Yale University in New Haven, Conn., who is interested in developing biomarkers for guiding heart failure management. “Metrics like blood pressure and heart rate are relatively crude measures of cardiac health. We need to see in a large trial if we can use these more objective measures of cardiac health to decide how to treat patients,” In addition to BNP and NT-proBNP, Dr. Ahmad cited ST2 and galectin-3 as other promising biomarkers in the blood that may better gauge a person’s risk for developing heart failure and the need for intensified risk-factor control. The current inability of PCPs to better risk stratify people who meet the stage A heart failure definition so that those at highest risk could undergo more intensified interventions constitutes a missed opportunity for heart failure prevention, he said.

“The STOP-HF trial is really important and desperately needs replication,” said Dr. Margaret M. Redfield, professor of medicine and a heart failure physician at Mayo Clinic in Rochester, Minn.

She, and her Mayo associates, including Dr. McKie, are planning to launch a research protocol this year to finally test a STOP-HF type of program in a U.S. setting. They are planning to measure NT-proBNP levels in patients with stage A heart failure and then randomize some to an intervention arm with intensified risk reduction treatments.

“The problem with stage A today is, if we apply it according to the ACC and AHA definition, it would include quite a large number of patients, and not all of them – in fact a minority – would go on to develop symptomatic heart failure,” said Dr. McKie. “How you can further risk stratify the stage A population with simple testing is an issue for ongoing research,” he said. “The STOP-HF and PONTIAC strategies need more testing. Both studies were done in Europe, and we haven’t studied this approach in the U.S. Their approach makes sense and is appealing but it needs more testing.”

The economic barrier to intensified stage-A management

Even if a U.S. based study could replicate the STOP-HF results and provide an evidence base for improved prevention of symptomatic heart failure by interventions instituted by PCPs, it’s not clear whether the U.S. health care system as it currently is structured provides a framework that is able to invest in intensified upfront management of risk factors to achieve a reduced incidence of symptomatic heart failure several years later.

“One of the interesting aspects of STOP-HF was its use of a nurse-based intervention. We don’t have the resources for that in our practices right now,” noted Dr. Cunningham, the PCP at Brigham and Women’s Hospital who is medical director of the hospital’s Integrated Care Management Program for medically complex patients. While that program uses nurse care coordinators to pull together the disparate elements of care for heart failure patients and others with more severe, chronic illnesses, the program currently serves only patients with advanced disease, not presymptomatic patients who face a potentially elevated risk for bad outcomes that would happen many years in the future.

“This speaks to the need for more population-based preventive management, which PCPs are trying to start to do, but currently we are nowhere near fulfilling that potential,” said Dr. Cunningham. The barrier is having clinical resources for help in managing lower-risk patients, to make sure they receive all the interventions they should. We’re now trying to start using care teams for patients with diabetes or other conditions. The biggest gap is that we don’t have the resources; we don’t have enough nurses on our staff to intervene” for all the patients who could potentially benefit. “Right now, we can only afford to use nurses for selected, high-risk patients.” The challenge is to have a care model that allows a lot of upfront costs to generate savings over a long-term time horizon, he said. “It’s very important for improving population health, but it’s hard to make it happen in our current health care system.”

Dr. Ahmad noted the enormous downside of a health system that is not proactive and often waits for heart failure patients to declare themselves with severe illness.

“The majority of heart failure patients I see drifted through the health care system” without recognition of their accumulating morbidity. “By the time they show heart failure symptoms, their disease is pretty advanced and we have real difficulty managing it. A lot of patients do not have their heart failure managed until they fall off the edge and their condition is much less modifiable. If we could identify these patients sooner, it would help both them and the health care system. It would be great to have objective measures that could help PCPs identify early abnormal patients who need more aggressive management. In much of U.S. practice, heart failure management is more specialty driven. It might be different in closed systems, but in many heart failure practices there is no PCP coordination. The health care system is not set up to allow PCPs to take care of these issues.”

Dr. Bauman said she sees some reason for optimism in looming reimbursement changes, where population management might help drive a shift toward more team care for heart failure and a focus on earlier identification of patients at risk and intervention at early stages of their disease.

