David L. Longworth, MD

The passage of the Patient Protection and Affordable Care Act will profoundly affect the way physicians—particularly those engaged in primary care—practice medicine. Clinicians and their colleagues will be obliged to meet government-mandated performance quality measures while achieving cost efficiencies. Two concepts are central to the implementation of reform in the US health care system: accountable care organizations (ACOs) and the patient-centered medical home (PCMH). To get some perspective on what these changes mean for the practicing clinician, Cleveland Clinic Journal of Medicine (CCJM) interviewed David Longworth, MD, who chairs the Cleveland Clinic Medicine Institute and directs strategy and implementation of Cleveland Clinic ACO-related activities.

CCJM: Please explain briefly the concept of PCMH.

Dr. Longworth: PCMH is not a new concept; first advanced by the American Academy of Pediatrics in 1967,¹ it represents a model of care in which an individual patient has a primary relationship with one provider who manages and coordinates the different aspects of the patient’s health care. The provider collaborates with a team of health care professionals. The concept caught on about a decade ago when a consortium of family medicine organizations and ultimately industry, including IBM, endorsed the concept. IBM and others created the Primary Care Consortium and began to drive the concept of PCMH.

Increasingly, care delivered through PCMH is team-based. The team coordinates the patient’s care and, when appropriate, enlists specialists or subspecialists to provide necessary components of care, all while maintaining responsibility for care coordination across the continuum of care. The medical home model provides an opportunity for enhanced access and care coordination utilizing care outside of the office walls, such as through retail clinics, eVisits, online diagnostic services, phone and electronic communication, and house call services.

Patient-centered medical homes are springing up across the country. In 2008, the National Committee for Quality Assurance (NCQA) developed criteria for recognition of PCMHs.² It scored the sophistication of medical homes at three levels, level 1 being the lowest and level 3 the highest. Between 2008 and the end of 2010, NCQA had recognized more than 1,500 PCMHs. According to the latest figures, more than 3,000 practices have now earned PCMH recognition from the NCQA.³

At Cleveland Clinic, pilot projects at three family health centers that cover 60,000 persons have recently been rolled out with the goal of determining the model of team care that yields the highest value, with value defined by the equation of quality over cost. Ideally, higher quality is delivered at lower cost to increase value.

CCJM: What are the goals of ACOs?

Dr. Longworth: The term “accountable care,” first used in 2006 by Elliot Fisher, Dartmouth Institute of Health Policy and Clinical Practice,⁶ expresses the idea that health care organizations be accountable for the care they deliver, with the three-part aim of better health for populations, better care for individuals, and reduced cost inefficiencies without compromised care.

With accountable care, institutions take on risk with the expectation that they will improve quality but reduce costs, and if they reduce costs and achieve certain quality targets for populations of patients, they will share in the savings accrued. The Affordable Care Act laid the groundwork for creation of ACOs. The regulation for ACOs released by the Centers for Medicare & Medicaid Services (CMS) became effective in January 2012.^7,8 Many health care organizations opposed the rule for reasons related to complexity, prescriptiveness, onerous detail around governance and marketing, and shared savings arrangements, among others. The final rule addressed many of these concerns and enabled the creation of the first wave of ACOs.⁸ At present, 153 ACOs have been approved by CMS.⁹ Other ACOs funded by commercial payers are also being formed in many locations.

For ACOs to be effective, I believe that the cornerstone of management has to be PCMHs.

CCJM: You mentioned that institutions will take on risk. What kind of risk are you referring to?

Dr. Longworth: Added value must be rewarded with sustainable payment models. There are two payment models in the final ACO rule from CMS. Both models require 3-year commitments and both require involvement of primary care physicians. One model for organizations that want to stick a toe in the water has no downside risk and modest potential for gain if they hit certain quality and cost targets. For those organizations that are further along and want to assume risk, the second option is a shared savings/risk payment model, which creates greater incentives for efficiency and quality. In the shared savings/risk model, the ACO can retain a portion of savings if it meets performance and expenditure benchmarks based on its performance during the previous 3 years. It is also at risk for loss if expenditures are greater than a certain amount compared with benchmark expenditures. Ultimately, the final destination for ACOs will be a risk of loss if they don’t perform.

CCJM: How can these two structures—PCMHs and ACOs—optimize the use of home health?

Dr. Longworth: Home health, which is part of the postacute care continuum, will be vitally important for managing individuals and populations of patients as we move toward PCMHs and ACOs. Coordination of care will require communication between home health services and the primary care physicians who are integral to PCMHs. There will have to be an emphasis on transitions of care, from the hospital to home, from skilled nursing facilities to home, and so forth.

Accountable care organizations are responsible for a population of patients, and ACOs receive a fixed amount of money per year to cover an individual life in that population. Thus, managing quality and controlling cost is the name of the game no matter where the patient is in the health care continuum— the office, the emergency room, the hospital, a skilled nursing facility, or a home health setting. For some chronic diseases, managing patients in the home health setting may be vitally important to prevent unnecessary trips to the emergency room and hospital readmissions, thereby reducing expenditures while providing quality care.

CCJM: Do you expect an increase in the number of PCMHs and ACOs to increase the demand for home health services?

Dr. Longworth: Given the necessity of optimizing quality at lower cost, I anticipate a push to deliver as much care as we can in the least expensive “right” setting, which might be the home in some situations. Certainly, we don’t want to send patients home prematurely only to have them return to emergency departments or hospitals, but I think the demand for home health will increase as we try to decrease the number of days in skilled nursing facilities, which are expensive, and to move care from skilled nursing facilities to the home setting.

CCJM: Is there evidence that integrated delivery models such as PCMHs deliver value?

Dr. Longworth: The Patient-Centered Primary Care Collaborative demonstrated quality improvements in selected outcomes domains while also realizing savings through reductions in admissions, emergency department visits, skilled nursing facility days, and pharmacy costs.¹⁰

CCJM: What challenges do PCMHs and ACOs present to home health agencies and the way they provide services, and how will these challenges affect patients and clinicians?

Dr. Longworth: One challenge will be communication between home health services and primary care providers during transitions of care. A second will be managing costs for home health, which entails leveraging new technologies such as in-home devices and telemedicine to provide optimal and ideal monitoring of patients at the lowest potential cost. Home health, like other players along the care continuum, will face increasing scrutiny regarding quality metrics. Home health agencies will likely need to distinguish themselves from one another on the basis of performance measures such as emergency department utilization, unnecessary hospital readmissions, medication errors, and quality of service to patients as well as to primary care providers.

CCJM: How does personalized health care fit into the PCMH model?

Dr. Longworth: Personalized health care, which includes the use of genetic testing in certain situations, is an emerging field that is still in its infancy. Like PCMHs, personalized health care is proactive rather than reactive. Application of personalized health care can help deliver value with better prediction of disease and appropriate use of targeted therapies to improve outcomes for certain individuals. Such individualized treatment not only enables higher quality of care but wiser use of resources. For instance, genetic markers can be used to predict drug metabolism and adverse drug events for certain medications. In the field of oncology, the expression of genetic mutations in certain tumor types can help identify patients most likely to respond to specific targeted therapies. In these ways, personalized health care is patient-centered health care. As part of its proactive nature, personalized health care, beyond genetic testing, also implies advance planning of appointments with a focus on chronic care and keeping patients in the care system.

CCJM: How does participation in a PCMH or an ACO benefit the primary care provider? Are there any disadvantages to participation?

Dr. Longworth: In the current fee-for-service world, primary care physicians and all providers are paid on a widget-by-widget basis. Some primary care physicians and other specialists fear moving to this new world in which they will ultimately be accountable for quality and cost. Not everyone has embraced the concept, but I do think it is inevitable. Primary care physicians especially will be under increasing pressure to care for populations as opposed to individual patients. They will need to redesign the care delivery model to provide team-based, proactive care focusing on the highest-risk patients to try to keep them out of the emergency department and hospital. There will also be a greater emphasis on wellness moving forward, in an attempt to prevent the development of chronic diseases such as diabetes and obesity in individual patients and populations. All of these changes represent a different paradigm for the delivery of care, compared with the present model.

The benefit of participation for a primary care physician depends on the structure of an ACO, particularly the amount of personal financial liability an individual practitioner might have. In a staff-model, fixed-salary institution, primary care physicians would probably be more immune to financial liability than they would in other markets or other compensation models in which salary can fluctuate.

CCJM: What are some of the barriers to ACO implementation that are relevant to office-based practice, and how can they be overcome?

Dr. Longworth: There are a number of barriers to ACOs and true PCMHs. The barriers revolve around redefining workflows and moving away from reactive care—a physician-centric model in which a patient comes into the office with a problem and the physician reacts—to proactive care with the goal being to recognize how the patient is doing over time to prevent unnecessary trips to the emergency department and, ultimately, hospitalization. It is a fundamentally different mindset that involves proactive outreach targeted at high-risk patients whose chronic diseases are managed through a team-based approach. An essential feature of primary care practice will be care coordinators who will manage and proactively anticipate the needs of medically complex, high-risk patients who use a disproportionately large share of services.

In addition, a greater emphasis on wellness will be necessary to prevent the development of chronic diseases such as diabetes, obesity, and hypertension in the large segment of the population that is reasonably healthy.

CCJM: What steps can a clinician take to prepare his or her practice for ACO implementation?

Dr. Longworth: Small practices will be challenged. It is difficult to imagine accountable care without an electronic health record. To understand the population, the practitioner will need to do continuous performance management, which can’t be done without access to data from a population of patients. An increasing number of physicians are aligning with organizations that have the necessary infrastructure to provide the myriad data required to measure quality, to enable continuous improvement in performance, and to enhance the patient experience. Small practices may not have the resources to complete the administrative work necessary to become part of an ACO.

There are ways to align with an ACO that do not constitute full employment; for example, the Cleveland (Ohio) Quality Alliance has aligned with community-based physicians to provide informatics support. Linking with larger organizations that have the resources to provide quality measurement and contracting support will permit smaller community-based physicians’ practices to be part of the game.

CCJM: What steps should PCMHs and ACOs take to leverage and optimize home health services among other parts of the medical neighborhood?

Dr. Longworth: Frankly, the postacute continuum is a challenge for most systems across the country because postacute care is fragmented. Our strategy at Cleveland Clinic is to identify and align with preferred providers of home health services. The criteria that I look for are commitment to quality and transparency, service that is oriented to both patients and PCMHs, and openness to innovation for leveraging health care technology to deliver care at the best value. Home health providers need to think about how to best accomplish these results to position themselves to partner with ACOs.

CCJM: How do PCMHs and ACOs apply to special patient populations and their needs? Is there a population that’s best suited for the medical home model?

Dr. Longworth: Certain populations of higher-risk patients are ideally suited to home health coupled with chronic disease management using care coordinators. Some examples are children with asthma and children with intellectual and developmental disabilities (eg, autism) who have high utilization of emergency services. Another population is patients with heart failure who are often in and out of the emergency department and hospital; there has been a concerted effort to reduce 30-day readmission rates, which are as high as 30%, for this group. (Also see “Home-based care for heart failure: Cleveland Clinic’s ‘Heart Care at Home’ transitional care program”)

CCJM: What are the specific expectations for patient involvement in the PCMH setting?

Dr. Longworth: Our challenge lies in how best to motivate patients and engage them in their own care, especially patients who have chronic diseases. We all struggle to resolve the engagement question. Coaching and patient engagement are functions of PCMHs and at every point along the care continuum. Home health providers can serve as health coaches to promote adherence to medications, healthy lifestyles, and follow-up visits with patients’ doctors—these all need to happen to better engage patients. How to engage patients and motivate them to be more involved in their health is a basic challenge.

CCJM: Along similar lines, how can home health providers work with physicians to achieve patient-centered care?

Dr. Longworth: They can communicate early when they think that things are amiss, serve as health coaches, create technologic solutions that enhance efficiency of communication, and anticipate care needs of patients in the home setting.

CCJM: How might bundling affect the financial picture of PCMHs and patient care?

Dr. Longworth: When one talks about bundling, the devil is in the definition. In bundling, one gets paid for an episode of service. So, for example, a total knee replacement might be compensated by a 30-day bundle that covers only the surgery and the immediate postoperative period. Or it might be a 90-day bundle that includes hospitalization and perhaps some days in skilled nursing facility, but ideally transitioning from hospital to home. In the latter example, the bundle, or the total payment, will be split between the hospital and the home care services. If home health is included in a bundle, there will be tremendous pressure on the home health service to prevent readmission and emergency room visits and to eliminate waste of care. Home health’s vulnerability will depend upon how a bundle is defined for specific service.

CCJM: Who defines the terms of the bundle?

Dr. Longworth: Whoever is applying for the bundle—usually, a health care system, hospital, or ACO. It may be that home health services will subcontract for a fat fee in order to immunize themselves against risk, and shift all of the risk to the contracting organization. If I were a home health provider, I might try to minimize my own risk, but still offer my services at a price that is financially viable.

The passage of the Patient Protection and Affordable Care Act will profoundly affect the way physicians—particularly those engaged in primary care—practice medicine. Clinicians and their colleagues will be obliged to meet government-mandated performance quality measures while achieving cost efficiencies. Two concepts are central to the implementation of reform in the US health care system: accountable care organizations (ACOs) and the patient-centered medical home (PCMH). To get some perspective on what these changes mean for the practicing clinician, Cleveland Clinic Journal of Medicine (CCJM) interviewed David Longworth, MD, who chairs the Cleveland Clinic Medicine Institute and directs strategy and implementation of Cleveland Clinic ACO-related activities.

CCJM: Please explain briefly the concept of PCMH.

Dr. Longworth: PCMH is not a new concept; first advanced by the American Academy of Pediatrics in 1967,¹ it represents a model of care in which an individual patient has a primary relationship with one provider who manages and coordinates the different aspects of the patient’s health care. The provider collaborates with a team of health care professionals. The concept caught on about a decade ago when a consortium of family medicine organizations and ultimately industry, including IBM, endorsed the concept. IBM and others created the Primary Care Consortium and began to drive the concept of PCMH.

Increasingly, care delivered through PCMH is team-based. The team coordinates the patient’s care and, when appropriate, enlists specialists or subspecialists to provide necessary components of care, all while maintaining responsibility for care coordination across the continuum of care. The medical home model provides an opportunity for enhanced access and care coordination utilizing care outside of the office walls, such as through retail clinics, eVisits, online diagnostic services, phone and electronic communication, and house call services.

Patient-centered medical homes are springing up across the country. In 2008, the National Committee for Quality Assurance (NCQA) developed criteria for recognition of PCMHs.² It scored the sophistication of medical homes at three levels, level 1 being the lowest and level 3 the highest. Between 2008 and the end of 2010, NCQA had recognized more than 1,500 PCMHs. According to the latest figures, more than 3,000 practices have now earned PCMH recognition from the NCQA.³

At Cleveland Clinic, pilot projects at three family health centers that cover 60,000 persons have recently been rolled out with the goal of determining the model of team care that yields the highest value, with value defined by the equation of quality over cost. Ideally, higher quality is delivered at lower cost to increase value.

CCJM: What are the goals of ACOs?

Dr. Longworth: The term “accountable care,” first used in 2006 by Elliot Fisher, Dartmouth Institute of Health Policy and Clinical Practice,⁶ expresses the idea that health care organizations be accountable for the care they deliver, with the three-part aim of better health for populations, better care for individuals, and reduced cost inefficiencies without compromised care.

With accountable care, institutions take on risk with the expectation that they will improve quality but reduce costs, and if they reduce costs and achieve certain quality targets for populations of patients, they will share in the savings accrued. The Affordable Care Act laid the groundwork for creation of ACOs. The regulation for ACOs released by the Centers for Medicare & Medicaid Services (CMS) became effective in January 2012.^7,8 Many health care organizations opposed the rule for reasons related to complexity, prescriptiveness, onerous detail around governance and marketing, and shared savings arrangements, among others. The final rule addressed many of these concerns and enabled the creation of the first wave of ACOs.⁸ At present, 153 ACOs have been approved by CMS.⁹ Other ACOs funded by commercial payers are also being formed in many locations.

For ACOs to be effective, I believe that the cornerstone of management has to be PCMHs.

CCJM: You mentioned that institutions will take on risk. What kind of risk are you referring to?

Dr. Longworth: Added value must be rewarded with sustainable payment models. There are two payment models in the final ACO rule from CMS. Both models require 3-year commitments and both require involvement of primary care physicians. One model for organizations that want to stick a toe in the water has no downside risk and modest potential for gain if they hit certain quality and cost targets. For those organizations that are further along and want to assume risk, the second option is a shared savings/risk payment model, which creates greater incentives for efficiency and quality. In the shared savings/risk model, the ACO can retain a portion of savings if it meets performance and expenditure benchmarks based on its performance during the previous 3 years. It is also at risk for loss if expenditures are greater than a certain amount compared with benchmark expenditures. Ultimately, the final destination for ACOs will be a risk of loss if they don’t perform.

CCJM: How can these two structures—PCMHs and ACOs—optimize the use of home health?

Dr. Longworth: Home health, which is part of the postacute care continuum, will be vitally important for managing individuals and populations of patients as we move toward PCMHs and ACOs. Coordination of care will require communication between home health services and the primary care physicians who are integral to PCMHs. There will have to be an emphasis on transitions of care, from the hospital to home, from skilled nursing facilities to home, and so forth.

Accountable care organizations are responsible for a population of patients, and ACOs receive a fixed amount of money per year to cover an individual life in that population. Thus, managing quality and controlling cost is the name of the game no matter where the patient is in the health care continuum— the office, the emergency room, the hospital, a skilled nursing facility, or a home health setting. For some chronic diseases, managing patients in the home health setting may be vitally important to prevent unnecessary trips to the emergency room and hospital readmissions, thereby reducing expenditures while providing quality care.

CCJM: Do you expect an increase in the number of PCMHs and ACOs to increase the demand for home health services?

Dr. Longworth: Given the necessity of optimizing quality at lower cost, I anticipate a push to deliver as much care as we can in the least expensive “right” setting, which might be the home in some situations. Certainly, we don’t want to send patients home prematurely only to have them return to emergency departments or hospitals, but I think the demand for home health will increase as we try to decrease the number of days in skilled nursing facilities, which are expensive, and to move care from skilled nursing facilities to the home setting.

CCJM: Is there evidence that integrated delivery models such as PCMHs deliver value?

Dr. Longworth: The Patient-Centered Primary Care Collaborative demonstrated quality improvements in selected outcomes domains while also realizing savings through reductions in admissions, emergency department visits, skilled nursing facility days, and pharmacy costs.¹⁰

CCJM: What challenges do PCMHs and ACOs present to home health agencies and the way they provide services, and how will these challenges affect patients and clinicians?

Dr. Longworth: One challenge will be communication between home health services and primary care providers during transitions of care. A second will be managing costs for home health, which entails leveraging new technologies such as in-home devices and telemedicine to provide optimal and ideal monitoring of patients at the lowest potential cost. Home health, like other players along the care continuum, will face increasing scrutiny regarding quality metrics. Home health agencies will likely need to distinguish themselves from one another on the basis of performance measures such as emergency department utilization, unnecessary hospital readmissions, medication errors, and quality of service to patients as well as to primary care providers.

CCJM: How does personalized health care fit into the PCMH model?

Dr. Longworth: Personalized health care, which includes the use of genetic testing in certain situations, is an emerging field that is still in its infancy. Like PCMHs, personalized health care is proactive rather than reactive. Application of personalized health care can help deliver value with better prediction of disease and appropriate use of targeted therapies to improve outcomes for certain individuals. Such individualized treatment not only enables higher quality of care but wiser use of resources. For instance, genetic markers can be used to predict drug metabolism and adverse drug events for certain medications. In the field of oncology, the expression of genetic mutations in certain tumor types can help identify patients most likely to respond to specific targeted therapies. In these ways, personalized health care is patient-centered health care. As part of its proactive nature, personalized health care, beyond genetic testing, also implies advance planning of appointments with a focus on chronic care and keeping patients in the care system.

CCJM: How does participation in a PCMH or an ACO benefit the primary care provider? Are there any disadvantages to participation?

Dr. Longworth: In the current fee-for-service world, primary care physicians and all providers are paid on a widget-by-widget basis. Some primary care physicians and other specialists fear moving to this new world in which they will ultimately be accountable for quality and cost. Not everyone has embraced the concept, but I do think it is inevitable. Primary care physicians especially will be under increasing pressure to care for populations as opposed to individual patients. They will need to redesign the care delivery model to provide team-based, proactive care focusing on the highest-risk patients to try to keep them out of the emergency department and hospital. There will also be a greater emphasis on wellness moving forward, in an attempt to prevent the development of chronic diseases such as diabetes and obesity in individual patients and populations. All of these changes represent a different paradigm for the delivery of care, compared with the present model.

The benefit of participation for a primary care physician depends on the structure of an ACO, particularly the amount of personal financial liability an individual practitioner might have. In a staff-model, fixed-salary institution, primary care physicians would probably be more immune to financial liability than they would in other markets or other compensation models in which salary can fluctuate.

CCJM: What are some of the barriers to ACO implementation that are relevant to office-based practice, and how can they be overcome?

Dr. Longworth: There are a number of barriers to ACOs and true PCMHs. The barriers revolve around redefining workflows and moving away from reactive care—a physician-centric model in which a patient comes into the office with a problem and the physician reacts—to proactive care with the goal being to recognize how the patient is doing over time to prevent unnecessary trips to the emergency department and, ultimately, hospitalization. It is a fundamentally different mindset that involves proactive outreach targeted at high-risk patients whose chronic diseases are managed through a team-based approach. An essential feature of primary care practice will be care coordinators who will manage and proactively anticipate the needs of medically complex, high-risk patients who use a disproportionately large share of services.

