As my wife is a hospitalist, I was taken aback to find pictures of Ghazni on the front cover of her trade publication for February 2010. Your article was interesting from the vantage point that I actually lived it. I would add the following clarifications:

Maj. (Ramey) Wilson was the battalion surgeon in Ghazni from 2007 to April of 2008. I succeeded him as the sole American physician in the province for 2008 until Ghazni was turned over to the Polish battle group in November of that year. During that time, combat with enemy forces and IED (improvised explosive device) attacks became significantly more common than in the preceding years.

As a neurologist and clinical neurophysiologist, my expertise prior to coming to Afghanistan in trauma care and first aid was quite limited. Our physician assistant was deployed to another base in the province. As indicated in your article, the practice environment was exceedingly crude, without radiologic, lab, or nursing support. While Dr. Wilson had made tremendous strides with the provincial hospital system, the local Afghan health officials encouraged their physicians to send patients to our base when they felt uncomfortable, rather than proceeding through the Afghan system. This overburdened the aid station when the Afghan facility had superior equipment and resources.

Certainly, both the local population and NATO forces in Ghazni were very fortunate to have a physician of Maj. Wilson’s caliber, as he was a one-man state department and Level I trauma center all wrapped into a single package. When the mission became more combat-focused, the humanitarian portion became both more difficult and more dangerous, and tensions increased between the provincial government and our battalion. Further, only briefly alluded to in your article was the additional effect of prolonged family separation, which adds significant and severe psychological stressors during deployment and on return to the U.S.

In short, I suspect that Maj. Wilson’s “challenges met, success exemplified” is atypical of battalion surgeons in the Middle East combat theatre, and definitely was at odds with my own experience in the same area just months later.

John Ney, MD

Former Maj., U.S. Army;

former Battalion Surgeon,

1-506th Infantry, 4th Brigade, 101st Airborne; senior fellow,

clinical research, University of Washington Department of Neurology, Seattle

Consider HM-Pharmacist Collaborations to Solve Manpower Issues, Improve LOS, and Reduce Medication Costs

The 2008 American Society of Hospital Pharmacists and the Society of Hospital Medicine (ASHP-SHM) Statement on Hospitalist-Pharmacist Collaboration encouraged the development of partnerships in order to optimize outcomes in hospitalized patients.1 This alliance comes naturally, as hospitalists and clinical pharmacists share a common goal: improve patient care through implementation of evidence-based medicine. Despite strong encouragement, little literature exists to describe successful collaborations.

In 2008, Mercy Hospital of Iowa City and the University of Iowa College of Pharmacy jointly hired a clinical pharmacist to be devoted to the hospitalist group at Mercy Hospital. This new hire also became a member of a multidisciplinary team. The pharmacists’ duties were established through implementation of facets of the 2008 ASHP-SHM statement.1 Each of the following duties is incorporated into daily practice:

• Attend daily hospitalist morning rounds and interdisciplinary rounds;
• Review patient records on daily basis; confer information or recommendations to physicians as needed throughout the day;
• Reconcile medication at admission and across the continuum of the hospital stay, including discharge;
• Provide patient education and counseling as needed;
• Serve as a drug information resource as needed to physicians, nurses, and other members of the interdisciplinary team;
• Review medication regimens and prescribing practices to ensure adherence to evidence-based medicine and core measures;
• Provide recommendations on pharmacokinetic drug monitoring, as well as renal dose adjustment or other dose adjustments; and
• Assist in the creation and implementation of medication-use policies and protocols, and participate in active, continued surveillance of medication protocols.

It might not be feasible to hire clinical pharmacists to be solely assigned to hospitalist teams, although success has been found at Mercy through the development of a shared clinical position with the College of Pharmacy. Although described as a 50-50 position, a majority of the teaching duties occur on-site at Mercy, working with fourth-year pharmacy students on clinical rotations. It has become a win-win situation: The hospitalist team benefits from a dedicated clinical pharmacist, and the students benefit from a clinical setting with vast opportunities to review general internal-medicine cases.

In contrast to developing a new position, reallocation of resources often is the route by which collaborations evolve. In a 2005 article by Cohen et al at Brookhaven Memorial Hospital in Patchogue, N.Y., patients treated by voluntary attending physicians were compared with patients treated by hospitalists who collaborated with residents from the institution’s accredited pharmacy residency program. Analyses revealed the hospitalist/pharmacist group achieved a 23% shorter length of stay, 21% lower cost of medication, and 1.5 fewer medications per patient.2 The hospitalist/pharmacist group also had a reduced length of IV antibiotic therapy and gastrointestinal medications by 1.7 and 0.9 days, respectively.2

Although anecdotal, an added benefit to having a clinical pharmacist assigned to the HM team at Mercy is continuity and familiarity with the physicians and patients. The clinical pharmacist inherently has a vested interest in the success of the hospitalists as well as the pharmacy department, which provides ongoing momentum for joint projects.

The recent development of the HM model of inpatient care has coincided with a rapid evolution in the role of hospital-based clinical pharmacists. Pharmacologic interventions are utilized for virtually all hospitalized patients, and they are inherently complex and potentially hazardous. Pharmacist involvement with the multidisciplinary hospitalist team provides a mechanism to address and minimize these complexities.

Innovative approaches to reallocate or create collaborative models are needed as the two disciplines, hospitalists and clinical pharmacists, continue to transform inpatient care.

Phyllis Hemerson, PharmD, BCPS

clinical pharmacy specialist

Mercy Hospital, Iowa City

assistant professor, University of Iowa College of Pharmacy

Martin Izakovic, MD, PhD, CPE, FHM, FACP, FACPE

vice president of medical staff affairs and chief medical officer

hospitalist program medical director, Mercy Hospital

References

1. Cobaugh DJ, Amin A, Bookwalter T, et al. ASHP-SHM Joint Statement on Hospitalist-Pharmacist Collaboration. Am J Health Syst Pharm. 2008;65(3):260-263.
2. Cohen K, Syed S. Hospitalists, pharmacists partner to cut errors. Healthcare Benchmarks Qual Improv. 2005;12(2):18-19.

As my wife is a hospitalist, I was taken aback to find pictures of Ghazni on the front cover of her trade publication for February 2010. Your article was interesting from the vantage point that I actually lived it. I would add the following clarifications:

Maj. (Ramey) Wilson was the battalion surgeon in Ghazni from 2007 to April of 2008. I succeeded him as the sole American physician in the province for 2008 until Ghazni was turned over to the Polish battle group in November of that year. During that time, combat with enemy forces and IED (improvised explosive device) attacks became significantly more common than in the preceding years.

As a neurologist and clinical neurophysiologist, my expertise prior to coming to Afghanistan in trauma care and first aid was quite limited. Our physician assistant was deployed to another base in the province. As indicated in your article, the practice environment was exceedingly crude, without radiologic, lab, or nursing support. While Dr. Wilson had made tremendous strides with the provincial hospital system, the local Afghan health officials encouraged their physicians to send patients to our base when they felt uncomfortable, rather than proceeding through the Afghan system. This overburdened the aid station when the Afghan facility had superior equipment and resources.

Certainly, both the local population and NATO forces in Ghazni were very fortunate to have a physician of Maj. Wilson’s caliber, as he was a one-man state department and Level I trauma center all wrapped into a single package. When the mission became more combat-focused, the humanitarian portion became both more difficult and more dangerous, and tensions increased between the provincial government and our battalion. Further, only briefly alluded to in your article was the additional effect of prolonged family separation, which adds significant and severe psychological stressors during deployment and on return to the U.S.

In short, I suspect that Maj. Wilson’s “challenges met, success exemplified” is atypical of battalion surgeons in the Middle East combat theatre, and definitely was at odds with my own experience in the same area just months later.

John Ney, MD

Former Maj., U.S. Army;

former Battalion Surgeon,

1-506th Infantry, 4th Brigade, 101st Airborne; senior fellow,

clinical research, University of Washington Department of Neurology, Seattle

Consider HM-Pharmacist Collaborations to Solve Manpower Issues, Improve LOS, and Reduce Medication Costs

The 2008 American Society of Hospital Pharmacists and the Society of Hospital Medicine (ASHP-SHM) Statement on Hospitalist-Pharmacist Collaboration encouraged the development of partnerships in order to optimize outcomes in hospitalized patients.1 This alliance comes naturally, as hospitalists and clinical pharmacists share a common goal: improve patient care through implementation of evidence-based medicine. Despite strong encouragement, little literature exists to describe successful collaborations.

In 2008, Mercy Hospital of Iowa City and the University of Iowa College of Pharmacy jointly hired a clinical pharmacist to be devoted to the hospitalist group at Mercy Hospital. This new hire also became a member of a multidisciplinary team. The pharmacists’ duties were established through implementation of facets of the 2008 ASHP-SHM statement.1 Each of the following duties is incorporated into daily practice:

• Attend daily hospitalist morning rounds and interdisciplinary rounds;
• Review patient records on daily basis; confer information or recommendations to physicians as needed throughout the day;
• Reconcile medication at admission and across the continuum of the hospital stay, including discharge;
• Provide patient education and counseling as needed;
• Serve as a drug information resource as needed to physicians, nurses, and other members of the interdisciplinary team;
• Review medication regimens and prescribing practices to ensure adherence to evidence-based medicine and core measures;
• Provide recommendations on pharmacokinetic drug monitoring, as well as renal dose adjustment or other dose adjustments; and
• Assist in the creation and implementation of medication-use policies and protocols, and participate in active, continued surveillance of medication protocols.

It might not be feasible to hire clinical pharmacists to be solely assigned to hospitalist teams, although success has been found at Mercy through the development of a shared clinical position with the College of Pharmacy. Although described as a 50-50 position, a majority of the teaching duties occur on-site at Mercy, working with fourth-year pharmacy students on clinical rotations. It has become a win-win situation: The hospitalist team benefits from a dedicated clinical pharmacist, and the students benefit from a clinical setting with vast opportunities to review general internal-medicine cases.

In contrast to developing a new position, reallocation of resources often is the route by which collaborations evolve. In a 2005 article by Cohen et al at Brookhaven Memorial Hospital in Patchogue, N.Y., patients treated by voluntary attending physicians were compared with patients treated by hospitalists who collaborated with residents from the institution’s accredited pharmacy residency program. Analyses revealed the hospitalist/pharmacist group achieved a 23% shorter length of stay, 21% lower cost of medication, and 1.5 fewer medications per patient.2 The hospitalist/pharmacist group also had a reduced length of IV antibiotic therapy and gastrointestinal medications by 1.7 and 0.9 days, respectively.2

Although anecdotal, an added benefit to having a clinical pharmacist assigned to the HM team at Mercy is continuity and familiarity with the physicians and patients. The clinical pharmacist inherently has a vested interest in the success of the hospitalists as well as the pharmacy department, which provides ongoing momentum for joint projects.

The recent development of the HM model of inpatient care has coincided with a rapid evolution in the role of hospital-based clinical pharmacists. Pharmacologic interventions are utilized for virtually all hospitalized patients, and they are inherently complex and potentially hazardous. Pharmacist involvement with the multidisciplinary hospitalist team provides a mechanism to address and minimize these complexities.

Innovative approaches to reallocate or create collaborative models are needed as the two disciplines, hospitalists and clinical pharmacists, continue to transform inpatient care.

Phyllis Hemerson, PharmD, BCPS

clinical pharmacy specialist

Mercy Hospital, Iowa City

assistant professor, University of Iowa College of Pharmacy

Martin Izakovic, MD, PhD, CPE, FHM, FACP, FACPE

vice president of medical staff affairs and chief medical officer

hospitalist program medical director, Mercy Hospital

References

1. Cobaugh DJ, Amin A, Bookwalter T, et al. ASHP-SHM Joint Statement on Hospitalist-Pharmacist Collaboration. Am J Health Syst Pharm. 2008;65(3):260-263.
2. Cohen K, Syed S. Hospitalists, pharmacists partner to cut errors. Healthcare Benchmarks Qual Improv. 2005;12(2):18-19.

As my wife is a hospitalist, I was taken aback to find pictures of Ghazni on the front cover of her trade publication for February 2010. Your article was interesting from the vantage point that I actually lived it. I would add the following clarifications:

Maj. (Ramey) Wilson was the battalion surgeon in Ghazni from 2007 to April of 2008. I succeeded him as the sole American physician in the province for 2008 until Ghazni was turned over to the Polish battle group in November of that year. During that time, combat with enemy forces and IED (improvised explosive device) attacks became significantly more common than in the preceding years.

As a neurologist and clinical neurophysiologist, my expertise prior to coming to Afghanistan in trauma care and first aid was quite limited. Our physician assistant was deployed to another base in the province. As indicated in your article, the practice environment was exceedingly crude, without radiologic, lab, or nursing support. While Dr. Wilson had made tremendous strides with the provincial hospital system, the local Afghan health officials encouraged their physicians to send patients to our base when they felt uncomfortable, rather than proceeding through the Afghan system. This overburdened the aid station when the Afghan facility had superior equipment and resources.

Certainly, both the local population and NATO forces in Ghazni were very fortunate to have a physician of Maj. Wilson’s caliber, as he was a one-man state department and Level I trauma center all wrapped into a single package. When the mission became more combat-focused, the humanitarian portion became both more difficult and more dangerous, and tensions increased between the provincial government and our battalion. Further, only briefly alluded to in your article was the additional effect of prolonged family separation, which adds significant and severe psychological stressors during deployment and on return to the U.S.

In short, I suspect that Maj. Wilson’s “challenges met, success exemplified” is atypical of battalion surgeons in the Middle East combat theatre, and definitely was at odds with my own experience in the same area just months later.

John Ney, MD

Former Maj., U.S. Army;

former Battalion Surgeon,

1-506th Infantry, 4th Brigade, 101st Airborne; senior fellow,

clinical research, University of Washington Department of Neurology, Seattle

Consider HM-Pharmacist Collaborations to Solve Manpower Issues, Improve LOS, and Reduce Medication Costs

The 2008 American Society of Hospital Pharmacists and the Society of Hospital Medicine (ASHP-SHM) Statement on Hospitalist-Pharmacist Collaboration encouraged the development of partnerships in order to optimize outcomes in hospitalized patients.1 This alliance comes naturally, as hospitalists and clinical pharmacists share a common goal: improve patient care through implementation of evidence-based medicine. Despite strong encouragement, little literature exists to describe successful collaborations.

In 2008, Mercy Hospital of Iowa City and the University of Iowa College of Pharmacy jointly hired a clinical pharmacist to be devoted to the hospitalist group at Mercy Hospital. This new hire also became a member of a multidisciplinary team. The pharmacists’ duties were established through implementation of facets of the 2008 ASHP-SHM statement.1 Each of the following duties is incorporated into daily practice:

• Attend daily hospitalist morning rounds and interdisciplinary rounds;
• Review patient records on daily basis; confer information or recommendations to physicians as needed throughout the day;
• Reconcile medication at admission and across the continuum of the hospital stay, including discharge;
• Provide patient education and counseling as needed;
• Serve as a drug information resource as needed to physicians, nurses, and other members of the interdisciplinary team;
• Review medication regimens and prescribing practices to ensure adherence to evidence-based medicine and core measures;
• Provide recommendations on pharmacokinetic drug monitoring, as well as renal dose adjustment or other dose adjustments; and
• Assist in the creation and implementation of medication-use policies and protocols, and participate in active, continued surveillance of medication protocols.

It might not be feasible to hire clinical pharmacists to be solely assigned to hospitalist teams, although success has been found at Mercy through the development of a shared clinical position with the College of Pharmacy. Although described as a 50-50 position, a majority of the teaching duties occur on-site at Mercy, working with fourth-year pharmacy students on clinical rotations. It has become a win-win situation: The hospitalist team benefits from a dedicated clinical pharmacist, and the students benefit from a clinical setting with vast opportunities to review general internal-medicine cases.

In contrast to developing a new position, reallocation of resources often is the route by which collaborations evolve. In a 2005 article by Cohen et al at Brookhaven Memorial Hospital in Patchogue, N.Y., patients treated by voluntary attending physicians were compared with patients treated by hospitalists who collaborated with residents from the institution’s accredited pharmacy residency program. Analyses revealed the hospitalist/pharmacist group achieved a 23% shorter length of stay, 21% lower cost of medication, and 1.5 fewer medications per patient.2 The hospitalist/pharmacist group also had a reduced length of IV antibiotic therapy and gastrointestinal medications by 1.7 and 0.9 days, respectively.2

Although anecdotal, an added benefit to having a clinical pharmacist assigned to the HM team at Mercy is continuity and familiarity with the physicians and patients. The clinical pharmacist inherently has a vested interest in the success of the hospitalists as well as the pharmacy department, which provides ongoing momentum for joint projects.

The recent development of the HM model of inpatient care has coincided with a rapid evolution in the role of hospital-based clinical pharmacists. Pharmacologic interventions are utilized for virtually all hospitalized patients, and they are inherently complex and potentially hazardous. Pharmacist involvement with the multidisciplinary hospitalist team provides a mechanism to address and minimize these complexities.

Innovative approaches to reallocate or create collaborative models are needed as the two disciplines, hospitalists and clinical pharmacists, continue to transform inpatient care.

Phyllis Hemerson, PharmD, BCPS

clinical pharmacy specialist

Mercy Hospital, Iowa City

assistant professor, University of Iowa College of Pharmacy

Martin Izakovic, MD, PhD, CPE, FHM, FACP, FACPE

vice president of medical staff affairs and chief medical officer

hospitalist program medical director, Mercy Hospital

References

1. Cobaugh DJ, Amin A, Bookwalter T, et al. ASHP-SHM Joint Statement on Hospitalist-Pharmacist Collaboration. Am J Health Syst Pharm. 2008;65(3):260-263.
2. Cohen K, Syed S. Hospitalists, pharmacists partner to cut errors. Healthcare Benchmarks Qual Improv. 2005;12(2):18-19.

Click here to listen to the audio file

Click here to listen to the audio file

Click here to listen to the audio file

Are states doing enough to discipline problem doctors? The sensitive question has flared again with the release of an annual report by Washington, D.C.-based consumer advocacy group Public Citizen.

The report analyzed statistics released by the Federation of State Medical Boards on serious disciplinary actions taken by the boards of all 50 states and the District of Columbia in 2009. Those actions include revocations, surrenders, suspensions, and probations or restrictions. Public Citizen used a three-year average (2007 to 2009) to arrive at its rate of actions per 1,000 physicians licensed in each state.

For the fourth year in a row, Alaska had the most actions, 7.89 per 1,000 doctors. Meanwhile, Minnesota had the fewest actions (1.07 per 1,000 doctors) for the second year running. For the record, the numbers aren’t broken down by specialty (see Table 1, p. 5).

So what does it all mean? Do Alaska’s doctors really require more punitive measures than those in other states, or is the state board simply more vigilant? Are Minnesota doctors that much better, or is that state failing in its duty to provide adequate oversight? Is such a ranking system even warranted?

Nearly everyone agrees on the importance of protecting the public and the integrity of the medical profession. But the aggressive jousting over what the new numbers do or do not mean suggests just how difficult it can be to come up with a metric for medical accountability that everyone agrees is both fair and reliable.

Sidney Wolfe, MD, director of Public Citizen’s Health Research Group and the lead author of the new report, dismisses the notion that Minnesota’s doctors are so good that they don’t require as many disciplinary actions. “There is not a shred of evidence for that,” he says. Instead, he calls out what he views as an ineffective board.

In turn, Robert Leach, executive director of the Minnesota Board of Medical Practice, dismisses the significance of the report’s findings. “It’s a fair ranking the way their formula applies. It’s the formula we disagree with,” he says. “It’s fairly simplistic and indicative of nothing.”

And Lisa Robin, senior vice president for advocacy and member services at the Federation of State Medical Boards, says the federation doesn’t even encourage rankings because of the variable laws and sanctions from state to state. “It doesn’t give you a true picture of what boards do, to rank them,” she says.

click for large version

A Row Over Rankings

Minnesota’s Leach has a detailed list of grievances against the report. But his biggest beef is with the fact that it ranks medical boards on the number of serious disciplinary actions per 1,000 physicians licensed by the state. “The more precise number should be the number of licensed physicians who are actually practicing in the state,” he says.

From 2008 to 2009, for example, more than 19,000 physicians were licensed in Minnesota. Yet Leach says that only a little more than 14,000 were actually practicing within the state, which he describes as a large exporter of trained doctors. “So we had 5,000 physicians who weren’t even practicing here that were counted against our one disciplinary action per thousand physicians,” he says.