“As we move toward population management it becomes more obvious that you need a team approach to managing heart failure, involving not just physicians but also pharmacists, nurses, social workers, and care coordinators. In my system, INTEGRIS, the whole-team management approach is beginning to happen. It’s new to primary care to apply a large team of clinicians; it takes a lot of resources. Being able to afford a team was a problem when we were paid by fee-for-service, it wasn’t practical. Population management will make it possible.”

Dr. Desai has been a consultant to Novartis, Merck, St. Jude, and Relypsa and has received research funding from Novartis and AtCor Medical. Dr. Redfield has been a consultant to Merck and Eli Lilly. Dr. Ahmad has been a consultant to Roche. Dr. Ong, Dr. Walsh, Dr. Jessup, Dr. McKie, Dr. Bauman, Dr. Shah, and Dr. Cunningham had no disclosures.

[email protected]

On Twitter @mitchelzoler

Heart failure management has become increasingly complex over the past couple of decades, with new drugs and drug combinations, new uses for potentially life-saving implanted devices, and a more sophisticated appreciation of the ways that various comorbidities complicate a heart failure patient’s clinical status. These expanded dimensions of heart failure care resulted in the establishment in 2008 of a new secondary subspecialty, Advanced Heart Failure and Transplant Cardiology, aimed at training and certifying physicians in all the nuances of complex heart failure diagnostics and care.

But as the 2009 manifesto announcing this new heart failure subspecialty detailed, care for the vast majority of U.S. patients with heart failure remains in the hands of internal medicine primary care physicians (PCPs) and general cardiologists (J Am Coll Cardiol. 2009 Mar 10;53[10]:834-6). To some extent this is a manpower issue. The estimated number of Americans living with heart failure exceeds 5 million, a figure that dwarfs the very modest number of U.S. physicians and clinicians who are certified or self-identified heart failure specialists.

As of today, fewer than 1,000 U.S. physicians have received formal certification as heart failure subspecialists through the examination administered in 2010, 2012, and 2014, said Michele Blair, chief executive officer of the Heart Failure Society of America. A more liberal definition of a heart failure specialist might include the roughly 3,000 unique physicians (mostly cardiologists, but also some hospitalists and emergency physicians) who have recently attended an annual meeting of the HFSA, as well as the roughly 2,300 physician assistants and nurse practitioners who have shown a heart failure interest by coming to a recent HFSA meeting. But even these expanded estimates calculate out to about 1 clinician with a special interest in heart failure for each 1,000 heart failure patients, not a very reassuring ratio.

The burgeoning numbers of heart failure patients, compared with the relative scarcity of both heart failure experts and general cardiologists, raises issues of how primary-care internists best share this management responsibility. Recent interviews with several heart failure subspecialists and primary care internists provide some insight into how this division of labor is now playing out in routine U.S. practice. What often occurs is that primary care internists take exclusive responsibility for caring for heart failure patients until they feel they are getting in over their heads, at which time they’ll consult with a cardiology colleague or refer the patient to a cardiologist. That moment of recognition by the generalist – that the demands and complexity of the case exceed their comfort level – varies widely, with some PCPs referring patients as soon as heart failure symptoms appear while others stay comfortable as the primary care giver even as a patient’s disease deteriorates to a more advanced stage.

Heart failure specialists highlighted their reliance on PCPs to take an ongoing, active role even for patients with significantly advanced heart failure, as generalists are well suited to coordinating the multispecialty care that such patients usually require, with attention to their need for lifestyle modifications as well as management of their diabetes, sleep apnea, chronic obstructive pulmonary disease, renal failure, and other comorbidities.

Mitchel L. Zoler/Frontline Medical News

As Dr. Michael K. Ong, a primary care internist at the University of California, Los Angeles, said in an interview, his heart failure specialist colleague manages patients’ heart failure; “I manage [or refer] everything else not directly related to the heart failure.”