In addition, a greater emphasis on wellness will be necessary to prevent the development of chronic diseases such as diabetes, obesity, and hypertension in the large segment of the population that is reasonably healthy.

CCJM: What steps can a clinician take to prepare his or her practice for ACO implementation?

Dr. Longworth: Small practices will be challenged. It is difficult to imagine accountable care without an electronic health record. To understand the population, the practitioner will need to do continuous performance management, which can’t be done without access to data from a population of patients. An increasing number of physicians are aligning with organizations that have the necessary infrastructure to provide the myriad data required to measure quality, to enable continuous improvement in performance, and to enhance the patient experience. Small practices may not have the resources to complete the administrative work necessary to become part of an ACO.

There are ways to align with an ACO that do not constitute full employment; for example, the Cleveland (Ohio) Quality Alliance has aligned with community-based physicians to provide informatics support. Linking with larger organizations that have the resources to provide quality measurement and contracting support will permit smaller community-based physicians’ practices to be part of the game.

CCJM: What steps should PCMHs and ACOs take to leverage and optimize home health services among other parts of the medical neighborhood?

Dr. Longworth: Frankly, the postacute continuum is a challenge for most systems across the country because postacute care is fragmented. Our strategy at Cleveland Clinic is to identify and align with preferred providers of home health services. The criteria that I look for are commitment to quality and transparency, service that is oriented to both patients and PCMHs, and openness to innovation for leveraging health care technology to deliver care at the best value. Home health providers need to think about how to best accomplish these results to position themselves to partner with ACOs.

CCJM: How do PCMHs and ACOs apply to special patient populations and their needs? Is there a population that’s best suited for the medical home model?

Dr. Longworth: Certain populations of higher-risk patients are ideally suited to home health coupled with chronic disease management using care coordinators. Some examples are children with asthma and children with intellectual and developmental disabilities (eg, autism) who have high utilization of emergency services. Another population is patients with heart failure who are often in and out of the emergency department and hospital; there has been a concerted effort to reduce 30-day readmission rates, which are as high as 30%, for this group. (Also see “Home-based care for heart failure: Cleveland Clinic’s ‘Heart Care at Home’ transitional care program”)

CCJM: What are the specific expectations for patient involvement in the PCMH setting?

Dr. Longworth: Our challenge lies in how best to motivate patients and engage them in their own care, especially patients who have chronic diseases. We all struggle to resolve the engagement question. Coaching and patient engagement are functions of PCMHs and at every point along the care continuum. Home health providers can serve as health coaches to promote adherence to medications, healthy lifestyles, and follow-up visits with patients’ doctors—these all need to happen to better engage patients. How to engage patients and motivate them to be more involved in their health is a basic challenge.

CCJM: Along similar lines, how can home health providers work with physicians to achieve patient-centered care?

Dr. Longworth: They can communicate early when they think that things are amiss, serve as health coaches, create technologic solutions that enhance efficiency of communication, and anticipate care needs of patients in the home setting.

CCJM: How might bundling affect the financial picture of PCMHs and patient care?

Dr. Longworth: When one talks about bundling, the devil is in the definition. In bundling, one gets paid for an episode of service. So, for example, a total knee replacement might be compensated by a 30-day bundle that covers only the surgery and the immediate postoperative period. Or it might be a 90-day bundle that includes hospitalization and perhaps some days in skilled nursing facility, but ideally transitioning from hospital to home. In the latter example, the bundle, or the total payment, will be split between the hospital and the home care services. If home health is included in a bundle, there will be tremendous pressure on the home health service to prevent readmission and emergency room visits and to eliminate waste of care. Home health’s vulnerability will depend upon how a bundle is defined for specific service.

CCJM: Who defines the terms of the bundle?

Dr. Longworth: Whoever is applying for the bundle—usually, a health care system, hospital, or ACO. It may be that home health services will subcontract for a fat fee in order to immunize themselves against risk, and shift all of the risk to the contracting organization. If I were a home health provider, I might try to minimize my own risk, but still offer my services at a price that is financially viable.

The passage of the Patient Protection and Affordable Care Act will profoundly affect the way physicians—particularly those engaged in primary care—practice medicine. Clinicians and their colleagues will be obliged to meet government-mandated performance quality measures while achieving cost efficiencies. Two concepts are central to the implementation of reform in the US health care system: accountable care organizations (ACOs) and the patient-centered medical home (PCMH). To get some perspective on what these changes mean for the practicing clinician, Cleveland Clinic Journal of Medicine (CCJM) interviewed David Longworth, MD, who chairs the Cleveland Clinic Medicine Institute and directs strategy and implementation of Cleveland Clinic ACO-related activities.

CCJM: Please explain briefly the concept of PCMH.

Dr. Longworth: PCMH is not a new concept; first advanced by the American Academy of Pediatrics in 1967,¹ it represents a model of care in which an individual patient has a primary relationship with one provider who manages and coordinates the different aspects of the patient’s health care. The provider collaborates with a team of health care professionals. The concept caught on about a decade ago when a consortium of family medicine organizations and ultimately industry, including IBM, endorsed the concept. IBM and others created the Primary Care Consortium and began to drive the concept of PCMH.

Increasingly, care delivered through PCMH is team-based. The team coordinates the patient’s care and, when appropriate, enlists specialists or subspecialists to provide necessary components of care, all while maintaining responsibility for care coordination across the continuum of care. The medical home model provides an opportunity for enhanced access and care coordination utilizing care outside of the office walls, such as through retail clinics, eVisits, online diagnostic services, phone and electronic communication, and house call services.

Patient-centered medical homes are springing up across the country. In 2008, the National Committee for Quality Assurance (NCQA) developed criteria for recognition of PCMHs.² It scored the sophistication of medical homes at three levels, level 1 being the lowest and level 3 the highest. Between 2008 and the end of 2010, NCQA had recognized more than 1,500 PCMHs. According to the latest figures, more than 3,000 practices have now earned PCMH recognition from the NCQA.³

At Cleveland Clinic, pilot projects at three family health centers that cover 60,000 persons have recently been rolled out with the goal of determining the model of team care that yields the highest value, with value defined by the equation of quality over cost. Ideally, higher quality is delivered at lower cost to increase value.

CCJM: What are the goals of ACOs?

Dr. Longworth: The term “accountable care,” first used in 2006 by Elliot Fisher, Dartmouth Institute of Health Policy and Clinical Practice,⁶ expresses the idea that health care organizations be accountable for the care they deliver, with the three-part aim of better health for populations, better care for individuals, and reduced cost inefficiencies without compromised care.

With accountable care, institutions take on risk with the expectation that they will improve quality but reduce costs, and if they reduce costs and achieve certain quality targets for populations of patients, they will share in the savings accrued. The Affordable Care Act laid the groundwork for creation of ACOs. The regulation for ACOs released by the Centers for Medicare & Medicaid Services (CMS) became effective in January 2012.^7,8 Many health care organizations opposed the rule for reasons related to complexity, prescriptiveness, onerous detail around governance and marketing, and shared savings arrangements, among others. The final rule addressed many of these concerns and enabled the creation of the first wave of ACOs.⁸ At present, 153 ACOs have been approved by CMS.⁹ Other ACOs funded by commercial payers are also being formed in many locations.

For ACOs to be effective, I believe that the cornerstone of management has to be PCMHs.

CCJM: You mentioned that institutions will take on risk. What kind of risk are you referring to?

Dr. Longworth: Added value must be rewarded with sustainable payment models. There are two payment models in the final ACO rule from CMS. Both models require 3-year commitments and both require involvement of primary care physicians. One model for organizations that want to stick a toe in the water has no downside risk and modest potential for gain if they hit certain quality and cost targets. For those organizations that are further along and want to assume risk, the second option is a shared savings/risk payment model, which creates greater incentives for efficiency and quality. In the shared savings/risk model, the ACO can retain a portion of savings if it meets performance and expenditure benchmarks based on its performance during the previous 3 years. It is also at risk for loss if expenditures are greater than a certain amount compared with benchmark expenditures. Ultimately, the final destination for ACOs will be a risk of loss if they don’t perform.

CCJM: How can these two structures—PCMHs and ACOs—optimize the use of home health?

Dr. Longworth: Home health, which is part of the postacute care continuum, will be vitally important for managing individuals and populations of patients as we move toward PCMHs and ACOs. Coordination of care will require communication between home health services and the primary care physicians who are integral to PCMHs. There will have to be an emphasis on transitions of care, from the hospital to home, from skilled nursing facilities to home, and so forth.

Accountable care organizations are responsible for a population of patients, and ACOs receive a fixed amount of money per year to cover an individual life in that population. Thus, managing quality and controlling cost is the name of the game no matter where the patient is in the health care continuum— the office, the emergency room, the hospital, a skilled nursing facility, or a home health setting. For some chronic diseases, managing patients in the home health setting may be vitally important to prevent unnecessary trips to the emergency room and hospital readmissions, thereby reducing expenditures while providing quality care.

CCJM: Do you expect an increase in the number of PCMHs and ACOs to increase the demand for home health services?

Dr. Longworth: Given the necessity of optimizing quality at lower cost, I anticipate a push to deliver as much care as we can in the least expensive “right” setting, which might be the home in some situations. Certainly, we don’t want to send patients home prematurely only to have them return to emergency departments or hospitals, but I think the demand for home health will increase as we try to decrease the number of days in skilled nursing facilities, which are expensive, and to move care from skilled nursing facilities to the home setting.

CCJM: Is there evidence that integrated delivery models such as PCMHs deliver value?

Dr. Longworth: The Patient-Centered Primary Care Collaborative demonstrated quality improvements in selected outcomes domains while also realizing savings through reductions in admissions, emergency department visits, skilled nursing facility days, and pharmacy costs.¹⁰

CCJM: What challenges do PCMHs and ACOs present to home health agencies and the way they provide services, and how will these challenges affect patients and clinicians?

Dr. Longworth: One challenge will be communication between home health services and primary care providers during transitions of care. A second will be managing costs for home health, which entails leveraging new technologies such as in-home devices and telemedicine to provide optimal and ideal monitoring of patients at the lowest potential cost. Home health, like other players along the care continuum, will face increasing scrutiny regarding quality metrics. Home health agencies will likely need to distinguish themselves from one another on the basis of performance measures such as emergency department utilization, unnecessary hospital readmissions, medication errors, and quality of service to patients as well as to primary care providers.

CCJM: How does personalized health care fit into the PCMH model?

Dr. Longworth: Personalized health care, which includes the use of genetic testing in certain situations, is an emerging field that is still in its infancy. Like PCMHs, personalized health care is proactive rather than reactive. Application of personalized health care can help deliver value with better prediction of disease and appropriate use of targeted therapies to improve outcomes for certain individuals. Such individualized treatment not only enables higher quality of care but wiser use of resources. For instance, genetic markers can be used to predict drug metabolism and adverse drug events for certain medications. In the field of oncology, the expression of genetic mutations in certain tumor types can help identify patients most likely to respond to specific targeted therapies. In these ways, personalized health care is patient-centered health care. As part of its proactive nature, personalized health care, beyond genetic testing, also implies advance planning of appointments with a focus on chronic care and keeping patients in the care system.

CCJM: How does participation in a PCMH or an ACO benefit the primary care provider? Are there any disadvantages to participation?

Dr. Longworth: In the current fee-for-service world, primary care physicians and all providers are paid on a widget-by-widget basis. Some primary care physicians and other specialists fear moving to this new world in which they will ultimately be accountable for quality and cost. Not everyone has embraced the concept, but I do think it is inevitable. Primary care physicians especially will be under increasing pressure to care for populations as opposed to individual patients. They will need to redesign the care delivery model to provide team-based, proactive care focusing on the highest-risk patients to try to keep them out of the emergency department and hospital. There will also be a greater emphasis on wellness moving forward, in an attempt to prevent the development of chronic diseases such as diabetes and obesity in individual patients and populations. All of these changes represent a different paradigm for the delivery of care, compared with the present model.

The benefit of participation for a primary care physician depends on the structure of an ACO, particularly the amount of personal financial liability an individual practitioner might have. In a staff-model, fixed-salary institution, primary care physicians would probably be more immune to financial liability than they would in other markets or other compensation models in which salary can fluctuate.

CCJM: What are some of the barriers to ACO implementation that are relevant to office-based practice, and how can they be overcome?

Dr. Longworth: There are a number of barriers to ACOs and true PCMHs. The barriers revolve around redefining workflows and moving away from reactive care—a physician-centric model in which a patient comes into the office with a problem and the physician reacts—to proactive care with the goal being to recognize how the patient is doing over time to prevent unnecessary trips to the emergency department and, ultimately, hospitalization. It is a fundamentally different mindset that involves proactive outreach targeted at high-risk patients whose chronic diseases are managed through a team-based approach. An essential feature of primary care practice will be care coordinators who will manage and proactively anticipate the needs of medically complex, high-risk patients who use a disproportionately large share of services.

In addition, a greater emphasis on wellness will be necessary to prevent the development of chronic diseases such as diabetes, obesity, and hypertension in the large segment of the population that is reasonably healthy.

CCJM: What steps can a clinician take to prepare his or her practice for ACO implementation?

Dr. Longworth: Small practices will be challenged. It is difficult to imagine accountable care without an electronic health record. To understand the population, the practitioner will need to do continuous performance management, which can’t be done without access to data from a population of patients. An increasing number of physicians are aligning with organizations that have the necessary infrastructure to provide the myriad data required to measure quality, to enable continuous improvement in performance, and to enhance the patient experience. Small practices may not have the resources to complete the administrative work necessary to become part of an ACO.

There are ways to align with an ACO that do not constitute full employment; for example, the Cleveland (Ohio) Quality Alliance has aligned with community-based physicians to provide informatics support. Linking with larger organizations that have the resources to provide quality measurement and contracting support will permit smaller community-based physicians’ practices to be part of the game.

CCJM: What steps should PCMHs and ACOs take to leverage and optimize home health services among other parts of the medical neighborhood?

Dr. Longworth: Frankly, the postacute continuum is a challenge for most systems across the country because postacute care is fragmented. Our strategy at Cleveland Clinic is to identify and align with preferred providers of home health services. The criteria that I look for are commitment to quality and transparency, service that is oriented to both patients and PCMHs, and openness to innovation for leveraging health care technology to deliver care at the best value. Home health providers need to think about how to best accomplish these results to position themselves to partner with ACOs.

CCJM: How do PCMHs and ACOs apply to special patient populations and their needs? Is there a population that’s best suited for the medical home model?

Dr. Longworth: Certain populations of higher-risk patients are ideally suited to home health coupled with chronic disease management using care coordinators. Some examples are children with asthma and children with intellectual and developmental disabilities (eg, autism) who have high utilization of emergency services. Another population is patients with heart failure who are often in and out of the emergency department and hospital; there has been a concerted effort to reduce 30-day readmission rates, which are as high as 30%, for this group. (Also see “Home-based care for heart failure: Cleveland Clinic’s ‘Heart Care at Home’ transitional care program”)

CCJM: What are the specific expectations for patient involvement in the PCMH setting?

Dr. Longworth: Our challenge lies in how best to motivate patients and engage them in their own care, especially patients who have chronic diseases. We all struggle to resolve the engagement question. Coaching and patient engagement are functions of PCMHs and at every point along the care continuum. Home health providers can serve as health coaches to promote adherence to medications, healthy lifestyles, and follow-up visits with patients’ doctors—these all need to happen to better engage patients. How to engage patients and motivate them to be more involved in their health is a basic challenge.

CCJM: Along similar lines, how can home health providers work with physicians to achieve patient-centered care?

Dr. Longworth: They can communicate early when they think that things are amiss, serve as health coaches, create technologic solutions that enhance efficiency of communication, and anticipate care needs of patients in the home setting.

CCJM: How might bundling affect the financial picture of PCMHs and patient care?

Dr. Longworth: When one talks about bundling, the devil is in the definition. In bundling, one gets paid for an episode of service. So, for example, a total knee replacement might be compensated by a 30-day bundle that covers only the surgery and the immediate postoperative period. Or it might be a 90-day bundle that includes hospitalization and perhaps some days in skilled nursing facility, but ideally transitioning from hospital to home. In the latter example, the bundle, or the total payment, will be split between the hospital and the home care services. If home health is included in a bundle, there will be tremendous pressure on the home health service to prevent readmission and emergency room visits and to eliminate waste of care. Home health’s vulnerability will depend upon how a bundle is defined for specific service.

CCJM: Who defines the terms of the bundle?

Dr. Longworth: Whoever is applying for the bundle—usually, a health care system, hospital, or ACO. It may be that home health services will subcontract for a fat fee in order to immunize themselves against risk, and shift all of the risk to the contracting organization. If I were a home health provider, I might try to minimize my own risk, but still offer my services at a price that is financially viable.

The US health care system cannot continue with “business as usual.” The current model is broken: it does not deliver the kind of care we want for our patients, ourselves, our families, and our communities. It is our role as professionals to help drive change and make medical care more cost-effective and of higher quality, with better satisfaction for patients as well as for providers.

Central to efforts to reform the system are two concepts. One is the “patient-centered medical home,” in which a single provider is responsible for coordinating care for individual patients. The other is “accountable care organizations,” a new way of organizing care along a continuum from doctor to hospital, mandated by the new health care reform law (technically known as the Patient Protection and Affordable Care Act).

CURRENT STATE OF HEALTH CARE: HIGH COST AND POOR QUALITY

Since health care reform was initially proposed in the 1990s, trends in the United States have grown steadily worse. Escalating health care costs have outstripped inflation, consuming an increasing percentage of the gross domestic product (GDP) at an unsustainable rate. Despite increased spending, quality outcomes are suboptimal. In addition, with the emergence of specialization and technology, care is increasingly fragmented and poorly coordinated, with multiple providers and poorly managed resources.

Over the last 15 years, the United States has far surpassed most countries in the developed world for total health care expenditures per capita.^1,2 In 2009, we spent 17.4% of our GDP on health care, translating to $7,960 per capita, while Japan spent only 8.5% of its GDP, averaging $2,878 per capita.² At the current rate, health care spending in the United States will increase from $2.5 trillion in 2009 to over $4.6 trillion in 2020.³

Paradoxically, costlier care is often of poorer quality. Many countries that spend far less per capita on health care achieve far better outcomes. Even within the United States, greater Medicare spending on a state and regional basis tends to correlate with poorer quality of care.⁴ Spending among Medicare beneficiaries is not standardized and varies widely throughout the country.⁵ The amount of care a patient receives also varies dramatically by region. The number of specialists involved in care during the last year of life is steadily increasing in many regions of the country, indicating poor care coordination.⁶

PATIENT-CENTERED MEDICAL HOMES: A POSITIVE TREND

The problems of high cost, poor quality, and poor coordination of care have led to the emergence of the concept of the patient-centered medical home. Originally proposed in 1967 by the American Academy of Pediatrics in response to the need for care coordination by a single physician, the idea did not really take root until the early 1990s. In 2002, the American Academy of Family Medicine embraced the concept and moved it forward.

According to the National Committee for Quality Assurance (NCQA), a nonprofit organization that provides voluntary certification for medical organizations, the patient-centered medical home is a model of care in which “patients have a direct relationship with a provider who coordinates a cooperative team of healthcare professionals, takes collective responsibility for the care provided to the patient, and arranges for appropriate care with other qualified providers as needed.”⁷

Patient-centered medical homes are supposed to improve quality outcomes and lower costs. In addition, they can compete for public or private incentives that reward this model of care and, as we will see later, are at the heart of ACO readiness.

Medical homes meet certification standards

NCQA first formally licensed patient-centered medical homes in 2008, based on nine standards and six key elements. A scoring system was used to rank the level of certification from level 1 (the lowest) to level 3. From 2008 to the end of 2010, the number of certified homes grew from 28 to 1,506. New York has the largest number of medical homes.

The new elements in the NCQA program align more closely with federal programs that are designed to drive quality, including the Centers for Medicare and Medicaid Services program to encourage the use of the electronic medical record, and with federal rule-making this last spring designed to implement accountable care organizations (ACOs).

Same-day access is now emphasized, as is managing patient populations—rather than just individual patients—with certain chronic diseases, such as diabetes and congestive heart failure. The requirements for tracking and coordinating care have profound implications about how resources are allocated. Ideally, coordinators of chronic disease management are embedded within practices to help manage high-risk patients, although the current reimbursement mechanism does not support this model. Population management may not be feasible for institutions that still rely on paper-based medical records.

Integrated delivery system models such as patient-centered medical homes have demonstrated cost-savings while improving quality of care.^8,9 Reducing hospital admissions and visits to the emergency department shows the greatest cost-savings in these models. Several projects have shown significant cost-savings¹⁰:

The Group Health Cooperative of Puget Sound reduced total costs by $10 per member per month (from $498 to $488, P = 0.76), with a 16% reduction in hospital admissions (P < .001) and a 29% reduction in emergency department visits (P < .001).

The Geisinger Health System Proven-Health Navigator in Pennsylvania reduced readmissions by 18% (P < .01). They also had a 7% reduction in total costs per member per month relative to a matched control group also in the Geisinger system but not in a medical home, although this difference did not reach statistical significance. Private payer demonstration projects of patient-centered medical homes have also shown cost-savings.

Blue Cross Blue Shield of South Carolina randomized patients to participate in either a patient-centered medical home or their standard system. The patient-centered medical home group had 36% fewer hospital days, 12.4% fewer emergency department visits, and a 6.5% reduction in total medical and pharmacy costs compared with controls.