Public Citizen, he says, also doesn’t recognize other interventions, such as Minnesota’s “agreements for corrective action,” that normally include training or remedial coursework for doctors with an identified weakness in subject areas such as prescribing or chronic-pain management. “Not every doctor needs to be hit over the head with a hammer of serious disciplinary action to address a problem,” Leach says.

And then there’s the sticky matter of peer review. In Minnesota, “virtually every physician now practicing works for a large health plan or a facility,” he says. “We have virtually no solo practice or isolated practice in Minnesota, and those are the physicians who get in trouble: the ones who don’t have the advantage of periodic peer review, who don’t have the advantage of adequate supervision to help keep them out of trouble.”

Doctors like those in Alaska? “You always see Alaska is rated real high,” Leach says. “You have a bunch of people out there practicing in the wilderness, out in solo practice. Physicians need to have that ability to have peer review, to be able to address problem cases with their colleagues. In Minnesota, a lot of these facilities and health plans address these problems at the practice level before they even reach the board.”

A Call To Action

Dr. Wolfe isn’t buying the notion that Minnesota doctors require less formal discipline while their colleagues in Alaska need more. Whenever other low-ranking states have provided sufficient funding, replaced ineffective leadership, granted more independence, and met the other conditions necessary for a better medical board, he notes, their rate of disciplinary actions often “rockets up.”

The medical boards of North Carolina and Washington, D.C., have risen dramatically in the rankings in recent years, and Dr. Wolfe cites effective intervention in both cases. In formerly low-ranking Arizona, he says, similar corrective action in the late 1990s led to a tripling of the rate of serious disciplinary action within three years. “That’s obviously not a period of time that’s long enough to be explained by some inward migration of bad doctors or outward migration of good doctors,” he says. “It’s because the board started functioning better.”

Meanwhile, boards in South Carolina and Massachusetts have slumped in the ratings—a decline he attributes to the loss of leadership and funds.

“One area I can agree with Dr. Wolfe on is that medical boards need resources; they need adequate structure, resources, and authority to do their job and be able to protect the public,” says Robin, of the Federation of State Medical Boards. “If they’re in a big umbrella agency and they’re just one of many and share their pool of investigators with everyone, as you can imagine, that’s probably not as efficient.”

Hospitals also share in the blame, according to a separate Public Citizen report released last year that cites a chronic underreporting of doctor misconduct or incompetence to the National Practitioner Data Bank by hospitals. Robin agrees that more diligence is needed to ensure that medical boards have the information they need to properly do their jobs. As one of her board members told her, “They can’t gain information by osmosis.”

Hospitalists, however, might be well suited for addressing the underreporting issue. HM is in a “really good position to observe behavior that needs to be brought to the attention of hospital medical staff,” Dr. Wolfe says.

He recommends that one or more hospitalists should sit on each hospital’s medical peer review committee, where they can put their expertise to good use. “Hospitalists really need to get more active in this,” he says. “It’s for the betterment of the patients in the hospital, it’s for the betterment for the reputation of the hospital and the medical staff.” TH

Bryn Nelson is a freelance medical writer based in Seattle.

Are states doing enough to discipline problem doctors? The sensitive question has flared again with the release of an annual report by Washington, D.C.-based consumer advocacy group Public Citizen.

The report analyzed statistics released by the Federation of State Medical Boards on serious disciplinary actions taken by the boards of all 50 states and the District of Columbia in 2009. Those actions include revocations, surrenders, suspensions, and probations or restrictions. Public Citizen used a three-year average (2007 to 2009) to arrive at its rate of actions per 1,000 physicians licensed in each state.

For the fourth year in a row, Alaska had the most actions, 7.89 per 1,000 doctors. Meanwhile, Minnesota had the fewest actions (1.07 per 1,000 doctors) for the second year running. For the record, the numbers aren’t broken down by specialty (see Table 1, p. 5).

So what does it all mean? Do Alaska’s doctors really require more punitive measures than those in other states, or is the state board simply more vigilant? Are Minnesota doctors that much better, or is that state failing in its duty to provide adequate oversight? Is such a ranking system even warranted?

Nearly everyone agrees on the importance of protecting the public and the integrity of the medical profession. But the aggressive jousting over what the new numbers do or do not mean suggests just how difficult it can be to come up with a metric for medical accountability that everyone agrees is both fair and reliable.

Sidney Wolfe, MD, director of Public Citizen’s Health Research Group and the lead author of the new report, dismisses the notion that Minnesota’s doctors are so good that they don’t require as many disciplinary actions. “There is not a shred of evidence for that,” he says. Instead, he calls out what he views as an ineffective board.

In turn, Robert Leach, executive director of the Minnesota Board of Medical Practice, dismisses the significance of the report’s findings. “It’s a fair ranking the way their formula applies. It’s the formula we disagree with,” he says. “It’s fairly simplistic and indicative of nothing.”

And Lisa Robin, senior vice president for advocacy and member services at the Federation of State Medical Boards, says the federation doesn’t even encourage rankings because of the variable laws and sanctions from state to state. “It doesn’t give you a true picture of what boards do, to rank them,” she says.

click for large version

A Row Over Rankings

Minnesota’s Leach has a detailed list of grievances against the report. But his biggest beef is with the fact that it ranks medical boards on the number of serious disciplinary actions per 1,000 physicians licensed by the state. “The more precise number should be the number of licensed physicians who are actually practicing in the state,” he says.

From 2008 to 2009, for example, more than 19,000 physicians were licensed in Minnesota. Yet Leach says that only a little more than 14,000 were actually practicing within the state, which he describes as a large exporter of trained doctors. “So we had 5,000 physicians who weren’t even practicing here that were counted against our one disciplinary action per thousand physicians,” he says.

Public Citizen, he says, also doesn’t recognize other interventions, such as Minnesota’s “agreements for corrective action,” that normally include training or remedial coursework for doctors with an identified weakness in subject areas such as prescribing or chronic-pain management. “Not every doctor needs to be hit over the head with a hammer of serious disciplinary action to address a problem,” Leach says.

And then there’s the sticky matter of peer review. In Minnesota, “virtually every physician now practicing works for a large health plan or a facility,” he says. “We have virtually no solo practice or isolated practice in Minnesota, and those are the physicians who get in trouble: the ones who don’t have the advantage of periodic peer review, who don’t have the advantage of adequate supervision to help keep them out of trouble.”

Doctors like those in Alaska? “You always see Alaska is rated real high,” Leach says. “You have a bunch of people out there practicing in the wilderness, out in solo practice. Physicians need to have that ability to have peer review, to be able to address problem cases with their colleagues. In Minnesota, a lot of these facilities and health plans address these problems at the practice level before they even reach the board.”

A Call To Action

Dr. Wolfe isn’t buying the notion that Minnesota doctors require less formal discipline while their colleagues in Alaska need more. Whenever other low-ranking states have provided sufficient funding, replaced ineffective leadership, granted more independence, and met the other conditions necessary for a better medical board, he notes, their rate of disciplinary actions often “rockets up.”

The medical boards of North Carolina and Washington, D.C., have risen dramatically in the rankings in recent years, and Dr. Wolfe cites effective intervention in both cases. In formerly low-ranking Arizona, he says, similar corrective action in the late 1990s led to a tripling of the rate of serious disciplinary action within three years. “That’s obviously not a period of time that’s long enough to be explained by some inward migration of bad doctors or outward migration of good doctors,” he says. “It’s because the board started functioning better.”

Meanwhile, boards in South Carolina and Massachusetts have slumped in the ratings—a decline he attributes to the loss of leadership and funds.

“One area I can agree with Dr. Wolfe on is that medical boards need resources; they need adequate structure, resources, and authority to do their job and be able to protect the public,” says Robin, of the Federation of State Medical Boards. “If they’re in a big umbrella agency and they’re just one of many and share their pool of investigators with everyone, as you can imagine, that’s probably not as efficient.”

Hospitals also share in the blame, according to a separate Public Citizen report released last year that cites a chronic underreporting of doctor misconduct or incompetence to the National Practitioner Data Bank by hospitals. Robin agrees that more diligence is needed to ensure that medical boards have the information they need to properly do their jobs. As one of her board members told her, “They can’t gain information by osmosis.”

Hospitalists, however, might be well suited for addressing the underreporting issue. HM is in a “really good position to observe behavior that needs to be brought to the attention of hospital medical staff,” Dr. Wolfe says.

He recommends that one or more hospitalists should sit on each hospital’s medical peer review committee, where they can put their expertise to good use. “Hospitalists really need to get more active in this,” he says. “It’s for the betterment of the patients in the hospital, it’s for the betterment for the reputation of the hospital and the medical staff.” TH

Bryn Nelson is a freelance medical writer based in Seattle.

Are states doing enough to discipline problem doctors? The sensitive question has flared again with the release of an annual report by Washington, D.C.-based consumer advocacy group Public Citizen.

The report analyzed statistics released by the Federation of State Medical Boards on serious disciplinary actions taken by the boards of all 50 states and the District of Columbia in 2009. Those actions include revocations, surrenders, suspensions, and probations or restrictions. Public Citizen used a three-year average (2007 to 2009) to arrive at its rate of actions per 1,000 physicians licensed in each state.

For the fourth year in a row, Alaska had the most actions, 7.89 per 1,000 doctors. Meanwhile, Minnesota had the fewest actions (1.07 per 1,000 doctors) for the second year running. For the record, the numbers aren’t broken down by specialty (see Table 1, p. 5).

So what does it all mean? Do Alaska’s doctors really require more punitive measures than those in other states, or is the state board simply more vigilant? Are Minnesota doctors that much better, or is that state failing in its duty to provide adequate oversight? Is such a ranking system even warranted?

Nearly everyone agrees on the importance of protecting the public and the integrity of the medical profession. But the aggressive jousting over what the new numbers do or do not mean suggests just how difficult it can be to come up with a metric for medical accountability that everyone agrees is both fair and reliable.

Sidney Wolfe, MD, director of Public Citizen’s Health Research Group and the lead author of the new report, dismisses the notion that Minnesota’s doctors are so good that they don’t require as many disciplinary actions. “There is not a shred of evidence for that,” he says. Instead, he calls out what he views as an ineffective board.

In turn, Robert Leach, executive director of the Minnesota Board of Medical Practice, dismisses the significance of the report’s findings. “It’s a fair ranking the way their formula applies. It’s the formula we disagree with,” he says. “It’s fairly simplistic and indicative of nothing.”

And Lisa Robin, senior vice president for advocacy and member services at the Federation of State Medical Boards, says the federation doesn’t even encourage rankings because of the variable laws and sanctions from state to state. “It doesn’t give you a true picture of what boards do, to rank them,” she says.

click for large version

A Row Over Rankings

Minnesota’s Leach has a detailed list of grievances against the report. But his biggest beef is with the fact that it ranks medical boards on the number of serious disciplinary actions per 1,000 physicians licensed by the state. “The more precise number should be the number of licensed physicians who are actually practicing in the state,” he says.

From 2008 to 2009, for example, more than 19,000 physicians were licensed in Minnesota. Yet Leach says that only a little more than 14,000 were actually practicing within the state, which he describes as a large exporter of trained doctors. “So we had 5,000 physicians who weren’t even practicing here that were counted against our one disciplinary action per thousand physicians,” he says.

Public Citizen, he says, also doesn’t recognize other interventions, such as Minnesota’s “agreements for corrective action,” that normally include training or remedial coursework for doctors with an identified weakness in subject areas such as prescribing or chronic-pain management. “Not every doctor needs to be hit over the head with a hammer of serious disciplinary action to address a problem,” Leach says.

And then there’s the sticky matter of peer review. In Minnesota, “virtually every physician now practicing works for a large health plan or a facility,” he says. “We have virtually no solo practice or isolated practice in Minnesota, and those are the physicians who get in trouble: the ones who don’t have the advantage of periodic peer review, who don’t have the advantage of adequate supervision to help keep them out of trouble.”

Doctors like those in Alaska? “You always see Alaska is rated real high,” Leach says. “You have a bunch of people out there practicing in the wilderness, out in solo practice. Physicians need to have that ability to have peer review, to be able to address problem cases with their colleagues. In Minnesota, a lot of these facilities and health plans address these problems at the practice level before they even reach the board.”

A Call To Action

Dr. Wolfe isn’t buying the notion that Minnesota doctors require less formal discipline while their colleagues in Alaska need more. Whenever other low-ranking states have provided sufficient funding, replaced ineffective leadership, granted more independence, and met the other conditions necessary for a better medical board, he notes, their rate of disciplinary actions often “rockets up.”

The medical boards of North Carolina and Washington, D.C., have risen dramatically in the rankings in recent years, and Dr. Wolfe cites effective intervention in both cases. In formerly low-ranking Arizona, he says, similar corrective action in the late 1990s led to a tripling of the rate of serious disciplinary action within three years. “That’s obviously not a period of time that’s long enough to be explained by some inward migration of bad doctors or outward migration of good doctors,” he says. “It’s because the board started functioning better.”

Meanwhile, boards in South Carolina and Massachusetts have slumped in the ratings—a decline he attributes to the loss of leadership and funds.

“One area I can agree with Dr. Wolfe on is that medical boards need resources; they need adequate structure, resources, and authority to do their job and be able to protect the public,” says Robin, of the Federation of State Medical Boards. “If they’re in a big umbrella agency and they’re just one of many and share their pool of investigators with everyone, as you can imagine, that’s probably not as efficient.”

Hospitals also share in the blame, according to a separate Public Citizen report released last year that cites a chronic underreporting of doctor misconduct or incompetence to the National Practitioner Data Bank by hospitals. Robin agrees that more diligence is needed to ensure that medical boards have the information they need to properly do their jobs. As one of her board members told her, “They can’t gain information by osmosis.”

Hospitalists, however, might be well suited for addressing the underreporting issue. HM is in a “really good position to observe behavior that needs to be brought to the attention of hospital medical staff,” Dr. Wolfe says.

He recommends that one or more hospitalists should sit on each hospital’s medical peer review committee, where they can put their expertise to good use. “Hospitalists really need to get more active in this,” he says. “It’s for the betterment of the patients in the hospital, it’s for the betterment for the reputation of the hospital and the medical staff.” TH

Bryn Nelson is a freelance medical writer based in Seattle.

The impact of last summer’s new restrictions from the Accreditation Council for Graduate Medical Education (ACGME) on how many hospitalized patients a first-year resident can treat on an internal-medicine (IM) rotation was as immediate as it was evident at Monmouth Medical Center, a 527-bed teaching hospital in Long Branch, N.J. The institution had a class of eight rookie residents whose caseloads were cut from 12 to the new threshold of 10.

Physicians “had to find some other way of getting attention . . . for 16 patients,” says Sarah Wallach, MD, FACP, director of Monmouth’s IM residency program and vice chair of the department of medicine at the hospital. At Monmouth, the solution came in the form of a new hire—a nurse practitioner (NP)—to handle the overflow. The NP service is used predominantly for referral patients from primary-care physicians (PCPs), as opposed to independent hospital admissions.

But because the NP service does not provide 24-hour coverage, the hospital can get away with only one person in the position. To extend coverage all day long, Dr. Wallach estimates she would need to hire two or three additional NPs, plus another one or two administrative positions to provide relief on holidays and vacations. “You would need five people,” she says. “I can’t afford that.”

Few hospitals or HM groups can afford new hires in today’s world of Medicare reimbursement cuts, shrinking budgets, and—courtesy of the newest rules—restricting patient caps for residents. The latest rules took hold about a year ago, but hospitalists in both academic and community settings say the impact already is noticeable.

Many hospitals have had to craft solutions, which have included burdening academic hospitals with more clinical responsibilities, turning to private HM groups (HMGs) to assume the patients residents can no longer care for, or hiring nonphysician providers (NPPs) to pick up the slack. As Dr. Wallach pointedly notes, the latter two solutions cost money at a time when hospitals have less to go around.

Already, teaching hospitals have begun discussions about how the newest rules—and the future changes they presage—will change the playing field. Will a wave of academics flee their classroom (the teaching hospital), as nonteaching duties become an intrusion? Will teaching hospitals face financial pressure as they struggle to replace the low-cost labor force that residents represent?

Perhaps most importantly from a medical perspective, will graduate trainees be as prepared as their predecessors when they enter practice?

Dr. Wallach

The answers will have a direct correlation to private HMGs, which are poised to see more patients in the wake of residency restrictions, particularly on overnight services. The cost of hospital care will increase for hospitals, putting more pressure on hospitalist groups that tout themselves to C-suites as engines for cost savings. Long-term implications, unfortunately, remain murky, as the newest rules have been in place for a relatively short time. Plus, ACGME is expected—at the end of this month, according to a recent memo to program directors—to announce more changes to residency guidelines.

“Hospitalists will always be involved in teaching—it will never go away,” says Julia Wright, MD, FHM, clinical professor of medicine and director of hospital medicine at the University of Wisconsin School of Medicine and Public Health in Madison and a member of Team Hospitalist. “But it will be a very different balance, a different kind of feel.”

The Past to the Future

To understand the concerns moving forward, it’s important to first look back. In July 2003, new ACGME rules went into place capping the workweeks of residents at 80 hours. Rules were put into place that regulated the number of patients that residents could be assigned, and those thresholds were further tightened on July 1, 2009. The most notable 2009 change: A first-year resident’s patient census must not exceed 10 patients. ACGME CEO Thomas J. Nasca, MD, MACP, sent a letter to program directors in early May announcing more changes to resident work hours. The letter indicates proposals will be announced by the end of this month, and public comment will follow. At the earliest, new rules changes would go into effect in 2011. “The board may adopt a modification to the duty-hours standard,” says Julie Jacob, a spokeswoman for Chicago-based ACGME. “Any proposed standards would get a public comment.”

Jacob declined further comment, but various hospitalists and academics say they wouldn’t be surprised if new rules reflect 2008 Institute of Medicine (IOM) recommendations.1 The IOM report called for a maximum resident shift length of 30 hours, with admission of patients for up to 16 hours, plus a five-hour uninterrupted sleep period between 10 p.m. and 8 a.m. It also suggested the remaining workweek hours be used for transitional and educational activities.

However those IOM recommendations are incorporated, one thing is clear: Any adoption of those standards will have a financial impact. In fact, a study published last year reported that annual labor costs from implementing the IOM standards was estimated to be $1.6 billion in 2006 dollars (see “The Cost of Progress,” p. 25).2

“Any replacement of a resident costs more than a resident, whether it’s an NP, a PA (physician assistant), an MD, or a DO,” says Kevin O’Leary, MD, MS, associate program director of the IM residency program at Northwestern University’s Feinberg School of Medicine in Chicago. “Everybody costs more.”

Dr. Wallach

The Fate of Teachers

Some of the largest academic centers, including the Feinberg School, the University of Michigan, and the teaching service at St. Luke’s-Roosevelt Hospital in New York City, reduced patient caseloads ahead of the 2009 round of residency rule changes. Hospitalists and educators at those institutions say the proactive approach helped them adjust to the newest rules, which by some estimates reduce resident productivity by 20%.

But the changes shift the workload to academic hospitalists, many of whom forego higher-paying positions to pursue teaching and research. According to the latest SHM survey data, academic hospitalists make about $50,000 less per year than the average community hospitalist. But as clinical work intrudes further, as residents are unable to assume the patient care they once did, educators are put into positions of having to balance the educational portion of their job with patient care, says John Del Valle, MD, professor and residency program director in the department of internal medicine at the University of Michigan Health System in Ann Arbor.

“This is where difficult decisions have to be made,” Dr. Del Valle says. “This is not the blend of activities that traditional academics signed up for.”

Solutions to relieve current and impending pressure on teaching hospitalists have presented themselves in different ways. In Dr. Del Valle’s hospital, there is a split between the hospitalist service and the house staff, which is aimed at keeping up with the growth in IM admissions. That tally has climbed an average of 4% per year for the past five years, reaching some 18,000 admissions last year. To handle that workload, the nonresident service last year added three clinical full-time equivalents (FTEs) to bring its total to nearly 30 FTEs.

Dr. Del Valle notes his institution has been fortunate to be able to afford growth, thanks in large part to a payor mix with a relatively low percentage of charity care and high level of activity.

At Brigham and Women’s Hospital in Boston, the answer is a freestanding PA service that has been in place since 2005. Last summer, the program went to a 24-hour rotation to increase continuity for overnight services and to provide coverage on night shifts, an area most in the industry agree will be hit hardest by the resident caps. Physicians at Brigham’s, a teaching affiliate of Harvard Medical School, are now discussing an expansion of the PA service, or perhaps even an overhaul to a more cost-efficient solution, says Danielle Scheurer, MD, MSc, FHM, assistant professor of medicine at Harvard and director of Brigham’s general medicine service.