The most successful U.S. care models seem to be some variation on a team-care approach, in which physicians collaborate with pharmacists, nurses, rehabilitation specialists, and social workers as well as specialists, a team that would include and perhaps be led by either a primary care internist, a cardiologist, or a heart failure specialist but would also broadly include physicians able to deal with all the morbidity facets of heart failure. It’s a model that remains unavailable in many U.S. settings or is just starting to emerge, as fee-for-service coverage of patients gets replaced by population-management models that better accommodate the upfront financial demands of coordinated team care. It makes financial sense a few years down the road when improved patient outcomes result in cost savings.

Primary care and patients with symptomatic heart failure

The heart failure definitions and staging system established in 2001 by a guidelines panel of the American College of Cardiology and American Heart Association defined stage A heart failure as starting before a patient exhibits any heart failure symptoms (the classic ones include dyspnea, rales, and peripheral edema). The panel designated symptomatic heart failure patients as stage C. Patients without heart failure symptoms but with one or more risk factors (such as hypertension, diabetes, obesity, and cardiovascular disease) plus structural heart disease (such as cardiomyopathy or other forms of heart remodeling) were designated stage B. The panel said that people at stage A had one or more risk factors but no structural heart changes and no heart failure symptoms.

Although stage-A heart failure patients are clearly the types of people most often seen and cared for by PCPs, many of these physicians, as well as many heart failure specialists, don’t consider patients who have only hypertension or only diabetes or only obesity as yet having heart failure. That paradox deserves more discussion, but the best way to begin talking about PCPs and heart failure patients is when patients are symptomatic and have what everyone would agree is heart failure.

Even though the ACC/AHA staging system places stage C patients well down the heart failure road, stage C is usually when patients are first diagnosed with heart failure. Although the diagnosis is often first made by a hospitalist or emergency-department physician when severe and sudden-onset heart failure symptoms drive the patient to a hospital, or the diagnosis originates with a cardiologist or heart failure specialist when the patient’s presentation and differential diagnosis isn’t straightforward, most commonly the diagnosis starts with a PCP in an office encounter with a patient who is symptomatic but not acutely ill.

“Patients with shortness of breath or other forms of effort intolerance most often seek care from PCPs. The differential diagnosis of dyspnea is long and complex. Recognition that a patient with dyspnea may have HF is crucial” for timely management and treatment, said Dr. Mary Norine Walsh, medical director of Heart Failure and Cardiac Transplantation at St. Vincent Heart Center in Indianapolis.

At the Mayo Clinic in Rochester, Minn., “most of the heart failure diagnoses are done by PCPs, usually first identified at stage C when a patient comes in with symptoms. Stage B heart failure is usually only identified as an incidental finding when echocardiography is done for some other reason,” said Dr. Paul M. McKie, a heart failure cardiologist who works closely with the primary-care staff at Mayo as an embedded consultant cardiologist.

Mitchel L. Zoler/Frontline Medical News

According to Dr. Mariell L. Jessup, a heart failure physician and professor at the University of Pennsylvania in Philadelphia, a key to PCPs promptly identifying patients with recent-onset, stage C heart failure is to keep the disease as well as its prominent risk factors at the top of their differential-diagnosis list for at-risk patients. “Heart failure is a common disorder,” Dr. Jessup said, and must be considered for patients with shortness of breath. “The leading causes of heart failure are hypertension, obesity, and diabetes. So keep heart failure in mind, especially for patients with one or more of these risk factors.”

Although PCPs might order an echocardiography examination or a lab test like measurement of brain natriuretic protein (BNP) to help nail down the diagnosis, they often leave reading the echocardiography results to a cardiologist colleague. “When a PCP orders an echo it’s automatically read by a cardiologist, and then we get the cardiologist’s report. I don’t read echos myself,” said Dr. Rebecca J. Cunningham, an internal medicine PCP at Brigham and Women’s Hospital in Boston who frequently sees patients with heart failure as medical director of the hospital’s Integrated Care Management Program. “I had one PCP colleague who undertook additional training to learn to read echos himself, but that’s unusual.”