Finally, the use of chronic care coordinators in a patient-centered medical home has been shown to be cost-effective and can lower the overall cost of care despite the investment to hire them. Johns Hopkins Guided Care program demonstrated a 24% reduction in hospital days, 15% fewer emergency department visits, and a 37% reduction in days in a skilled nursing facility. The annual net Medicare savings was $75,000 per coordinator nurse hired.

ACCOUNTABLE CARE ORGANIZATIONS: A NEW SYSTEM OF HEALTH CARE DELIVERY

While the patient-centered medical home is designed to improve the coordination of care among physicians, ACOs have the broader goal of coordinating care across the entire continuum of health care, from physicians to hospitals to other clinicians. The concept of ACOs was spawned in 2006 by Elliott S. Fisher, MD, MPH, of the Dartmouth Institute for Health Policy and Clinical Practice. The idea is that, by improving care coordination within an ACO and reducing fragmented care, costs can be controlled and outcomes improved. Of course, the devil is in the details.

As part of its health care reform initiative, the state of Massachusetts’ Special Commission on the Health Care Payment System defined ACOs as health care delivery systems composed of hospitals, physicians, and other clinician and nonclinician providers that manage care across the entire spectrum of care. An ACO could be a real (incorporated) or virtual (contractually networked) organization, for example, a large physician organization that would contract with one or more hospitals and ancillary providers.¹¹

In a 2009 report to Congress, the Medicare Payment Advisory Committee (MedPac) similarly defined ACOs for the Medicare population. But MedPac also introduced the concept of financial risk: providers in the ACO would share in efficiency gains from improved care coordination and could be subjected to financial penalties for poor performance, depending on the structure of the ACO.¹²

But what has placed ACOs at center stage is the new health care reform law, which encourages the formation of ACOs. On March 31, 2011, the Centers for Medicare and Medicaid Services published proposed rules to implement ACOs for Medicare patients (they appeared in the Federal Register on April 7, 2011).^13,14 Comments on the 129-page proposed rules were due by June 6, 2011. Final rules are supposed to be published later this year.

The proposed new rule has a three-part aim:

• Better care for individuals, as described by all six dimensions of quality in the Institute of Medicine report “Crossing the Quality Chasm”¹⁵: safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity
• Better health for populations, with respect to educating beneficiaries about the major causes of ill health—poor nutrition, physical inactivity, substance abuse, and poverty—as well as about the importance of preventive services such as an annual physical examination and annual influenza vaccination
• Lower growth in expenditures by eliminating waste and inefficiencies while not withholding any needed care that helps beneficiaries.

DETAILS OF THE PROPOSED ACO RULE

Here are some of the highlights of the proposed ACO rule.

Two shared-savings options

Although the program could start as soon as January 1, 2012, the application process is formidable, so this timeline may not be realistic. Moreover, a final rule is pending.

The proposed rule requires at least a 3-year contract, and primary care physicians must be included. Shared savings will be available and will depend on an ACO’s ability to manage costs and to achieve quality target performances. Two shared-savings options will be available: one with no risk until the third year and the other with risk during all 3 years but greater potential benefit. In the one-sided model with no risk until year 3, an ACO would begin to accrue shared savings at a rate of 50% after an initial 2% of savings compared with a risk-adjusted per capita benchmark based on performance during the previous 3 years. In the second plan, an ACO would immediately realize shared savings at a rate of 60% as long as savings were achieved compared with prior benchmark performance. However, in this second model, the ACO would be at risk to repay a share of all losses that were more than 2% higher than the benchmark expenditures, with loss caps of 5%, 7.5%, and 10% above benchmark in years 1, 2, and 3, respectively.

Under the proposed rule, the minimum population size of Medicare beneficiaries is 5,000 patients, with some exceptions in rural or other shortage areas, or areas with critical access hospitals. ACO founders can be primary care physicians, primary care independent practice associations, or employee groups. Participants may include hospitals, critical access hospitals, specialists, and other providers. The ACO must be a legal entity with its own tax identification number and its own governance and management structure.

Concerns have been expressed that, in some markets, certain groups may come together and achieve market dominance with more than half of the population. Proposed ACOs with less than 30% of the market share will be exempt from antitrust concerns, and those with greater than 50% of market share will undergo detailed review.

Patient assignment

Patients will be assigned to an ACO retrospectively, at the end of the 3 years. The Centers for Medicare and Medicaid Services argues that retrospective assignment will encourage the ACO to design a system to help all patients, not just those assigned to the ACO.

Patients may not opt out of being counted against ACO performance measures. Although Medicare will share beneficiaries’ data with the ACO retrospectively so that it can learn more about costs per patient, patients may opt out of this data-sharing. Patients also retain unrestricted choice to see other providers, with attribution of costs incurred to the ACO.

Quality and reporting

The proposed rule has 65 equally weighted quality measures, many of which are not presently reported by most health care organizations. The measures fall within five broad categories: patient and caregiver experience, care coordination, patient safety, preventive health, and managing at-risk populations, including the frail elderly. Bonus payments for cost-savings will be adjusted based on meeting the quality measures.

Governance and management

Under the proposed rule, an ACO must meet stringent governance requirements. It must be a distinct legal entity as governed by state law. There must be proportional representation of all participants (eg, hospitals, community organizations, providers), comprising at least 75% of its Board of Trustees. These members must have authority to execute statutory functions of the ACO. Medicare beneficiaries and community stakeholder organizations must also be represented on the Board.

ACO operations must be managed by an executive director, manager, or general partner, who may or may not be a physician. A board-certified physician who is licensed in the state in which the ACO is domiciled must serve on location as the full-time, senior-level medical director, overseeing and managing clinical operations. A leadership team must be able to influence clinical practice, and a physician-directed process-improvement and quality-assurance committee is required.

Infrastructure and policies

The proposed rule outlines a number of infrastructure and policy requirements that must be addressed in the application process. These include:

• Written performance standards for quality and efficiency
• Evidence-based practice guidelines
• Tools to collect, evaluate, and share data to influence decision-making at the point of care
• Processes to identify and correct poor performance
• Description of how shared savings will be used to further improve care.

CONCERNS ABOUT THE PROPOSED NEW ACO RULE

While there is broad consensus in the health care community that the current system of care delivery fails to achieve the desired outcomes and is financially unsustainable and in need of reform, many concerns have been expressed about the proposed new ACO rule.

The regulations are too detailed. The regulations are highly prescriptive with detailed application, reporting, and regulatory requirements that create significant administrative burdens. Small medical groups are unlikely to have the administrative infrastructure to become involved.

Potential savings are inadequate. The shared savings concept has modest upside gain when modeled with holdback.¹⁶ Moreover, a recent analysis from the University Health System Consortium suggested that 50% of ACOs with 5,000 or more attributed lives would sustain unwarranted penalties as a result of random fluctuation of expenditures in the population.¹⁷

Participation involves a big investment. Participation requires significant resource investment, such as hiring chronic-disease managers and, in some practices, creating a whole new concept of managing wellness and continuity of care.

Retrospective beneficiary assignment is unpopular. Groups would generally prefer to know beforehand for whom they are responsible financially. A prospective assignment model was considered for the proposed rule but was ultimately rejected.

The patient assignment system is too risky. The plurality rule requires only a single visit with the ACO in order to be responsible for a patient for the entire year. In addition, the fact that the patient has the freedom to choose care elsewhere with expense assigned to the ACO confers significant financial risk.

There are too many quality measures. The high number of quality metrics—65—required to be measured and reported is onerous for most organizations.

Advertising is micromanaged. All marketing materials that are sent to patients about the ACO and any subsequent revisions must first be approved by Medicare, a potentially burdensome and time-consuming requirement.

Specialists are excluded. Using only generalists could actually be less cost-effective for some patients, such as those with human immunodeficiency virus, end-stage renal disease, certain malignancies, or advanced congestive heart failure.

Provider replacement is prohibited. Providers cannot be replaced over the 3 years of the demonstration, but the departing physician’s patients are still the responsibility of the plan. This would be especially problematic for small practices.

PREDICTING ACO READINESS

I believe there are five core competencies that are required to be an ACO:

• Operational excellence in care delivery
• Ability to deliver care across the continuum
• Cultural alignment among participating organizations
• Technical and informatics support to manage individual and population data
• Physician alignment around the concept of the ACO.

Certain strategies will increase the chances of success of an ACO:

Reduce emergency department usage and hospitalization. Cost-savings in patient-centered medical homes have been greatest by reducing hospitalizations, rehospitalizations, and emergency department visits.

Develop a high-quality, efficient primary care network. Have enough of a share in the primary care physician network to deliver effective primary care. Make sure there is good access to care and effective communication between patients and the primary care network. Deliver comprehensive services and have good care coordination. Aggressively manage communication, care coordination, and “hand-offs” across the care continuum and with specialists.

Create an effective patient-centered medical home. The current reimbursement climate fails to incentivize all of the necessary elements, which ultimately need to include chronic-care coordinators for medically complex patients, pharmacy support for patient medication management, adequate support staff to optimize efficiency, and a culture of wellness and necessary resources to support wellness.

PHYSICIANS NEED TO DRIVE SOLUTIONS

Soaring health care costs in the United States, poor quality outcomes, and increasing fragmentation of care are the major drivers of health care reform. The Patient Centered Medical Home is a key component to the solution and has already been shown to improve outcomes and lower costs. Further refinement of this concept and implementation should be priorities for primary care physicians and health care organizations.

The ACO concept attempts to further improve quality and lower costs. The proposed ACO rule released by the Centers for Medicare and Medicaid Services on March 31, 2011, has generated significant controversy in the health care community. In its current form, few health care systems are likely to participate. A revised rule is awaited in the coming months. In the meantime, the Centers for Medicare and Medicaid Services has released a request for application for a Pioneer ACO model, which offers up to 30 organizations the opportunity to participate in an ACO pilot that allows for prospective patient assignment and greater shared savings.

Whether ACOs as proposed achieve widespread implementation remains to be seen. However, the current system of health care delivery in this country is broken. Physicians and health care systems need to drive solutions to the challenges we face about quality, cost, access, care coordination, and outcomes.

The US health care system cannot continue with “business as usual.” The current model is broken: it does not deliver the kind of care we want for our patients, ourselves, our families, and our communities. It is our role as professionals to help drive change and make medical care more cost-effective and of higher quality, with better satisfaction for patients as well as for providers.

Central to efforts to reform the system are two concepts. One is the “patient-centered medical home,” in which a single provider is responsible for coordinating care for individual patients. The other is “accountable care organizations,” a new way of organizing care along a continuum from doctor to hospital, mandated by the new health care reform law (technically known as the Patient Protection and Affordable Care Act).

CURRENT STATE OF HEALTH CARE: HIGH COST AND POOR QUALITY

Since health care reform was initially proposed in the 1990s, trends in the United States have grown steadily worse. Escalating health care costs have outstripped inflation, consuming an increasing percentage of the gross domestic product (GDP) at an unsustainable rate. Despite increased spending, quality outcomes are suboptimal. In addition, with the emergence of specialization and technology, care is increasingly fragmented and poorly coordinated, with multiple providers and poorly managed resources.

Over the last 15 years, the United States has far surpassed most countries in the developed world for total health care expenditures per capita.^1,2 In 2009, we spent 17.4% of our GDP on health care, translating to $7,960 per capita, while Japan spent only 8.5% of its GDP, averaging $2,878 per capita.² At the current rate, health care spending in the United States will increase from $2.5 trillion in 2009 to over $4.6 trillion in 2020.³

Paradoxically, costlier care is often of poorer quality. Many countries that spend far less per capita on health care achieve far better outcomes. Even within the United States, greater Medicare spending on a state and regional basis tends to correlate with poorer quality of care.⁴ Spending among Medicare beneficiaries is not standardized and varies widely throughout the country.⁵ The amount of care a patient receives also varies dramatically by region. The number of specialists involved in care during the last year of life is steadily increasing in many regions of the country, indicating poor care coordination.⁶

PATIENT-CENTERED MEDICAL HOMES: A POSITIVE TREND

The problems of high cost, poor quality, and poor coordination of care have led to the emergence of the concept of the patient-centered medical home. Originally proposed in 1967 by the American Academy of Pediatrics in response to the need for care coordination by a single physician, the idea did not really take root until the early 1990s. In 2002, the American Academy of Family Medicine embraced the concept and moved it forward.

According to the National Committee for Quality Assurance (NCQA), a nonprofit organization that provides voluntary certification for medical organizations, the patient-centered medical home is a model of care in which “patients have a direct relationship with a provider who coordinates a cooperative team of healthcare professionals, takes collective responsibility for the care provided to the patient, and arranges for appropriate care with other qualified providers as needed.”⁷

Patient-centered medical homes are supposed to improve quality outcomes and lower costs. In addition, they can compete for public or private incentives that reward this model of care and, as we will see later, are at the heart of ACO readiness.

Medical homes meet certification standards

NCQA first formally licensed patient-centered medical homes in 2008, based on nine standards and six key elements. A scoring system was used to rank the level of certification from level 1 (the lowest) to level 3. From 2008 to the end of 2010, the number of certified homes grew from 28 to 1,506. New York has the largest number of medical homes.

The new elements in the NCQA program align more closely with federal programs that are designed to drive quality, including the Centers for Medicare and Medicaid Services program to encourage the use of the electronic medical record, and with federal rule-making this last spring designed to implement accountable care organizations (ACOs).

Same-day access is now emphasized, as is managing patient populations—rather than just individual patients—with certain chronic diseases, such as diabetes and congestive heart failure. The requirements for tracking and coordinating care have profound implications about how resources are allocated. Ideally, coordinators of chronic disease management are embedded within practices to help manage high-risk patients, although the current reimbursement mechanism does not support this model. Population management may not be feasible for institutions that still rely on paper-based medical records.

Integrated delivery system models such as patient-centered medical homes have demonstrated cost-savings while improving quality of care.^8,9 Reducing hospital admissions and visits to the emergency department shows the greatest cost-savings in these models. Several projects have shown significant cost-savings¹⁰:

The Group Health Cooperative of Puget Sound reduced total costs by $10 per member per month (from $498 to $488, P = 0.76), with a 16% reduction in hospital admissions (P < .001) and a 29% reduction in emergency department visits (P < .001).

The Geisinger Health System Proven-Health Navigator in Pennsylvania reduced readmissions by 18% (P < .01). They also had a 7% reduction in total costs per member per month relative to a matched control group also in the Geisinger system but not in a medical home, although this difference did not reach statistical significance. Private payer demonstration projects of patient-centered medical homes have also shown cost-savings.

Blue Cross Blue Shield of South Carolina randomized patients to participate in either a patient-centered medical home or their standard system. The patient-centered medical home group had 36% fewer hospital days, 12.4% fewer emergency department visits, and a 6.5% reduction in total medical and pharmacy costs compared with controls.

Finally, the use of chronic care coordinators in a patient-centered medical home has been shown to be cost-effective and can lower the overall cost of care despite the investment to hire them. Johns Hopkins Guided Care program demonstrated a 24% reduction in hospital days, 15% fewer emergency department visits, and a 37% reduction in days in a skilled nursing facility. The annual net Medicare savings was $75,000 per coordinator nurse hired.

ACCOUNTABLE CARE ORGANIZATIONS: A NEW SYSTEM OF HEALTH CARE DELIVERY

While the patient-centered medical home is designed to improve the coordination of care among physicians, ACOs have the broader goal of coordinating care across the entire continuum of health care, from physicians to hospitals to other clinicians. The concept of ACOs was spawned in 2006 by Elliott S. Fisher, MD, MPH, of the Dartmouth Institute for Health Policy and Clinical Practice. The idea is that, by improving care coordination within an ACO and reducing fragmented care, costs can be controlled and outcomes improved. Of course, the devil is in the details.

As part of its health care reform initiative, the state of Massachusetts’ Special Commission on the Health Care Payment System defined ACOs as health care delivery systems composed of hospitals, physicians, and other clinician and nonclinician providers that manage care across the entire spectrum of care. An ACO could be a real (incorporated) or virtual (contractually networked) organization, for example, a large physician organization that would contract with one or more hospitals and ancillary providers.¹¹

In a 2009 report to Congress, the Medicare Payment Advisory Committee (MedPac) similarly defined ACOs for the Medicare population. But MedPac also introduced the concept of financial risk: providers in the ACO would share in efficiency gains from improved care coordination and could be subjected to financial penalties for poor performance, depending on the structure of the ACO.¹²

But what has placed ACOs at center stage is the new health care reform law, which encourages the formation of ACOs. On March 31, 2011, the Centers for Medicare and Medicaid Services published proposed rules to implement ACOs for Medicare patients (they appeared in the Federal Register on April 7, 2011).^13,14 Comments on the 129-page proposed rules were due by June 6, 2011. Final rules are supposed to be published later this year.

The proposed new rule has a three-part aim:

• Better care for individuals, as described by all six dimensions of quality in the Institute of Medicine report “Crossing the Quality Chasm”¹⁵: safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity
• Better health for populations, with respect to educating beneficiaries about the major causes of ill health—poor nutrition, physical inactivity, substance abuse, and poverty—as well as about the importance of preventive services such as an annual physical examination and annual influenza vaccination
• Lower growth in expenditures by eliminating waste and inefficiencies while not withholding any needed care that helps beneficiaries.

DETAILS OF THE PROPOSED ACO RULE

Here are some of the highlights of the proposed ACO rule.

Two shared-savings options

Although the program could start as soon as January 1, 2012, the application process is formidable, so this timeline may not be realistic. Moreover, a final rule is pending.

The proposed rule requires at least a 3-year contract, and primary care physicians must be included. Shared savings will be available and will depend on an ACO’s ability to manage costs and to achieve quality target performances. Two shared-savings options will be available: one with no risk until the third year and the other with risk during all 3 years but greater potential benefit. In the one-sided model with no risk until year 3, an ACO would begin to accrue shared savings at a rate of 50% after an initial 2% of savings compared with a risk-adjusted per capita benchmark based on performance during the previous 3 years. In the second plan, an ACO would immediately realize shared savings at a rate of 60% as long as savings were achieved compared with prior benchmark performance. However, in this second model, the ACO would be at risk to repay a share of all losses that were more than 2% higher than the benchmark expenditures, with loss caps of 5%, 7.5%, and 10% above benchmark in years 1, 2, and 3, respectively.

Under the proposed rule, the minimum population size of Medicare beneficiaries is 5,000 patients, with some exceptions in rural or other shortage areas, or areas with critical access hospitals. ACO founders can be primary care physicians, primary care independent practice associations, or employee groups. Participants may include hospitals, critical access hospitals, specialists, and other providers. The ACO must be a legal entity with its own tax identification number and its own governance and management structure.

Concerns have been expressed that, in some markets, certain groups may come together and achieve market dominance with more than half of the population. Proposed ACOs with less than 30% of the market share will be exempt from antitrust concerns, and those with greater than 50% of market share will undergo detailed review.

Patient assignment

Patients will be assigned to an ACO retrospectively, at the end of the 3 years. The Centers for Medicare and Medicaid Services argues that retrospective assignment will encourage the ACO to design a system to help all patients, not just those assigned to the ACO.

Patients may not opt out of being counted against ACO performance measures. Although Medicare will share beneficiaries’ data with the ACO retrospectively so that it can learn more about costs per patient, patients may opt out of this data-sharing. Patients also retain unrestricted choice to see other providers, with attribution of costs incurred to the ACO.

Quality and reporting

The proposed rule has 65 equally weighted quality measures, many of which are not presently reported by most health care organizations. The measures fall within five broad categories: patient and caregiver experience, care coordination, patient safety, preventive health, and managing at-risk populations, including the frail elderly. Bonus payments for cost-savings will be adjusted based on meeting the quality measures.

Governance and management

Under the proposed rule, an ACO must meet stringent governance requirements. It must be a distinct legal entity as governed by state law. There must be proportional representation of all participants (eg, hospitals, community organizations, providers), comprising at least 75% of its Board of Trustees. These members must have authority to execute statutory functions of the ACO. Medicare beneficiaries and community stakeholder organizations must also be represented on the Board.

ACO operations must be managed by an executive director, manager, or general partner, who may or may not be a physician. A board-certified physician who is licensed in the state in which the ACO is domiciled must serve on location as the full-time, senior-level medical director, overseeing and managing clinical operations. A leadership team must be able to influence clinical practice, and a physician-directed process-improvement and quality-assurance committee is required.

Infrastructure and policies

The proposed rule outlines a number of infrastructure and policy requirements that must be addressed in the application process. These include:

• Written performance standards for quality and efficiency
• Evidence-based practice guidelines
• Tools to collect, evaluate, and share data to influence decision-making at the point of care
• Processes to identify and correct poor performance
• Description of how shared savings will be used to further improve care.

CONCERNS ABOUT THE PROPOSED NEW ACO RULE

While there is broad consensus in the health care community that the current system of care delivery fails to achieve the desired outcomes and is financially unsustainable and in need of reform, many concerns have been expressed about the proposed new ACO rule.

The regulations are too detailed. The regulations are highly prescriptive with detailed application, reporting, and regulatory requirements that create significant administrative burdens. Small medical groups are unlikely to have the administrative infrastructure to become involved.

Potential savings are inadequate. The shared savings concept has modest upside gain when modeled with holdback.¹⁶ Moreover, a recent analysis from the University Health System Consortium suggested that 50% of ACOs with 5,000 or more attributed lives would sustain unwarranted penalties as a result of random fluctuation of expenditures in the population.¹⁷

Participation involves a big investment. Participation requires significant resource investment, such as hiring chronic-disease managers and, in some practices, creating a whole new concept of managing wellness and continuity of care.