Dr. Frost

At Medical Center Hospital (MCH) in Odessa, Texas, the hospitalists were added to the ED call schedule once every five nights. The plan was under discussion before the new residency rules went into place; however, it was implemented to keep the IM residency program within the new limits, says Bruce Becker, MD, MCH’s chief medical officer.

And at St. Luke’s-Roosevelt Hospital, discussions are under way on how to best extend the nonteaching staff, says Ethan Fried, MD, MS, FACP, assistant professor of clinical medicine at Columbia University, vice chair for education in the department of medicine and director of graduate medical education at St. Luke’s-Roosevelt. “The adjustment has to come from the nonteaching side because the house staff at this point is saturated,” says Dr. Fried, president-elect of the Association of Program Directors in Internal Medicine (APDIM). “You can’t be cheap about acquiring your nonteaching staff.”

The Fate of Students

Perhaps paramount to the fears of how teaching hospitalists will react to current or future restrictions is the effect those limits have on the residents they safeguard. Some physicians think the new rules will produce crops of ill-prepared residents because they have been coddled with limited patient censuses. Other physicians argue that the new thresholds will actually better prepare physicians when HM groups are hiring residents for full-time positions.

Dr. Del Valle acknowledges there is as yet no rigorous data to show the impact of the current restrictions, but he agrees it’s a simple equation of patient-care mathematics. “You can’t [easily] replace 100-110 hours [of care per week],” he says.

Others say patient caps and rules to limit how much work residents do are in line with the purpose of medical training programs. “I’ve bought into the fact that these programs exist to train residents, not to provide clinical care,” Dr. O’Leary says. “I’ve drunk that Kool-Aid. … I think there’s more variation, person to person, than ‘my era vs. the current era.’ Like any new hospitalist that you hire, you need to give an orientation and give enough support to them so when they begin to see patients that they are not overwhelmed.”

Shaun Frost, MD, FACP, FHM, might be best described as halfway between those two extremes. A regional director for the eastern U.S. for Cogent Healthcare, he says duty-hour restrictions have had deleterious impacts but also create learning opportunities.

“The residency work-hour restrictions have inhibited our ability to train people to work as efficiently as trainees who were taught in the past,” says Dr. Frost, an SHM board member. “That doesn’t necessarily mean you can’t teach people to work more efficiently . . . but in the future, my hope is that residency training programs will recognize the deficit that exists in personal work efficiencies between their completion and their responsibilities as a hospitalist.”

To that end, Dr. Frost works with others to develop both structured curriculum and classroom didactics that help new hospitalists make up for gaps in preparation that weren’t addressed in residency. In some cases, that can be practice management and billing issues, but often, according to Dr. Frost, it is addressing personal workflow and bridging the “unnatural discontinuity” in patient care from residency to the real world.

“There is a cost to this investment for the future,” Dr. Frost adds. “If people don’t recognize the potential return on investment as being critical to the development of an educated workforce—an efficient and competent workforce—and thus critical to the retention of high-performing hospitalists, they are selling themselves, unfortunately, significantly short.”

Caught in the Middle

One man’s trash is another man’s treasure, the axiom tells us. Well, in healthcare circles, that could just as easily read: The woes of academic hospitalists are the wealth of community hospitalists.

The new rules “may result in more opportunities for hospitalists to provide needed clinical services,” Dr. Wright says.

The long-term implications, though, remain to be seen. While academic hospitalists say they have seen preliminary increases in care-delivery costs because of the latest rules changes, many say it’s too soon to tell just how high those costs might climb and what ripple effect might follow.

Some physicians, including Dr. Del Valle, note that while the 2009 changes and the expectation of more changes in 2011 are cause for attention, that doesn’t translate to cause for concern. In 2003, months before the 80-hour workweek rules were first put in place by ACGME, many of the same debates were already under way: How will the faculty of IM residency programs cope? How will institutions pay the bills while putting money aside for other physicians picking up the slack?

“This is a pendulum,” Dr. Del Valle says. “I think it will come back to a balanced place.”

Dr. Fried, who is more optimistic that the residency rules can have a positive, long-term effect, agrees. He says residency caps and limits should not be viewed as “things that limit education. We [should] look at them as things that ensure education continues while patient care continues.” TH

Richard Quinn is a freelance writer based in New Jersey.

References

1. Institute of Medicine. Resident Duty Hours: Enhancing Sleep, Supervision, and Safety. Ulmer C, Wolman DM, Johns MM, eds. Washington, D.C.: The National Academies Press; 2008.
2. Nuckols TK, Bhattacharya J, Wolman DM, Ulmer C, Escarce JJ. Cost implications of reduced work hours and workloads for resident physicians. N Engl J Med. 2009:360(21):2202-2215.

The impact of last summer’s new restrictions from the Accreditation Council for Graduate Medical Education (ACGME) on how many hospitalized patients a first-year resident can treat on an internal-medicine (IM) rotation was as immediate as it was evident at Monmouth Medical Center, a 527-bed teaching hospital in Long Branch, N.J. The institution had a class of eight rookie residents whose caseloads were cut from 12 to the new threshold of 10.

Physicians “had to find some other way of getting attention . . . for 16 patients,” says Sarah Wallach, MD, FACP, director of Monmouth’s IM residency program and vice chair of the department of medicine at the hospital. At Monmouth, the solution came in the form of a new hire—a nurse practitioner (NP)—to handle the overflow. The NP service is used predominantly for referral patients from primary-care physicians (PCPs), as opposed to independent hospital admissions.

But because the NP service does not provide 24-hour coverage, the hospital can get away with only one person in the position. To extend coverage all day long, Dr. Wallach estimates she would need to hire two or three additional NPs, plus another one or two administrative positions to provide relief on holidays and vacations. “You would need five people,” she says. “I can’t afford that.”

Few hospitals or HM groups can afford new hires in today’s world of Medicare reimbursement cuts, shrinking budgets, and—courtesy of the newest rules—restricting patient caps for residents. The latest rules took hold about a year ago, but hospitalists in both academic and community settings say the impact already is noticeable.

Many hospitals have had to craft solutions, which have included burdening academic hospitals with more clinical responsibilities, turning to private HM groups (HMGs) to assume the patients residents can no longer care for, or hiring nonphysician providers (NPPs) to pick up the slack. As Dr. Wallach pointedly notes, the latter two solutions cost money at a time when hospitals have less to go around.

Already, teaching hospitals have begun discussions about how the newest rules—and the future changes they presage—will change the playing field. Will a wave of academics flee their classroom (the teaching hospital), as nonteaching duties become an intrusion? Will teaching hospitals face financial pressure as they struggle to replace the low-cost labor force that residents represent?

Perhaps most importantly from a medical perspective, will graduate trainees be as prepared as their predecessors when they enter practice?

Dr. Wallach

The answers will have a direct correlation to private HMGs, which are poised to see more patients in the wake of residency restrictions, particularly on overnight services. The cost of hospital care will increase for hospitals, putting more pressure on hospitalist groups that tout themselves to C-suites as engines for cost savings. Long-term implications, unfortunately, remain murky, as the newest rules have been in place for a relatively short time. Plus, ACGME is expected—at the end of this month, according to a recent memo to program directors—to announce more changes to residency guidelines.

“Hospitalists will always be involved in teaching—it will never go away,” says Julia Wright, MD, FHM, clinical professor of medicine and director of hospital medicine at the University of Wisconsin School of Medicine and Public Health in Madison and a member of Team Hospitalist. “But it will be a very different balance, a different kind of feel.”

The Past to the Future

To understand the concerns moving forward, it’s important to first look back. In July 2003, new ACGME rules went into place capping the workweeks of residents at 80 hours. Rules were put into place that regulated the number of patients that residents could be assigned, and those thresholds were further tightened on July 1, 2009. The most notable 2009 change: A first-year resident’s patient census must not exceed 10 patients. ACGME CEO Thomas J. Nasca, MD, MACP, sent a letter to program directors in early May announcing more changes to resident work hours. The letter indicates proposals will be announced by the end of this month, and public comment will follow. At the earliest, new rules changes would go into effect in 2011. “The board may adopt a modification to the duty-hours standard,” says Julie Jacob, a spokeswoman for Chicago-based ACGME. “Any proposed standards would get a public comment.”

Jacob declined further comment, but various hospitalists and academics say they wouldn’t be surprised if new rules reflect 2008 Institute of Medicine (IOM) recommendations.1 The IOM report called for a maximum resident shift length of 30 hours, with admission of patients for up to 16 hours, plus a five-hour uninterrupted sleep period between 10 p.m. and 8 a.m. It also suggested the remaining workweek hours be used for transitional and educational activities.

However those IOM recommendations are incorporated, one thing is clear: Any adoption of those standards will have a financial impact. In fact, a study published last year reported that annual labor costs from implementing the IOM standards was estimated to be $1.6 billion in 2006 dollars (see “The Cost of Progress,” p. 25).2

“Any replacement of a resident costs more than a resident, whether it’s an NP, a PA (physician assistant), an MD, or a DO,” says Kevin O’Leary, MD, MS, associate program director of the IM residency program at Northwestern University’s Feinberg School of Medicine in Chicago. “Everybody costs more.”

Dr. Wallach

The Fate of Teachers

Some of the largest academic centers, including the Feinberg School, the University of Michigan, and the teaching service at St. Luke’s-Roosevelt Hospital in New York City, reduced patient caseloads ahead of the 2009 round of residency rule changes. Hospitalists and educators at those institutions say the proactive approach helped them adjust to the newest rules, which by some estimates reduce resident productivity by 20%.

But the changes shift the workload to academic hospitalists, many of whom forego higher-paying positions to pursue teaching and research. According to the latest SHM survey data, academic hospitalists make about $50,000 less per year than the average community hospitalist. But as clinical work intrudes further, as residents are unable to assume the patient care they once did, educators are put into positions of having to balance the educational portion of their job with patient care, says John Del Valle, MD, professor and residency program director in the department of internal medicine at the University of Michigan Health System in Ann Arbor.

“This is where difficult decisions have to be made,” Dr. Del Valle says. “This is not the blend of activities that traditional academics signed up for.”

Solutions to relieve current and impending pressure on teaching hospitalists have presented themselves in different ways. In Dr. Del Valle’s hospital, there is a split between the hospitalist service and the house staff, which is aimed at keeping up with the growth in IM admissions. That tally has climbed an average of 4% per year for the past five years, reaching some 18,000 admissions last year. To handle that workload, the nonresident service last year added three clinical full-time equivalents (FTEs) to bring its total to nearly 30 FTEs.

Dr. Del Valle notes his institution has been fortunate to be able to afford growth, thanks in large part to a payor mix with a relatively low percentage of charity care and high level of activity.

At Brigham and Women’s Hospital in Boston, the answer is a freestanding PA service that has been in place since 2005. Last summer, the program went to a 24-hour rotation to increase continuity for overnight services and to provide coverage on night shifts, an area most in the industry agree will be hit hardest by the resident caps. Physicians at Brigham’s, a teaching affiliate of Harvard Medical School, are now discussing an expansion of the PA service, or perhaps even an overhaul to a more cost-efficient solution, says Danielle Scheurer, MD, MSc, FHM, assistant professor of medicine at Harvard and director of Brigham’s general medicine service.

Dr. Frost

At Medical Center Hospital (MCH) in Odessa, Texas, the hospitalists were added to the ED call schedule once every five nights. The plan was under discussion before the new residency rules went into place; however, it was implemented to keep the IM residency program within the new limits, says Bruce Becker, MD, MCH’s chief medical officer.

And at St. Luke’s-Roosevelt Hospital, discussions are under way on how to best extend the nonteaching staff, says Ethan Fried, MD, MS, FACP, assistant professor of clinical medicine at Columbia University, vice chair for education in the department of medicine and director of graduate medical education at St. Luke’s-Roosevelt. “The adjustment has to come from the nonteaching side because the house staff at this point is saturated,” says Dr. Fried, president-elect of the Association of Program Directors in Internal Medicine (APDIM). “You can’t be cheap about acquiring your nonteaching staff.”

The Fate of Students

Perhaps paramount to the fears of how teaching hospitalists will react to current or future restrictions is the effect those limits have on the residents they safeguard. Some physicians think the new rules will produce crops of ill-prepared residents because they have been coddled with limited patient censuses. Other physicians argue that the new thresholds will actually better prepare physicians when HM groups are hiring residents for full-time positions.

Dr. Del Valle acknowledges there is as yet no rigorous data to show the impact of the current restrictions, but he agrees it’s a simple equation of patient-care mathematics. “You can’t [easily] replace 100-110 hours [of care per week],” he says.

Others say patient caps and rules to limit how much work residents do are in line with the purpose of medical training programs. “I’ve bought into the fact that these programs exist to train residents, not to provide clinical care,” Dr. O’Leary says. “I’ve drunk that Kool-Aid. … I think there’s more variation, person to person, than ‘my era vs. the current era.’ Like any new hospitalist that you hire, you need to give an orientation and give enough support to them so when they begin to see patients that they are not overwhelmed.”

Shaun Frost, MD, FACP, FHM, might be best described as halfway between those two extremes. A regional director for the eastern U.S. for Cogent Healthcare, he says duty-hour restrictions have had deleterious impacts but also create learning opportunities.

“The residency work-hour restrictions have inhibited our ability to train people to work as efficiently as trainees who were taught in the past,” says Dr. Frost, an SHM board member. “That doesn’t necessarily mean you can’t teach people to work more efficiently . . . but in the future, my hope is that residency training programs will recognize the deficit that exists in personal work efficiencies between their completion and their responsibilities as a hospitalist.”

To that end, Dr. Frost works with others to develop both structured curriculum and classroom didactics that help new hospitalists make up for gaps in preparation that weren’t addressed in residency. In some cases, that can be practice management and billing issues, but often, according to Dr. Frost, it is addressing personal workflow and bridging the “unnatural discontinuity” in patient care from residency to the real world.

“There is a cost to this investment for the future,” Dr. Frost adds. “If people don’t recognize the potential return on investment as being critical to the development of an educated workforce—an efficient and competent workforce—and thus critical to the retention of high-performing hospitalists, they are selling themselves, unfortunately, significantly short.”

Caught in the Middle

One man’s trash is another man’s treasure, the axiom tells us. Well, in healthcare circles, that could just as easily read: The woes of academic hospitalists are the wealth of community hospitalists.

The new rules “may result in more opportunities for hospitalists to provide needed clinical services,” Dr. Wright says.

The long-term implications, though, remain to be seen. While academic hospitalists say they have seen preliminary increases in care-delivery costs because of the latest rules changes, many say it’s too soon to tell just how high those costs might climb and what ripple effect might follow.

Some physicians, including Dr. Del Valle, note that while the 2009 changes and the expectation of more changes in 2011 are cause for attention, that doesn’t translate to cause for concern. In 2003, months before the 80-hour workweek rules were first put in place by ACGME, many of the same debates were already under way: How will the faculty of IM residency programs cope? How will institutions pay the bills while putting money aside for other physicians picking up the slack?

“This is a pendulum,” Dr. Del Valle says. “I think it will come back to a balanced place.”

Dr. Fried, who is more optimistic that the residency rules can have a positive, long-term effect, agrees. He says residency caps and limits should not be viewed as “things that limit education. We [should] look at them as things that ensure education continues while patient care continues.” TH

Richard Quinn is a freelance writer based in New Jersey.

References

1. Institute of Medicine. Resident Duty Hours: Enhancing Sleep, Supervision, and Safety. Ulmer C, Wolman DM, Johns MM, eds. Washington, D.C.: The National Academies Press; 2008.
2. Nuckols TK, Bhattacharya J, Wolman DM, Ulmer C, Escarce JJ. Cost implications of reduced work hours and workloads for resident physicians. N Engl J Med. 2009:360(21):2202-2215.

The impact of last summer’s new restrictions from the Accreditation Council for Graduate Medical Education (ACGME) on how many hospitalized patients a first-year resident can treat on an internal-medicine (IM) rotation was as immediate as it was evident at Monmouth Medical Center, a 527-bed teaching hospital in Long Branch, N.J. The institution had a class of eight rookie residents whose caseloads were cut from 12 to the new threshold of 10.

Physicians “had to find some other way of getting attention . . . for 16 patients,” says Sarah Wallach, MD, FACP, director of Monmouth’s IM residency program and vice chair of the department of medicine at the hospital. At Monmouth, the solution came in the form of a new hire—a nurse practitioner (NP)—to handle the overflow. The NP service is used predominantly for referral patients from primary-care physicians (PCPs), as opposed to independent hospital admissions.

But because the NP service does not provide 24-hour coverage, the hospital can get away with only one person in the position. To extend coverage all day long, Dr. Wallach estimates she would need to hire two or three additional NPs, plus another one or two administrative positions to provide relief on holidays and vacations. “You would need five people,” she says. “I can’t afford that.”

Few hospitals or HM groups can afford new hires in today’s world of Medicare reimbursement cuts, shrinking budgets, and—courtesy of the newest rules—restricting patient caps for residents. The latest rules took hold about a year ago, but hospitalists in both academic and community settings say the impact already is noticeable.

Many hospitals have had to craft solutions, which have included burdening academic hospitals with more clinical responsibilities, turning to private HM groups (HMGs) to assume the patients residents can no longer care for, or hiring nonphysician providers (NPPs) to pick up the slack. As Dr. Wallach pointedly notes, the latter two solutions cost money at a time when hospitals have less to go around.

Already, teaching hospitals have begun discussions about how the newest rules—and the future changes they presage—will change the playing field. Will a wave of academics flee their classroom (the teaching hospital), as nonteaching duties become an intrusion? Will teaching hospitals face financial pressure as they struggle to replace the low-cost labor force that residents represent?

Perhaps most importantly from a medical perspective, will graduate trainees be as prepared as their predecessors when they enter practice?

Dr. Wallach

The answers will have a direct correlation to private HMGs, which are poised to see more patients in the wake of residency restrictions, particularly on overnight services. The cost of hospital care will increase for hospitals, putting more pressure on hospitalist groups that tout themselves to C-suites as engines for cost savings. Long-term implications, unfortunately, remain murky, as the newest rules have been in place for a relatively short time. Plus, ACGME is expected—at the end of this month, according to a recent memo to program directors—to announce more changes to residency guidelines.

“Hospitalists will always be involved in teaching—it will never go away,” says Julia Wright, MD, FHM, clinical professor of medicine and director of hospital medicine at the University of Wisconsin School of Medicine and Public Health in Madison and a member of Team Hospitalist. “But it will be a very different balance, a different kind of feel.”

The Past to the Future

To understand the concerns moving forward, it’s important to first look back. In July 2003, new ACGME rules went into place capping the workweeks of residents at 80 hours. Rules were put into place that regulated the number of patients that residents could be assigned, and those thresholds were further tightened on July 1, 2009. The most notable 2009 change: A first-year resident’s patient census must not exceed 10 patients. ACGME CEO Thomas J. Nasca, MD, MACP, sent a letter to program directors in early May announcing more changes to resident work hours. The letter indicates proposals will be announced by the end of this month, and public comment will follow. At the earliest, new rules changes would go into effect in 2011. “The board may adopt a modification to the duty-hours standard,” says Julie Jacob, a spokeswoman for Chicago-based ACGME. “Any proposed standards would get a public comment.”

Jacob declined further comment, but various hospitalists and academics say they wouldn’t be surprised if new rules reflect 2008 Institute of Medicine (IOM) recommendations.1 The IOM report called for a maximum resident shift length of 30 hours, with admission of patients for up to 16 hours, plus a five-hour uninterrupted sleep period between 10 p.m. and 8 a.m. It also suggested the remaining workweek hours be used for transitional and educational activities.

However those IOM recommendations are incorporated, one thing is clear: Any adoption of those standards will have a financial impact. In fact, a study published last year reported that annual labor costs from implementing the IOM standards was estimated to be $1.6 billion in 2006 dollars (see “The Cost of Progress,” p. 25).2

“Any replacement of a resident costs more than a resident, whether it’s an NP, a PA (physician assistant), an MD, or a DO,” says Kevin O’Leary, MD, MS, associate program director of the IM residency program at Northwestern University’s Feinberg School of Medicine in Chicago. “Everybody costs more.”