Dr. Mary Ann Bauman, an internal medicine PCP and medical director for Women’s Health and Community Relations at INTEGRIS Health in Oklahoma City, noted a similar division of labor. “If a patient has shortness of breath, maybe some edema, and I hear a few rales, but is totally functional, I always order an echo but I don’t read it. I refer the echo to a cardiologist who then sends me a report,” Dr. Bauman said in an interview. “If I think the patient may have heart failure I’ll also order a BNP or NT-proBNP test. If I suspect heart failure and the BNP is high, it’s a red flag. BNP is another tool for getting the diagnosis right.”

The next step seems much more variable. Some PCPs retain primary control of heart failure management for many of their patients, especially when stage C patients remain stable and functional on simple, straightforward treatment and particularly when they have heart failure with preserved ejection fraction (HFpEF), usually defined as a left ventricular ejection fraction that is at least 40%-45%. Consultation or referral to a cardiologist or heart-failure physician seems much more common for patients with frequent decompensations and hospitalizations or patients with heart failure with reduced ejection fraction (HFrEF). But the main thread reported by both PCPs and cardiologists is that it all depends and varies for each patient and for each PCP depending on what patient responsibilities a PCP feels comfortable taking on.

Dr. Bauman sits at one end of the spectrum: “If it looks like a patient has heart failure, I refer them right away; I don’t wait for decompensation to occur. I want to be sure that there are no nuances in the patient that need something before I recognize it. Most of my PCP partners do the same. You don’t know what it is you don’t know. For me, it’s better to refer the patient right away so the patient has a cardiologist who already knows them who can be called if they start to decompensate.”

Dr. Bauman cited the increasing complexity of heart failure management as the main driver of her current approach, which she contrasted to how she dealt with heart failure patients 20 years ago. “It’s become so complicated that, as a PCP, I don’t feel that I can keep up” with the optimal ways to manage every heart failure patient. “I might not give my heart failure patients the best care they could receive.” The aspects of care that Dr. Bauman said she can provide to heart failure patients she has referred include “dealing with lifestyle changes, making sure patients are taking their medications and getting to their appointments, adjusting their heart-failure medication dosages as needed once they start on the drugs, and seeing that their diabetes and hypertension are well controlled. That is the role of the PCP. But when it comes to deciding which HF medications to use, that’s when I like to have a cardiologist involved.”

But the PCPs at Mayo Clinic often take a different tack, said Dr. McKie. “If the patient is a simple case of heart failure with no red flags and the patient is doing relatively well on treatment with simple diuretic treatment, then initiation of heart failure medications and ongoing management is often directed by the PCP with some cardiology backup as needed,” he said. But Dr. McKie conceded that a spectrum of PCP approaches exists at Mayo as well. “A lot depends on the patient and on the specific provider. Some patients we never get calls about; their PCPs are excellent at managing diuretics and uptitrating beta-blockers and ACE inhibitors. We may only get called if the patient decompensates, But other PCPs are very uncomfortable and they request that we get involved as soon as the diagnosis of stage C heart failure is made. So there is a wide range.” Dr. McKie noted that he thinks it is appropriate for himself or one of his cardiology colleagues to get more active when the HFrEF patient’s ejection fraction drops below 40% and certainly below 35%. That’s because at this stage, patients also need treatment with an aldosterone receptor antagonist such as spironolactone, and they undergo consideration for receiving an implantable cardioverter defibrillator or a cardiac resynchronization therapy device.

Mitchel L. Zoler/Frontline Medical News

“There is nothing magic about heart failure management; it is very well proscribed by guidelines. Nothing precludes a PCP from taking ownership” of heart failure patients, said Dr. Akshay S. Desai, a heart failure cardiologist at Brigham and Women’s Hospital. “I think there is some fear among PCPs that they intrude” by managing heart failure patients. But for patients with structural heart disease or even left ventricular dysfunction, “PCPs should feel empowered to start standard heart failure treatments, including ACE inhibitors and beta-blockers, especially because half of heart failure patients have HFpEF, and PCPs often don’t refer HFpEF patients to cardiologists. It’s the patients with left ventricular dysfunction who end up in heart failure clinics,” Dr. Desai said.

On the other hand, Dr. Desai cautioned PCPs against waiting too long to bring more complex, sicker, and harder-to-manage patients to the attention of a heart failure specialist.