Retrospective beneficiary assignment is unpopular. Groups would generally prefer to know beforehand for whom they are responsible financially. A prospective assignment model was considered for the proposed rule but was ultimately rejected.

The patient assignment system is too risky. The plurality rule requires only a single visit with the ACO in order to be responsible for a patient for the entire year. In addition, the fact that the patient has the freedom to choose care elsewhere with expense assigned to the ACO confers significant financial risk.

There are too many quality measures. The high number of quality metrics—65—required to be measured and reported is onerous for most organizations.

Advertising is micromanaged. All marketing materials that are sent to patients about the ACO and any subsequent revisions must first be approved by Medicare, a potentially burdensome and time-consuming requirement.

Specialists are excluded. Using only generalists could actually be less cost-effective for some patients, such as those with human immunodeficiency virus, end-stage renal disease, certain malignancies, or advanced congestive heart failure.

Provider replacement is prohibited. Providers cannot be replaced over the 3 years of the demonstration, but the departing physician’s patients are still the responsibility of the plan. This would be especially problematic for small practices.

PREDICTING ACO READINESS

I believe there are five core competencies that are required to be an ACO:

• Operational excellence in care delivery
• Ability to deliver care across the continuum
• Cultural alignment among participating organizations
• Technical and informatics support to manage individual and population data
• Physician alignment around the concept of the ACO.

Certain strategies will increase the chances of success of an ACO:

Reduce emergency department usage and hospitalization. Cost-savings in patient-centered medical homes have been greatest by reducing hospitalizations, rehospitalizations, and emergency department visits.

Develop a high-quality, efficient primary care network. Have enough of a share in the primary care physician network to deliver effective primary care. Make sure there is good access to care and effective communication between patients and the primary care network. Deliver comprehensive services and have good care coordination. Aggressively manage communication, care coordination, and “hand-offs” across the care continuum and with specialists.

Create an effective patient-centered medical home. The current reimbursement climate fails to incentivize all of the necessary elements, which ultimately need to include chronic-care coordinators for medically complex patients, pharmacy support for patient medication management, adequate support staff to optimize efficiency, and a culture of wellness and necessary resources to support wellness.

PHYSICIANS NEED TO DRIVE SOLUTIONS

Soaring health care costs in the United States, poor quality outcomes, and increasing fragmentation of care are the major drivers of health care reform. The Patient Centered Medical Home is a key component to the solution and has already been shown to improve outcomes and lower costs. Further refinement of this concept and implementation should be priorities for primary care physicians and health care organizations.

The ACO concept attempts to further improve quality and lower costs. The proposed ACO rule released by the Centers for Medicare and Medicaid Services on March 31, 2011, has generated significant controversy in the health care community. In its current form, few health care systems are likely to participate. A revised rule is awaited in the coming months. In the meantime, the Centers for Medicare and Medicaid Services has released a request for application for a Pioneer ACO model, which offers up to 30 organizations the opportunity to participate in an ACO pilot that allows for prospective patient assignment and greater shared savings.

Whether ACOs as proposed achieve widespread implementation remains to be seen. However, the current system of health care delivery in this country is broken. Physicians and health care systems need to drive solutions to the challenges we face about quality, cost, access, care coordination, and outcomes.

The US health care system cannot continue with “business as usual.” The current model is broken: it does not deliver the kind of care we want for our patients, ourselves, our families, and our communities. It is our role as professionals to help drive change and make medical care more cost-effective and of higher quality, with better satisfaction for patients as well as for providers.

Central to efforts to reform the system are two concepts. One is the “patient-centered medical home,” in which a single provider is responsible for coordinating care for individual patients. The other is “accountable care organizations,” a new way of organizing care along a continuum from doctor to hospital, mandated by the new health care reform law (technically known as the Patient Protection and Affordable Care Act).

CURRENT STATE OF HEALTH CARE: HIGH COST AND POOR QUALITY

Since health care reform was initially proposed in the 1990s, trends in the United States have grown steadily worse. Escalating health care costs have outstripped inflation, consuming an increasing percentage of the gross domestic product (GDP) at an unsustainable rate. Despite increased spending, quality outcomes are suboptimal. In addition, with the emergence of specialization and technology, care is increasingly fragmented and poorly coordinated, with multiple providers and poorly managed resources.

Over the last 15 years, the United States has far surpassed most countries in the developed world for total health care expenditures per capita.^1,2 In 2009, we spent 17.4% of our GDP on health care, translating to $7,960 per capita, while Japan spent only 8.5% of its GDP, averaging $2,878 per capita.² At the current rate, health care spending in the United States will increase from $2.5 trillion in 2009 to over $4.6 trillion in 2020.³

Paradoxically, costlier care is often of poorer quality. Many countries that spend far less per capita on health care achieve far better outcomes. Even within the United States, greater Medicare spending on a state and regional basis tends to correlate with poorer quality of care.⁴ Spending among Medicare beneficiaries is not standardized and varies widely throughout the country.⁵ The amount of care a patient receives also varies dramatically by region. The number of specialists involved in care during the last year of life is steadily increasing in many regions of the country, indicating poor care coordination.⁶

PATIENT-CENTERED MEDICAL HOMES: A POSITIVE TREND

The problems of high cost, poor quality, and poor coordination of care have led to the emergence of the concept of the patient-centered medical home. Originally proposed in 1967 by the American Academy of Pediatrics in response to the need for care coordination by a single physician, the idea did not really take root until the early 1990s. In 2002, the American Academy of Family Medicine embraced the concept and moved it forward.

According to the National Committee for Quality Assurance (NCQA), a nonprofit organization that provides voluntary certification for medical organizations, the patient-centered medical home is a model of care in which “patients have a direct relationship with a provider who coordinates a cooperative team of healthcare professionals, takes collective responsibility for the care provided to the patient, and arranges for appropriate care with other qualified providers as needed.”⁷

Patient-centered medical homes are supposed to improve quality outcomes and lower costs. In addition, they can compete for public or private incentives that reward this model of care and, as we will see later, are at the heart of ACO readiness.

Medical homes meet certification standards

NCQA first formally licensed patient-centered medical homes in 2008, based on nine standards and six key elements. A scoring system was used to rank the level of certification from level 1 (the lowest) to level 3. From 2008 to the end of 2010, the number of certified homes grew from 28 to 1,506. New York has the largest number of medical homes.

The new elements in the NCQA program align more closely with federal programs that are designed to drive quality, including the Centers for Medicare and Medicaid Services program to encourage the use of the electronic medical record, and with federal rule-making this last spring designed to implement accountable care organizations (ACOs).

Same-day access is now emphasized, as is managing patient populations—rather than just individual patients—with certain chronic diseases, such as diabetes and congestive heart failure. The requirements for tracking and coordinating care have profound implications about how resources are allocated. Ideally, coordinators of chronic disease management are embedded within practices to help manage high-risk patients, although the current reimbursement mechanism does not support this model. Population management may not be feasible for institutions that still rely on paper-based medical records.

Integrated delivery system models such as patient-centered medical homes have demonstrated cost-savings while improving quality of care.^8,9 Reducing hospital admissions and visits to the emergency department shows the greatest cost-savings in these models. Several projects have shown significant cost-savings¹⁰:

The Group Health Cooperative of Puget Sound reduced total costs by $10 per member per month (from $498 to $488, P = 0.76), with a 16% reduction in hospital admissions (P < .001) and a 29% reduction in emergency department visits (P < .001).

The Geisinger Health System Proven-Health Navigator in Pennsylvania reduced readmissions by 18% (P < .01). They also had a 7% reduction in total costs per member per month relative to a matched control group also in the Geisinger system but not in a medical home, although this difference did not reach statistical significance. Private payer demonstration projects of patient-centered medical homes have also shown cost-savings.

Blue Cross Blue Shield of South Carolina randomized patients to participate in either a patient-centered medical home or their standard system. The patient-centered medical home group had 36% fewer hospital days, 12.4% fewer emergency department visits, and a 6.5% reduction in total medical and pharmacy costs compared with controls.

Finally, the use of chronic care coordinators in a patient-centered medical home has been shown to be cost-effective and can lower the overall cost of care despite the investment to hire them. Johns Hopkins Guided Care program demonstrated a 24% reduction in hospital days, 15% fewer emergency department visits, and a 37% reduction in days in a skilled nursing facility. The annual net Medicare savings was $75,000 per coordinator nurse hired.

ACCOUNTABLE CARE ORGANIZATIONS: A NEW SYSTEM OF HEALTH CARE DELIVERY

While the patient-centered medical home is designed to improve the coordination of care among physicians, ACOs have the broader goal of coordinating care across the entire continuum of health care, from physicians to hospitals to other clinicians. The concept of ACOs was spawned in 2006 by Elliott S. Fisher, MD, MPH, of the Dartmouth Institute for Health Policy and Clinical Practice. The idea is that, by improving care coordination within an ACO and reducing fragmented care, costs can be controlled and outcomes improved. Of course, the devil is in the details.

As part of its health care reform initiative, the state of Massachusetts’ Special Commission on the Health Care Payment System defined ACOs as health care delivery systems composed of hospitals, physicians, and other clinician and nonclinician providers that manage care across the entire spectrum of care. An ACO could be a real (incorporated) or virtual (contractually networked) organization, for example, a large physician organization that would contract with one or more hospitals and ancillary providers.¹¹

In a 2009 report to Congress, the Medicare Payment Advisory Committee (MedPac) similarly defined ACOs for the Medicare population. But MedPac also introduced the concept of financial risk: providers in the ACO would share in efficiency gains from improved care coordination and could be subjected to financial penalties for poor performance, depending on the structure of the ACO.¹²

But what has placed ACOs at center stage is the new health care reform law, which encourages the formation of ACOs. On March 31, 2011, the Centers for Medicare and Medicaid Services published proposed rules to implement ACOs for Medicare patients (they appeared in the Federal Register on April 7, 2011).^13,14 Comments on the 129-page proposed rules were due by June 6, 2011. Final rules are supposed to be published later this year.

The proposed new rule has a three-part aim:

• Better care for individuals, as described by all six dimensions of quality in the Institute of Medicine report “Crossing the Quality Chasm”¹⁵: safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity
• Better health for populations, with respect to educating beneficiaries about the major causes of ill health—poor nutrition, physical inactivity, substance abuse, and poverty—as well as about the importance of preventive services such as an annual physical examination and annual influenza vaccination
• Lower growth in expenditures by eliminating waste and inefficiencies while not withholding any needed care that helps beneficiaries.

DETAILS OF THE PROPOSED ACO RULE

Here are some of the highlights of the proposed ACO rule.

Two shared-savings options

Although the program could start as soon as January 1, 2012, the application process is formidable, so this timeline may not be realistic. Moreover, a final rule is pending.

The proposed rule requires at least a 3-year contract, and primary care physicians must be included. Shared savings will be available and will depend on an ACO’s ability to manage costs and to achieve quality target performances. Two shared-savings options will be available: one with no risk until the third year and the other with risk during all 3 years but greater potential benefit. In the one-sided model with no risk until year 3, an ACO would begin to accrue shared savings at a rate of 50% after an initial 2% of savings compared with a risk-adjusted per capita benchmark based on performance during the previous 3 years. In the second plan, an ACO would immediately realize shared savings at a rate of 60% as long as savings were achieved compared with prior benchmark performance. However, in this second model, the ACO would be at risk to repay a share of all losses that were more than 2% higher than the benchmark expenditures, with loss caps of 5%, 7.5%, and 10% above benchmark in years 1, 2, and 3, respectively.

Under the proposed rule, the minimum population size of Medicare beneficiaries is 5,000 patients, with some exceptions in rural or other shortage areas, or areas with critical access hospitals. ACO founders can be primary care physicians, primary care independent practice associations, or employee groups. Participants may include hospitals, critical access hospitals, specialists, and other providers. The ACO must be a legal entity with its own tax identification number and its own governance and management structure.

Concerns have been expressed that, in some markets, certain groups may come together and achieve market dominance with more than half of the population. Proposed ACOs with less than 30% of the market share will be exempt from antitrust concerns, and those with greater than 50% of market share will undergo detailed review.

Patient assignment

Patients will be assigned to an ACO retrospectively, at the end of the 3 years. The Centers for Medicare and Medicaid Services argues that retrospective assignment will encourage the ACO to design a system to help all patients, not just those assigned to the ACO.

Patients may not opt out of being counted against ACO performance measures. Although Medicare will share beneficiaries’ data with the ACO retrospectively so that it can learn more about costs per patient, patients may opt out of this data-sharing. Patients also retain unrestricted choice to see other providers, with attribution of costs incurred to the ACO.

Quality and reporting

The proposed rule has 65 equally weighted quality measures, many of which are not presently reported by most health care organizations. The measures fall within five broad categories: patient and caregiver experience, care coordination, patient safety, preventive health, and managing at-risk populations, including the frail elderly. Bonus payments for cost-savings will be adjusted based on meeting the quality measures.

Governance and management

Under the proposed rule, an ACO must meet stringent governance requirements. It must be a distinct legal entity as governed by state law. There must be proportional representation of all participants (eg, hospitals, community organizations, providers), comprising at least 75% of its Board of Trustees. These members must have authority to execute statutory functions of the ACO. Medicare beneficiaries and community stakeholder organizations must also be represented on the Board.

ACO operations must be managed by an executive director, manager, or general partner, who may or may not be a physician. A board-certified physician who is licensed in the state in which the ACO is domiciled must serve on location as the full-time, senior-level medical director, overseeing and managing clinical operations. A leadership team must be able to influence clinical practice, and a physician-directed process-improvement and quality-assurance committee is required.

Infrastructure and policies

The proposed rule outlines a number of infrastructure and policy requirements that must be addressed in the application process. These include:

• Written performance standards for quality and efficiency
• Evidence-based practice guidelines
• Tools to collect, evaluate, and share data to influence decision-making at the point of care
• Processes to identify and correct poor performance
• Description of how shared savings will be used to further improve care.

CONCERNS ABOUT THE PROPOSED NEW ACO RULE

While there is broad consensus in the health care community that the current system of care delivery fails to achieve the desired outcomes and is financially unsustainable and in need of reform, many concerns have been expressed about the proposed new ACO rule.

The regulations are too detailed. The regulations are highly prescriptive with detailed application, reporting, and regulatory requirements that create significant administrative burdens. Small medical groups are unlikely to have the administrative infrastructure to become involved.

Potential savings are inadequate. The shared savings concept has modest upside gain when modeled with holdback.¹⁶ Moreover, a recent analysis from the University Health System Consortium suggested that 50% of ACOs with 5,000 or more attributed lives would sustain unwarranted penalties as a result of random fluctuation of expenditures in the population.¹⁷

Participation involves a big investment. Participation requires significant resource investment, such as hiring chronic-disease managers and, in some practices, creating a whole new concept of managing wellness and continuity of care.

Retrospective beneficiary assignment is unpopular. Groups would generally prefer to know beforehand for whom they are responsible financially. A prospective assignment model was considered for the proposed rule but was ultimately rejected.

The patient assignment system is too risky. The plurality rule requires only a single visit with the ACO in order to be responsible for a patient for the entire year. In addition, the fact that the patient has the freedom to choose care elsewhere with expense assigned to the ACO confers significant financial risk.

There are too many quality measures. The high number of quality metrics—65—required to be measured and reported is onerous for most organizations.

Advertising is micromanaged. All marketing materials that are sent to patients about the ACO and any subsequent revisions must first be approved by Medicare, a potentially burdensome and time-consuming requirement.

Specialists are excluded. Using only generalists could actually be less cost-effective for some patients, such as those with human immunodeficiency virus, end-stage renal disease, certain malignancies, or advanced congestive heart failure.

Provider replacement is prohibited. Providers cannot be replaced over the 3 years of the demonstration, but the departing physician’s patients are still the responsibility of the plan. This would be especially problematic for small practices.

PREDICTING ACO READINESS

I believe there are five core competencies that are required to be an ACO:

• Operational excellence in care delivery
• Ability to deliver care across the continuum
• Cultural alignment among participating organizations
• Technical and informatics support to manage individual and population data
• Physician alignment around the concept of the ACO.

Certain strategies will increase the chances of success of an ACO:

Reduce emergency department usage and hospitalization. Cost-savings in patient-centered medical homes have been greatest by reducing hospitalizations, rehospitalizations, and emergency department visits.

Develop a high-quality, efficient primary care network. Have enough of a share in the primary care physician network to deliver effective primary care. Make sure there is good access to care and effective communication between patients and the primary care network. Deliver comprehensive services and have good care coordination. Aggressively manage communication, care coordination, and “hand-offs” across the care continuum and with specialists.

Create an effective patient-centered medical home. The current reimbursement climate fails to incentivize all of the necessary elements, which ultimately need to include chronic-care coordinators for medically complex patients, pharmacy support for patient medication management, adequate support staff to optimize efficiency, and a culture of wellness and necessary resources to support wellness.

PHYSICIANS NEED TO DRIVE SOLUTIONS

Soaring health care costs in the United States, poor quality outcomes, and increasing fragmentation of care are the major drivers of health care reform. The Patient Centered Medical Home is a key component to the solution and has already been shown to improve outcomes and lower costs. Further refinement of this concept and implementation should be priorities for primary care physicians and health care organizations.

The ACO concept attempts to further improve quality and lower costs. The proposed ACO rule released by the Centers for Medicare and Medicaid Services on March 31, 2011, has generated significant controversy in the health care community. In its current form, few health care systems are likely to participate. A revised rule is awaited in the coming months. In the meantime, the Centers for Medicare and Medicaid Services has released a request for application for a Pioneer ACO model, which offers up to 30 organizations the opportunity to participate in an ACO pilot that allows for prospective patient assignment and greater shared savings.

Whether ACOs as proposed achieve widespread implementation remains to be seen. However, the current system of health care delivery in this country is broken. Physicians and health care systems need to drive solutions to the challenges we face about quality, cost, access, care coordination, and outcomes.

Studies published during the past year provide information that could influence how we treat several infectious diseases in daily practice. Here is a brief overview of these “impact” studies.

VANCOMYCIN BEATS METRONIDAZOLE FOR SEVERE C DIFFICILE DIARRHEA

Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-assoicated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45:302–307.

Clostridium difficile is the most common infectious cause of nosocomial diarrhea. Furthermore, a unique and highly virulent strain has emerged.

Which drug should be the treatment of choice: metronidazole (Flagyl) or oral vancomycin (Vancocin)? Over time, some infectious disease practitioners have believed that oral vancomycin is superior to oral metronidazole for the treatment of severe C difficile-associated diarrhea. Indeed, in a recently published survey, more than 25% of infectious disease practitioners said they used vancomycin as initial therapy for C difficile-associated diarrhea.¹ Until recently, there has been no evidence to support this preference.

Ever since the first description of C difficile-associated diarrhea in the late 1970s, only two head-to-head studies have compared the efficacy of metronidazole vs vancomycin for the treatment of this disorder. Both studies were underpowered and neither was blinded. In 1983, Teasley et al² treated 101 patients with metronidazole or vancomycin in a non-blinded, nonrandomized study and found no difference in efficacy. In 1996, Wenisch et al,³ in a prospective, randomized, but nonblinded study in 119 patients, compared vancomycin, metronidazole, fusidic acid, and teicoplanin (Targocid) and also found no significant difference in efficacy.

The study. Zar et al,⁴ in a prospective, double-blind trial at a single institution over an 8-year period, randomized 172 patients with C difficile-associated diarrhea to receive either oral metronidazole 250 mg four times a day or oral vancomycin 125 mg four times a day, both for 10 days. (The appropriate dosage of vancomycin has been debated over the years. In 1989, Fekety et al⁵ treated patients who had antibiotic-associated C difficile colitis with either 125 or 500 mg of vancomycin, four times a day, and found that the low dosage was as effective as the high dosage.) Both groups also received an oral placebo in addition to the study drug.

In the study of Zar et al, criteria for inclusion were diarrhea (defined as having more than two nonformed stools per 24 hours) and the finding of either toxin A in the stool or pseudomembranes on endoscopic examination. Patients were excluded if they were pregnant, had suspected or proven life-threatening intra-abdominal complications, were allergic to either study drug, had taken one of the study drugs during the last 14 days, or had previously had C difficile-associated diarrhea that did not respond to either study drug.

Patients were followed for up to 21 days. The primary end points were cure, treatment failure, or relapse. Cure was defined as the resolution of diarrhea and no C difficile toxin A detected on stool assay at days 6 and 10.

Disease severity was classified as either mild or severe based on a point system: patients received a single point each for being older than 60 years, being febrile, having an albumin level of less than 2.5 mg/dL, or having a white blood cell count of more than 15 × 10⁹/L. Patients were classified as having severe disease if they had two or more points. They received two points (ie, they were automatically classified as having severe disease) if they had pseudomembranous colitis or if they developed C difficile infection that required treatment in an intensive care unit.

Findings. The overall cure rate in patients receiving vancomycin was 97%, compared with 84% for those on metronidazole (P = .006). This difference was attributable to the group of patients with severe disease; no difference in treatment outcome was found in patients with mild disease. The relapse rates did not differ significantly between treatment groups in patients with either mild or severe disease.

Comments. The study was limited in that it was done at a single center and was done before the current highly virulent strain emerged. Whether these data can be extrapolated to today’s epidemic is unclear. Moreover, the investigators did not test for antimicrobial susceptibility (although metronidazole resistance is still uncommon). Finally, the development of colonization with vancomycin-resistant enterococci, one of the reasons that oral vancomycin is often not recommended, was not assessed.