Dr. Wallach

The Fate of Teachers

Some of the largest academic centers, including the Feinberg School, the University of Michigan, and the teaching service at St. Luke’s-Roosevelt Hospital in New York City, reduced patient caseloads ahead of the 2009 round of residency rule changes. Hospitalists and educators at those institutions say the proactive approach helped them adjust to the newest rules, which by some estimates reduce resident productivity by 20%.

But the changes shift the workload to academic hospitalists, many of whom forego higher-paying positions to pursue teaching and research. According to the latest SHM survey data, academic hospitalists make about $50,000 less per year than the average community hospitalist. But as clinical work intrudes further, as residents are unable to assume the patient care they once did, educators are put into positions of having to balance the educational portion of their job with patient care, says John Del Valle, MD, professor and residency program director in the department of internal medicine at the University of Michigan Health System in Ann Arbor.

“This is where difficult decisions have to be made,” Dr. Del Valle says. “This is not the blend of activities that traditional academics signed up for.”

Solutions to relieve current and impending pressure on teaching hospitalists have presented themselves in different ways. In Dr. Del Valle’s hospital, there is a split between the hospitalist service and the house staff, which is aimed at keeping up with the growth in IM admissions. That tally has climbed an average of 4% per year for the past five years, reaching some 18,000 admissions last year. To handle that workload, the nonresident service last year added three clinical full-time equivalents (FTEs) to bring its total to nearly 30 FTEs.

Dr. Del Valle notes his institution has been fortunate to be able to afford growth, thanks in large part to a payor mix with a relatively low percentage of charity care and high level of activity.

At Brigham and Women’s Hospital in Boston, the answer is a freestanding PA service that has been in place since 2005. Last summer, the program went to a 24-hour rotation to increase continuity for overnight services and to provide coverage on night shifts, an area most in the industry agree will be hit hardest by the resident caps. Physicians at Brigham’s, a teaching affiliate of Harvard Medical School, are now discussing an expansion of the PA service, or perhaps even an overhaul to a more cost-efficient solution, says Danielle Scheurer, MD, MSc, FHM, assistant professor of medicine at Harvard and director of Brigham’s general medicine service.

Dr. Frost

At Medical Center Hospital (MCH) in Odessa, Texas, the hospitalists were added to the ED call schedule once every five nights. The plan was under discussion before the new residency rules went into place; however, it was implemented to keep the IM residency program within the new limits, says Bruce Becker, MD, MCH’s chief medical officer.

And at St. Luke’s-Roosevelt Hospital, discussions are under way on how to best extend the nonteaching staff, says Ethan Fried, MD, MS, FACP, assistant professor of clinical medicine at Columbia University, vice chair for education in the department of medicine and director of graduate medical education at St. Luke’s-Roosevelt. “The adjustment has to come from the nonteaching side because the house staff at this point is saturated,” says Dr. Fried, president-elect of the Association of Program Directors in Internal Medicine (APDIM). “You can’t be cheap about acquiring your nonteaching staff.”

The Fate of Students

Perhaps paramount to the fears of how teaching hospitalists will react to current or future restrictions is the effect those limits have on the residents they safeguard. Some physicians think the new rules will produce crops of ill-prepared residents because they have been coddled with limited patient censuses. Other physicians argue that the new thresholds will actually better prepare physicians when HM groups are hiring residents for full-time positions.

Dr. Del Valle acknowledges there is as yet no rigorous data to show the impact of the current restrictions, but he agrees it’s a simple equation of patient-care mathematics. “You can’t [easily] replace 100-110 hours [of care per week],” he says.

Others say patient caps and rules to limit how much work residents do are in line with the purpose of medical training programs. “I’ve bought into the fact that these programs exist to train residents, not to provide clinical care,” Dr. O’Leary says. “I’ve drunk that Kool-Aid. … I think there’s more variation, person to person, than ‘my era vs. the current era.’ Like any new hospitalist that you hire, you need to give an orientation and give enough support to them so when they begin to see patients that they are not overwhelmed.”

Shaun Frost, MD, FACP, FHM, might be best described as halfway between those two extremes. A regional director for the eastern U.S. for Cogent Healthcare, he says duty-hour restrictions have had deleterious impacts but also create learning opportunities.

“The residency work-hour restrictions have inhibited our ability to train people to work as efficiently as trainees who were taught in the past,” says Dr. Frost, an SHM board member. “That doesn’t necessarily mean you can’t teach people to work more efficiently . . . but in the future, my hope is that residency training programs will recognize the deficit that exists in personal work efficiencies between their completion and their responsibilities as a hospitalist.”

To that end, Dr. Frost works with others to develop both structured curriculum and classroom didactics that help new hospitalists make up for gaps in preparation that weren’t addressed in residency. In some cases, that can be practice management and billing issues, but often, according to Dr. Frost, it is addressing personal workflow and bridging the “unnatural discontinuity” in patient care from residency to the real world.

“There is a cost to this investment for the future,” Dr. Frost adds. “If people don’t recognize the potential return on investment as being critical to the development of an educated workforce—an efficient and competent workforce—and thus critical to the retention of high-performing hospitalists, they are selling themselves, unfortunately, significantly short.”

Caught in the Middle

One man’s trash is another man’s treasure, the axiom tells us. Well, in healthcare circles, that could just as easily read: The woes of academic hospitalists are the wealth of community hospitalists.

The new rules “may result in more opportunities for hospitalists to provide needed clinical services,” Dr. Wright says.

The long-term implications, though, remain to be seen. While academic hospitalists say they have seen preliminary increases in care-delivery costs because of the latest rules changes, many say it’s too soon to tell just how high those costs might climb and what ripple effect might follow.

Some physicians, including Dr. Del Valle, note that while the 2009 changes and the expectation of more changes in 2011 are cause for attention, that doesn’t translate to cause for concern. In 2003, months before the 80-hour workweek rules were first put in place by ACGME, many of the same debates were already under way: How will the faculty of IM residency programs cope? How will institutions pay the bills while putting money aside for other physicians picking up the slack?

“This is a pendulum,” Dr. Del Valle says. “I think it will come back to a balanced place.”

Dr. Fried, who is more optimistic that the residency rules can have a positive, long-term effect, agrees. He says residency caps and limits should not be viewed as “things that limit education. We [should] look at them as things that ensure education continues while patient care continues.” TH

Richard Quinn is a freelance writer based in New Jersey.

References

1. Institute of Medicine. Resident Duty Hours: Enhancing Sleep, Supervision, and Safety. Ulmer C, Wolman DM, Johns MM, eds. Washington, D.C.: The National Academies Press; 2008.
2. Nuckols TK, Bhattacharya J, Wolman DM, Ulmer C, Escarce JJ. Cost implications of reduced work hours and workloads for resident physicians. N Engl J Med. 2009:360(21):2202-2215.

Supplement Editor:
Brian F. Mandell, MD, PhD

Contents

Preventing and treating acute gout attacks across the clinical spectrum: A roundtable discussion
Brian F. Mandell, MD, PhD; N. Lawrence Edwards, MD; John S. Sundy, MD, PhD; Peter A. Simkin, MD; and James C. Pile, MD

Supplement Editor:
Brian F. Mandell, MD, PhD

Contents

Preventing and treating acute gout attacks across the clinical spectrum: A roundtable discussion
Brian F. Mandell, MD, PhD; N. Lawrence Edwards, MD; John S. Sundy, MD, PhD; Peter A. Simkin, MD; and James C. Pile, MD

Supplement Editor:
Brian F. Mandell, MD, PhD

Contents

Preventing and treating acute gout attacks across the clinical spectrum: A roundtable discussion
Brian F. Mandell, MD, PhD; N. Lawrence Edwards, MD; John S. Sundy, MD, PhD; Peter A. Simkin, MD; and James C. Pile, MD

Gout is a chronic, often silent disorder in its early stages that is punctuated by acute, extremely painful arthritic flares. Over time, untreated or insufficiently treated gout may progress, with more frequent flares and formation of urate crystal deposits (tophi) and associated chronic, deforming arthritis (gouty arthropathy). One major aim in the management of gout is to treat the pain of acute flares aggressively with anti-inflammatory agents to reduce flare intensity and duration. This CME supplement discusses the risk factors and comorbidities that contribute to and exacerbate acute gout flares, the criteria for establishing a diagnosis of gout and how to establish goals for achieving, sustaining, and monitoring clinically meaningful urate lowering and means for optimizing patient adherence to long-term urate-lowering treatment.

Gout is a chronic, often silent disorder in its early stages that is punctuated by acute, extremely painful arthritic flares. Over time, untreated or insufficiently treated gout may progress, with more frequent flares and formation of urate crystal deposits (tophi) and associated chronic, deforming arthritis (gouty arthropathy). One major aim in the management of gout is to treat the pain of acute flares aggressively with anti-inflammatory agents to reduce flare intensity and duration. This CME supplement discusses the risk factors and comorbidities that contribute to and exacerbate acute gout flares, the criteria for establishing a diagnosis of gout and how to establish goals for achieving, sustaining, and monitoring clinically meaningful urate lowering and means for optimizing patient adherence to long-term urate-lowering treatment.

Gout is a chronic, often silent disorder in its early stages that is punctuated by acute, extremely painful arthritic flares. Over time, untreated or insufficiently treated gout may progress, with more frequent flares and formation of urate crystal deposits (tophi) and associated chronic, deforming arthritis (gouty arthropathy). One major aim in the management of gout is to treat the pain of acute flares aggressively with anti-inflammatory agents to reduce flare intensity and duration. This CME supplement discusses the risk factors and comorbidities that contribute to and exacerbate acute gout flares, the criteria for establishing a diagnosis of gout and how to establish goals for achieving, sustaining, and monitoring clinically meaningful urate lowering and means for optimizing patient adherence to long-term urate-lowering treatment.

The medical management of non-ST-elevation acute coronary syndromes focuses on blocking the coagulation cascade and inhibiting platelets. This—plus diagnostic angiography followed, if needed, by revascularization—has reduced the rates of death and recurrent ischemic events.¹ However, the combination of potent antithrombotic drugs and invasive procedures also increases the risk of bleeding.

This review discusses the incidence and complications associated with bleeding during the treatment of acute coronary syndromes and summarizes recommendations for preventing and managing bleeding in this setting.

THE TRUE INCIDENCE OF BLEEDING IS HARD TO DETERMINE

The optimal way to detect and analyze bleeding events in clinical trials and registries is highly debated. The reported incidences of bleeding during antithrombotic and antiplatelet therapy for non-ST-elevation acute coronary syndromes depend on how bleeding was defined, how the acute coronary syndromes were treated, and on other factors such as how the study was designed.

How was bleeding defined?

Since these classification schemes are based on different types of data, they yield different numbers when applied to the same study population. For instance, Rao et al⁴ pooled the data from the PURSUIT and PARAGON B trials (15,454 patients in all) and found that the incidence of severe bleeding (by the GUSTO criteria) was 1.2%, while the rate of major bleeding (by the TIMI criteria) was 8.2%.

What was the treatment strategy?

Another reason that the true incidence of bleeding is hard to determine is that different studies used treatment strategies that differed in the type, timing, and dose of antithrombotic agents and whether invasive procedures were used early. For example, if unfractionated heparin is used aggressively in regimens that are not adjusted for weight and with a higher target for the activated clotting time, the risk of bleeding is higher than with conservative dosing.^5–7

Subherwal et al⁸ evaluated the effect of treatment strategy on the incidence of bleeding in patients with non-ST-elevation acute coronary syndromes who received two or more antithrombotic drugs in the CRUSADE Quality Improvement Initiative. The risk of bleeding was higher with an invasive approach (catheterization) than with a conservative approach (no catheterization), regardless of baseline bleeding risk.

What type of study was it?

Another source of variation is the design of the study. Registries differ from clinical trials in patient characteristics and in the way data are gathered (prospectively vs retrospectively).

In registries, data are often collected retrospectively, whereas in clinical trials the data are prospectively collected. For this reason, the definition of bleeding in registries is often based on events that are easily identified through chart review, such as transfusion. This may lead to a lower reported rate of bleeding, since other, less serious bleeding events such as access-site hematomas and epistaxis may not be documented in the medical record.

On the other hand, registries often include older and sicker patients, who may be more prone to bleeding and who are often excluded from clinical trials. This may lead to a higher rate of reported bleeding.⁹

Where the study was conducted makes a difference as well, owing to regional practice differences. For example, Moscucci et al¹⁰ reported that the incidence of major bleeding in 24,045 patients with non-ST-elevation acute coronary syndromes in the GRACE registry (in 14 countries worldwide) was 3.9%. In contrast, Yang et al¹¹ reported that the rate of bleeding in the CRUSADE registry (in the United States) was 10.3%.

This difference was partly influenced by different definitions of bleeding. The GRACE registry defined major bleeding as life-threatening events requiring transfusion of two or more units of packed red blood cells, or resulting in an absolute decrease in the hematocrit of 10% or more or death, or hemorrhagic subdural hematoma. In contrast, the CRUSADE data reflect bleeding requiring transfusion. However, practice patterns such as greater use of invasive procedures in the United States may also be responsible.

Rao and colleagues¹² examined international variation in blood transfusion rates among patients with acute coronary syndromes. Patients outside the United States were significantly less likely to receive transfusions, even after adjusting for patient and practice differences.

Taking these confounders into account, it is reasonable to estimate that the frequency of bleeding in patients with non-ST-elevation acute coronary syndromes ranges from less than 1% to 10%.¹³

BLEEDING IS ASSOCIATED WITH POOR OUTCOMES

Regardless of the definition or the data source, hemorrhagic complications are associated with a higher risk of death and nonfatal adverse events, both in the short term and in the long term.

Short-term outcomes

A higher risk of death. In the GRACE registry study by Moscucci et al¹⁰ discussed above, patients who had major bleeding were significantly more likely to die during their hospitalization than those who did not (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.18–2.28).

Rao et al¹⁴ evaluated pooled data from the multicenter international GUSTO IIb, PURSUIT, and PARAGON A and B trials and found that the effects of bleeding in non-ST-elevation acute coronary syndromes extended beyond the hospital stay. The more severe the bleeding (by the GUSTO criteria), the greater the adjusted hazard ratio (HR) for death within 30 days:

• With mild bleeding—HR 1.6, 95% CI 1.3–1.9
• With moderate bleeding—HR 2.7, 95% CI 2.3–3.4
• With severe bleeding—HR 10.6, 95% CI 8.3–13.6.

The pattern was the same for death within 6 months:

• With mild bleeding—HR 1.4, 95% CI 1.2–1.6
• With moderate bleeding—HR 2.1, 95% CI 1.8–2.4
• With severe bleeding, HR 7.5, 95% CI 6.1–9.3.

These findings were confirmed by Eikelboom et al¹⁵ in 34,146 patients with acute coronary syndromes in the OASIS registry, the OASIS-2 trial, and the CURE randomized trial. In the first 30 days, five times as many patients died (12.8% vs 2.5%; P < .0009) among those who developed major bleeding compared with those who did not. These investigators defined major bleeding as bleeding that was life-threatening or significantly disabling or that required transfusion of two or more units of packed red blood cells.

A higher risk of nonfatal adverse events. Bleeding after antithrombotic therapy for non-ST-elevation acute coronary syndromes has also been associated with nonfatal adverse events such as stroke and stent thrombosis.

For example, in the study by Eikelboom et al,¹⁵ major bleeding was associated with a higher risk of recurrent ischemic events. Approximately 1 in 5 patients in the OASIS trials who developed major bleeding during the first 30 days died or had a myocardial infarction or stroke by 30 days, compared with 1 in 20 of those who did not develop major bleeding during the first 30 days. However, after events that occurred during the first 30 days were excluded, the association between major bleeding and both myocardial infarction and stroke was no longer evident between 30 days and 6 months.

Manoukian et al¹⁶ evaluated the impact of major bleeding in 13,819 patients with highrisk acute coronary syndromes undergoing treatment with an early invasive strategy in the ACUITY trial. At 30 days, patients with major bleeding had higher rates of the composite end point of death, myocardial infarction, or unplanned revascularization for ischemia (23.1% vs 6.8%, P < .0001) and of stent thrombosis (3.4% vs 0.6%, P < .0001).

Long-term outcomes

The association between bleeding and adverse outcomes persists in the long term as well, although the mechanisms underlying this association are not well studied.

Kinnaird et al¹⁷ examined the data from 10,974 unselected patients who underwent percutaneous coronary intervention. At 1 year, the following percentages of patients had died:

• After TIMI major bleeding—17.2%
• After TIMI minor bleeding—9.1%
• After no bleeding—5.5%.

However, after adjustment for potential confounders, only transfusion remained a significant predictor of 1-year mortality.

Mehran et al¹⁸ evaluated 1-year mortality data from the ACUITY trial. Compared with the rate in patients who had no major bleeding and no myocardial infarction, the hazard ratios for death were:

• After major bleeding—HR 3.5, 95% CI 2.7–4.4
• After myocardial infarction—HR 3.1, 95% CI 2.4–3.9.

Interestingly, the risk of death associated with myocardial infarction abated after 7 days, while the risk associated with bleeding persisted beyond 30 days and remained constant throughout the first year following the bleeding event.

Similarly, Ndrepepa and colleagues¹⁹ examined pooled data from four ISAR trials using the TIMI bleeding scale and found that myocardial infarction, target vessel revascularization, and major bleeding all had similar discriminatory ability at predicting 1-year mortality.

In patients undergoing elective or urgent percutaneous coronary intervention in the REPLACE-2 trial,²⁰ independent predictors of death by 1 year were²¹:

• Major hemorrhage (OR 2.66, 95% CI 1.44–4.92)
• Periprocedural myocardial infarction (OR 2.46, 95% CI 1.44–4.20).

THEORIES OF HOW BLEEDING MAY CAUSE ADVERSE OUTCOMES

Several mechanisms have been proposed to explain the association between bleeding during treatment for acute coronary syndromes and adverse clinical outcomes.^13,22

The immediate effects of bleeding are thought to be hypotension and a reflex hyperadrenergic state to compensate for the loss of intravascular volume.²³ This physiologic response is believed to contribute to myocardial ischemia by further decreasing myocardial oxygen supply in obstructive coronary disease.

Trying to minimize blood loss, physicians may withhold anticoagulation and antiplatelet therapy, which in turn may lead to further ischemia.²⁴ To compensate for blood loss, physicians may also resort to blood transfusion. However, depletion of 2,3-diphosphoglycerate and nitric oxide in stored donor red blood cells is postulated to reduce oxygen delivery by increasing hemoglobin’s affinity for oxygen, leading to induced microvascular obstruction and adverse inflammatory reactions.^15,25

Recent data have also begun to elucidate the long-term effects of bleeding during acute coronary syndrome management. Patients with anemia during the acute phase of infarction have greater neurohormonal activation.²⁶ These adaptive responses to anemia may lead to eccentric left ventricular remodeling that may lead to higher oxygen consumption, increased diastolic wall stress, interstitial fibrosis, and accelerated myocyte loss.^27–30

Nevertheless, we must point out that although strong associations between bleeding and adverse outcomes have been established, direct causality has not.

TO PREVENT BLEEDING, START BY ASSESSING RISK

The CRUSADE bleeding risk score

The CRUSADE bleeding score (calculator available at http://www.crusadebleedingscore.org/) was developed and validated in more than 89,000 community-treated patients with non-ST-elevation acute coronary syndromes.⁸ It is based on eight variables:

• Sex (higher risk in women)
• History of diabetes (higher risk)
• Prior vascular disease (higher risk)
• Heart rate (the higher the rate, the higher the risk)
• Systolic blood pressure (higher risk with pressures above or below the 121–180 mm Hg range)
• Signs of congestive heart failure (higher risk)
• Baseline hematocrit (the lower the hematocrit, the higher the risk)
• Creatinine clearance (by the Cockcroft-Gault formula; the lower the creatinine clearance, the higher the risk).

Patients who are found to have bleeding scores suggesting a moderate or higher risk of bleeding should be considered for medications associated with a favorable bleeding profile, and for radial access at the time of coronary angiography. Scores are graded as follows⁸:

• < 21: Very low risk
• 21–30: Low risk
• 31–40: Moderate risk
• 41–50: High risk
• > 50: Very high risk.