“What we worry about are late referrals, when patients are profoundly decompensated,” he said. “By the time they show up [at a heart failure clinic or emergency department] they have end-organ dysfunction,” which makes them much harder to treat and maybe irreversible. “Recognizing heart failure early is the key, and early referral is an obligation” when a heart failure patient is deteriorating or becomes too complex for a PCP to properly manage, Dr. Desai advised.

But even when heart failure patients develop more severe disease, with significantly depressed left ventricular function or frequent decompensations, PCPs continue to play a valuable role in coordinating the wide range of treatments patients need for their various comorbidities.

“Once a cardiologist or heart failure physician is involved there is still a role for PCPs” said Dr. Monica R. Shah, deputy chief of the Heart Failure and Arrhythmia Branch of the National Heart, Lung, and Blood Institute in Bethesda, Md. “Heart failure patients are complex, it’s not just one organ system that’s affected, and you need a partnership between cardiologists and PCPs to coordinate all of a patient’s care. A heart failure physician needs to work with a PCP to be sure that the patient’s health is optimal. Collaboration between cardiologists and PCPs is key to ensure that optimal care is effectively delivered to patients,” Dr. Shah said in an interview.

“Keeping the PCP at the center of the care team is critical, especially with the multiple comorbidities that HF patients can have, including chronic obstructive pulmonary disease, diabetes, renal failure, sleep apnea, atrial fibrillation, and degenerative joint disease. Before you know it you have a half-dozen subspecialists involved in care and it can become uncoordinated. Keeping the PCP at the center of the team and providing the PCP with support from specialists as needed is critical,” said Dr. McKie.

Even for the most severe heart failure patients, PCPs can still play an important role by providing palliative care and dealing with end-of-life issues, specialists said.

Primary care and heart failure’s antecedents

The other, obvious time in heart failure’s severity spectrum for PCPs to take a very active role is with presymptomatic, stage A patients. Perhaps the only controversial element of this is whether such patients really have a form of heart failure and whether is it important to conceptualize heart failure this way.

The notion of stage A heart failure dates back to the 2001 edition of heart failure diagnosis and management recommendations issued by a panel organized by the ACC and AHA (J Am Coll Cardiol. 2001 Dec;38[7]:2101-13). The 2001 writing committee members said that they “decided to take a new approach to the classification of heart failure that emphasized both the evolution and progression of the disease.” They defined stage A patients as presymptomatic and without structural heart disease but with “conditions strongly associated with the development of heart failure,” specifically systemic hypertension, coronary artery disease, diabetes, a history of cardiotoxic drug therapy or alcohol abuse, a history of rheumatic fever, or a family history of cardiomyopathy.

When the ACC and AHA panel members next updated the heart failure recommendations in 2005, they seemed to take a rhetorical step back, saying that stage A and B “are clearly not heart failure but are an attempt to help healthcare providers identify patients early who are at risk for developing heart failure. Stage A and B patients are best defined as those with risk factors that clearly predispose toward the development of HF.” (J Am Coll Cardiol. 2005 Sept. 46[6]:1116-43) In 2005, the panel also streamlined the list of risk factors that identify stage A heart failure patients: hypertension, atherosclerotic disease, diabetes, obesity, metabolic syndrome, patients who have taken cardiotoxins, or patients with a family history of cardiomyopathy. The 2009 recommendation update left this definition of stage A heart failure unchanged, but in 2013 the most recent update devoted less attention to explaining the significance of the stage-A heart failure, although it clearly highlighted the importance of controlling hypertension, diabetes, and obesity as ways to prevent patients from developing symptomatic heart failure (J Am Coll Cardiol. 2013 Oct 15;62[16]:e147-e239).

The subtle, official tweaking of the stage A (and B) heart failure concept during 2001-2013, as well establishment of stage A in the first place, seems to have left both PCPs and heart failure specialists unsure on exactly how to think about presymptomatic people with one or more of the prominent heart failure risk factors of hypertension, diabetes, and obesity. While they uniformly agree that identifying these risk factors and then treating them according to contemporary guidelines is hugely important for stopping or deferring the onset of heart failure, and they also agree that this aspect of patient care is clearly a core responsibility for PCPs, many also say that they don’t think of presymptomatic patients as having heart failure of any type despite the stage A designation on the books.