Despite the study’s limitations, it shows that for severely ill patients with C difficile-associated diarrhea, oral vancomycin should be the treatment of choice.

IS CEFEPIME SAFE?

Yahav D, Paul M, Fraser A, Sarid N, Leibovici L. Efficacy and safety of cefepime: a systematic review and meta-analysis. Lancet Infect Dis 2007; 7:338 348.

Cefepime (Maxipime) is a broad-spectrum, fourth-generation cephalosporin. It is widely used for its approved indications: pneumonia; bacteremia; urinary tract, abdominal, skin, and soft-tissue infections; and febrile neutropenia.

In 2006, Paul et al⁶ reviewed 33 controlled trials of empiric cefepime monotherapy for febrile neutropenia and found a higher death rate with cefepime than with other beta-lactam antibiotics. That preliminary study spawned the following more comprehensive review by the same group.

The study. Yahav et al⁷ performed a meta-analysis of randomized trials that compared cefepime with another beta-lactam antibiotic alone or combined with a non-beta-lactam drug given in both treatment groups. Two reviewers independently identified studies from a number of databases and extracted data.

The primary end point was the rate of death from all causes at 30 days. Secondary end points were clinical failure (defined as unresolved infection, treatment modification, or death from infection), failure to eradicate the causative pathogens, superinfection with different bacterial, fungal, or viral organisms, and adverse events.

More than 8,000 patients were involved in 57 trials: 20 trials evaluated therapy for neutropenic fever, 18 for pneumonia, 5 for urogenital infections, 2 for meningitis, and 10 for mixed infections.

Comparison drugs for febrile neutropenia were ceftazidime (Ceptaz, Fortaz, Tazicef); im-ipenem-cilastatin (Primaxin) or meropenem (Merrem); piperacillin-tazobactam (Zosyn); and ceftriaxone (Rocephin). Aminoglycosides were added to both treatment groups in six trials and vancomycin was added in one trial.

For pneumonia, comparison drugs were ceftazidime, ceftriaxone, cefotaxime (Claforan), and cefoperazone-sulbactam.

Adequate allocation concealment and allocation-sequence generation were described in 30 studies. Scores for baseline patient risk factors did not differ significantly between study populations.

Findings. The death rate from all causes was higher in patients taking cefepime than with other beta-lactam antibiotics (risk ratio [RR] 1.26, 95% confidence interval [CI] 1.08–1.49, P = .005). The rate was lower with each of the alternative antibiotics, but the difference was statistically significant only for cefepime vs piperacillin-tazobactam (RR 2.14, 95% CI 1.17–3.89, P = .05).

The rate of death from all causes was higher for cefepime in all types of infections (except urinary tract infection, in which no deaths occurred in any of the treatment arms), although the difference was statistically significant only for febrile neutropenia (RR 1.42, 95% CI 1.09–1.84, P = .009). No differences were found in secondary outcomes, either by disease or by drug used.

Comments. This meta-analysis supports previous findings that more patients die when cefepime is used. The mechanism, however, is unclear. The authors call for reconsideration of the use of cefepime for febrile neutropenia, community-acquired pneumonia, and health-care associated pneumonia. In November 2007, the US Food and Drug Administration (FDA) launched an investigation into the risk of cefepime but has not yet made recommendations. Practitioners should be aware of these data when considering antimicrobial options for treatment in these settings. Knowledge of local antimicrobial susceptibility data of key pathogens is essential in determining optimal empiric and pathogen-specific therapy.

AN ANTIBIOTIC AND A NASAL STEROID ARE INEFFECTIVE IN ACUTE SINUSITIS

Williamson IG, Rumsby K, Benge S, et al. Antibiotics and topical nasal steroid for treatment of acute maxillary sinusitis: a randomized controlled trial. JAMA 2007; 298:2487 2496.

In the United States and Europe 1% to 2% of all primary care office visits are for acute sinusitis. Studies indicate that 67% to nearly 100% of patients with symptoms of sinusitis receive an antibiotic for it, even though the evidence of efficacy is weak and guidelines do not support this practice. Cochrane reviews⁸,⁹ have suggested that topical corticosteroids, penicillin, and amoxicillin have marginal benefit in acute sinusitis, but the studies on which the analyses were based were flawed.

The Berg and Carenfelt criteria were developed to help diagnose bacterial sinusitis.¹⁰ At the time they were developed, computed tomography was not routinely done to search for sinusitis, so plain film diagnosis was compared with clinical criteria. The Berg and Carenfelt criteria include three symptoms and one sign: a history of purulent unilateral nasal discharge, unilateral facial pain, or bilateral purulent discharge and pus in the nares on inspection. The presence of two criteria has reasonable sensitivity (81%), specificity (89%), and positive predictive value (86%) for detecting acute bacterial or maxillary sinusitis in the office setting.

The study. Williamson et al¹¹ conducted a double-blind, randomized, placebo-controlled trial of antibiotic and topical nasal steroid use in patients with suspected acute maxillary sinusitis. The trial included 240 patients who were seen in 58 family practices over 4 years in the United Kingdom and who had acute nonrecurrent sinusitis based on Berg and Carenfelt criteria. Patients were at least 16 years old; the average age was 44. Three-quarters were women. Few had fever, and 70% met only two Berg and Carenfelt criteria; the remaining 30% met three or all four criteria. Patients were excluded who had at least two sinusitis attacks per year, underlying nasal pathology, significant comorbidities, or a history of penicillin allergy, or if they had been treated with antibiotics or steroids during the past month.

Patients were randomized to receive one of four treatments:

• Amoxicillin 500 mg three times a day for 7 days plus budesonide (Rhinocort) 200 μg in each nostril once a day for 10 days
• Placebo amoxicillin plus real budesonide
• Amoxicillin plus placebo budesonide
• Placebo amoxicillin plus placebo budes-onide.

The groups were well matched. Outcomes were based on a questionnaire and a patient diary that assessed the duration and severity of 11 symptoms.

Findings. No difference was found between the treatment groups in overall outcome, in the proportion of those with symptoms at 10 days, or in daily symptom severity. The secondary analysis suggested that nasal steroids were marginally more effective in patients with less severe symptoms.

The authors concluded that neither an antibiotic nor a nasal steroid, alone or in combination, is effective for acute maxillary sinusitis in the primary care setting, and they recommended against their routine use.

Comments. This study had limitations. Some cases of viral disease may have been included: no objective reference standard (ie, computed tomography of the sinuses or sinus aspiration) was used, and although the Berg and Carenfelt criteria have been validated in secondary care settings, they have not been validated in primary care settings. In addition, fever was absent in most patients, and mild symptoms were poorly defined. Moreover, recruitment of patients was slow, raising questions of bias and generalizability. The study also did not address patients with comorbidities.

Nevertheless, the study shows that outpatients with symptoms of sinusitis without fever or significant comorbidities should not be treated with oral antibiotics or nasal steroids. Otherwise, antibiotic therapy may still be appropriate in certain patients at high risk and in those with fever.

PREDNISOLONE IS BENEFICIAL IN ACUTE BELL PALSY, ACYCLOVIR IS NOT

Sullivan FM, Swan IR, Donnan PT, et al. Early treatment with prednisolone or acyclovir in Bell palsy. N Engl J Med 2007; 357:1598 1607.

Bell palsy accounts for about two-thirds of cases of acute unilateral facial nerve palsy in the United States. Virologic studies from patients undergoing surgery for facial nerve decompression have suggested a possible association with herpes simplex virus. Other causes of acute unilateral facial nerve palsy include Lyme disease, sarcoidosis, Sjögren syndrome, trauma, carotid tumors, and diabetes. Bell palsy occurs most often during middle age, peaking between ages 30 and 45. As many as 30% of patients are left with significant neurologic residua. Corticosteroids and antiviral medications are commonly used to treat Bell palsy, but evidence for their efficacy is weak.

The study. Sullivan et al¹² conducted a double-blind, placebo-controlled, randomized trial over 2 years in Scotland with 551 patients, age 16 years or older, recruited within 72 hours of the onset of symptoms. Patients who were pregnant or breastfeeding or who had uncontrolled diabetes, peptic ulcer disease, suppurative otitis, zoster, multiple sclerosis, sarcoidosis, or systemic infection were excluded. They were randomized to treatment for 10 days with either acyclovir (Zovirax) 400 mg five times daily or prednisolone 25 mg twice daily, both agents, or placebo.

The primary outcome was recovery of facial function based on the House-Brackmann grading system. Digital photographs of patients at 3 and 9 months of treatment were evaluated independently by three experts who were unaware of study group assignment or stage of assessment. These included a neurologist, an otorhinolaryn-gologist, and a plastic surgeon. The secondary outcomes were quality of life, facial appearance, and pain, as assessed by the patients.

Findings. At 3 months, 83% of the prednisolone recipients had no facial asymmetry, increasing to 94% at 9 months. In comparison, the numbers were 64% and 82% in those who did not receive prednisolone, and these differences were statistically significant. Acyclovir was found to be of no benefit at either 3 or 9 months.

The authors concluded that early treatment of Bell palsy with prednisolone improves the chance of complete recovery, and that acyclovir alone or in combination with steroids confers no benefit.

Comments. At about the same time that this study was published, Hato et al¹³ evaluated valacyclovir (Valtrex) plus prednisolone vs placebo plus prednisolone and found that patients with severe Bell palsy (defined as complete facial nerve paralysis) benefited from antiviral therapy.

Corticosteroids are indicated for acute Bell palsy. In patients with complete facial nerve paralysis, valacyclovir should be considered.

POSACONAZOLE AS PROPHYLAXIS IN FEBRILE NEUTROPENIA

Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356:348 359.

For many years, amphotericin B was the only drug available for antifungal prophylaxis and therapy. Then, in the early 1990s, a number of studies suggested that the triazoles, notably fluconazole (Diflucan), were effective in a variety of clinical settings for both prophylaxis and therapy of serious fungal infections. In 1992 and 1995, two studies found that fluconazole prophylaxis was as effective as amphotericin B in preventing fungal infections in patients undergoing hematopoietic stem cell transplantation.¹⁴,¹⁵ Based on these studies, clinical practice changed, not only for patients undergoing hematopoietic stem cell transplantation, but also for empiric antifungal prophylaxis in patients receiving myeloablative chemotherapy to treat hematologic malignancies.

Fluconazole is not active against invasive molds, and newer drugs—itraconazole (Sporanox), voriconazole (Vfend), and most recently posaconazole (Noxafil)—were developed with expanded clinical activity. Studies in the 1990s found that itraconazole and voriconazole performed better than fluconazole but did not provide complete prophylaxis.

The study. Cornely et al¹⁶ compared posaconazole with fluconazole or itraconazole in 602 patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplasia. Although patients were randomized to either the posaconazole group or the fluconazole-or-itraconazole group, investigators could choose either fluconazole or itraconazole for patients randomized to that group. Most patients in the latter group (240 of 298) received fluconazole.

Patients were at least 13 years old, were able to take oral medications, had newly diagnosed disease or were having a first relapse, and had or were anticipated to have neutropenia for at least 7 days. The study excluded patients with invasive fungal infection within 30 days, significant liver or kidney dysfunction, an abnormal QT interval corrected for heart rate, an Eastern Cooperative Oncology Group performance status score of more than 2 (in bed more than half of the day), or allergy or a contraindication to azoles.

The trial treatment was started with each cycle of chemotherapy and was continued until recovery from neutropenia and complete remission, until invasive fungal infection developed, or for up to 12 weeks, whichever came first.

The primary end point was the incidence of proven or probable invasive fungal infection during the treatment phase. Secondary end points included death from any cause and time to death.

Findings. Posaconazole recipients fared significantly better than patients in the other treatment group with respect to the incidence of proven or probable invasive fungal infection, invasive aspergillosis, probability of death, death at 100 days, and death secondary to fungal infection. Treatment-related severe adverse events were a bit more common with posaconazole.

The authors suggest that posaconazole prophylaxis may have a place in prophylaxis in patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplasia.

Comments. It is not surprising that posaconazole performed better, because the standard treatment arm contained an agent (fluconazole) that did not cover Aspergillus, the most frequently identified source of invasive fungal infection during the treatment phase of the study.

In an editorial accompanying the article, De Pauw and Donnelly¹⁷ pointed out that whether posaconazole prophylaxis would be appropriate in a given case depends upon how likely infection is with Aspergillus. An institution with very few Aspergillus infections would have a much higher number needed to treat with posaconazole to prevent one case of aspergillosis than in this study, in which the number needed to treat was 16. Thus, knowledge of local epidemiology and incidence of invasive mold infections should guide selection of the optimal antifungal agent for prophylaxis in patients undergoing myeloablative chemotherapy for acute myelogenous leukemia or myelodysplasia.

ANIDULAFUNGIN VS FLUCONAZOLE FOR INVASIVE CANDIDIASIS

Reboli AC, Rotstein C, Pappas PG, et al; Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356:2472 2482.

In 2002, caspofungin (Cancidas) was the first of a new class of drugs, the echinocandins, to be approved by the FDA. The echinocandins have been shown to be as effective as amphotericin B for the treatment of invasive candidiasis, but how they compare with azoles is an ongoing debate. Currently approved treatments for candidiasis, an important cause of disease and death in hospitalized patients, include fluconazole, voriconazole, caspofungin, and amphotericin B. Anidulafungin is the newest echinocandin and has been shown in a phase 2 study to be effective against invasive candidiasis.

The study. Reboli et al¹⁸ performed a randomized, double-blind, noninferiority trial comparing anidulafungin and fluconazole to treat candidemia and other forms of candidiasis. The trial was conducted in multiple centers over 15 months and involved 245 patients at least 16 years old who had a single blood culture or culture from a normally sterile site that was positive for Candida species, and who also had one or more of the following: fever, hypothermia, hypotension, local signs and symptoms, or radiographic findings of candidiasis. Patients were excluded if they had had more than 48 hours of systemic therapy with either of these agents or another antifungal drug, if they had had prophylaxis with an azole for more than 7 of the previous 30 days, or if they had refractory candidal infection, elevated liver function test results, Candida krusei infection, meningitis, endocarditis, or osteomyelitis. Removal of central venous catheters was recommended for all patients with candidemia.

Patients were initially stratified by severity of illness based on the Acute Physiology and Chronic Health Evaluation (APACHE II) score (= 20 or > 20, with higher scores indicating more severe disease) and the presence or absence of neutropenia at enrollment. They were then randomly assigned to receive either intravenous anidulafungin (200 mg on day 1 and then 100 mg daily) or intravenous fluconazole (800 mg on day 1 and then 400 mg daily, with the dose adjusted according to creatinine clearance) for at least 14 days after a negative blood culture and improved clinical state and for up to 42 days in total. After 10 days of intravenous therapy, all patients could receive oral fluconazole 400 mg daily at the investigators’ discretion if clinical improvement criteria were met.

The primary end point was global response at the end of intravenous therapy, defined as clinical and microbiologic improvement. A number of secondary end points were also studied. Response failure was defined as no significant clinical improvement, death due to candidiasis, persistent or recurrent candidiasis or a new Candida infection, or an indeterminate response (eg, loss to follow-up or death not attributed to candidiasis).

Of the 245 patients in the primary analysis, 89% had candidemia alone, and nearly two-thirds of those cases were caused by Candida albicans. Only 3% of patients had neutropenia at baseline. Fluconazole resistance was monitored and was rare.

Findings. Intravenous therapy was successful in 76% of patients receiving anidulafungin and in 60% of fluconazole recipients, a difference of 15.4 percentage points (95% CI 3.9–27.0). Results were similar for other efficacy end points. The rate of death from all causes was 31% in the fluconazole group and 23% in the anidulafungin group (P = .13). The frequency and types of adverse events were similar in the two groups. The authors concluded that anidulafungin was not inferior to fluconazole in the treatment of invasive candidiasis.

Comments. Does this study prove that anidulafungin is the treatment of choice for invasive candidiasis? Although the study noted trends in favor of anidulafungin, the differences did not achieve statistical significance for superiority. In addition, the study included so few patients with neutropenia that the results are not applicable to those patients. Finally, anidulafungin is several times more expensive than fluconazole.

Fluconazole has stood the test of time and is probably still the treatment of choice in patients who have suspected or proven candidemia or invasive candidiasis, unless they have already been treated with azoles or are critically ill. In those settings, echinocandins may be the preferred treatment.

Studies published during the past year provide information that could influence how we treat several infectious diseases in daily practice. Here is a brief overview of these “impact” studies.

VANCOMYCIN BEATS METRONIDAZOLE FOR SEVERE C DIFFICILE DIARRHEA

Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-assoicated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45:302–307.

Clostridium difficile is the most common infectious cause of nosocomial diarrhea. Furthermore, a unique and highly virulent strain has emerged.

Which drug should be the treatment of choice: metronidazole (Flagyl) or oral vancomycin (Vancocin)? Over time, some infectious disease practitioners have believed that oral vancomycin is superior to oral metronidazole for the treatment of severe C difficile-associated diarrhea. Indeed, in a recently published survey, more than 25% of infectious disease practitioners said they used vancomycin as initial therapy for C difficile-associated diarrhea.¹ Until recently, there has been no evidence to support this preference.

Ever since the first description of C difficile-associated diarrhea in the late 1970s, only two head-to-head studies have compared the efficacy of metronidazole vs vancomycin for the treatment of this disorder. Both studies were underpowered and neither was blinded. In 1983, Teasley et al² treated 101 patients with metronidazole or vancomycin in a non-blinded, nonrandomized study and found no difference in efficacy. In 1996, Wenisch et al,³ in a prospective, randomized, but nonblinded study in 119 patients, compared vancomycin, metronidazole, fusidic acid, and teicoplanin (Targocid) and also found no significant difference in efficacy.

The study. Zar et al,⁴ in a prospective, double-blind trial at a single institution over an 8-year period, randomized 172 patients with C difficile-associated diarrhea to receive either oral metronidazole 250 mg four times a day or oral vancomycin 125 mg four times a day, both for 10 days. (The appropriate dosage of vancomycin has been debated over the years. In 1989, Fekety et al⁵ treated patients who had antibiotic-associated C difficile colitis with either 125 or 500 mg of vancomycin, four times a day, and found that the low dosage was as effective as the high dosage.) Both groups also received an oral placebo in addition to the study drug.

In the study of Zar et al, criteria for inclusion were diarrhea (defined as having more than two nonformed stools per 24 hours) and the finding of either toxin A in the stool or pseudomembranes on endoscopic examination. Patients were excluded if they were pregnant, had suspected or proven life-threatening intra-abdominal complications, were allergic to either study drug, had taken one of the study drugs during the last 14 days, or had previously had C difficile-associated diarrhea that did not respond to either study drug.

Patients were followed for up to 21 days. The primary end points were cure, treatment failure, or relapse. Cure was defined as the resolution of diarrhea and no C difficile toxin A detected on stool assay at days 6 and 10.

Disease severity was classified as either mild or severe based on a point system: patients received a single point each for being older than 60 years, being febrile, having an albumin level of less than 2.5 mg/dL, or having a white blood cell count of more than 15 × 10⁹/L. Patients were classified as having severe disease if they had two or more points. They received two points (ie, they were automatically classified as having severe disease) if they had pseudomembranous colitis or if they developed C difficile infection that required treatment in an intensive care unit.

Findings. The overall cure rate in patients receiving vancomycin was 97%, compared with 84% for those on metronidazole (P = .006). This difference was attributable to the group of patients with severe disease; no difference in treatment outcome was found in patients with mild disease. The relapse rates did not differ significantly between treatment groups in patients with either mild or severe disease.

Comments. The study was limited in that it was done at a single center and was done before the current highly virulent strain emerged. Whether these data can be extrapolated to today’s epidemic is unclear. Moreover, the investigators did not test for antimicrobial susceptibility (although metronidazole resistance is still uncommon). Finally, the development of colonization with vancomycin-resistant enterococci, one of the reasons that oral vancomycin is often not recommended, was not assessed.

Despite the study’s limitations, it shows that for severely ill patients with C difficile-associated diarrhea, oral vancomycin should be the treatment of choice.

IS CEFEPIME SAFE?

Yahav D, Paul M, Fraser A, Sarid N, Leibovici L. Efficacy and safety of cefepime: a systematic review and meta-analysis. Lancet Infect Dis 2007; 7:338 348.

Cefepime (Maxipime) is a broad-spectrum, fourth-generation cephalosporin. It is widely used for its approved indications: pneumonia; bacteremia; urinary tract, abdominal, skin, and soft-tissue infections; and febrile neutropenia.

In 2006, Paul et al⁶ reviewed 33 controlled trials of empiric cefepime monotherapy for febrile neutropenia and found a higher death rate with cefepime than with other beta-lactam antibiotics. That preliminary study spawned the following more comprehensive review by the same group.

The study. Yahav et al⁷ performed a meta-analysis of randomized trials that compared cefepime with another beta-lactam antibiotic alone or combined with a non-beta-lactam drug given in both treatment groups. Two reviewers independently identified studies from a number of databases and extracted data.

The primary end point was the rate of death from all causes at 30 days. Secondary end points were clinical failure (defined as unresolved infection, treatment modification, or death from infection), failure to eradicate the causative pathogens, superinfection with different bacterial, fungal, or viral organisms, and adverse events.

More than 8,000 patients were involved in 57 trials: 20 trials evaluated therapy for neutropenic fever, 18 for pneumonia, 5 for urogenital infections, 2 for meningitis, and 10 for mixed infections.