The CRUSADE bleeding score is unique in that, unlike earlier risk stratification tools, it was developed in a “real world” population, not in subgroups or in a clinical trial. It can be calculated at baseline to help guide the selection of treatment.⁸

Adjusting the heparin regimen in patients at risk of bleeding

Both the joint American College of Cardiology/American Heart Association¹ and the European Society of Cardiology guidelines³¹ for the treatment of non-ST-elevation acute coronary syndromes recommend taking steps to prevent bleeding, such as adjusting the dosage of unfractionated heparin, using safer drugs, reducing the duration of antithrombotic treatment, and using combinations of antithrombotic and antiplatelet agents according to proven indications.³¹

In the CRUSADE registry, 42% of patients with non-ST-elevation acute coronary syndromes received at least one initial dose of antithrombotic drug outside the recommended range, resulting in an estimated 15% excess of bleeding events.³² Thus, proper dosing is a target for prevention.

Appropriate antithrombotic dosing takes into account the patient’s age, weight, and renal function. However, heparin dosage in the current guidelines¹ is based on weight only: a loading dose of 60 U/kg (maximum 4,000 U) by intravenous bolus, then 12 U/kg/hour (maximum 1,000 U/hour) to maintain an activated partial thromboplastin time of 50 to 70 seconds.¹

Renal dysfunction is particularly worrisome in patients with non-ST-elevation acute coronary syndromes because it is associated with higher rates of major bleeding and death. In the OASIS-5 trial,³³ the overall risk of death was approximately five times higher in patients in the lowest quartile of renal function (glomerular filtration rate < 58 mL/min/1.73 m²) than in the highest quartile (glomerular filtration rate ≥ 86 mL/min/1.73 m²).

Renal function must be evaluated not only on admission but also throughout the hospital stay. Patients presenting with acute coronary syndromes often experience fluctuations in renal function that would call for adjustment of heparin dosing, either increasing the dose to maximize the drug’s efficacy if renal function is recovering or decreasing the dose to prevent bleeding if renal function is deteriorating.

Clopidogrel vs prasugrel

Certain medications should be avoided when the risk of bleeding outweighs any potential benefit in terms of ischemia.

For example, in a randomized trial,³⁴ prasugrel (Effient), a potent thienopyridine, was associated with a significantly lower rate of the composite end point of stroke, myocardial infarction, or death than clopidogrel (Plavix) in patients with acute coronary syndromes undergoing percutaneous coronary interventions. However, it did not seem to offer any advantage in patients 75 years old and older, those with prior stroke or transient ischemic attack, or those weighing less than 60 kg, and it posed a substantially higher risk of bleeding.

With clopidogrel, the risk of acute bleeding is primarily in patients who undergo coronary artery bypass grafting within 5 days of receiving a dose.^35,36 Therefore, clopidogrel should be stopped 5 to 7 days before bypass surgery.¹ Importantly, there is no increased risk of recurrent ischemic events during this 5-day waiting period in patients who receive clopidogrel early. Therefore, the recommendation to stop clopidogrel before surgery does not negate the benefits of early treatment.³⁶

Lower-risk drugs: Fondaparinux and bivalirudin

At this time, only two agents have been studied in clinical trials that have specifically focused on reducing bleeding risk: fondaparinux (Arixtra) and bivalirudin (Angiomax).^20,37–39

Fondaparinux

OASIS-5 was a randomized, double-blind trial that compared fondaparinux and enoxaparin (Lovenox) in patients with acute coronary syndromes.³⁸ Fondaparinux was similar to enoxaparin in terms of the combined end point of death, myocardial infarction, or refractory ischemia at 9 days, and fewer patients on fondaparinux developed bleeding (2.2% vs 4.1%, HR 0.52; 95% CI 0.44–0.61). This difference persisted during long-term follow-up.

Importantly, fewer patients died in the fondaparinux group. At 180 days, 638 (6.5%) of the patients in the enoxaparin group had died, compared with 574 (5.8%) in the fondaparinux group, a difference of 64 deaths (P = .05). The authors found that 41 fewer patients in the fondaparinux group than in the enoxaparin group died after major bleeding, and 20 fewer patients in the fondaparinux group died after minor bleeding.³⁸ Thus, most of the difference in mortality rates between the two groups was attributed to a lower incidence of bleeding with fondaparinux.

Unfortunately, despite its safe bleeding profile, fondaparinux has fallen out of favor for use in acute coronary syndromes, owing to a higher risk of catheter thrombosis in the fondaparinux group (0.9%) than in those undergoing percutaneous coronary interventions with enoxaparin alone (0.4%) in the OASIS-5 trial.⁴⁰

The direct thrombin inhibitor bivalirudin has been studied in three large randomized trials in patients undergoing percutaneous coronary interventions.^20,37,41

The ACUITY trial³⁷ was a prospective, open-label, randomized, multicenter trial that compared three regimens in patients with moderate or high-risk non-ST-elevation acute coronary syndromes:

• Heparin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

Bivalirudin alone was as effective as heparin plus a glycoprotein IIb/IIIa inhibitor with respect to the composite ischemia end point, which at 30 days had occurred in 7.8% vs 7.3% of the patients in these treatment groups (P = .32, RR 1.08; 95% CI 0.93–1.24), and it was superior with respect to major bleeding (3.0% vs 5.7%, P < .001, RR 0.53; 95% CI 0.43–0.65).

The HORIZONS-AMI study⁴¹ was a prospective, open-label, randomized, multicenter trial that compared bivalirudin alone vs heparin plus a glycoprotein IIb/IIIa inhibitor in patients with ST-elevation acute coronary syndromes who were undergoing primary percutaneous coronary interventions. The two primary end points were major bleeding and net adverse events.

At 1 year, patients assigned to bivalirudin had a lower rate of major bleeding than did controls (5.8% vs 9.2%, HR 0.61, 95% CI 0.48–0.78, P < .0001), with similar rates of major adverse cardiac events in both groups (11.9% vs 11.9%, HR 1.00, 95% CI 0.82– 1.21, P = .98).⁴¹

Both OASIS 5 and HORIZONS-AMI are examples of clinical trials in which strategies that reduced bleeding risk were also associated with improved survival.

For cardiac catheterization, inserting the catheter in the wrist poses less risk

Bleeding is currently the most common noncardiac complication in patients undergoing percutaneous coronary interventions, and it most often occurs at the vascular access site.¹⁷

Rao et al¹² evaluated data from 593,094 procedures in the National Cardiovascular Data Registry and found that, compared with the femoral approach, the use of transradial percutaneous coronary intervention was associated with a similar rate of procedural success (OR 1.02, 95% CI 0.93–1.12) but a significantly lower risk of bleeding complications (OR 0.42, 95% CI 0.31–0.56) after multivariable adjustment.

The use of smaller sheath sizes (4F–6F) and preferential use of bivalirudin over unfractionated heparin and glycoprotein IIb/IIIa inhibitor therapy are other methods described to decrease the risk of bleeding after percutaneous coronary interventions.^20,41–49

IF BLEEDING OCCURS

Once a bleeding complication occurs, cessation of therapy is a potential option. Stopping or reversing antithrombotic and antiplatelet therapy is warranted in the event of major bleeding (eg, gastrointestinal, retroperitoneal, intracranial).³¹

Stopping antithrombotic and antiplatelet therapy

Whether bleeding is minor or major, the risk of a recurrent thrombotic event must be considered, especially in patients who have undergone revascularization, stent implantation, or both. The risk of acute thrombotic events after interrupting antithrombotic or antiplatelet agents is considered greatest 4 to 5 days following revascularization or percutaneous coronary intervention.¹⁵ If bleeding can be controlled with local treatment such as pressure, packing, or dressing, antithrombotic and antiplatelet therapy need not be interrupted.⁵⁰

Current guidelines recommend strict control of hemorrhage for at least 24 hours before reintroducing antiplatelet or antithrombotic agents.

It is also important to remember that in the setting of gastrointestinal bleeding due to peptic ulcer disease, adjunctive proton pump inhibitors are recommended after restarting antiplatelet or antithrombotic therapy or both.

Importantly, evidence-based antithrombotic medications (especially dual antiplatelet therapy) should be restarted once the acute bleeding event has resolved.³¹

Reversal of anticoagulant and antiplatelet therapies

Unfractionated heparin is reversed with infusion of protamine sulfate at a dose of 1 mg per 100 U of unfractionated heparin given over the previous 4 hours.^51,52 The rate of protamine sulfate infusion should be less than 100 mg over 2 hours, with 50% of the dose given initially and subsequent doses titrated according to bleeding response.^52,53 Protamine sulfate is associated with a risk of hypotension and bradycardia, and for this reason it should be given no faster than 5 mg/min.

Low-molecular-weight heparin (LMWH) can be inhibited by 1 mg of protamine sulfate for each 1 mg of LMWH given over the previous 4 hours.^51,52

However, protamine sulfate only partially neutralizes the anticoagulant effect of LMWH. In cases in which protamine sulfate is unsuccessful in abating bleeding associated with LMWH use, guidelines allow for the use of recombinant factor VIIa (NovoSeven).³¹ In healthy volunteers given fondaparinux, recombinant factor VIIa normalized coagulation times and thrombin generation within 1.5 hours, with a sustained effect for 6 hours.⁵²

It is important to note that the use of this agent has not been fully studied, it is very costly (a single dose of 40 μg/kg costs from $3,000 to $4,000), and it is linked to reports of increased risk of thrombotic complications.^54,55

Antiplatelet agents are more complex to reverse. The antiplatelet actions of aspirin and clopidogrel wear off as new platelets are produced. Approximately 10% of a patient’s platelet count is produced daily; thus, the antiplatelet effects of aspirin and clopidogrel can persist for 5 to 10 days.^31,56

If these agents need to be reversed quickly to stop bleeding, according to expert consensus the aspirin effect can be reversed by transfusion of one unit of platelets. The antiplatelet effect of clopidogrel is more significant than that of aspirin; thus, two units of platelets are recommended.⁵⁶

Glycoprotein IIb/IIIa inhibitors. If a major bleeding event requires the reversal of glycoprotein IIb/IIIa inhibitor therapy, the treatment must take into consideration the pharmacodynamics of the target drug. Both eptifibatide (Integrilin) and tirofiban (Aggrastat) competitively inhibit glycoprotein IIb/IIIa receptors; thus, their effects depend on dosing, elimination, and time. Due to the stoichiometry of both drugs, transfusion of platelets is ineffective. Both eptifibatide and tirofiban are eliminated by the kidney; thus, normal renal function is key to the amount of time it takes for platelet function to return to baseline.⁵⁷ Evidence suggests that fibrinogen-rich plasma can be administered to restore platelet function.^31,58,59

Abciximab (ReoPro). Whereas reversal of eptifibatide and tirofiban focuses on overcoming competitive inhibition, neutralization of abciximab involves overcoming its high receptor affinity. At 24 hours after abciximab infusion is stopped, platelet aggregation may still be inhibited by up to 50%. Fortunately, owing to abciximab’s short plasma half-life and its dilution in serum, platelet transfusion is effective in reversing its antiplatelet effects.^31,57

Long considered beneficial to critically ill patients, blood transfusion to maintain hematocrit levels during acute coronary syndromes has come under intense scrutiny. Randomized trials have shown that transfusion should not be given aggressively to critically ill patients.⁶⁰ In acute coronary syndromes, there are only observational data.

Rao et al⁶¹ used detailed clinical data from 24,112 patients with acute coronary syndromes in the GUSTO IIb, PURSUIT, and PARAGON B trials to determine the association between blood transfusion and outcomes in patients who developed moderate to severe bleeding, anemia, or both during their hospitalization. The rates of death in the hospital and at 30 days were significantly higher in patients who received a transfusion (30-day mortality HR 3.94; 95% CI 3.36–4.75). However, there was no significant association between transfusion and the 30-day mortality rate if the nadir hematocrit was 25% or less.

Of note: no randomized clinical trial has evaluated transfusion strategies in acute coronary syndromes at this time. Until such data are available, it is reasonable to follow published guidelines and to avoid transfusion in stable patients with ischemic heart disease unless the hematocrit is 25% or less.³¹ The risks and benefits of blood transfusion should be carefully weighed. Routine use of transfusion to maintain predefined hemoglobin levels is not recommended in stable patients.

The medical management of non-ST-elevation acute coronary syndromes focuses on blocking the coagulation cascade and inhibiting platelets. This—plus diagnostic angiography followed, if needed, by revascularization—has reduced the rates of death and recurrent ischemic events.¹ However, the combination of potent antithrombotic drugs and invasive procedures also increases the risk of bleeding.

This review discusses the incidence and complications associated with bleeding during the treatment of acute coronary syndromes and summarizes recommendations for preventing and managing bleeding in this setting.

THE TRUE INCIDENCE OF BLEEDING IS HARD TO DETERMINE

The optimal way to detect and analyze bleeding events in clinical trials and registries is highly debated. The reported incidences of bleeding during antithrombotic and antiplatelet therapy for non-ST-elevation acute coronary syndromes depend on how bleeding was defined, how the acute coronary syndromes were treated, and on other factors such as how the study was designed.

How was bleeding defined?

Since these classification schemes are based on different types of data, they yield different numbers when applied to the same study population. For instance, Rao et al⁴ pooled the data from the PURSUIT and PARAGON B trials (15,454 patients in all) and found that the incidence of severe bleeding (by the GUSTO criteria) was 1.2%, while the rate of major bleeding (by the TIMI criteria) was 8.2%.

What was the treatment strategy?

Another reason that the true incidence of bleeding is hard to determine is that different studies used treatment strategies that differed in the type, timing, and dose of antithrombotic agents and whether invasive procedures were used early. For example, if unfractionated heparin is used aggressively in regimens that are not adjusted for weight and with a higher target for the activated clotting time, the risk of bleeding is higher than with conservative dosing.^5–7

Subherwal et al⁸ evaluated the effect of treatment strategy on the incidence of bleeding in patients with non-ST-elevation acute coronary syndromes who received two or more antithrombotic drugs in the CRUSADE Quality Improvement Initiative. The risk of bleeding was higher with an invasive approach (catheterization) than with a conservative approach (no catheterization), regardless of baseline bleeding risk.

What type of study was it?

Another source of variation is the design of the study. Registries differ from clinical trials in patient characteristics and in the way data are gathered (prospectively vs retrospectively).

In registries, data are often collected retrospectively, whereas in clinical trials the data are prospectively collected. For this reason, the definition of bleeding in registries is often based on events that are easily identified through chart review, such as transfusion. This may lead to a lower reported rate of bleeding, since other, less serious bleeding events such as access-site hematomas and epistaxis may not be documented in the medical record.

On the other hand, registries often include older and sicker patients, who may be more prone to bleeding and who are often excluded from clinical trials. This may lead to a higher rate of reported bleeding.⁹

Where the study was conducted makes a difference as well, owing to regional practice differences. For example, Moscucci et al¹⁰ reported that the incidence of major bleeding in 24,045 patients with non-ST-elevation acute coronary syndromes in the GRACE registry (in 14 countries worldwide) was 3.9%. In contrast, Yang et al¹¹ reported that the rate of bleeding in the CRUSADE registry (in the United States) was 10.3%.

This difference was partly influenced by different definitions of bleeding. The GRACE registry defined major bleeding as life-threatening events requiring transfusion of two or more units of packed red blood cells, or resulting in an absolute decrease in the hematocrit of 10% or more or death, or hemorrhagic subdural hematoma. In contrast, the CRUSADE data reflect bleeding requiring transfusion. However, practice patterns such as greater use of invasive procedures in the United States may also be responsible.

Rao and colleagues¹² examined international variation in blood transfusion rates among patients with acute coronary syndromes. Patients outside the United States were significantly less likely to receive transfusions, even after adjusting for patient and practice differences.

Taking these confounders into account, it is reasonable to estimate that the frequency of bleeding in patients with non-ST-elevation acute coronary syndromes ranges from less than 1% to 10%.¹³

BLEEDING IS ASSOCIATED WITH POOR OUTCOMES

Regardless of the definition or the data source, hemorrhagic complications are associated with a higher risk of death and nonfatal adverse events, both in the short term and in the long term.

Short-term outcomes

A higher risk of death. In the GRACE registry study by Moscucci et al¹⁰ discussed above, patients who had major bleeding were significantly more likely to die during their hospitalization than those who did not (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.18–2.28).

Rao et al¹⁴ evaluated pooled data from the multicenter international GUSTO IIb, PURSUIT, and PARAGON A and B trials and found that the effects of bleeding in non-ST-elevation acute coronary syndromes extended beyond the hospital stay. The more severe the bleeding (by the GUSTO criteria), the greater the adjusted hazard ratio (HR) for death within 30 days:

• With mild bleeding—HR 1.6, 95% CI 1.3–1.9
• With moderate bleeding—HR 2.7, 95% CI 2.3–3.4
• With severe bleeding—HR 10.6, 95% CI 8.3–13.6.

The pattern was the same for death within 6 months:

• With mild bleeding—HR 1.4, 95% CI 1.2–1.6
• With moderate bleeding—HR 2.1, 95% CI 1.8–2.4
• With severe bleeding, HR 7.5, 95% CI 6.1–9.3.

These findings were confirmed by Eikelboom et al¹⁵ in 34,146 patients with acute coronary syndromes in the OASIS registry, the OASIS-2 trial, and the CURE randomized trial. In the first 30 days, five times as many patients died (12.8% vs 2.5%; P < .0009) among those who developed major bleeding compared with those who did not. These investigators defined major bleeding as bleeding that was life-threatening or significantly disabling or that required transfusion of two or more units of packed red blood cells.

A higher risk of nonfatal adverse events. Bleeding after antithrombotic therapy for non-ST-elevation acute coronary syndromes has also been associated with nonfatal adverse events such as stroke and stent thrombosis.

For example, in the study by Eikelboom et al,¹⁵ major bleeding was associated with a higher risk of recurrent ischemic events. Approximately 1 in 5 patients in the OASIS trials who developed major bleeding during the first 30 days died or had a myocardial infarction or stroke by 30 days, compared with 1 in 20 of those who did not develop major bleeding during the first 30 days. However, after events that occurred during the first 30 days were excluded, the association between major bleeding and both myocardial infarction and stroke was no longer evident between 30 days and 6 months.

Manoukian et al¹⁶ evaluated the impact of major bleeding in 13,819 patients with highrisk acute coronary syndromes undergoing treatment with an early invasive strategy in the ACUITY trial. At 30 days, patients with major bleeding had higher rates of the composite end point of death, myocardial infarction, or unplanned revascularization for ischemia (23.1% vs 6.8%, P < .0001) and of stent thrombosis (3.4% vs 0.6%, P < .0001).

Long-term outcomes

The association between bleeding and adverse outcomes persists in the long term as well, although the mechanisms underlying this association are not well studied.

Kinnaird et al¹⁷ examined the data from 10,974 unselected patients who underwent percutaneous coronary intervention. At 1 year, the following percentages of patients had died:

• After TIMI major bleeding—17.2%
• After TIMI minor bleeding—9.1%
• After no bleeding—5.5%.

However, after adjustment for potential confounders, only transfusion remained a significant predictor of 1-year mortality.

Mehran et al¹⁸ evaluated 1-year mortality data from the ACUITY trial. Compared with the rate in patients who had no major bleeding and no myocardial infarction, the hazard ratios for death were:

• After major bleeding—HR 3.5, 95% CI 2.7–4.4
• After myocardial infarction—HR 3.1, 95% CI 2.4–3.9.

Interestingly, the risk of death associated with myocardial infarction abated after 7 days, while the risk associated with bleeding persisted beyond 30 days and remained constant throughout the first year following the bleeding event.

Similarly, Ndrepepa and colleagues¹⁹ examined pooled data from four ISAR trials using the TIMI bleeding scale and found that myocardial infarction, target vessel revascularization, and major bleeding all had similar discriminatory ability at predicting 1-year mortality.

In patients undergoing elective or urgent percutaneous coronary intervention in the REPLACE-2 trial,²⁰ independent predictors of death by 1 year were²¹:

• Major hemorrhage (OR 2.66, 95% CI 1.44–4.92)
• Periprocedural myocardial infarction (OR 2.46, 95% CI 1.44–4.20).

THEORIES OF HOW BLEEDING MAY CAUSE ADVERSE OUTCOMES

Several mechanisms have been proposed to explain the association between bleeding during treatment for acute coronary syndromes and adverse clinical outcomes.^13,22

The immediate effects of bleeding are thought to be hypotension and a reflex hyperadrenergic state to compensate for the loss of intravascular volume.²³ This physiologic response is believed to contribute to myocardial ischemia by further decreasing myocardial oxygen supply in obstructive coronary disease.