One exception is St. Vincent’s Dr. Walsh. “I think the writers of the 2001 heart failure guidelines had an inspired approach. Identifying patients with hypertension, diabetes, coronary artery disease, etc., as patients with heart failure has helped drive home the point that treatment and control of these diseases is crucial,” she said in an interview. “But I am not sure all physicians have adopted the concept. “Uncontrolled hypertension is prevalent, and not viewed by all as resulting in heart failure down the road. Diabetes and hypertension are very important risk factors for the development of heart failure in women,” she added. “I’m especially diligent in ensuring that women with one or both of these diseases get treated aggressively.”

Highlighting specifically the fundamental role that uncontrolled hypertension plays in causing heart failure, the University of Pennsylvania’s Dr. Jessup estimated that controlling hypertension throughout the U.S. population could probably cut heart failure incidence in half.

Others draw a sharper contrast between the risk factor stage and the symptomatic stages of heart failure, though they all agree on the importance of risk factor management by PCPs. “Hypertension does not mean that a patient has heart failure; it means they have a risk factor for heart failure and the patient is in the prevention stage,” said the NHLBI’s Dr. Shah. ”The most important role for PCPs is to identify the risk factors and prevent development of [symptomatic] heart failure. This is where PCPs are critically important because patients present to them at the early stages.”

Dr. Bauman, the PCP with INTEGRIS in Oklahoma City, generally doesn’t conflate risk factors with stage A heart failure. “I look at every patient with hypertension or diabetes as a person at risk for cardiovascular disease. I push them to get their blood pressure and glycemia under control. But I don’t think of them as stage A heart failure patients. I think of them as patients at risk for heart failure, but also at risk for atrial fibrillation, MI, and stroke. I think about their risk, but I don’t label them in my mind as having stage A heart failure. I think that this is a patient at risk for cardiovascular disease and that I must do what I should to manage their risk factors.”

“I don’t personally think about patients having stage A heart failure,” agreed Dr. Cunningham, a PCP at Brigham and Women’s Hospital. “When I see patients with hypertension, I counsel them about what matters to them so that they will take their medications, because if they currently feel fine they may not understand the long-term risk they face. So I invest time in making the patient understand why their hypertension is important and the risks it poses, so that in the long-run they won’t have a stroke or MI or develop heart failure. But I don’t think that the stage A definition has changed my approach; I already think of hypertension as a precursor to a variety of bad downstream consequences. I don’t think of someone as a heart failure patient just because they have hypertension, and I don’t think that every patient with hypertension will develop heart failure.” Speaking of her colleagues, Dr. Cunningham added, “I don’t have a sense that the stages of heart failure have made much of an impact on how other PCPs talk with patients or plan their care.”

“The heart failure staging system is useful from the standpoint of emphasizing that the disease begins with primordial risk and progresses through a period of structural injury during which patients may not be symptomatic,” summed up Dr. Desai. “But practically, most of us confront the diagnosis of heart failure when patients become symptomatic and reach stage C.”

Can an intensified approach better slow stage A progression?

One of the inherent limitations right now in referring to patients as having stage A heart failure is that it adds little to how heart failure risk factors are managed. A patient with hypertension undergoing appropriate care will receive treatment to lower blood pressure to recommended goal levels. The antihypertensive treatment remains the same regardless of whether the patient is considered to have only hypertension or whether the treating physician also thinks of the patient as having stage A heart failure. The same applies to patients diagnosed with diabetes; their hyperglycemia-controlling treatment remains unchanged whether or not their physician labels them as stage A heart failure patients.

But what if an evidence-based way existed to not only identify patients with hypertension or diabetes, but to identify within those patients the subset who faced a particularly increased risk for developing heart failure? And what if an evidence-based intervention existed that could be added to standard blood pressure–lowering or hyperglycemia-controlling interventions and had proved to slow or stop progression of patients to heart failure?