Comparison drugs for febrile neutropenia were ceftazidime (Ceptaz, Fortaz, Tazicef); im-ipenem-cilastatin (Primaxin) or meropenem (Merrem); piperacillin-tazobactam (Zosyn); and ceftriaxone (Rocephin). Aminoglycosides were added to both treatment groups in six trials and vancomycin was added in one trial.

For pneumonia, comparison drugs were ceftazidime, ceftriaxone, cefotaxime (Claforan), and cefoperazone-sulbactam.

Adequate allocation concealment and allocation-sequence generation were described in 30 studies. Scores for baseline patient risk factors did not differ significantly between study populations.

Findings. The death rate from all causes was higher in patients taking cefepime than with other beta-lactam antibiotics (risk ratio [RR] 1.26, 95% confidence interval [CI] 1.08–1.49, P = .005). The rate was lower with each of the alternative antibiotics, but the difference was statistically significant only for cefepime vs piperacillin-tazobactam (RR 2.14, 95% CI 1.17–3.89, P = .05).

The rate of death from all causes was higher for cefepime in all types of infections (except urinary tract infection, in which no deaths occurred in any of the treatment arms), although the difference was statistically significant only for febrile neutropenia (RR 1.42, 95% CI 1.09–1.84, P = .009). No differences were found in secondary outcomes, either by disease or by drug used.

Comments. This meta-analysis supports previous findings that more patients die when cefepime is used. The mechanism, however, is unclear. The authors call for reconsideration of the use of cefepime for febrile neutropenia, community-acquired pneumonia, and health-care associated pneumonia. In November 2007, the US Food and Drug Administration (FDA) launched an investigation into the risk of cefepime but has not yet made recommendations. Practitioners should be aware of these data when considering antimicrobial options for treatment in these settings. Knowledge of local antimicrobial susceptibility data of key pathogens is essential in determining optimal empiric and pathogen-specific therapy.

AN ANTIBIOTIC AND A NASAL STEROID ARE INEFFECTIVE IN ACUTE SINUSITIS

Williamson IG, Rumsby K, Benge S, et al. Antibiotics and topical nasal steroid for treatment of acute maxillary sinusitis: a randomized controlled trial. JAMA 2007; 298:2487 2496.

In the United States and Europe 1% to 2% of all primary care office visits are for acute sinusitis. Studies indicate that 67% to nearly 100% of patients with symptoms of sinusitis receive an antibiotic for it, even though the evidence of efficacy is weak and guidelines do not support this practice. Cochrane reviews⁸,⁹ have suggested that topical corticosteroids, penicillin, and amoxicillin have marginal benefit in acute sinusitis, but the studies on which the analyses were based were flawed.

The Berg and Carenfelt criteria were developed to help diagnose bacterial sinusitis.¹⁰ At the time they were developed, computed tomography was not routinely done to search for sinusitis, so plain film diagnosis was compared with clinical criteria. The Berg and Carenfelt criteria include three symptoms and one sign: a history of purulent unilateral nasal discharge, unilateral facial pain, or bilateral purulent discharge and pus in the nares on inspection. The presence of two criteria has reasonable sensitivity (81%), specificity (89%), and positive predictive value (86%) for detecting acute bacterial or maxillary sinusitis in the office setting.

The study. Williamson et al¹¹ conducted a double-blind, randomized, placebo-controlled trial of antibiotic and topical nasal steroid use in patients with suspected acute maxillary sinusitis. The trial included 240 patients who were seen in 58 family practices over 4 years in the United Kingdom and who had acute nonrecurrent sinusitis based on Berg and Carenfelt criteria. Patients were at least 16 years old; the average age was 44. Three-quarters were women. Few had fever, and 70% met only two Berg and Carenfelt criteria; the remaining 30% met three or all four criteria. Patients were excluded who had at least two sinusitis attacks per year, underlying nasal pathology, significant comorbidities, or a history of penicillin allergy, or if they had been treated with antibiotics or steroids during the past month.

Patients were randomized to receive one of four treatments:

• Amoxicillin 500 mg three times a day for 7 days plus budesonide (Rhinocort) 200 μg in each nostril once a day for 10 days
• Placebo amoxicillin plus real budesonide
• Amoxicillin plus placebo budesonide
• Placebo amoxicillin plus placebo budes-onide.

The groups were well matched. Outcomes were based on a questionnaire and a patient diary that assessed the duration and severity of 11 symptoms.

Findings. No difference was found between the treatment groups in overall outcome, in the proportion of those with symptoms at 10 days, or in daily symptom severity. The secondary analysis suggested that nasal steroids were marginally more effective in patients with less severe symptoms.

The authors concluded that neither an antibiotic nor a nasal steroid, alone or in combination, is effective for acute maxillary sinusitis in the primary care setting, and they recommended against their routine use.

Comments. This study had limitations. Some cases of viral disease may have been included: no objective reference standard (ie, computed tomography of the sinuses or sinus aspiration) was used, and although the Berg and Carenfelt criteria have been validated in secondary care settings, they have not been validated in primary care settings. In addition, fever was absent in most patients, and mild symptoms were poorly defined. Moreover, recruitment of patients was slow, raising questions of bias and generalizability. The study also did not address patients with comorbidities.

Nevertheless, the study shows that outpatients with symptoms of sinusitis without fever or significant comorbidities should not be treated with oral antibiotics or nasal steroids. Otherwise, antibiotic therapy may still be appropriate in certain patients at high risk and in those with fever.

PREDNISOLONE IS BENEFICIAL IN ACUTE BELL PALSY, ACYCLOVIR IS NOT

Sullivan FM, Swan IR, Donnan PT, et al. Early treatment with prednisolone or acyclovir in Bell palsy. N Engl J Med 2007; 357:1598 1607.

Bell palsy accounts for about two-thirds of cases of acute unilateral facial nerve palsy in the United States. Virologic studies from patients undergoing surgery for facial nerve decompression have suggested a possible association with herpes simplex virus. Other causes of acute unilateral facial nerve palsy include Lyme disease, sarcoidosis, Sjögren syndrome, trauma, carotid tumors, and diabetes. Bell palsy occurs most often during middle age, peaking between ages 30 and 45. As many as 30% of patients are left with significant neurologic residua. Corticosteroids and antiviral medications are commonly used to treat Bell palsy, but evidence for their efficacy is weak.

The study. Sullivan et al¹² conducted a double-blind, placebo-controlled, randomized trial over 2 years in Scotland with 551 patients, age 16 years or older, recruited within 72 hours of the onset of symptoms. Patients who were pregnant or breastfeeding or who had uncontrolled diabetes, peptic ulcer disease, suppurative otitis, zoster, multiple sclerosis, sarcoidosis, or systemic infection were excluded. They were randomized to treatment for 10 days with either acyclovir (Zovirax) 400 mg five times daily or prednisolone 25 mg twice daily, both agents, or placebo.

The primary outcome was recovery of facial function based on the House-Brackmann grading system. Digital photographs of patients at 3 and 9 months of treatment were evaluated independently by three experts who were unaware of study group assignment or stage of assessment. These included a neurologist, an otorhinolaryn-gologist, and a plastic surgeon. The secondary outcomes were quality of life, facial appearance, and pain, as assessed by the patients.

Findings. At 3 months, 83% of the prednisolone recipients had no facial asymmetry, increasing to 94% at 9 months. In comparison, the numbers were 64% and 82% in those who did not receive prednisolone, and these differences were statistically significant. Acyclovir was found to be of no benefit at either 3 or 9 months.

The authors concluded that early treatment of Bell palsy with prednisolone improves the chance of complete recovery, and that acyclovir alone or in combination with steroids confers no benefit.

Comments. At about the same time that this study was published, Hato et al¹³ evaluated valacyclovir (Valtrex) plus prednisolone vs placebo plus prednisolone and found that patients with severe Bell palsy (defined as complete facial nerve paralysis) benefited from antiviral therapy.

Corticosteroids are indicated for acute Bell palsy. In patients with complete facial nerve paralysis, valacyclovir should be considered.

POSACONAZOLE AS PROPHYLAXIS IN FEBRILE NEUTROPENIA

Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356:348 359.

For many years, amphotericin B was the only drug available for antifungal prophylaxis and therapy. Then, in the early 1990s, a number of studies suggested that the triazoles, notably fluconazole (Diflucan), were effective in a variety of clinical settings for both prophylaxis and therapy of serious fungal infections. In 1992 and 1995, two studies found that fluconazole prophylaxis was as effective as amphotericin B in preventing fungal infections in patients undergoing hematopoietic stem cell transplantation.¹⁴,¹⁵ Based on these studies, clinical practice changed, not only for patients undergoing hematopoietic stem cell transplantation, but also for empiric antifungal prophylaxis in patients receiving myeloablative chemotherapy to treat hematologic malignancies.

Fluconazole is not active against invasive molds, and newer drugs—itraconazole (Sporanox), voriconazole (Vfend), and most recently posaconazole (Noxafil)—were developed with expanded clinical activity. Studies in the 1990s found that itraconazole and voriconazole performed better than fluconazole but did not provide complete prophylaxis.

The study. Cornely et al¹⁶ compared posaconazole with fluconazole or itraconazole in 602 patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplasia. Although patients were randomized to either the posaconazole group or the fluconazole-or-itraconazole group, investigators could choose either fluconazole or itraconazole for patients randomized to that group. Most patients in the latter group (240 of 298) received fluconazole.

Patients were at least 13 years old, were able to take oral medications, had newly diagnosed disease or were having a first relapse, and had or were anticipated to have neutropenia for at least 7 days. The study excluded patients with invasive fungal infection within 30 days, significant liver or kidney dysfunction, an abnormal QT interval corrected for heart rate, an Eastern Cooperative Oncology Group performance status score of more than 2 (in bed more than half of the day), or allergy or a contraindication to azoles.

The trial treatment was started with each cycle of chemotherapy and was continued until recovery from neutropenia and complete remission, until invasive fungal infection developed, or for up to 12 weeks, whichever came first.

The primary end point was the incidence of proven or probable invasive fungal infection during the treatment phase. Secondary end points included death from any cause and time to death.

Findings. Posaconazole recipients fared significantly better than patients in the other treatment group with respect to the incidence of proven or probable invasive fungal infection, invasive aspergillosis, probability of death, death at 100 days, and death secondary to fungal infection. Treatment-related severe adverse events were a bit more common with posaconazole.

The authors suggest that posaconazole prophylaxis may have a place in prophylaxis in patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplasia.

Comments. It is not surprising that posaconazole performed better, because the standard treatment arm contained an agent (fluconazole) that did not cover Aspergillus, the most frequently identified source of invasive fungal infection during the treatment phase of the study.

In an editorial accompanying the article, De Pauw and Donnelly¹⁷ pointed out that whether posaconazole prophylaxis would be appropriate in a given case depends upon how likely infection is with Aspergillus. An institution with very few Aspergillus infections would have a much higher number needed to treat with posaconazole to prevent one case of aspergillosis than in this study, in which the number needed to treat was 16. Thus, knowledge of local epidemiology and incidence of invasive mold infections should guide selection of the optimal antifungal agent for prophylaxis in patients undergoing myeloablative chemotherapy for acute myelogenous leukemia or myelodysplasia.

ANIDULAFUNGIN VS FLUCONAZOLE FOR INVASIVE CANDIDIASIS

Reboli AC, Rotstein C, Pappas PG, et al; Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356:2472 2482.

In 2002, caspofungin (Cancidas) was the first of a new class of drugs, the echinocandins, to be approved by the FDA. The echinocandins have been shown to be as effective as amphotericin B for the treatment of invasive candidiasis, but how they compare with azoles is an ongoing debate. Currently approved treatments for candidiasis, an important cause of disease and death in hospitalized patients, include fluconazole, voriconazole, caspofungin, and amphotericin B. Anidulafungin is the newest echinocandin and has been shown in a phase 2 study to be effective against invasive candidiasis.

The study. Reboli et al¹⁸ performed a randomized, double-blind, noninferiority trial comparing anidulafungin and fluconazole to treat candidemia and other forms of candidiasis. The trial was conducted in multiple centers over 15 months and involved 245 patients at least 16 years old who had a single blood culture or culture from a normally sterile site that was positive for Candida species, and who also had one or more of the following: fever, hypothermia, hypotension, local signs and symptoms, or radiographic findings of candidiasis. Patients were excluded if they had had more than 48 hours of systemic therapy with either of these agents or another antifungal drug, if they had had prophylaxis with an azole for more than 7 of the previous 30 days, or if they had refractory candidal infection, elevated liver function test results, Candida krusei infection, meningitis, endocarditis, or osteomyelitis. Removal of central venous catheters was recommended for all patients with candidemia.

Patients were initially stratified by severity of illness based on the Acute Physiology and Chronic Health Evaluation (APACHE II) score (= 20 or > 20, with higher scores indicating more severe disease) and the presence or absence of neutropenia at enrollment. They were then randomly assigned to receive either intravenous anidulafungin (200 mg on day 1 and then 100 mg daily) or intravenous fluconazole (800 mg on day 1 and then 400 mg daily, with the dose adjusted according to creatinine clearance) for at least 14 days after a negative blood culture and improved clinical state and for up to 42 days in total. After 10 days of intravenous therapy, all patients could receive oral fluconazole 400 mg daily at the investigators’ discretion if clinical improvement criteria were met.

The primary end point was global response at the end of intravenous therapy, defined as clinical and microbiologic improvement. A number of secondary end points were also studied. Response failure was defined as no significant clinical improvement, death due to candidiasis, persistent or recurrent candidiasis or a new Candida infection, or an indeterminate response (eg, loss to follow-up or death not attributed to candidiasis).

Of the 245 patients in the primary analysis, 89% had candidemia alone, and nearly two-thirds of those cases were caused by Candida albicans. Only 3% of patients had neutropenia at baseline. Fluconazole resistance was monitored and was rare.

Findings. Intravenous therapy was successful in 76% of patients receiving anidulafungin and in 60% of fluconazole recipients, a difference of 15.4 percentage points (95% CI 3.9–27.0). Results were similar for other efficacy end points. The rate of death from all causes was 31% in the fluconazole group and 23% in the anidulafungin group (P = .13). The frequency and types of adverse events were similar in the two groups. The authors concluded that anidulafungin was not inferior to fluconazole in the treatment of invasive candidiasis.

Comments. Does this study prove that anidulafungin is the treatment of choice for invasive candidiasis? Although the study noted trends in favor of anidulafungin, the differences did not achieve statistical significance for superiority. In addition, the study included so few patients with neutropenia that the results are not applicable to those patients. Finally, anidulafungin is several times more expensive than fluconazole.

Fluconazole has stood the test of time and is probably still the treatment of choice in patients who have suspected or proven candidemia or invasive candidiasis, unless they have already been treated with azoles or are critically ill. In those settings, echinocandins may be the preferred treatment.

Studies published during the past year provide information that could influence how we treat several infectious diseases in daily practice. Here is a brief overview of these “impact” studies.

VANCOMYCIN BEATS METRONIDAZOLE FOR SEVERE C DIFFICILE DIARRHEA

Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-assoicated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45:302–307.

Clostridium difficile is the most common infectious cause of nosocomial diarrhea. Furthermore, a unique and highly virulent strain has emerged.

Which drug should be the treatment of choice: metronidazole (Flagyl) or oral vancomycin (Vancocin)? Over time, some infectious disease practitioners have believed that oral vancomycin is superior to oral metronidazole for the treatment of severe C difficile-associated diarrhea. Indeed, in a recently published survey, more than 25% of infectious disease practitioners said they used vancomycin as initial therapy for C difficile-associated diarrhea.¹ Until recently, there has been no evidence to support this preference.

Ever since the first description of C difficile-associated diarrhea in the late 1970s, only two head-to-head studies have compared the efficacy of metronidazole vs vancomycin for the treatment of this disorder. Both studies were underpowered and neither was blinded. In 1983, Teasley et al² treated 101 patients with metronidazole or vancomycin in a non-blinded, nonrandomized study and found no difference in efficacy. In 1996, Wenisch et al,³ in a prospective, randomized, but nonblinded study in 119 patients, compared vancomycin, metronidazole, fusidic acid, and teicoplanin (Targocid) and also found no significant difference in efficacy.

The study. Zar et al,⁴ in a prospective, double-blind trial at a single institution over an 8-year period, randomized 172 patients with C difficile-associated diarrhea to receive either oral metronidazole 250 mg four times a day or oral vancomycin 125 mg four times a day, both for 10 days. (The appropriate dosage of vancomycin has been debated over the years. In 1989, Fekety et al⁵ treated patients who had antibiotic-associated C difficile colitis with either 125 or 500 mg of vancomycin, four times a day, and found that the low dosage was as effective as the high dosage.) Both groups also received an oral placebo in addition to the study drug.

In the study of Zar et al, criteria for inclusion were diarrhea (defined as having more than two nonformed stools per 24 hours) and the finding of either toxin A in the stool or pseudomembranes on endoscopic examination. Patients were excluded if they were pregnant, had suspected or proven life-threatening intra-abdominal complications, were allergic to either study drug, had taken one of the study drugs during the last 14 days, or had previously had C difficile-associated diarrhea that did not respond to either study drug.

Patients were followed for up to 21 days. The primary end points were cure, treatment failure, or relapse. Cure was defined as the resolution of diarrhea and no C difficile toxin A detected on stool assay at days 6 and 10.

Disease severity was classified as either mild or severe based on a point system: patients received a single point each for being older than 60 years, being febrile, having an albumin level of less than 2.5 mg/dL, or having a white blood cell count of more than 15 × 10⁹/L. Patients were classified as having severe disease if they had two or more points. They received two points (ie, they were automatically classified as having severe disease) if they had pseudomembranous colitis or if they developed C difficile infection that required treatment in an intensive care unit.

Findings. The overall cure rate in patients receiving vancomycin was 97%, compared with 84% for those on metronidazole (P = .006). This difference was attributable to the group of patients with severe disease; no difference in treatment outcome was found in patients with mild disease. The relapse rates did not differ significantly between treatment groups in patients with either mild or severe disease.

Comments. The study was limited in that it was done at a single center and was done before the current highly virulent strain emerged. Whether these data can be extrapolated to today’s epidemic is unclear. Moreover, the investigators did not test for antimicrobial susceptibility (although metronidazole resistance is still uncommon). Finally, the development of colonization with vancomycin-resistant enterococci, one of the reasons that oral vancomycin is often not recommended, was not assessed.

Despite the study’s limitations, it shows that for severely ill patients with C difficile-associated diarrhea, oral vancomycin should be the treatment of choice.

IS CEFEPIME SAFE?

Yahav D, Paul M, Fraser A, Sarid N, Leibovici L. Efficacy and safety of cefepime: a systematic review and meta-analysis. Lancet Infect Dis 2007; 7:338 348.

Cefepime (Maxipime) is a broad-spectrum, fourth-generation cephalosporin. It is widely used for its approved indications: pneumonia; bacteremia; urinary tract, abdominal, skin, and soft-tissue infections; and febrile neutropenia.

In 2006, Paul et al⁶ reviewed 33 controlled trials of empiric cefepime monotherapy for febrile neutropenia and found a higher death rate with cefepime than with other beta-lactam antibiotics. That preliminary study spawned the following more comprehensive review by the same group.

The study. Yahav et al⁷ performed a meta-analysis of randomized trials that compared cefepime with another beta-lactam antibiotic alone or combined with a non-beta-lactam drug given in both treatment groups. Two reviewers independently identified studies from a number of databases and extracted data.

The primary end point was the rate of death from all causes at 30 days. Secondary end points were clinical failure (defined as unresolved infection, treatment modification, or death from infection), failure to eradicate the causative pathogens, superinfection with different bacterial, fungal, or viral organisms, and adverse events.

More than 8,000 patients were involved in 57 trials: 20 trials evaluated therapy for neutropenic fever, 18 for pneumonia, 5 for urogenital infections, 2 for meningitis, and 10 for mixed infections.

Comparison drugs for febrile neutropenia were ceftazidime (Ceptaz, Fortaz, Tazicef); im-ipenem-cilastatin (Primaxin) or meropenem (Merrem); piperacillin-tazobactam (Zosyn); and ceftriaxone (Rocephin). Aminoglycosides were added to both treatment groups in six trials and vancomycin was added in one trial.

For pneumonia, comparison drugs were ceftazidime, ceftriaxone, cefotaxime (Claforan), and cefoperazone-sulbactam.

Adequate allocation concealment and allocation-sequence generation were described in 30 studies. Scores for baseline patient risk factors did not differ significantly between study populations.

Findings. The death rate from all causes was higher in patients taking cefepime than with other beta-lactam antibiotics (risk ratio [RR] 1.26, 95% confidence interval [CI] 1.08–1.49, P = .005). The rate was lower with each of the alternative antibiotics, but the difference was statistically significant only for cefepime vs piperacillin-tazobactam (RR 2.14, 95% CI 1.17–3.89, P = .05).

The rate of death from all causes was higher for cefepime in all types of infections (except urinary tract infection, in which no deaths occurred in any of the treatment arms), although the difference was statistically significant only for febrile neutropenia (RR 1.42, 95% CI 1.09–1.84, P = .009). No differences were found in secondary outcomes, either by disease or by drug used.

Comments. This meta-analysis supports previous findings that more patients die when cefepime is used. The mechanism, however, is unclear. The authors call for reconsideration of the use of cefepime for febrile neutropenia, community-acquired pneumonia, and health-care associated pneumonia. In November 2007, the US Food and Drug Administration (FDA) launched an investigation into the risk of cefepime but has not yet made recommendations. Practitioners should be aware of these data when considering antimicrobial options for treatment in these settings. Knowledge of local antimicrobial susceptibility data of key pathogens is essential in determining optimal empiric and pathogen-specific therapy.