Trying to minimize blood loss, physicians may withhold anticoagulation and antiplatelet therapy, which in turn may lead to further ischemia.²⁴ To compensate for blood loss, physicians may also resort to blood transfusion. However, depletion of 2,3-diphosphoglycerate and nitric oxide in stored donor red blood cells is postulated to reduce oxygen delivery by increasing hemoglobin’s affinity for oxygen, leading to induced microvascular obstruction and adverse inflammatory reactions.^15,25

Recent data have also begun to elucidate the long-term effects of bleeding during acute coronary syndrome management. Patients with anemia during the acute phase of infarction have greater neurohormonal activation.²⁶ These adaptive responses to anemia may lead to eccentric left ventricular remodeling that may lead to higher oxygen consumption, increased diastolic wall stress, interstitial fibrosis, and accelerated myocyte loss.^27–30

Nevertheless, we must point out that although strong associations between bleeding and adverse outcomes have been established, direct causality has not.

TO PREVENT BLEEDING, START BY ASSESSING RISK

The CRUSADE bleeding risk score

The CRUSADE bleeding score (calculator available at http://www.crusadebleedingscore.org/) was developed and validated in more than 89,000 community-treated patients with non-ST-elevation acute coronary syndromes.⁸ It is based on eight variables:

• Sex (higher risk in women)
• History of diabetes (higher risk)
• Prior vascular disease (higher risk)
• Heart rate (the higher the rate, the higher the risk)
• Systolic blood pressure (higher risk with pressures above or below the 121–180 mm Hg range)
• Signs of congestive heart failure (higher risk)
• Baseline hematocrit (the lower the hematocrit, the higher the risk)
• Creatinine clearance (by the Cockcroft-Gault formula; the lower the creatinine clearance, the higher the risk).

Patients who are found to have bleeding scores suggesting a moderate or higher risk of bleeding should be considered for medications associated with a favorable bleeding profile, and for radial access at the time of coronary angiography. Scores are graded as follows⁸:

• < 21: Very low risk
• 21–30: Low risk
• 31–40: Moderate risk
• 41–50: High risk
• > 50: Very high risk.

The CRUSADE bleeding score is unique in that, unlike earlier risk stratification tools, it was developed in a “real world” population, not in subgroups or in a clinical trial. It can be calculated at baseline to help guide the selection of treatment.⁸

Adjusting the heparin regimen in patients at risk of bleeding

Both the joint American College of Cardiology/American Heart Association¹ and the European Society of Cardiology guidelines³¹ for the treatment of non-ST-elevation acute coronary syndromes recommend taking steps to prevent bleeding, such as adjusting the dosage of unfractionated heparin, using safer drugs, reducing the duration of antithrombotic treatment, and using combinations of antithrombotic and antiplatelet agents according to proven indications.³¹

In the CRUSADE registry, 42% of patients with non-ST-elevation acute coronary syndromes received at least one initial dose of antithrombotic drug outside the recommended range, resulting in an estimated 15% excess of bleeding events.³² Thus, proper dosing is a target for prevention.

Appropriate antithrombotic dosing takes into account the patient’s age, weight, and renal function. However, heparin dosage in the current guidelines¹ is based on weight only: a loading dose of 60 U/kg (maximum 4,000 U) by intravenous bolus, then 12 U/kg/hour (maximum 1,000 U/hour) to maintain an activated partial thromboplastin time of 50 to 70 seconds.¹

Renal dysfunction is particularly worrisome in patients with non-ST-elevation acute coronary syndromes because it is associated with higher rates of major bleeding and death. In the OASIS-5 trial,³³ the overall risk of death was approximately five times higher in patients in the lowest quartile of renal function (glomerular filtration rate < 58 mL/min/1.73 m²) than in the highest quartile (glomerular filtration rate ≥ 86 mL/min/1.73 m²).

Renal function must be evaluated not only on admission but also throughout the hospital stay. Patients presenting with acute coronary syndromes often experience fluctuations in renal function that would call for adjustment of heparin dosing, either increasing the dose to maximize the drug’s efficacy if renal function is recovering or decreasing the dose to prevent bleeding if renal function is deteriorating.

Clopidogrel vs prasugrel

Certain medications should be avoided when the risk of bleeding outweighs any potential benefit in terms of ischemia.

For example, in a randomized trial,³⁴ prasugrel (Effient), a potent thienopyridine, was associated with a significantly lower rate of the composite end point of stroke, myocardial infarction, or death than clopidogrel (Plavix) in patients with acute coronary syndromes undergoing percutaneous coronary interventions. However, it did not seem to offer any advantage in patients 75 years old and older, those with prior stroke or transient ischemic attack, or those weighing less than 60 kg, and it posed a substantially higher risk of bleeding.

With clopidogrel, the risk of acute bleeding is primarily in patients who undergo coronary artery bypass grafting within 5 days of receiving a dose.^35,36 Therefore, clopidogrel should be stopped 5 to 7 days before bypass surgery.¹ Importantly, there is no increased risk of recurrent ischemic events during this 5-day waiting period in patients who receive clopidogrel early. Therefore, the recommendation to stop clopidogrel before surgery does not negate the benefits of early treatment.³⁶

Lower-risk drugs: Fondaparinux and bivalirudin

At this time, only two agents have been studied in clinical trials that have specifically focused on reducing bleeding risk: fondaparinux (Arixtra) and bivalirudin (Angiomax).^20,37–39

Fondaparinux

OASIS-5 was a randomized, double-blind trial that compared fondaparinux and enoxaparin (Lovenox) in patients with acute coronary syndromes.³⁸ Fondaparinux was similar to enoxaparin in terms of the combined end point of death, myocardial infarction, or refractory ischemia at 9 days, and fewer patients on fondaparinux developed bleeding (2.2% vs 4.1%, HR 0.52; 95% CI 0.44–0.61). This difference persisted during long-term follow-up.

Importantly, fewer patients died in the fondaparinux group. At 180 days, 638 (6.5%) of the patients in the enoxaparin group had died, compared with 574 (5.8%) in the fondaparinux group, a difference of 64 deaths (P = .05). The authors found that 41 fewer patients in the fondaparinux group than in the enoxaparin group died after major bleeding, and 20 fewer patients in the fondaparinux group died after minor bleeding.³⁸ Thus, most of the difference in mortality rates between the two groups was attributed to a lower incidence of bleeding with fondaparinux.

Unfortunately, despite its safe bleeding profile, fondaparinux has fallen out of favor for use in acute coronary syndromes, owing to a higher risk of catheter thrombosis in the fondaparinux group (0.9%) than in those undergoing percutaneous coronary interventions with enoxaparin alone (0.4%) in the OASIS-5 trial.⁴⁰

The direct thrombin inhibitor bivalirudin has been studied in three large randomized trials in patients undergoing percutaneous coronary interventions.^20,37,41

The ACUITY trial³⁷ was a prospective, open-label, randomized, multicenter trial that compared three regimens in patients with moderate or high-risk non-ST-elevation acute coronary syndromes:

• Heparin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

Bivalirudin alone was as effective as heparin plus a glycoprotein IIb/IIIa inhibitor with respect to the composite ischemia end point, which at 30 days had occurred in 7.8% vs 7.3% of the patients in these treatment groups (P = .32, RR 1.08; 95% CI 0.93–1.24), and it was superior with respect to major bleeding (3.0% vs 5.7%, P < .001, RR 0.53; 95% CI 0.43–0.65).

The HORIZONS-AMI study⁴¹ was a prospective, open-label, randomized, multicenter trial that compared bivalirudin alone vs heparin plus a glycoprotein IIb/IIIa inhibitor in patients with ST-elevation acute coronary syndromes who were undergoing primary percutaneous coronary interventions. The two primary end points were major bleeding and net adverse events.

At 1 year, patients assigned to bivalirudin had a lower rate of major bleeding than did controls (5.8% vs 9.2%, HR 0.61, 95% CI 0.48–0.78, P < .0001), with similar rates of major adverse cardiac events in both groups (11.9% vs 11.9%, HR 1.00, 95% CI 0.82– 1.21, P = .98).⁴¹

Both OASIS 5 and HORIZONS-AMI are examples of clinical trials in which strategies that reduced bleeding risk were also associated with improved survival.

For cardiac catheterization, inserting the catheter in the wrist poses less risk

Bleeding is currently the most common noncardiac complication in patients undergoing percutaneous coronary interventions, and it most often occurs at the vascular access site.¹⁷

Rao et al¹² evaluated data from 593,094 procedures in the National Cardiovascular Data Registry and found that, compared with the femoral approach, the use of transradial percutaneous coronary intervention was associated with a similar rate of procedural success (OR 1.02, 95% CI 0.93–1.12) but a significantly lower risk of bleeding complications (OR 0.42, 95% CI 0.31–0.56) after multivariable adjustment.

The use of smaller sheath sizes (4F–6F) and preferential use of bivalirudin over unfractionated heparin and glycoprotein IIb/IIIa inhibitor therapy are other methods described to decrease the risk of bleeding after percutaneous coronary interventions.^20,41–49

IF BLEEDING OCCURS

Once a bleeding complication occurs, cessation of therapy is a potential option. Stopping or reversing antithrombotic and antiplatelet therapy is warranted in the event of major bleeding (eg, gastrointestinal, retroperitoneal, intracranial).³¹

Stopping antithrombotic and antiplatelet therapy

Whether bleeding is minor or major, the risk of a recurrent thrombotic event must be considered, especially in patients who have undergone revascularization, stent implantation, or both. The risk of acute thrombotic events after interrupting antithrombotic or antiplatelet agents is considered greatest 4 to 5 days following revascularization or percutaneous coronary intervention.¹⁵ If bleeding can be controlled with local treatment such as pressure, packing, or dressing, antithrombotic and antiplatelet therapy need not be interrupted.⁵⁰

Current guidelines recommend strict control of hemorrhage for at least 24 hours before reintroducing antiplatelet or antithrombotic agents.

It is also important to remember that in the setting of gastrointestinal bleeding due to peptic ulcer disease, adjunctive proton pump inhibitors are recommended after restarting antiplatelet or antithrombotic therapy or both.

Importantly, evidence-based antithrombotic medications (especially dual antiplatelet therapy) should be restarted once the acute bleeding event has resolved.³¹

Reversal of anticoagulant and antiplatelet therapies

Unfractionated heparin is reversed with infusion of protamine sulfate at a dose of 1 mg per 100 U of unfractionated heparin given over the previous 4 hours.^51,52 The rate of protamine sulfate infusion should be less than 100 mg over 2 hours, with 50% of the dose given initially and subsequent doses titrated according to bleeding response.^52,53 Protamine sulfate is associated with a risk of hypotension and bradycardia, and for this reason it should be given no faster than 5 mg/min.

Low-molecular-weight heparin (LMWH) can be inhibited by 1 mg of protamine sulfate for each 1 mg of LMWH given over the previous 4 hours.^51,52

However, protamine sulfate only partially neutralizes the anticoagulant effect of LMWH. In cases in which protamine sulfate is unsuccessful in abating bleeding associated with LMWH use, guidelines allow for the use of recombinant factor VIIa (NovoSeven).³¹ In healthy volunteers given fondaparinux, recombinant factor VIIa normalized coagulation times and thrombin generation within 1.5 hours, with a sustained effect for 6 hours.⁵²

It is important to note that the use of this agent has not been fully studied, it is very costly (a single dose of 40 μg/kg costs from $3,000 to $4,000), and it is linked to reports of increased risk of thrombotic complications.^54,55

Antiplatelet agents are more complex to reverse. The antiplatelet actions of aspirin and clopidogrel wear off as new platelets are produced. Approximately 10% of a patient’s platelet count is produced daily; thus, the antiplatelet effects of aspirin and clopidogrel can persist for 5 to 10 days.^31,56

If these agents need to be reversed quickly to stop bleeding, according to expert consensus the aspirin effect can be reversed by transfusion of one unit of platelets. The antiplatelet effect of clopidogrel is more significant than that of aspirin; thus, two units of platelets are recommended.⁵⁶

Glycoprotein IIb/IIIa inhibitors. If a major bleeding event requires the reversal of glycoprotein IIb/IIIa inhibitor therapy, the treatment must take into consideration the pharmacodynamics of the target drug. Both eptifibatide (Integrilin) and tirofiban (Aggrastat) competitively inhibit glycoprotein IIb/IIIa receptors; thus, their effects depend on dosing, elimination, and time. Due to the stoichiometry of both drugs, transfusion of platelets is ineffective. Both eptifibatide and tirofiban are eliminated by the kidney; thus, normal renal function is key to the amount of time it takes for platelet function to return to baseline.⁵⁷ Evidence suggests that fibrinogen-rich plasma can be administered to restore platelet function.^31,58,59

Abciximab (ReoPro). Whereas reversal of eptifibatide and tirofiban focuses on overcoming competitive inhibition, neutralization of abciximab involves overcoming its high receptor affinity. At 24 hours after abciximab infusion is stopped, platelet aggregation may still be inhibited by up to 50%. Fortunately, owing to abciximab’s short plasma half-life and its dilution in serum, platelet transfusion is effective in reversing its antiplatelet effects.^31,57

Long considered beneficial to critically ill patients, blood transfusion to maintain hematocrit levels during acute coronary syndromes has come under intense scrutiny. Randomized trials have shown that transfusion should not be given aggressively to critically ill patients.⁶⁰ In acute coronary syndromes, there are only observational data.

Rao et al⁶¹ used detailed clinical data from 24,112 patients with acute coronary syndromes in the GUSTO IIb, PURSUIT, and PARAGON B trials to determine the association between blood transfusion and outcomes in patients who developed moderate to severe bleeding, anemia, or both during their hospitalization. The rates of death in the hospital and at 30 days were significantly higher in patients who received a transfusion (30-day mortality HR 3.94; 95% CI 3.36–4.75). However, there was no significant association between transfusion and the 30-day mortality rate if the nadir hematocrit was 25% or less.

Of note: no randomized clinical trial has evaluated transfusion strategies in acute coronary syndromes at this time. Until such data are available, it is reasonable to follow published guidelines and to avoid transfusion in stable patients with ischemic heart disease unless the hematocrit is 25% or less.³¹ The risks and benefits of blood transfusion should be carefully weighed. Routine use of transfusion to maintain predefined hemoglobin levels is not recommended in stable patients.

The medical management of non-ST-elevation acute coronary syndromes focuses on blocking the coagulation cascade and inhibiting platelets. This—plus diagnostic angiography followed, if needed, by revascularization—has reduced the rates of death and recurrent ischemic events.¹ However, the combination of potent antithrombotic drugs and invasive procedures also increases the risk of bleeding.

This review discusses the incidence and complications associated with bleeding during the treatment of acute coronary syndromes and summarizes recommendations for preventing and managing bleeding in this setting.

THE TRUE INCIDENCE OF BLEEDING IS HARD TO DETERMINE

The optimal way to detect and analyze bleeding events in clinical trials and registries is highly debated. The reported incidences of bleeding during antithrombotic and antiplatelet therapy for non-ST-elevation acute coronary syndromes depend on how bleeding was defined, how the acute coronary syndromes were treated, and on other factors such as how the study was designed.

How was bleeding defined?

Since these classification schemes are based on different types of data, they yield different numbers when applied to the same study population. For instance, Rao et al⁴ pooled the data from the PURSUIT and PARAGON B trials (15,454 patients in all) and found that the incidence of severe bleeding (by the GUSTO criteria) was 1.2%, while the rate of major bleeding (by the TIMI criteria) was 8.2%.

What was the treatment strategy?

Another reason that the true incidence of bleeding is hard to determine is that different studies used treatment strategies that differed in the type, timing, and dose of antithrombotic agents and whether invasive procedures were used early. For example, if unfractionated heparin is used aggressively in regimens that are not adjusted for weight and with a higher target for the activated clotting time, the risk of bleeding is higher than with conservative dosing.^5–7

Subherwal et al⁸ evaluated the effect of treatment strategy on the incidence of bleeding in patients with non-ST-elevation acute coronary syndromes who received two or more antithrombotic drugs in the CRUSADE Quality Improvement Initiative. The risk of bleeding was higher with an invasive approach (catheterization) than with a conservative approach (no catheterization), regardless of baseline bleeding risk.

What type of study was it?

Another source of variation is the design of the study. Registries differ from clinical trials in patient characteristics and in the way data are gathered (prospectively vs retrospectively).

In registries, data are often collected retrospectively, whereas in clinical trials the data are prospectively collected. For this reason, the definition of bleeding in registries is often based on events that are easily identified through chart review, such as transfusion. This may lead to a lower reported rate of bleeding, since other, less serious bleeding events such as access-site hematomas and epistaxis may not be documented in the medical record.

On the other hand, registries often include older and sicker patients, who may be more prone to bleeding and who are often excluded from clinical trials. This may lead to a higher rate of reported bleeding.⁹

Where the study was conducted makes a difference as well, owing to regional practice differences. For example, Moscucci et al¹⁰ reported that the incidence of major bleeding in 24,045 patients with non-ST-elevation acute coronary syndromes in the GRACE registry (in 14 countries worldwide) was 3.9%. In contrast, Yang et al¹¹ reported that the rate of bleeding in the CRUSADE registry (in the United States) was 10.3%.

This difference was partly influenced by different definitions of bleeding. The GRACE registry defined major bleeding as life-threatening events requiring transfusion of two or more units of packed red blood cells, or resulting in an absolute decrease in the hematocrit of 10% or more or death, or hemorrhagic subdural hematoma. In contrast, the CRUSADE data reflect bleeding requiring transfusion. However, practice patterns such as greater use of invasive procedures in the United States may also be responsible.

Rao and colleagues¹² examined international variation in blood transfusion rates among patients with acute coronary syndromes. Patients outside the United States were significantly less likely to receive transfusions, even after adjusting for patient and practice differences.

Taking these confounders into account, it is reasonable to estimate that the frequency of bleeding in patients with non-ST-elevation acute coronary syndromes ranges from less than 1% to 10%.¹³

BLEEDING IS ASSOCIATED WITH POOR OUTCOMES

Regardless of the definition or the data source, hemorrhagic complications are associated with a higher risk of death and nonfatal adverse events, both in the short term and in the long term.

Short-term outcomes

A higher risk of death. In the GRACE registry study by Moscucci et al¹⁰ discussed above, patients who had major bleeding were significantly more likely to die during their hospitalization than those who did not (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.18–2.28).

Rao et al¹⁴ evaluated pooled data from the multicenter international GUSTO IIb, PURSUIT, and PARAGON A and B trials and found that the effects of bleeding in non-ST-elevation acute coronary syndromes extended beyond the hospital stay. The more severe the bleeding (by the GUSTO criteria), the greater the adjusted hazard ratio (HR) for death within 30 days:

• With mild bleeding—HR 1.6, 95% CI 1.3–1.9
• With moderate bleeding—HR 2.7, 95% CI 2.3–3.4
• With severe bleeding—HR 10.6, 95% CI 8.3–13.6.

The pattern was the same for death within 6 months:

• With mild bleeding—HR 1.4, 95% CI 1.2–1.6
• With moderate bleeding—HR 2.1, 95% CI 1.8–2.4
• With severe bleeding, HR 7.5, 95% CI 6.1–9.3.

These findings were confirmed by Eikelboom et al¹⁵ in 34,146 patients with acute coronary syndromes in the OASIS registry, the OASIS-2 trial, and the CURE randomized trial. In the first 30 days, five times as many patients died (12.8% vs 2.5%; P < .0009) among those who developed major bleeding compared with those who did not. These investigators defined major bleeding as bleeding that was life-threatening or significantly disabling or that required transfusion of two or more units of packed red blood cells.

A higher risk of nonfatal adverse events. Bleeding after antithrombotic therapy for non-ST-elevation acute coronary syndromes has also been associated with nonfatal adverse events such as stroke and stent thrombosis.

For example, in the study by Eikelboom et al,¹⁵ major bleeding was associated with a higher risk of recurrent ischemic events. Approximately 1 in 5 patients in the OASIS trials who developed major bleeding during the first 30 days died or had a myocardial infarction or stroke by 30 days, compared with 1 in 20 of those who did not develop major bleeding during the first 30 days. However, after events that occurred during the first 30 days were excluded, the association between major bleeding and both myocardial infarction and stroke was no longer evident between 30 days and 6 months.

Manoukian et al¹⁶ evaluated the impact of major bleeding in 13,819 patients with highrisk acute coronary syndromes undergoing treatment with an early invasive strategy in the ACUITY trial. At 30 days, patients with major bleeding had higher rates of the composite end point of death, myocardial infarction, or unplanned revascularization for ischemia (23.1% vs 6.8%, P < .0001) and of stent thrombosis (3.4% vs 0.6%, P < .0001).