Preliminary evidence that screening for stage A heart failure patients can successfully identify a subset at elevated risk for developing symptomatic heart failure and that intensified risk-factor control helped mitigate this risk appeared in two reports published in 2013. But both studies were relatively small, they ran in Europe, and neither has undergone replication in a U.S. study in the 2.5 years since their publication.

The larger study, STOP-HF (St. Vincent’s Screening to Prevent Heart Failure), included patients at 39 primary care practices in Ireland, a study organized by researchers at St. Vincent’s University Hospital in Dublin. They enrolled people without symptoms of heart failure who were at least 41 years old and had at least one of these risk factors: hypertension, hypercholesterolemia, obesity, vascular disease, diabetes, an arrhythmia, or valvular disease: In short, primarily stage A heart failure patients.

The researchers then tested 1,374 of these people for their baseline blood level of BNP and randomized them into two intervention arms. For those randomized to the active arm, the PCPs for these people received an unblinded report of the BNP results, and those with a level of 50 pg/mL or higher underwent further assessment by screening echocardiography and intensified risk-factor control, including risk-factor coaching by a nurse. Those randomized to this arm who had a lower BNP level at baseline underwent annual follow-up BNP screening, and if their level reached the 50 pg/ML threshold they switched to the more intensified protocol. Those randomized to the control arm received a more standard program of risk-factor modification and their BNP levels were never unblinded.

After an average follow-up of 4.2 years, people in the active intervention arm of STOP-HF had a 5% cumulative incidence of left ventricular dysfunction or heart failure, while those in the control arm had a 9% rate, a 45% relative risk reduction from the active intervention that was statistically significant for the study’s primary endpoint (JAMA. 2013 July 3;310[1]:66-74).

The second study, PONTIAC (NT-proBNP Selected Prevention of Cardiac Events in a Population of Diabetic Patients Without a History of Cardiac Disease), ran in Austria and Germany and involved 300 patients who had type 2 diabetes and were free from cardiac disease at baseline. At baseline, all people considered for the study underwent a screening measure of their blood level of NT-proBNP (a physiologic precursor to BNP) and those with a level above 125 pg/mL were randomized to either a usual-care group or an arm that underwent more intensified up-titration treatment with a renin-angiotensin system antagonist drug and with a beta-blocker. The primary endpoint was the incidence of hospitalization or death due to cardiac disease after 2 years, which was a relative 65% lower in the intensified intervention group, a statistically significant difference (J Am Coll Cardiol. 2013 Oct 8;62[15]:1365-72).

Both studies focused on people with common risk factors seen in primary care practices and used BNP or a BNP-like blood marker to identify people with an elevated risk for developing heart failure or other cardiac disease, and both studies showed that application of a more aggressive risk-factor intervention program resulted in a significant reduction in heart failure or heart failure–related outcomes after 2-4 years. Both studies appeared to offer models for improving risk-factor management by PCPs for people with stage A heart failure, but at the end of 2015 neither model had undergone U.S. testing.

“The STOP-HF and PONTIAC studies were proofs of concept for using biomarkers to gain a better sense of cardiac health,” said Dr. Tariq Ahmad, a heart failure physician at Yale University in New Haven, Conn., who is interested in developing biomarkers for guiding heart failure management. “Metrics like blood pressure and heart rate are relatively crude measures of cardiac health. We need to see in a large trial if we can use these more objective measures of cardiac health to decide how to treat patients,” In addition to BNP and NT-proBNP, Dr. Ahmad cited ST2 and galectin-3 as other promising biomarkers in the blood that may better gauge a person’s risk for developing heart failure and the need for intensified risk-factor control. The current inability of PCPs to better risk stratify people who meet the stage A heart failure definition so that those at highest risk could undergo more intensified interventions constitutes a missed opportunity for heart failure prevention, he said.

“The STOP-HF trial is really important and desperately needs replication,” said Dr. Margaret M. Redfield, professor of medicine and a heart failure physician at Mayo Clinic in Rochester, Minn.