AN ANTIBIOTIC AND A NASAL STEROID ARE INEFFECTIVE IN ACUTE SINUSITIS

Williamson IG, Rumsby K, Benge S, et al. Antibiotics and topical nasal steroid for treatment of acute maxillary sinusitis: a randomized controlled trial. JAMA 2007; 298:2487 2496.

In the United States and Europe 1% to 2% of all primary care office visits are for acute sinusitis. Studies indicate that 67% to nearly 100% of patients with symptoms of sinusitis receive an antibiotic for it, even though the evidence of efficacy is weak and guidelines do not support this practice. Cochrane reviews⁸,⁹ have suggested that topical corticosteroids, penicillin, and amoxicillin have marginal benefit in acute sinusitis, but the studies on which the analyses were based were flawed.

The Berg and Carenfelt criteria were developed to help diagnose bacterial sinusitis.¹⁰ At the time they were developed, computed tomography was not routinely done to search for sinusitis, so plain film diagnosis was compared with clinical criteria. The Berg and Carenfelt criteria include three symptoms and one sign: a history of purulent unilateral nasal discharge, unilateral facial pain, or bilateral purulent discharge and pus in the nares on inspection. The presence of two criteria has reasonable sensitivity (81%), specificity (89%), and positive predictive value (86%) for detecting acute bacterial or maxillary sinusitis in the office setting.

The study. Williamson et al¹¹ conducted a double-blind, randomized, placebo-controlled trial of antibiotic and topical nasal steroid use in patients with suspected acute maxillary sinusitis. The trial included 240 patients who were seen in 58 family practices over 4 years in the United Kingdom and who had acute nonrecurrent sinusitis based on Berg and Carenfelt criteria. Patients were at least 16 years old; the average age was 44. Three-quarters were women. Few had fever, and 70% met only two Berg and Carenfelt criteria; the remaining 30% met three or all four criteria. Patients were excluded who had at least two sinusitis attacks per year, underlying nasal pathology, significant comorbidities, or a history of penicillin allergy, or if they had been treated with antibiotics or steroids during the past month.

Patients were randomized to receive one of four treatments:

• Amoxicillin 500 mg three times a day for 7 days plus budesonide (Rhinocort) 200 μg in each nostril once a day for 10 days
• Placebo amoxicillin plus real budesonide
• Amoxicillin plus placebo budesonide
• Placebo amoxicillin plus placebo budes-onide.

The groups were well matched. Outcomes were based on a questionnaire and a patient diary that assessed the duration and severity of 11 symptoms.

Findings. No difference was found between the treatment groups in overall outcome, in the proportion of those with symptoms at 10 days, or in daily symptom severity. The secondary analysis suggested that nasal steroids were marginally more effective in patients with less severe symptoms.

The authors concluded that neither an antibiotic nor a nasal steroid, alone or in combination, is effective for acute maxillary sinusitis in the primary care setting, and they recommended against their routine use.

Comments. This study had limitations. Some cases of viral disease may have been included: no objective reference standard (ie, computed tomography of the sinuses or sinus aspiration) was used, and although the Berg and Carenfelt criteria have been validated in secondary care settings, they have not been validated in primary care settings. In addition, fever was absent in most patients, and mild symptoms were poorly defined. Moreover, recruitment of patients was slow, raising questions of bias and generalizability. The study also did not address patients with comorbidities.

Nevertheless, the study shows that outpatients with symptoms of sinusitis without fever or significant comorbidities should not be treated with oral antibiotics or nasal steroids. Otherwise, antibiotic therapy may still be appropriate in certain patients at high risk and in those with fever.

PREDNISOLONE IS BENEFICIAL IN ACUTE BELL PALSY, ACYCLOVIR IS NOT

Sullivan FM, Swan IR, Donnan PT, et al. Early treatment with prednisolone or acyclovir in Bell palsy. N Engl J Med 2007; 357:1598 1607.

Bell palsy accounts for about two-thirds of cases of acute unilateral facial nerve palsy in the United States. Virologic studies from patients undergoing surgery for facial nerve decompression have suggested a possible association with herpes simplex virus. Other causes of acute unilateral facial nerve palsy include Lyme disease, sarcoidosis, Sjögren syndrome, trauma, carotid tumors, and diabetes. Bell palsy occurs most often during middle age, peaking between ages 30 and 45. As many as 30% of patients are left with significant neurologic residua. Corticosteroids and antiviral medications are commonly used to treat Bell palsy, but evidence for their efficacy is weak.

The study. Sullivan et al¹² conducted a double-blind, placebo-controlled, randomized trial over 2 years in Scotland with 551 patients, age 16 years or older, recruited within 72 hours of the onset of symptoms. Patients who were pregnant or breastfeeding or who had uncontrolled diabetes, peptic ulcer disease, suppurative otitis, zoster, multiple sclerosis, sarcoidosis, or systemic infection were excluded. They were randomized to treatment for 10 days with either acyclovir (Zovirax) 400 mg five times daily or prednisolone 25 mg twice daily, both agents, or placebo.

The primary outcome was recovery of facial function based on the House-Brackmann grading system. Digital photographs of patients at 3 and 9 months of treatment were evaluated independently by three experts who were unaware of study group assignment or stage of assessment. These included a neurologist, an otorhinolaryn-gologist, and a plastic surgeon. The secondary outcomes were quality of life, facial appearance, and pain, as assessed by the patients.

Findings. At 3 months, 83% of the prednisolone recipients had no facial asymmetry, increasing to 94% at 9 months. In comparison, the numbers were 64% and 82% in those who did not receive prednisolone, and these differences were statistically significant. Acyclovir was found to be of no benefit at either 3 or 9 months.

The authors concluded that early treatment of Bell palsy with prednisolone improves the chance of complete recovery, and that acyclovir alone or in combination with steroids confers no benefit.

Comments. At about the same time that this study was published, Hato et al¹³ evaluated valacyclovir (Valtrex) plus prednisolone vs placebo plus prednisolone and found that patients with severe Bell palsy (defined as complete facial nerve paralysis) benefited from antiviral therapy.

Corticosteroids are indicated for acute Bell palsy. In patients with complete facial nerve paralysis, valacyclovir should be considered.

POSACONAZOLE AS PROPHYLAXIS IN FEBRILE NEUTROPENIA

Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356:348 359.

For many years, amphotericin B was the only drug available for antifungal prophylaxis and therapy. Then, in the early 1990s, a number of studies suggested that the triazoles, notably fluconazole (Diflucan), were effective in a variety of clinical settings for both prophylaxis and therapy of serious fungal infections. In 1992 and 1995, two studies found that fluconazole prophylaxis was as effective as amphotericin B in preventing fungal infections in patients undergoing hematopoietic stem cell transplantation.¹⁴,¹⁵ Based on these studies, clinical practice changed, not only for patients undergoing hematopoietic stem cell transplantation, but also for empiric antifungal prophylaxis in patients receiving myeloablative chemotherapy to treat hematologic malignancies.

Fluconazole is not active against invasive molds, and newer drugs—itraconazole (Sporanox), voriconazole (Vfend), and most recently posaconazole (Noxafil)—were developed with expanded clinical activity. Studies in the 1990s found that itraconazole and voriconazole performed better than fluconazole but did not provide complete prophylaxis.

The study. Cornely et al¹⁶ compared posaconazole with fluconazole or itraconazole in 602 patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplasia. Although patients were randomized to either the posaconazole group or the fluconazole-or-itraconazole group, investigators could choose either fluconazole or itraconazole for patients randomized to that group. Most patients in the latter group (240 of 298) received fluconazole.

Patients were at least 13 years old, were able to take oral medications, had newly diagnosed disease or were having a first relapse, and had or were anticipated to have neutropenia for at least 7 days. The study excluded patients with invasive fungal infection within 30 days, significant liver or kidney dysfunction, an abnormal QT interval corrected for heart rate, an Eastern Cooperative Oncology Group performance status score of more than 2 (in bed more than half of the day), or allergy or a contraindication to azoles.

The trial treatment was started with each cycle of chemotherapy and was continued until recovery from neutropenia and complete remission, until invasive fungal infection developed, or for up to 12 weeks, whichever came first.

The primary end point was the incidence of proven or probable invasive fungal infection during the treatment phase. Secondary end points included death from any cause and time to death.

Findings. Posaconazole recipients fared significantly better than patients in the other treatment group with respect to the incidence of proven or probable invasive fungal infection, invasive aspergillosis, probability of death, death at 100 days, and death secondary to fungal infection. Treatment-related severe adverse events were a bit more common with posaconazole.

The authors suggest that posaconazole prophylaxis may have a place in prophylaxis in patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplasia.

Comments. It is not surprising that posaconazole performed better, because the standard treatment arm contained an agent (fluconazole) that did not cover Aspergillus, the most frequently identified source of invasive fungal infection during the treatment phase of the study.

In an editorial accompanying the article, De Pauw and Donnelly¹⁷ pointed out that whether posaconazole prophylaxis would be appropriate in a given case depends upon how likely infection is with Aspergillus. An institution with very few Aspergillus infections would have a much higher number needed to treat with posaconazole to prevent one case of aspergillosis than in this study, in which the number needed to treat was 16. Thus, knowledge of local epidemiology and incidence of invasive mold infections should guide selection of the optimal antifungal agent for prophylaxis in patients undergoing myeloablative chemotherapy for acute myelogenous leukemia or myelodysplasia.

ANIDULAFUNGIN VS FLUCONAZOLE FOR INVASIVE CANDIDIASIS

Reboli AC, Rotstein C, Pappas PG, et al; Anidulafungin Study Group. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356:2472 2482.

In 2002, caspofungin (Cancidas) was the first of a new class of drugs, the echinocandins, to be approved by the FDA. The echinocandins have been shown to be as effective as amphotericin B for the treatment of invasive candidiasis, but how they compare with azoles is an ongoing debate. Currently approved treatments for candidiasis, an important cause of disease and death in hospitalized patients, include fluconazole, voriconazole, caspofungin, and amphotericin B. Anidulafungin is the newest echinocandin and has been shown in a phase 2 study to be effective against invasive candidiasis.

The study. Reboli et al¹⁸ performed a randomized, double-blind, noninferiority trial comparing anidulafungin and fluconazole to treat candidemia and other forms of candidiasis. The trial was conducted in multiple centers over 15 months and involved 245 patients at least 16 years old who had a single blood culture or culture from a normally sterile site that was positive for Candida species, and who also had one or more of the following: fever, hypothermia, hypotension, local signs and symptoms, or radiographic findings of candidiasis. Patients were excluded if they had had more than 48 hours of systemic therapy with either of these agents or another antifungal drug, if they had had prophylaxis with an azole for more than 7 of the previous 30 days, or if they had refractory candidal infection, elevated liver function test results, Candida krusei infection, meningitis, endocarditis, or osteomyelitis. Removal of central venous catheters was recommended for all patients with candidemia.

Patients were initially stratified by severity of illness based on the Acute Physiology and Chronic Health Evaluation (APACHE II) score (= 20 or > 20, with higher scores indicating more severe disease) and the presence or absence of neutropenia at enrollment. They were then randomly assigned to receive either intravenous anidulafungin (200 mg on day 1 and then 100 mg daily) or intravenous fluconazole (800 mg on day 1 and then 400 mg daily, with the dose adjusted according to creatinine clearance) for at least 14 days after a negative blood culture and improved clinical state and for up to 42 days in total. After 10 days of intravenous therapy, all patients could receive oral fluconazole 400 mg daily at the investigators’ discretion if clinical improvement criteria were met.

The primary end point was global response at the end of intravenous therapy, defined as clinical and microbiologic improvement. A number of secondary end points were also studied. Response failure was defined as no significant clinical improvement, death due to candidiasis, persistent or recurrent candidiasis or a new Candida infection, or an indeterminate response (eg, loss to follow-up or death not attributed to candidiasis).

Of the 245 patients in the primary analysis, 89% had candidemia alone, and nearly two-thirds of those cases were caused by Candida albicans. Only 3% of patients had neutropenia at baseline. Fluconazole resistance was monitored and was rare.

Findings. Intravenous therapy was successful in 76% of patients receiving anidulafungin and in 60% of fluconazole recipients, a difference of 15.4 percentage points (95% CI 3.9–27.0). Results were similar for other efficacy end points. The rate of death from all causes was 31% in the fluconazole group and 23% in the anidulafungin group (P = .13). The frequency and types of adverse events were similar in the two groups. The authors concluded that anidulafungin was not inferior to fluconazole in the treatment of invasive candidiasis.

Comments. Does this study prove that anidulafungin is the treatment of choice for invasive candidiasis? Although the study noted trends in favor of anidulafungin, the differences did not achieve statistical significance for superiority. In addition, the study included so few patients with neutropenia that the results are not applicable to those patients. Finally, anidulafungin is several times more expensive than fluconazole.

Fluconazole has stood the test of time and is probably still the treatment of choice in patients who have suspected or proven candidemia or invasive candidiasis, unless they have already been treated with azoles or are critically ill. In those settings, echinocandins may be the preferred treatment.

How we prevent human papillomavirus (HPV) infection, and how we prevent hepatitis A following exposure to an index case have changed, based on the results of several key clinical trials published during the past year. The results of these studies should influence the measures we take in our daily practice to prevent these diseases. Here is a brief overview of these “impact” studies.

QUADRIVALENT HPV VACCINE PREVENTS CERVICAL LESIONS

FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007; 356:1915–1927.

Cervical cancer is the second most common type of cancer in women and is the leading cause of cancer-related deaths in developing countries. More than 500,000 new cases of cervical cancer are reported worldwide each year, and about 250,000 women die of it.¹

Nearly all cases of cervical cancer are caused by HPVs, and the oncogenic types HPV-16 and HPV-18 together account for about 70%. These two types also cause vulvo-vaginal cancer, which accounts for about 6% of all gynecologic malignancies.² Two other HPV types, HPV-6 and HPV-11, cause genital warts and, less often, cervical intraepithelial neoplasia and cervical invasive cancers.

Two HPV vaccines have been developed. One, sold as Cervarix, is directed against HPV-16 and HPV-18; it is not yet available in the United States. The other, sold as Gardasil, is directed against four HPV types: 6, 11, 16, and 18, and it is currently available (reviewed by Widdice and Kahn³).

The study. The Females United to Unilaterally Reduce Endo/Ectocervical Cancer (FUTURE) II study⁴ assessed the ability of the quadrivalent vaccine to prevent high-grade cervical lesions. Between June 2002 and September 2003, more than 12,000 women ages 15 to 26 were enrolled at 90 sites in 13 countries. Eligible women were not pregnant, had no abnormal Papanicolaou (Pap) smear, had had four or fewer lifetime sexual partners, and agreed to use effective contraception throughout the course of the study.

In a randomized, double-blind fashion, patients received vaccine or a placebo injection at day 1 and again 2 and 6 months later. They returned for follow-up 1, 6, 24, 36, and 48 months after the third injection, with Pap smears and colposcopy of cervical lesions.

The primary composite end point was the development of grade 2 or 3 cervical intraepithelial neoplasia, adenocarcinoma in situ, or invasive cervical carcinoma, with detection of HPV-16 or HPV-18 or both in one or more of the adjacent sections of the same lesion.

In all, 6,087 patients received vaccine and 6,080 received placebo; the two groups were well matched. About 23% had serologic evidence of exposure to either HPV-16 or HPV-18 at enrollment.

Findings. In the analysis of the data, the patients were divided into three overlapping subgroups. The first comprised women who had no serologic evidence of HPV-16 or HPV-18 infection at enrollment, who received all three injections, who remained DNA-negative at month 7, and who had no protocol violations. In this “per-protocol susceptible population,” at an average of 3 years of follow-up, lesions associated with HPV-16 or HPV-18 had developed in 42 of 5,260 women who received placebo, compared with only 1 of 5,305 who received the vaccine. The vaccine efficacy was calculated at 98% (95% confidence interval [CI] 86–100).

The second subgroup were women who had no evidence of HPV-16 or HPV-18 infection at baseline, but whose compliance with the protocol was considered imperfect. In this “unrestricted susceptible population,” the vaccine efficacy was 95% (95% CI 85–99).

The third group included all comers, regardless of whether they were already infected at baseline. In this “intention-to-treat population,” the vaccine efficacy was 44% (95% CI 26–58).

The authors concluded that in young women not previously infected with HPV-16 or HPV-18, vaccine recipients had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to these two oncogenic HPV types.

QUADRIVALENT HPV VACCINE PREVENTS ANOGENITAL DISEASE

Garland SM, Hernandez-Avila M, Wheeler CM, et al; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. J Engl J Med 2007; 356:1928–1943.

The study. This double-blind, placebo-controlled study⁵ tested the usefulness of the quadrivalent HPV vaccine to prevent anogenital disease. It included 5,400 women ages 16 to 24 and was conducted over 14 months in 2002 and 2003 at 62 sites in 16 countries. Women received vaccine or placebo at day 1 and again 2 and 6 months later, and then underwent anogenital and gynecologic examinations at intervals for up to 4 years.

The co-primary composite end points were the incidence of genital warts, vulvar or vaginal intraepithelial neoplasia or cancer, cervical intraepithelial neoplasia, cervical adenocarcinoma in situ, or cervical cancer associated with HPV types 6, 11, 16, or 18.

Findings. In all, 2,700 women were assigned to receive vaccine and 2,700 to receive placebo, and they were followed for an average of 3 years. Twenty percent had pre-existing serologic evidence of infection with one of these four HPV types. In the per-protocol population who were seronegative at day 1 and were compliant, the vaccine efficacy was 100%. In the intention-to-treat group, vaccine reduced the rate of vulvar or vaginal perianal lesions regardless of HPV type by 34%, and reduced the rate of cervical lesions regardless of type by 20%.

HPV VACCINE LIKELY COST-EFFECTIVE IN GIRLS, BUT NOT BOYS

Newall AT, Beutels P, Wood JG, Edmunds WJ, MacIntyre CR. Cost-effectiveness analyses of human papillomavirus vaccination. Lancet Infect Dis  2007; 7:289–296.

The study. In a review, Newall et al⁶ looked at four studies that examined the cost-effectiveness of the HPV vaccine. These studies were not perfect and had methodologic limitations because of uncertainty about vaccine efficacy, duration of protection, and the contribution of herd immunity. The studies nevertheless suggested that immunization of young girls but not young boys may be cost-effective, though they suggested the need for further research.

Findings. Three of the studies showed an incremental cost-effectiveness ratio of $14,000 to $24,000 per quality-adjusted year of life gained, which is well within the range for many preventive strategies that we employ in this country.

One of the studies examined the cost-effectiveness of immunizing males, and in that study it was found not to be cost-effective.

TAKE-HOME POINTS ON HPV VACCINATION

Quadrivalent vaccine does indeed reduce the incidence of HPV-associated cervical intra-epithelial neoplasia, vulvar and vaginal intra-epithelial neoplasia, and anogenital diseases in young women, and it is likely cost-effective.

The vaccine works only against HPV types 6, 11, 16, and 18, and 30% of cervical cancers are due to types other than HPV-16 and HPV-18. Also, vaccination is much more effective in patients not yet exposed to HPV, so it would be best to vaccinate them before they become sexually active.

The Advisory Committee on Immunization Practices voted to recommend that girls ages 11 to 12 in this country should receive vaccine.

Regrettably, many third-party payers do not yet pay for the vaccine, and the cost (around $375) must be paid out of pocket. Also, this issue remains politically charged and controversial. Some states have mandated vaccination and another 15 are presently considering legislation mandating vaccination. Such legislation has been defeated in four states.

My own practice is to offer the vaccine to 11- and 12-year old girls, and to older girls and young women (not to boys), especially if the health insurance plan covers it or if the patient or the patient’s family can afford it.

HEPATITIS A VACCINE IS AS GOOD AS IMMUNE GLOBULIN AFTER EXPOSURE

Victor JC, Monto AS, Surdina TY, et al. Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med 2007; 357:1685–1694.

Before 1995, when the first hepatitis A vaccine was introduced, about 30,000 cases of hepatitis A were reported each year in the United States. This was thought to be the tip of the iceberg: since this infection is often subclinical, estimates of up to 300,000 cases per year were given.

At first, immunization against hepatitis A in this country was confined to children over age 2 in states in which hepatitis A occurred more often than the norm. In 2005, after it had become clear that the vaccine was highly effective, the Advisory Committee on Immunization Practices revised its recommendations to include immunization of children between the ages of 12 and 23 months,⁷ so that they would complete this two-stage vaccination procedure by the time they reached the age of 2 years. With that strategy, the annual occurrence of hepatitis A in the United States fell dramatically, to about 4,000 cases per year in 2005, the lowest number of cases reported in the last 40 years. At present, most hepatitis A infections in this country are not from casual idiosyncratic transmission but rather are food-borne.

Still, hepatitis A remains a major problem in many parts of the world. Moreover, the availability of immune globulin, the traditional recommended agent for postexposure pro-phylaxis, has been limited because only one company manufactures it and the price has steadily escalated.