Long-term outcomes

The association between bleeding and adverse outcomes persists in the long term as well, although the mechanisms underlying this association are not well studied.

Kinnaird et al¹⁷ examined the data from 10,974 unselected patients who underwent percutaneous coronary intervention. At 1 year, the following percentages of patients had died:

• After TIMI major bleeding—17.2%
• After TIMI minor bleeding—9.1%
• After no bleeding—5.5%.

However, after adjustment for potential confounders, only transfusion remained a significant predictor of 1-year mortality.

Mehran et al¹⁸ evaluated 1-year mortality data from the ACUITY trial. Compared with the rate in patients who had no major bleeding and no myocardial infarction, the hazard ratios for death were:

• After major bleeding—HR 3.5, 95% CI 2.7–4.4
• After myocardial infarction—HR 3.1, 95% CI 2.4–3.9.

Interestingly, the risk of death associated with myocardial infarction abated after 7 days, while the risk associated with bleeding persisted beyond 30 days and remained constant throughout the first year following the bleeding event.

Similarly, Ndrepepa and colleagues¹⁹ examined pooled data from four ISAR trials using the TIMI bleeding scale and found that myocardial infarction, target vessel revascularization, and major bleeding all had similar discriminatory ability at predicting 1-year mortality.

In patients undergoing elective or urgent percutaneous coronary intervention in the REPLACE-2 trial,²⁰ independent predictors of death by 1 year were²¹:

• Major hemorrhage (OR 2.66, 95% CI 1.44–4.92)
• Periprocedural myocardial infarction (OR 2.46, 95% CI 1.44–4.20).

THEORIES OF HOW BLEEDING MAY CAUSE ADVERSE OUTCOMES

Several mechanisms have been proposed to explain the association between bleeding during treatment for acute coronary syndromes and adverse clinical outcomes.^13,22

The immediate effects of bleeding are thought to be hypotension and a reflex hyperadrenergic state to compensate for the loss of intravascular volume.²³ This physiologic response is believed to contribute to myocardial ischemia by further decreasing myocardial oxygen supply in obstructive coronary disease.

Trying to minimize blood loss, physicians may withhold anticoagulation and antiplatelet therapy, which in turn may lead to further ischemia.²⁴ To compensate for blood loss, physicians may also resort to blood transfusion. However, depletion of 2,3-diphosphoglycerate and nitric oxide in stored donor red blood cells is postulated to reduce oxygen delivery by increasing hemoglobin’s affinity for oxygen, leading to induced microvascular obstruction and adverse inflammatory reactions.^15,25

Recent data have also begun to elucidate the long-term effects of bleeding during acute coronary syndrome management. Patients with anemia during the acute phase of infarction have greater neurohormonal activation.²⁶ These adaptive responses to anemia may lead to eccentric left ventricular remodeling that may lead to higher oxygen consumption, increased diastolic wall stress, interstitial fibrosis, and accelerated myocyte loss.^27–30

Nevertheless, we must point out that although strong associations between bleeding and adverse outcomes have been established, direct causality has not.

TO PREVENT BLEEDING, START BY ASSESSING RISK

The CRUSADE bleeding risk score

The CRUSADE bleeding score (calculator available at http://www.crusadebleedingscore.org/) was developed and validated in more than 89,000 community-treated patients with non-ST-elevation acute coronary syndromes.⁸ It is based on eight variables:

• Sex (higher risk in women)
• History of diabetes (higher risk)
• Prior vascular disease (higher risk)
• Heart rate (the higher the rate, the higher the risk)
• Systolic blood pressure (higher risk with pressures above or below the 121–180 mm Hg range)
• Signs of congestive heart failure (higher risk)
• Baseline hematocrit (the lower the hematocrit, the higher the risk)
• Creatinine clearance (by the Cockcroft-Gault formula; the lower the creatinine clearance, the higher the risk).

Patients who are found to have bleeding scores suggesting a moderate or higher risk of bleeding should be considered for medications associated with a favorable bleeding profile, and for radial access at the time of coronary angiography. Scores are graded as follows⁸:

• < 21: Very low risk
• 21–30: Low risk
• 31–40: Moderate risk
• 41–50: High risk
• > 50: Very high risk.

The CRUSADE bleeding score is unique in that, unlike earlier risk stratification tools, it was developed in a “real world” population, not in subgroups or in a clinical trial. It can be calculated at baseline to help guide the selection of treatment.⁸

Adjusting the heparin regimen in patients at risk of bleeding

Both the joint American College of Cardiology/American Heart Association¹ and the European Society of Cardiology guidelines³¹ for the treatment of non-ST-elevation acute coronary syndromes recommend taking steps to prevent bleeding, such as adjusting the dosage of unfractionated heparin, using safer drugs, reducing the duration of antithrombotic treatment, and using combinations of antithrombotic and antiplatelet agents according to proven indications.³¹

In the CRUSADE registry, 42% of patients with non-ST-elevation acute coronary syndromes received at least one initial dose of antithrombotic drug outside the recommended range, resulting in an estimated 15% excess of bleeding events.³² Thus, proper dosing is a target for prevention.

Appropriate antithrombotic dosing takes into account the patient’s age, weight, and renal function. However, heparin dosage in the current guidelines¹ is based on weight only: a loading dose of 60 U/kg (maximum 4,000 U) by intravenous bolus, then 12 U/kg/hour (maximum 1,000 U/hour) to maintain an activated partial thromboplastin time of 50 to 70 seconds.¹

Renal dysfunction is particularly worrisome in patients with non-ST-elevation acute coronary syndromes because it is associated with higher rates of major bleeding and death. In the OASIS-5 trial,³³ the overall risk of death was approximately five times higher in patients in the lowest quartile of renal function (glomerular filtration rate < 58 mL/min/1.73 m²) than in the highest quartile (glomerular filtration rate ≥ 86 mL/min/1.73 m²).

Renal function must be evaluated not only on admission but also throughout the hospital stay. Patients presenting with acute coronary syndromes often experience fluctuations in renal function that would call for adjustment of heparin dosing, either increasing the dose to maximize the drug’s efficacy if renal function is recovering or decreasing the dose to prevent bleeding if renal function is deteriorating.

Clopidogrel vs prasugrel

Certain medications should be avoided when the risk of bleeding outweighs any potential benefit in terms of ischemia.

For example, in a randomized trial,³⁴ prasugrel (Effient), a potent thienopyridine, was associated with a significantly lower rate of the composite end point of stroke, myocardial infarction, or death than clopidogrel (Plavix) in patients with acute coronary syndromes undergoing percutaneous coronary interventions. However, it did not seem to offer any advantage in patients 75 years old and older, those with prior stroke or transient ischemic attack, or those weighing less than 60 kg, and it posed a substantially higher risk of bleeding.

With clopidogrel, the risk of acute bleeding is primarily in patients who undergo coronary artery bypass grafting within 5 days of receiving a dose.^35,36 Therefore, clopidogrel should be stopped 5 to 7 days before bypass surgery.¹ Importantly, there is no increased risk of recurrent ischemic events during this 5-day waiting period in patients who receive clopidogrel early. Therefore, the recommendation to stop clopidogrel before surgery does not negate the benefits of early treatment.³⁶

Lower-risk drugs: Fondaparinux and bivalirudin

At this time, only two agents have been studied in clinical trials that have specifically focused on reducing bleeding risk: fondaparinux (Arixtra) and bivalirudin (Angiomax).^20,37–39

Fondaparinux

OASIS-5 was a randomized, double-blind trial that compared fondaparinux and enoxaparin (Lovenox) in patients with acute coronary syndromes.³⁸ Fondaparinux was similar to enoxaparin in terms of the combined end point of death, myocardial infarction, or refractory ischemia at 9 days, and fewer patients on fondaparinux developed bleeding (2.2% vs 4.1%, HR 0.52; 95% CI 0.44–0.61). This difference persisted during long-term follow-up.

Importantly, fewer patients died in the fondaparinux group. At 180 days, 638 (6.5%) of the patients in the enoxaparin group had died, compared with 574 (5.8%) in the fondaparinux group, a difference of 64 deaths (P = .05). The authors found that 41 fewer patients in the fondaparinux group than in the enoxaparin group died after major bleeding, and 20 fewer patients in the fondaparinux group died after minor bleeding.³⁸ Thus, most of the difference in mortality rates between the two groups was attributed to a lower incidence of bleeding with fondaparinux.

Unfortunately, despite its safe bleeding profile, fondaparinux has fallen out of favor for use in acute coronary syndromes, owing to a higher risk of catheter thrombosis in the fondaparinux group (0.9%) than in those undergoing percutaneous coronary interventions with enoxaparin alone (0.4%) in the OASIS-5 trial.⁴⁰

The direct thrombin inhibitor bivalirudin has been studied in three large randomized trials in patients undergoing percutaneous coronary interventions.^20,37,41

The ACUITY trial³⁷ was a prospective, open-label, randomized, multicenter trial that compared three regimens in patients with moderate or high-risk non-ST-elevation acute coronary syndromes:

• Heparin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

Bivalirudin alone was as effective as heparin plus a glycoprotein IIb/IIIa inhibitor with respect to the composite ischemia end point, which at 30 days had occurred in 7.8% vs 7.3% of the patients in these treatment groups (P = .32, RR 1.08; 95% CI 0.93–1.24), and it was superior with respect to major bleeding (3.0% vs 5.7%, P < .001, RR 0.53; 95% CI 0.43–0.65).

The HORIZONS-AMI study⁴¹ was a prospective, open-label, randomized, multicenter trial that compared bivalirudin alone vs heparin plus a glycoprotein IIb/IIIa inhibitor in patients with ST-elevation acute coronary syndromes who were undergoing primary percutaneous coronary interventions. The two primary end points were major bleeding and net adverse events.

At 1 year, patients assigned to bivalirudin had a lower rate of major bleeding than did controls (5.8% vs 9.2%, HR 0.61, 95% CI 0.48–0.78, P < .0001), with similar rates of major adverse cardiac events in both groups (11.9% vs 11.9%, HR 1.00, 95% CI 0.82– 1.21, P = .98).⁴¹

Both OASIS 5 and HORIZONS-AMI are examples of clinical trials in which strategies that reduced bleeding risk were also associated with improved survival.

For cardiac catheterization, inserting the catheter in the wrist poses less risk

Bleeding is currently the most common noncardiac complication in patients undergoing percutaneous coronary interventions, and it most often occurs at the vascular access site.¹⁷

Rao et al¹² evaluated data from 593,094 procedures in the National Cardiovascular Data Registry and found that, compared with the femoral approach, the use of transradial percutaneous coronary intervention was associated with a similar rate of procedural success (OR 1.02, 95% CI 0.93–1.12) but a significantly lower risk of bleeding complications (OR 0.42, 95% CI 0.31–0.56) after multivariable adjustment.

The use of smaller sheath sizes (4F–6F) and preferential use of bivalirudin over unfractionated heparin and glycoprotein IIb/IIIa inhibitor therapy are other methods described to decrease the risk of bleeding after percutaneous coronary interventions.^20,41–49

IF BLEEDING OCCURS

Once a bleeding complication occurs, cessation of therapy is a potential option. Stopping or reversing antithrombotic and antiplatelet therapy is warranted in the event of major bleeding (eg, gastrointestinal, retroperitoneal, intracranial).³¹

Stopping antithrombotic and antiplatelet therapy

Whether bleeding is minor or major, the risk of a recurrent thrombotic event must be considered, especially in patients who have undergone revascularization, stent implantation, or both. The risk of acute thrombotic events after interrupting antithrombotic or antiplatelet agents is considered greatest 4 to 5 days following revascularization or percutaneous coronary intervention.¹⁵ If bleeding can be controlled with local treatment such as pressure, packing, or dressing, antithrombotic and antiplatelet therapy need not be interrupted.⁵⁰

Current guidelines recommend strict control of hemorrhage for at least 24 hours before reintroducing antiplatelet or antithrombotic agents.

It is also important to remember that in the setting of gastrointestinal bleeding due to peptic ulcer disease, adjunctive proton pump inhibitors are recommended after restarting antiplatelet or antithrombotic therapy or both.

Importantly, evidence-based antithrombotic medications (especially dual antiplatelet therapy) should be restarted once the acute bleeding event has resolved.³¹

Reversal of anticoagulant and antiplatelet therapies

Unfractionated heparin is reversed with infusion of protamine sulfate at a dose of 1 mg per 100 U of unfractionated heparin given over the previous 4 hours.^51,52 The rate of protamine sulfate infusion should be less than 100 mg over 2 hours, with 50% of the dose given initially and subsequent doses titrated according to bleeding response.^52,53 Protamine sulfate is associated with a risk of hypotension and bradycardia, and for this reason it should be given no faster than 5 mg/min.

Low-molecular-weight heparin (LMWH) can be inhibited by 1 mg of protamine sulfate for each 1 mg of LMWH given over the previous 4 hours.^51,52

However, protamine sulfate only partially neutralizes the anticoagulant effect of LMWH. In cases in which protamine sulfate is unsuccessful in abating bleeding associated with LMWH use, guidelines allow for the use of recombinant factor VIIa (NovoSeven).³¹ In healthy volunteers given fondaparinux, recombinant factor VIIa normalized coagulation times and thrombin generation within 1.5 hours, with a sustained effect for 6 hours.⁵²

It is important to note that the use of this agent has not been fully studied, it is very costly (a single dose of 40 μg/kg costs from $3,000 to $4,000), and it is linked to reports of increased risk of thrombotic complications.^54,55

Antiplatelet agents are more complex to reverse. The antiplatelet actions of aspirin and clopidogrel wear off as new platelets are produced. Approximately 10% of a patient’s platelet count is produced daily; thus, the antiplatelet effects of aspirin and clopidogrel can persist for 5 to 10 days.^31,56

If these agents need to be reversed quickly to stop bleeding, according to expert consensus the aspirin effect can be reversed by transfusion of one unit of platelets. The antiplatelet effect of clopidogrel is more significant than that of aspirin; thus, two units of platelets are recommended.⁵⁶

Glycoprotein IIb/IIIa inhibitors. If a major bleeding event requires the reversal of glycoprotein IIb/IIIa inhibitor therapy, the treatment must take into consideration the pharmacodynamics of the target drug. Both eptifibatide (Integrilin) and tirofiban (Aggrastat) competitively inhibit glycoprotein IIb/IIIa receptors; thus, their effects depend on dosing, elimination, and time. Due to the stoichiometry of both drugs, transfusion of platelets is ineffective. Both eptifibatide and tirofiban are eliminated by the kidney; thus, normal renal function is key to the amount of time it takes for platelet function to return to baseline.⁵⁷ Evidence suggests that fibrinogen-rich plasma can be administered to restore platelet function.^31,58,59

Abciximab (ReoPro). Whereas reversal of eptifibatide and tirofiban focuses on overcoming competitive inhibition, neutralization of abciximab involves overcoming its high receptor affinity. At 24 hours after abciximab infusion is stopped, platelet aggregation may still be inhibited by up to 50%. Fortunately, owing to abciximab’s short plasma half-life and its dilution in serum, platelet transfusion is effective in reversing its antiplatelet effects.^31,57

Long considered beneficial to critically ill patients, blood transfusion to maintain hematocrit levels during acute coronary syndromes has come under intense scrutiny. Randomized trials have shown that transfusion should not be given aggressively to critically ill patients.⁶⁰ In acute coronary syndromes, there are only observational data.

Rao et al⁶¹ used detailed clinical data from 24,112 patients with acute coronary syndromes in the GUSTO IIb, PURSUIT, and PARAGON B trials to determine the association between blood transfusion and outcomes in patients who developed moderate to severe bleeding, anemia, or both during their hospitalization. The rates of death in the hospital and at 30 days were significantly higher in patients who received a transfusion (30-day mortality HR 3.94; 95% CI 3.36–4.75). However, there was no significant association between transfusion and the 30-day mortality rate if the nadir hematocrit was 25% or less.

Of note: no randomized clinical trial has evaluated transfusion strategies in acute coronary syndromes at this time. Until such data are available, it is reasonable to follow published guidelines and to avoid transfusion in stable patients with ischemic heart disease unless the hematocrit is 25% or less.³¹ The risks and benefits of blood transfusion should be carefully weighed. Routine use of transfusion to maintain predefined hemoglobin levels is not recommended in stable patients.

Yes. A number of large randomized controlled trials have shown inhaled corticosteroids to be beneficial in low doses for patients who have mild persistent asthma, and therefore these drugs are strongly recommended in this situation.¹

Asthma care providers should, however, consider this “yes” in the context of asthma severity, the goals of therapy, and the benefits and risks associated with inhaled corticosteroids.

CLASSIFICATION OF ASTHMA SEVERITY

Although the studies of asthma prevalence had methodologic limitations and therefore the true prevalence of mild persistent asthma cannot be determined, it is common. Fuhlbrigge et al² reported that most asthma patients have some form of persistent asthma. In contrast, Dusser et al³ reviewed available studies and concluded that most patients with asthma have either intermittent or mild persistent asthma.

GOALS: REDUCE IMPAIRMENT AND RISK

The goals of asthma management are to:

Reduce impairment by controlling symptoms so that normal activity levels can be maintained, by minimizing the need for short-acting bronchodilator use, and by maintaining normal pulmonary function; and to

Reduce risk by preventing progressive loss of lung function and recurrent exacerbations, and by optimizing pharmacotherapy while minimizing potential adverse effects.¹

EVIDENCE OF BENEFIT

The OPTIMA trial⁴ (Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma) was a double-blind, randomized trial carried out in 198 centers in 17 countries. Compared with those randomized to receive placebo, patients who were randomized to receive an inhaled corticosteroid, ie, budesonide (Pulmicort) 100 μg twice daily, had 60% fewer severe exacerbations (relative risk [RR] 0.4, 95% confidence interval [CI] 0.27–0.59) and 48% fewer days when their asthma was poorly controlled (RR 0.52, 95% CI 0.4–0.67). Adding a long-acting beta-agonist did not change this outcome.

The START study⁵ (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) showed that, compared with placebo, starting inhaled budesonide within the first 2 years of asthma symptoms in patients with mild persistent asthma was associated with better asthma control and less need for additional asthma medication.

The IMPACT study⁶ (Improving Asthma Control Trial) showed that inhaled steroids need to be taken daily, on a regular schedule, rather than intermittently as needed. Patients received either inhaled budesonide as needed, budesonide 200 μg twice daily every day, or zafirlukast (Accolate) 20 mg twice daily. Daily budesonide therapy resulted in better asthma control, less bronchial hyperresponsiveness, and less airway inflammation compared with intermittent use, zafirlukast therapy, or placebo. Daily zafirlukast and intermittent steroid treatment produced similar results for all outcomes measured.

Despite this strong evidence supporting regular use of inhaled corticosteroids in patients with mild persistent asthma, many patients choose to take them intermittently.

Suissa et al⁷ found, in a large observational cohort study, that fewer patients died of asthma if they were receiving low-dose inhaled corticosteroids than if they were not. The rate of death due to asthma was lower in patients who had used more inhaled corticosteroids over the previous year, and the death rate was higher in those who had discontinued inhaled corticosteroids in the previous 3 months than in those who continued using them.

STEROIDS DO NOT SLOW THE LOSS OF LUNG FUNCTION

Compared with people without asthma, asthma patients have substantially lower values of forced expiratory volume in the first second of expiration (FEV₁). They also have a faster rate of functional decline: the average decrease in FEV₁ in asthma patients is 38 mL per year, compared with 22 mL per year in nonasthmatic people.⁹

Although inhaled corticosteroids have been shown to increase lung function in asthma patients in the short term, there is little convincing evidence to suggest that they affect the rate of decline in the long term.¹⁰ In fact, airway inflammation and bronchial hyperresponsiveness return to baseline within 2 weeks after inhaled corticosteroids are discontinued.¹⁰

DO INHALED CORTICOSTEROIDS STUNT CHILDREN’S GROWTH?

The safety of long-term low-dose inhaled corticosteroids is well established in adults. However, two large randomized controlled trials found that children treated with low-dose inhaled steroids (budesonide 200–400 μg per day) grew 1 to 1.5 cm less over 3 to 5 years of treatment than children receiving placebo.¹¹ However, this effect was primarily evident within the first year of therapy, and growth velocity was similar to that with placebo at the end of the treatment period (4 to 6 years).¹²

Agertoft and Pedersen¹³ found that taking inhaled corticosteroids long-term is unlikely to have an effect on final height. Children who took inhaled budesonide (up to an average daily dose of 500 μg) into adulthood ended up no shorter than those who did not.