She, and her Mayo associates, including Dr. McKie, are planning to launch a research protocol this year to finally test a STOP-HF type of program in a U.S. setting. They are planning to measure NT-proBNP levels in patients with stage A heart failure and then randomize some to an intervention arm with intensified risk reduction treatments.

“The problem with stage A today is, if we apply it according to the ACC and AHA definition, it would include quite a large number of patients, and not all of them – in fact a minority – would go on to develop symptomatic heart failure,” said Dr. McKie. “How you can further risk stratify the stage A population with simple testing is an issue for ongoing research,” he said. “The STOP-HF and PONTIAC strategies need more testing. Both studies were done in Europe, and we haven’t studied this approach in the U.S. Their approach makes sense and is appealing but it needs more testing.”

The economic barrier to intensified stage-A management

Even if a U.S. based study could replicate the STOP-HF results and provide an evidence base for improved prevention of symptomatic heart failure by interventions instituted by PCPs, it’s not clear whether the U.S. health care system as it currently is structured provides a framework that is able to invest in intensified upfront management of risk factors to achieve a reduced incidence of symptomatic heart failure several years later.

“One of the interesting aspects of STOP-HF was its use of a nurse-based intervention. We don’t have the resources for that in our practices right now,” noted Dr. Cunningham, the PCP at Brigham and Women’s Hospital who is medical director of the hospital’s Integrated Care Management Program for medically complex patients. While that program uses nurse care coordinators to pull together the disparate elements of care for heart failure patients and others with more severe, chronic illnesses, the program currently serves only patients with advanced disease, not presymptomatic patients who face a potentially elevated risk for bad outcomes that would happen many years in the future.

“This speaks to the need for more population-based preventive management, which PCPs are trying to start to do, but currently we are nowhere near fulfilling that potential,” said Dr. Cunningham. The barrier is having clinical resources for help in managing lower-risk patients, to make sure they receive all the interventions they should. We’re now trying to start using care teams for patients with diabetes or other conditions. The biggest gap is that we don’t have the resources; we don’t have enough nurses on our staff to intervene” for all the patients who could potentially benefit. “Right now, we can only afford to use nurses for selected, high-risk patients.” The challenge is to have a care model that allows a lot of upfront costs to generate savings over a long-term time horizon, he said. “It’s very important for improving population health, but it’s hard to make it happen in our current health care system.”

Dr. Ahmad noted the enormous downside of a health system that is not proactive and often waits for heart failure patients to declare themselves with severe illness.

“The majority of heart failure patients I see drifted through the health care system” without recognition of their accumulating morbidity. “By the time they show heart failure symptoms, their disease is pretty advanced and we have real difficulty managing it. A lot of patients do not have their heart failure managed until they fall off the edge and their condition is much less modifiable. If we could identify these patients sooner, it would help both them and the health care system. It would be great to have objective measures that could help PCPs identify early abnormal patients who need more aggressive management. In much of U.S. practice, heart failure management is more specialty driven. It might be different in closed systems, but in many heart failure practices there is no PCP coordination. The health care system is not set up to allow PCPs to take care of these issues.”

Dr. Bauman said she sees some reason for optimism in looming reimbursement changes, where population management might help drive a shift toward more team care for heart failure and a focus on earlier identification of patients at risk and intervention at early stages of their disease.

“As we move toward population management it becomes more obvious that you need a team approach to managing heart failure, involving not just physicians but also pharmacists, nurses, social workers, and care coordinators. In my system, INTEGRIS, the whole-team management approach is beginning to happen. It’s new to primary care to apply a large team of clinicians; it takes a lot of resources. Being able to afford a team was a problem when we were paid by fee-for-service, it wasn’t practical. Population management will make it possible.”

Dr. Desai has been a consultant to Novartis, Merck, St. Jude, and Relypsa and has received research funding from Novartis and AtCor Medical. Dr. Redfield has been a consultant to Merck and Eli Lilly. Dr. Ahmad has been a consultant to Roche. Dr. Ong, Dr. Walsh, Dr. Jessup, Dr. McKie, Dr. Bauman, Dr. Shah, and Dr. Cunningham had no disclosures.

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