The study. Investigators at the University of Michigan and in Kazakhstan compared conventional doses of immune globulin vs hepatitis A vaccine as postexposure prophylaxis, given within 14 days of exposure to index cases of hepatitis A.⁸ Excluded were persons under the age of 2 years or over the age of 40, those with a history of hepatitis A or vaccination, those with liver disease, and those with other contraindications. The primary end point was the development of symptomatic, laboratory-confirmed hepatitis A, defined as a positive test for immunoglobulin M antibodies to hepatitis A; transaminase levels greater than two times the upper limit of normal; and symptoms consistent with hepatitis A in the absence of another identifiable disease that occurred within 15 to 56 days of exposure to the index case.

Findings. Of 4,524 contacts randomized, only 1,414 (31%) were susceptible to hepatitis A, suggesting that the prevalence of hepatitis A in Kazakhstan was high at that time. Of these, 1,090 completed the immunization and follow-up protocol and were eligible for the final analysis. Of these, 568 received vaccine and 522 received globulin. The average age was 12 years, the average time to vaccination after exposure was 10 days; 16% of the exposures occurred in the day-care setting, and 84% of the exposures occurred from household contacts.

Symptomatic hepatitis A occurred in 4.4% of vaccine recipients vs 3.3% of immunoglobulin recipients. The authors concluded that hepatitis A vaccine met the test of noninferiority, that both strategies were highly protective, but that immunoglobulin was modestly better. Thus, in June 2007, the Advisory Committee on Immunization Practices recommended hepatitis A vaccine as the preferred regimen for postexposure prophylaxis.⁹

This approach has several advantages:

• Hepatitis A vaccine confers immunity and long-term protection, which globulin does not
• The supply of vaccine is abundant
• Vaccine is relatively cheap
• Vaccine is easy to give.

This study, however, does not apply to people younger than 2 years or older than 40, those who are immunocompromised, or those who have chronic liver disease. In these groups, the recommendation is still to use immunoglobulin in postexposure prophylaxis.

How we prevent human papillomavirus (HPV) infection, and how we prevent hepatitis A following exposure to an index case have changed, based on the results of several key clinical trials published during the past year. The results of these studies should influence the measures we take in our daily practice to prevent these diseases. Here is a brief overview of these “impact” studies.

QUADRIVALENT HPV VACCINE PREVENTS CERVICAL LESIONS

FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007; 356:1915–1927.

Cervical cancer is the second most common type of cancer in women and is the leading cause of cancer-related deaths in developing countries. More than 500,000 new cases of cervical cancer are reported worldwide each year, and about 250,000 women die of it.¹

Nearly all cases of cervical cancer are caused by HPVs, and the oncogenic types HPV-16 and HPV-18 together account for about 70%. These two types also cause vulvo-vaginal cancer, which accounts for about 6% of all gynecologic malignancies.² Two other HPV types, HPV-6 and HPV-11, cause genital warts and, less often, cervical intraepithelial neoplasia and cervical invasive cancers.

Two HPV vaccines have been developed. One, sold as Cervarix, is directed against HPV-16 and HPV-18; it is not yet available in the United States. The other, sold as Gardasil, is directed against four HPV types: 6, 11, 16, and 18, and it is currently available (reviewed by Widdice and Kahn³).

The study. The Females United to Unilaterally Reduce Endo/Ectocervical Cancer (FUTURE) II study⁴ assessed the ability of the quadrivalent vaccine to prevent high-grade cervical lesions. Between June 2002 and September 2003, more than 12,000 women ages 15 to 26 were enrolled at 90 sites in 13 countries. Eligible women were not pregnant, had no abnormal Papanicolaou (Pap) smear, had had four or fewer lifetime sexual partners, and agreed to use effective contraception throughout the course of the study.

In a randomized, double-blind fashion, patients received vaccine or a placebo injection at day 1 and again 2 and 6 months later. They returned for follow-up 1, 6, 24, 36, and 48 months after the third injection, with Pap smears and colposcopy of cervical lesions.

The primary composite end point was the development of grade 2 or 3 cervical intraepithelial neoplasia, adenocarcinoma in situ, or invasive cervical carcinoma, with detection of HPV-16 or HPV-18 or both in one or more of the adjacent sections of the same lesion.

In all, 6,087 patients received vaccine and 6,080 received placebo; the two groups were well matched. About 23% had serologic evidence of exposure to either HPV-16 or HPV-18 at enrollment.

Findings. In the analysis of the data, the patients were divided into three overlapping subgroups. The first comprised women who had no serologic evidence of HPV-16 or HPV-18 infection at enrollment, who received all three injections, who remained DNA-negative at month 7, and who had no protocol violations. In this “per-protocol susceptible population,” at an average of 3 years of follow-up, lesions associated with HPV-16 or HPV-18 had developed in 42 of 5,260 women who received placebo, compared with only 1 of 5,305 who received the vaccine. The vaccine efficacy was calculated at 98% (95% confidence interval [CI] 86–100).

The second subgroup were women who had no evidence of HPV-16 or HPV-18 infection at baseline, but whose compliance with the protocol was considered imperfect. In this “unrestricted susceptible population,” the vaccine efficacy was 95% (95% CI 85–99).

The third group included all comers, regardless of whether they were already infected at baseline. In this “intention-to-treat population,” the vaccine efficacy was 44% (95% CI 26–58).

The authors concluded that in young women not previously infected with HPV-16 or HPV-18, vaccine recipients had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to these two oncogenic HPV types.

QUADRIVALENT HPV VACCINE PREVENTS ANOGENITAL DISEASE

Garland SM, Hernandez-Avila M, Wheeler CM, et al; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. J Engl J Med 2007; 356:1928–1943.

The study. This double-blind, placebo-controlled study⁵ tested the usefulness of the quadrivalent HPV vaccine to prevent anogenital disease. It included 5,400 women ages 16 to 24 and was conducted over 14 months in 2002 and 2003 at 62 sites in 16 countries. Women received vaccine or placebo at day 1 and again 2 and 6 months later, and then underwent anogenital and gynecologic examinations at intervals for up to 4 years.

The co-primary composite end points were the incidence of genital warts, vulvar or vaginal intraepithelial neoplasia or cancer, cervical intraepithelial neoplasia, cervical adenocarcinoma in situ, or cervical cancer associated with HPV types 6, 11, 16, or 18.

Findings. In all, 2,700 women were assigned to receive vaccine and 2,700 to receive placebo, and they were followed for an average of 3 years. Twenty percent had pre-existing serologic evidence of infection with one of these four HPV types. In the per-protocol population who were seronegative at day 1 and were compliant, the vaccine efficacy was 100%. In the intention-to-treat group, vaccine reduced the rate of vulvar or vaginal perianal lesions regardless of HPV type by 34%, and reduced the rate of cervical lesions regardless of type by 20%.

HPV VACCINE LIKELY COST-EFFECTIVE IN GIRLS, BUT NOT BOYS

Newall AT, Beutels P, Wood JG, Edmunds WJ, MacIntyre CR. Cost-effectiveness analyses of human papillomavirus vaccination. Lancet Infect Dis  2007; 7:289–296.

The study. In a review, Newall et al⁶ looked at four studies that examined the cost-effectiveness of the HPV vaccine. These studies were not perfect and had methodologic limitations because of uncertainty about vaccine efficacy, duration of protection, and the contribution of herd immunity. The studies nevertheless suggested that immunization of young girls but not young boys may be cost-effective, though they suggested the need for further research.

Findings. Three of the studies showed an incremental cost-effectiveness ratio of $14,000 to $24,000 per quality-adjusted year of life gained, which is well within the range for many preventive strategies that we employ in this country.

One of the studies examined the cost-effectiveness of immunizing males, and in that study it was found not to be cost-effective.

TAKE-HOME POINTS ON HPV VACCINATION

Quadrivalent vaccine does indeed reduce the incidence of HPV-associated cervical intra-epithelial neoplasia, vulvar and vaginal intra-epithelial neoplasia, and anogenital diseases in young women, and it is likely cost-effective.

The vaccine works only against HPV types 6, 11, 16, and 18, and 30% of cervical cancers are due to types other than HPV-16 and HPV-18. Also, vaccination is much more effective in patients not yet exposed to HPV, so it would be best to vaccinate them before they become sexually active.

The Advisory Committee on Immunization Practices voted to recommend that girls ages 11 to 12 in this country should receive vaccine.

Regrettably, many third-party payers do not yet pay for the vaccine, and the cost (around $375) must be paid out of pocket. Also, this issue remains politically charged and controversial. Some states have mandated vaccination and another 15 are presently considering legislation mandating vaccination. Such legislation has been defeated in four states.

My own practice is to offer the vaccine to 11- and 12-year old girls, and to older girls and young women (not to boys), especially if the health insurance plan covers it or if the patient or the patient’s family can afford it.

HEPATITIS A VACCINE IS AS GOOD AS IMMUNE GLOBULIN AFTER EXPOSURE

Victor JC, Monto AS, Surdina TY, et al. Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med 2007; 357:1685–1694.

Before 1995, when the first hepatitis A vaccine was introduced, about 30,000 cases of hepatitis A were reported each year in the United States. This was thought to be the tip of the iceberg: since this infection is often subclinical, estimates of up to 300,000 cases per year were given.

At first, immunization against hepatitis A in this country was confined to children over age 2 in states in which hepatitis A occurred more often than the norm. In 2005, after it had become clear that the vaccine was highly effective, the Advisory Committee on Immunization Practices revised its recommendations to include immunization of children between the ages of 12 and 23 months,⁷ so that they would complete this two-stage vaccination procedure by the time they reached the age of 2 years. With that strategy, the annual occurrence of hepatitis A in the United States fell dramatically, to about 4,000 cases per year in 2005, the lowest number of cases reported in the last 40 years. At present, most hepatitis A infections in this country are not from casual idiosyncratic transmission but rather are food-borne.

Still, hepatitis A remains a major problem in many parts of the world. Moreover, the availability of immune globulin, the traditional recommended agent for postexposure pro-phylaxis, has been limited because only one company manufactures it and the price has steadily escalated.

The study. Investigators at the University of Michigan and in Kazakhstan compared conventional doses of immune globulin vs hepatitis A vaccine as postexposure prophylaxis, given within 14 days of exposure to index cases of hepatitis A.⁸ Excluded were persons under the age of 2 years or over the age of 40, those with a history of hepatitis A or vaccination, those with liver disease, and those with other contraindications. The primary end point was the development of symptomatic, laboratory-confirmed hepatitis A, defined as a positive test for immunoglobulin M antibodies to hepatitis A; transaminase levels greater than two times the upper limit of normal; and symptoms consistent with hepatitis A in the absence of another identifiable disease that occurred within 15 to 56 days of exposure to the index case.

Findings. Of 4,524 contacts randomized, only 1,414 (31%) were susceptible to hepatitis A, suggesting that the prevalence of hepatitis A in Kazakhstan was high at that time. Of these, 1,090 completed the immunization and follow-up protocol and were eligible for the final analysis. Of these, 568 received vaccine and 522 received globulin. The average age was 12 years, the average time to vaccination after exposure was 10 days; 16% of the exposures occurred in the day-care setting, and 84% of the exposures occurred from household contacts.

Symptomatic hepatitis A occurred in 4.4% of vaccine recipients vs 3.3% of immunoglobulin recipients. The authors concluded that hepatitis A vaccine met the test of noninferiority, that both strategies were highly protective, but that immunoglobulin was modestly better. Thus, in June 2007, the Advisory Committee on Immunization Practices recommended hepatitis A vaccine as the preferred regimen for postexposure prophylaxis.⁹

This approach has several advantages:

• Hepatitis A vaccine confers immunity and long-term protection, which globulin does not
• The supply of vaccine is abundant
• Vaccine is relatively cheap
• Vaccine is easy to give.

This study, however, does not apply to people younger than 2 years or older than 40, those who are immunocompromised, or those who have chronic liver disease. In these groups, the recommendation is still to use immunoglobulin in postexposure prophylaxis.

How we prevent human papillomavirus (HPV) infection, and how we prevent hepatitis A following exposure to an index case have changed, based on the results of several key clinical trials published during the past year. The results of these studies should influence the measures we take in our daily practice to prevent these diseases. Here is a brief overview of these “impact” studies.

QUADRIVALENT HPV VACCINE PREVENTS CERVICAL LESIONS

FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007; 356:1915–1927.

Cervical cancer is the second most common type of cancer in women and is the leading cause of cancer-related deaths in developing countries. More than 500,000 new cases of cervical cancer are reported worldwide each year, and about 250,000 women die of it.¹

Nearly all cases of cervical cancer are caused by HPVs, and the oncogenic types HPV-16 and HPV-18 together account for about 70%. These two types also cause vulvo-vaginal cancer, which accounts for about 6% of all gynecologic malignancies.² Two other HPV types, HPV-6 and HPV-11, cause genital warts and, less often, cervical intraepithelial neoplasia and cervical invasive cancers.

Two HPV vaccines have been developed. One, sold as Cervarix, is directed against HPV-16 and HPV-18; it is not yet available in the United States. The other, sold as Gardasil, is directed against four HPV types: 6, 11, 16, and 18, and it is currently available (reviewed by Widdice and Kahn³).

The study. The Females United to Unilaterally Reduce Endo/Ectocervical Cancer (FUTURE) II study⁴ assessed the ability of the quadrivalent vaccine to prevent high-grade cervical lesions. Between June 2002 and September 2003, more than 12,000 women ages 15 to 26 were enrolled at 90 sites in 13 countries. Eligible women were not pregnant, had no abnormal Papanicolaou (Pap) smear, had had four or fewer lifetime sexual partners, and agreed to use effective contraception throughout the course of the study.

In a randomized, double-blind fashion, patients received vaccine or a placebo injection at day 1 and again 2 and 6 months later. They returned for follow-up 1, 6, 24, 36, and 48 months after the third injection, with Pap smears and colposcopy of cervical lesions.

The primary composite end point was the development of grade 2 or 3 cervical intraepithelial neoplasia, adenocarcinoma in situ, or invasive cervical carcinoma, with detection of HPV-16 or HPV-18 or both in one or more of the adjacent sections of the same lesion.

In all, 6,087 patients received vaccine and 6,080 received placebo; the two groups were well matched. About 23% had serologic evidence of exposure to either HPV-16 or HPV-18 at enrollment.

Findings. In the analysis of the data, the patients were divided into three overlapping subgroups. The first comprised women who had no serologic evidence of HPV-16 or HPV-18 infection at enrollment, who received all three injections, who remained DNA-negative at month 7, and who had no protocol violations. In this “per-protocol susceptible population,” at an average of 3 years of follow-up, lesions associated with HPV-16 or HPV-18 had developed in 42 of 5,260 women who received placebo, compared with only 1 of 5,305 who received the vaccine. The vaccine efficacy was calculated at 98% (95% confidence interval [CI] 86–100).

The second subgroup were women who had no evidence of HPV-16 or HPV-18 infection at baseline, but whose compliance with the protocol was considered imperfect. In this “unrestricted susceptible population,” the vaccine efficacy was 95% (95% CI 85–99).

The third group included all comers, regardless of whether they were already infected at baseline. In this “intention-to-treat population,” the vaccine efficacy was 44% (95% CI 26–58).

The authors concluded that in young women not previously infected with HPV-16 or HPV-18, vaccine recipients had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to these two oncogenic HPV types.

QUADRIVALENT HPV VACCINE PREVENTS ANOGENITAL DISEASE

Garland SM, Hernandez-Avila M, Wheeler CM, et al; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. J Engl J Med 2007; 356:1928–1943.

The study. This double-blind, placebo-controlled study⁵ tested the usefulness of the quadrivalent HPV vaccine to prevent anogenital disease. It included 5,400 women ages 16 to 24 and was conducted over 14 months in 2002 and 2003 at 62 sites in 16 countries. Women received vaccine or placebo at day 1 and again 2 and 6 months later, and then underwent anogenital and gynecologic examinations at intervals for up to 4 years.

The co-primary composite end points were the incidence of genital warts, vulvar or vaginal intraepithelial neoplasia or cancer, cervical intraepithelial neoplasia, cervical adenocarcinoma in situ, or cervical cancer associated with HPV types 6, 11, 16, or 18.

Findings. In all, 2,700 women were assigned to receive vaccine and 2,700 to receive placebo, and they were followed for an average of 3 years. Twenty percent had pre-existing serologic evidence of infection with one of these four HPV types. In the per-protocol population who were seronegative at day 1 and were compliant, the vaccine efficacy was 100%. In the intention-to-treat group, vaccine reduced the rate of vulvar or vaginal perianal lesions regardless of HPV type by 34%, and reduced the rate of cervical lesions regardless of type by 20%.

HPV VACCINE LIKELY COST-EFFECTIVE IN GIRLS, BUT NOT BOYS

Newall AT, Beutels P, Wood JG, Edmunds WJ, MacIntyre CR. Cost-effectiveness analyses of human papillomavirus vaccination. Lancet Infect Dis  2007; 7:289–296.

The study. In a review, Newall et al⁶ looked at four studies that examined the cost-effectiveness of the HPV vaccine. These studies were not perfect and had methodologic limitations because of uncertainty about vaccine efficacy, duration of protection, and the contribution of herd immunity. The studies nevertheless suggested that immunization of young girls but not young boys may be cost-effective, though they suggested the need for further research.

Findings. Three of the studies showed an incremental cost-effectiveness ratio of $14,000 to $24,000 per quality-adjusted year of life gained, which is well within the range for many preventive strategies that we employ in this country.

One of the studies examined the cost-effectiveness of immunizing males, and in that study it was found not to be cost-effective.

TAKE-HOME POINTS ON HPV VACCINATION

Quadrivalent vaccine does indeed reduce the incidence of HPV-associated cervical intra-epithelial neoplasia, vulvar and vaginal intra-epithelial neoplasia, and anogenital diseases in young women, and it is likely cost-effective.

The vaccine works only against HPV types 6, 11, 16, and 18, and 30% of cervical cancers are due to types other than HPV-16 and HPV-18. Also, vaccination is much more effective in patients not yet exposed to HPV, so it would be best to vaccinate them before they become sexually active.

The Advisory Committee on Immunization Practices voted to recommend that girls ages 11 to 12 in this country should receive vaccine.

Regrettably, many third-party payers do not yet pay for the vaccine, and the cost (around $375) must be paid out of pocket. Also, this issue remains politically charged and controversial. Some states have mandated vaccination and another 15 are presently considering legislation mandating vaccination. Such legislation has been defeated in four states.

My own practice is to offer the vaccine to 11- and 12-year old girls, and to older girls and young women (not to boys), especially if the health insurance plan covers it or if the patient or the patient’s family can afford it.

HEPATITIS A VACCINE IS AS GOOD AS IMMUNE GLOBULIN AFTER EXPOSURE

Victor JC, Monto AS, Surdina TY, et al. Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med 2007; 357:1685–1694.

Before 1995, when the first hepatitis A vaccine was introduced, about 30,000 cases of hepatitis A were reported each year in the United States. This was thought to be the tip of the iceberg: since this infection is often subclinical, estimates of up to 300,000 cases per year were given.

At first, immunization against hepatitis A in this country was confined to children over age 2 in states in which hepatitis A occurred more often than the norm. In 2005, after it had become clear that the vaccine was highly effective, the Advisory Committee on Immunization Practices revised its recommendations to include immunization of children between the ages of 12 and 23 months,⁷ so that they would complete this two-stage vaccination procedure by the time they reached the age of 2 years. With that strategy, the annual occurrence of hepatitis A in the United States fell dramatically, to about 4,000 cases per year in 2005, the lowest number of cases reported in the last 40 years. At present, most hepatitis A infections in this country are not from casual idiosyncratic transmission but rather are food-borne.

Still, hepatitis A remains a major problem in many parts of the world. Moreover, the availability of immune globulin, the traditional recommended agent for postexposure pro-phylaxis, has been limited because only one company manufactures it and the price has steadily escalated.

The study. Investigators at the University of Michigan and in Kazakhstan compared conventional doses of immune globulin vs hepatitis A vaccine as postexposure prophylaxis, given within 14 days of exposure to index cases of hepatitis A.⁸ Excluded were persons under the age of 2 years or over the age of 40, those with a history of hepatitis A or vaccination, those with liver disease, and those with other contraindications. The primary end point was the development of symptomatic, laboratory-confirmed hepatitis A, defined as a positive test for immunoglobulin M antibodies to hepatitis A; transaminase levels greater than two times the upper limit of normal; and symptoms consistent with hepatitis A in the absence of another identifiable disease that occurred within 15 to 56 days of exposure to the index case.

Findings. Of 4,524 contacts randomized, only 1,414 (31%) were susceptible to hepatitis A, suggesting that the prevalence of hepatitis A in Kazakhstan was high at that time. Of these, 1,090 completed the immunization and follow-up protocol and were eligible for the final analysis. Of these, 568 received vaccine and 522 received globulin. The average age was 12 years, the average time to vaccination after exposure was 10 days; 16% of the exposures occurred in the day-care setting, and 84% of the exposures occurred from household contacts.

Symptomatic hepatitis A occurred in 4.4% of vaccine recipients vs 3.3% of immunoglobulin recipients. The authors concluded that hepatitis A vaccine met the test of noninferiority, that both strategies were highly protective, but that immunoglobulin was modestly better. Thus, in June 2007, the Advisory Committee on Immunization Practices recommended hepatitis A vaccine as the preferred regimen for postexposure prophylaxis.⁹

This approach has several advantages:

• Hepatitis A vaccine confers immunity and long-term protection, which globulin does not
• The supply of vaccine is abundant
• Vaccine is relatively cheap
• Vaccine is easy to give.

This study, however, does not apply to people younger than 2 years or older than 40, those who are immunocompromised, or those who have chronic liver disease. In these groups, the recommendation is still to use immunoglobulin in postexposure prophylaxis.