Based on these and other data, inhaled corticosteroids are generally considered safe at recommended doses. However, the decision to prescribe them for long-term therapy should be based on the risks and benefits to the individual patient.¹

ALTERNATIVE DRUGS FOR MILD PERSISTENT ASTHMA

Leukotriene-modifying drugs include the leukotriene receptor antagonists montelukast (Singulair) and zafirlukast and the 5-lipoxygenase inhibitor zileuton (Zyflo CR). These drugs have been associated with statistically significant improvement in FEV₁ compared with placebo in patients with mild to moderate asthma, reductions in both blood and sputum eosinophils,¹⁴ and attenuation of bronchoconstriction with exercise.¹¹

Large randomized trials comparing leukotriene modifier therapy with low-dose inhaled steroids in adults and children with mild persistent asthma have found that although outcomes improve with either therapy, the improvement is statistically superior with inhaled steroids for most asthma-control measures. ^6,8 Low-dose inhaled steroid therapy in patients with mild persistent and moderate persistent asthma has been associated with superior clinical outcomes as well as greater improvement in pulmonary function than treatment with antileukotriene drugs (Table 2).⁸

Asthma is heterogeneous, and properly selected patients with mild persistent asthma may achieve good control with leukotrienemodifier monotherapy.¹⁵ Alternatives for patients with mild persistent asthma include the methylxanthine theophylline, but this drug is less desirable due to its narrow therapeutic index. ¹ The inhaled cromones nedocromil (Tilade) and cromolyn (Intal) were other options in this patient population, but their short half-lives made them less practical, and US production has been discontinued.

THE BOTTOM LINE

Though leukotriene receptor antagonists can be effective, the daily use of inhaled corticosteroids results in higher asthma control test scores, more symptom-free days, greater pre-bronchodilator FEV₁, and decreased percentage of sputum eosinophils⁶ in patients with mild persistent asthma, and the addition of a long-acting beta agonist does not provide additional benefit.⁴ Furthermore, daily use of inhaled corticosteroids in these patients has also been associated with a lower rate of asthma-related deaths and with less need for systemic corticosteroid therapy,^7,8 even though inhaled corticosteroids have not yet been shown to alter the progressive loss of lung function.¹⁰

Yes. A number of large randomized controlled trials have shown inhaled corticosteroids to be beneficial in low doses for patients who have mild persistent asthma, and therefore these drugs are strongly recommended in this situation.¹

Asthma care providers should, however, consider this “yes” in the context of asthma severity, the goals of therapy, and the benefits and risks associated with inhaled corticosteroids.

CLASSIFICATION OF ASTHMA SEVERITY

Although the studies of asthma prevalence had methodologic limitations and therefore the true prevalence of mild persistent asthma cannot be determined, it is common. Fuhlbrigge et al² reported that most asthma patients have some form of persistent asthma. In contrast, Dusser et al³ reviewed available studies and concluded that most patients with asthma have either intermittent or mild persistent asthma.

GOALS: REDUCE IMPAIRMENT AND RISK

The goals of asthma management are to:

Reduce impairment by controlling symptoms so that normal activity levels can be maintained, by minimizing the need for short-acting bronchodilator use, and by maintaining normal pulmonary function; and to

Reduce risk by preventing progressive loss of lung function and recurrent exacerbations, and by optimizing pharmacotherapy while minimizing potential adverse effects.¹

EVIDENCE OF BENEFIT

The OPTIMA trial⁴ (Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma) was a double-blind, randomized trial carried out in 198 centers in 17 countries. Compared with those randomized to receive placebo, patients who were randomized to receive an inhaled corticosteroid, ie, budesonide (Pulmicort) 100 μg twice daily, had 60% fewer severe exacerbations (relative risk [RR] 0.4, 95% confidence interval [CI] 0.27–0.59) and 48% fewer days when their asthma was poorly controlled (RR 0.52, 95% CI 0.4–0.67). Adding a long-acting beta-agonist did not change this outcome.

The START study⁵ (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) showed that, compared with placebo, starting inhaled budesonide within the first 2 years of asthma symptoms in patients with mild persistent asthma was associated with better asthma control and less need for additional asthma medication.

The IMPACT study⁶ (Improving Asthma Control Trial) showed that inhaled steroids need to be taken daily, on a regular schedule, rather than intermittently as needed. Patients received either inhaled budesonide as needed, budesonide 200 μg twice daily every day, or zafirlukast (Accolate) 20 mg twice daily. Daily budesonide therapy resulted in better asthma control, less bronchial hyperresponsiveness, and less airway inflammation compared with intermittent use, zafirlukast therapy, or placebo. Daily zafirlukast and intermittent steroid treatment produced similar results for all outcomes measured.

Despite this strong evidence supporting regular use of inhaled corticosteroids in patients with mild persistent asthma, many patients choose to take them intermittently.

Suissa et al⁷ found, in a large observational cohort study, that fewer patients died of asthma if they were receiving low-dose inhaled corticosteroids than if they were not. The rate of death due to asthma was lower in patients who had used more inhaled corticosteroids over the previous year, and the death rate was higher in those who had discontinued inhaled corticosteroids in the previous 3 months than in those who continued using them.

STEROIDS DO NOT SLOW THE LOSS OF LUNG FUNCTION

Compared with people without asthma, asthma patients have substantially lower values of forced expiratory volume in the first second of expiration (FEV₁). They also have a faster rate of functional decline: the average decrease in FEV₁ in asthma patients is 38 mL per year, compared with 22 mL per year in nonasthmatic people.⁹

Although inhaled corticosteroids have been shown to increase lung function in asthma patients in the short term, there is little convincing evidence to suggest that they affect the rate of decline in the long term.¹⁰ In fact, airway inflammation and bronchial hyperresponsiveness return to baseline within 2 weeks after inhaled corticosteroids are discontinued.¹⁰

DO INHALED CORTICOSTEROIDS STUNT CHILDREN’S GROWTH?

The safety of long-term low-dose inhaled corticosteroids is well established in adults. However, two large randomized controlled trials found that children treated with low-dose inhaled steroids (budesonide 200–400 μg per day) grew 1 to 1.5 cm less over 3 to 5 years of treatment than children receiving placebo.¹¹ However, this effect was primarily evident within the first year of therapy, and growth velocity was similar to that with placebo at the end of the treatment period (4 to 6 years).¹²

Agertoft and Pedersen¹³ found that taking inhaled corticosteroids long-term is unlikely to have an effect on final height. Children who took inhaled budesonide (up to an average daily dose of 500 μg) into adulthood ended up no shorter than those who did not.

Based on these and other data, inhaled corticosteroids are generally considered safe at recommended doses. However, the decision to prescribe them for long-term therapy should be based on the risks and benefits to the individual patient.¹

ALTERNATIVE DRUGS FOR MILD PERSISTENT ASTHMA

Leukotriene-modifying drugs include the leukotriene receptor antagonists montelukast (Singulair) and zafirlukast and the 5-lipoxygenase inhibitor zileuton (Zyflo CR). These drugs have been associated with statistically significant improvement in FEV₁ compared with placebo in patients with mild to moderate asthma, reductions in both blood and sputum eosinophils,¹⁴ and attenuation of bronchoconstriction with exercise.¹¹

Large randomized trials comparing leukotriene modifier therapy with low-dose inhaled steroids in adults and children with mild persistent asthma have found that although outcomes improve with either therapy, the improvement is statistically superior with inhaled steroids for most asthma-control measures. ^6,8 Low-dose inhaled steroid therapy in patients with mild persistent and moderate persistent asthma has been associated with superior clinical outcomes as well as greater improvement in pulmonary function than treatment with antileukotriene drugs (Table 2).⁸

Asthma is heterogeneous, and properly selected patients with mild persistent asthma may achieve good control with leukotrienemodifier monotherapy.¹⁵ Alternatives for patients with mild persistent asthma include the methylxanthine theophylline, but this drug is less desirable due to its narrow therapeutic index. ¹ The inhaled cromones nedocromil (Tilade) and cromolyn (Intal) were other options in this patient population, but their short half-lives made them less practical, and US production has been discontinued.

THE BOTTOM LINE

Though leukotriene receptor antagonists can be effective, the daily use of inhaled corticosteroids results in higher asthma control test scores, more symptom-free days, greater pre-bronchodilator FEV₁, and decreased percentage of sputum eosinophils⁶ in patients with mild persistent asthma, and the addition of a long-acting beta agonist does not provide additional benefit.⁴ Furthermore, daily use of inhaled corticosteroids in these patients has also been associated with a lower rate of asthma-related deaths and with less need for systemic corticosteroid therapy,^7,8 even though inhaled corticosteroids have not yet been shown to alter the progressive loss of lung function.¹⁰

Yes. A number of large randomized controlled trials have shown inhaled corticosteroids to be beneficial in low doses for patients who have mild persistent asthma, and therefore these drugs are strongly recommended in this situation.¹

Asthma care providers should, however, consider this “yes” in the context of asthma severity, the goals of therapy, and the benefits and risks associated with inhaled corticosteroids.

CLASSIFICATION OF ASTHMA SEVERITY

Although the studies of asthma prevalence had methodologic limitations and therefore the true prevalence of mild persistent asthma cannot be determined, it is common. Fuhlbrigge et al² reported that most asthma patients have some form of persistent asthma. In contrast, Dusser et al³ reviewed available studies and concluded that most patients with asthma have either intermittent or mild persistent asthma.

GOALS: REDUCE IMPAIRMENT AND RISK

The goals of asthma management are to:

Reduce impairment by controlling symptoms so that normal activity levels can be maintained, by minimizing the need for short-acting bronchodilator use, and by maintaining normal pulmonary function; and to

Reduce risk by preventing progressive loss of lung function and recurrent exacerbations, and by optimizing pharmacotherapy while minimizing potential adverse effects.¹

EVIDENCE OF BENEFIT

The OPTIMA trial⁴ (Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma) was a double-blind, randomized trial carried out in 198 centers in 17 countries. Compared with those randomized to receive placebo, patients who were randomized to receive an inhaled corticosteroid, ie, budesonide (Pulmicort) 100 μg twice daily, had 60% fewer severe exacerbations (relative risk [RR] 0.4, 95% confidence interval [CI] 0.27–0.59) and 48% fewer days when their asthma was poorly controlled (RR 0.52, 95% CI 0.4–0.67). Adding a long-acting beta-agonist did not change this outcome.

The START study⁵ (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) showed that, compared with placebo, starting inhaled budesonide within the first 2 years of asthma symptoms in patients with mild persistent asthma was associated with better asthma control and less need for additional asthma medication.

The IMPACT study⁶ (Improving Asthma Control Trial) showed that inhaled steroids need to be taken daily, on a regular schedule, rather than intermittently as needed. Patients received either inhaled budesonide as needed, budesonide 200 μg twice daily every day, or zafirlukast (Accolate) 20 mg twice daily. Daily budesonide therapy resulted in better asthma control, less bronchial hyperresponsiveness, and less airway inflammation compared with intermittent use, zafirlukast therapy, or placebo. Daily zafirlukast and intermittent steroid treatment produced similar results for all outcomes measured.

Despite this strong evidence supporting regular use of inhaled corticosteroids in patients with mild persistent asthma, many patients choose to take them intermittently.

Suissa et al⁷ found, in a large observational cohort study, that fewer patients died of asthma if they were receiving low-dose inhaled corticosteroids than if they were not. The rate of death due to asthma was lower in patients who had used more inhaled corticosteroids over the previous year, and the death rate was higher in those who had discontinued inhaled corticosteroids in the previous 3 months than in those who continued using them.

STEROIDS DO NOT SLOW THE LOSS OF LUNG FUNCTION

Compared with people without asthma, asthma patients have substantially lower values of forced expiratory volume in the first second of expiration (FEV₁). They also have a faster rate of functional decline: the average decrease in FEV₁ in asthma patients is 38 mL per year, compared with 22 mL per year in nonasthmatic people.⁹

Although inhaled corticosteroids have been shown to increase lung function in asthma patients in the short term, there is little convincing evidence to suggest that they affect the rate of decline in the long term.¹⁰ In fact, airway inflammation and bronchial hyperresponsiveness return to baseline within 2 weeks after inhaled corticosteroids are discontinued.¹⁰

DO INHALED CORTICOSTEROIDS STUNT CHILDREN’S GROWTH?

The safety of long-term low-dose inhaled corticosteroids is well established in adults. However, two large randomized controlled trials found that children treated with low-dose inhaled steroids (budesonide 200–400 μg per day) grew 1 to 1.5 cm less over 3 to 5 years of treatment than children receiving placebo.¹¹ However, this effect was primarily evident within the first year of therapy, and growth velocity was similar to that with placebo at the end of the treatment period (4 to 6 years).¹²

Agertoft and Pedersen¹³ found that taking inhaled corticosteroids long-term is unlikely to have an effect on final height. Children who took inhaled budesonide (up to an average daily dose of 500 μg) into adulthood ended up no shorter than those who did not.

Based on these and other data, inhaled corticosteroids are generally considered safe at recommended doses. However, the decision to prescribe them for long-term therapy should be based on the risks and benefits to the individual patient.¹

ALTERNATIVE DRUGS FOR MILD PERSISTENT ASTHMA

Leukotriene-modifying drugs include the leukotriene receptor antagonists montelukast (Singulair) and zafirlukast and the 5-lipoxygenase inhibitor zileuton (Zyflo CR). These drugs have been associated with statistically significant improvement in FEV₁ compared with placebo in patients with mild to moderate asthma, reductions in both blood and sputum eosinophils,¹⁴ and attenuation of bronchoconstriction with exercise.¹¹

Large randomized trials comparing leukotriene modifier therapy with low-dose inhaled steroids in adults and children with mild persistent asthma have found that although outcomes improve with either therapy, the improvement is statistically superior with inhaled steroids for most asthma-control measures. ^6,8 Low-dose inhaled steroid therapy in patients with mild persistent and moderate persistent asthma has been associated with superior clinical outcomes as well as greater improvement in pulmonary function than treatment with antileukotriene drugs (Table 2).⁸

Asthma is heterogeneous, and properly selected patients with mild persistent asthma may achieve good control with leukotrienemodifier monotherapy.¹⁵ Alternatives for patients with mild persistent asthma include the methylxanthine theophylline, but this drug is less desirable due to its narrow therapeutic index. ¹ The inhaled cromones nedocromil (Tilade) and cromolyn (Intal) were other options in this patient population, but their short half-lives made them less practical, and US production has been discontinued.

THE BOTTOM LINE

Though leukotriene receptor antagonists can be effective, the daily use of inhaled corticosteroids results in higher asthma control test scores, more symptom-free days, greater pre-bronchodilator FEV₁, and decreased percentage of sputum eosinophils⁶ in patients with mild persistent asthma, and the addition of a long-acting beta agonist does not provide additional benefit.⁴ Furthermore, daily use of inhaled corticosteroids in these patients has also been associated with a lower rate of asthma-related deaths and with less need for systemic corticosteroid therapy,^7,8 even though inhaled corticosteroids have not yet been shown to alter the progressive loss of lung function.¹⁰

A 61-year-old woman presents to her primary care physician because for the last 4 weeks she has had difficulty swallowing solid food and a feeling of food “getting stuck in the chest.” She also reports having nausea, mild epigastric pain, and heartburn. She denies having fevers, chills, night sweats, weight loss, vomiting, diarrhea, hematochezia, or melena.

Medical history

For the past 20 years, she has had gastroesophageal reflux disease (GERD), intermittently treated with a proton pump inhibitor. She also has arthritis, hyperlipidemia, hypertension, and asthma, and she has undergone right hip replacement for a hip fracture. She has no known allergies.

She lives in the Midwest region of the United States and is on disability due to her arthritis. She is divorced and has three children.

She quit smoking 3 years ago after smoking half a pack per day for 30 years. She drinks socially; she has never used recreational drugs.

She recalls that an uncle had cancer, but she does not know the specific type.

Physical examination

The patient’s temperature is 96.7°F (35.9°C), heart rate 86 per minute, blood pressure 150/92 mm Hg, respiratory rate 16 per minute, and oxygen saturation 100% on room air.

Differential diagnosis

Although the differential diagnosis at this stage is broad, a few conditions that commonly present like this are:

• Esophageal cancer
• Esophageal stricture
• Esophageal webs
• Esophagitis (infectious, inflammatory)
• Peptic ulcer disease.

WHICH TEST SHOULD BE ORDERED?

1. Which test will you order now for this patient?

• Endoscopy (esophagogastroduodenoscopy)
• Serum Helicobacter pylori antibody testing
• Wireless pH monitoring
• Barium swallow

Endoscopy would be the best test to order. Esophageal cancer and esophageal stricture must be ruled out, in view of her long history of GERD, gastritis, and smoking and her alarming symptoms of difficulty swallowing and food sticking. In this situation, endoscopy is the first test recommended. In addition to its diagnostic value, it offers an opportunity to obtain tissue samples and to perform a therapeutic intervention, if necessary.^1,2

H pyloriantibody testing is used in the “test-and-treat approach” for H pylori infection, an established management strategy for patients who have uninvestigated dyspepsia and who are younger than 55 years and have no “alarm features,” ie, red flags for cancer. The alarm features commonly described are anemia, early satiety, unexplained weight loss, bleeding, odynophagia, progressive dysphagia, unexplained vomiting, and a family history or prior history of gastrointestinal malignancy.³

Our patient’s symptoms raise the possibility of cancer, so that H pylori testing would not be the best test to order at this point.

Ambulatory wireless pH monitoring with a wireless pH capsule is useful for confirming GERD in those with persistent symptoms (whether typical or atypical) who do not have evidence of mucosal damage on initial endoscopy, particularly if a trial of acid suppression has failed.^4–6

Barium swallow is an x-ray examination of the esophagus with contrast. It can show both the anatomy and the function of the esophagus, and it would be the initial diagnostic procedure of choice for patients with dysphagia who have no alarm symptoms.⁷ However, our patient does have alarm symptoms.

First highlight point

• Endoscopy is the first test in patients with dysphagia with alarm symptoms.

CASE CONTINUES: ENDOSCOPY

Multiple biopsies of the nodules show atypical lymphoid infiltrates with small cleaved lymphocytes that are mostly positive for CD5, CD20, and CD43 and negative for CD10 and CD23 by flow cytometry. In addition, a staining test for H pylori is positive.

Comment. Our patient has had GERD for the past 20 years, intermittently treated with a proton pump inhibitor. Acid suppressive therapy with a proton pump inhibitor is the standard of care of patients with erosive esophagitis. In standard doses, these drugs control symptoms in most cases and heal esophagitis in almost 90% of cases within 4 to 8 weeks.⁹ Proton pump inhibitors are also effective for maintaining healing of esophagitis and controlling symptoms in patients who respond to an acute course of therapy for a period of 6 to 12 months.¹⁰

WHAT IS THE DIAGNOSIS?

2. Which is the most likely diagnosis for our patient?

• Fundic gland polyps
• Gastric hyperplastic polyps
• Gastric adenomas
• Mucosa-associated lymphoid tissue (MALT) lymphoma

Fundic gland polyps are small (0.1–0.8 cm), hyperemic, sessile, flat, nodular lesions that have a smooth surface. They occur exclusively in the gastric corpus and are composed of normal gastric corpus-type epithelium arranged in a disorderly or microcystic configuration. ¹¹ This pattern does not match our patient’s findings.

Gastric hyperplastic polyps are elongated, cystic, and distorted foveolar epithelium with marked regeneration. Other histologic findings are stromal inflammation, edema, and smooth muscle hyperplasia.¹² This does not match our patient’s findings.

Adenomas can be flat or polypoid and range in size from a few millimeters to several centimeters. Endoscopically, adenomatous polyps have a velvety, lobulated appearance. Most are solitary (82% of cases), located in the antrum, and less than 2 cm in diameter.¹³ This does not match our patient’s findings.

MALT lymphoma, the correct answer, is characterized by small cleaved lymphocytes positive for CD4, CD20, and CD43. Although CD5 positivity is not characteristic, rare cases of MALT lymphoma may be CD5-positive and may be more aggressive.¹⁴

Other common features of MALT lymphoma are erosions, small nodules, thickening of gastric folds—generally suggesting a benign condition—or hyperemic or even normal gastric mucosa.¹⁵ Our patient’s complaint of food sticking in her chest and difficulty swallowing was most likely related to the erosive esophagitis found on endoscopy.

A TYPE OF NON-HODGKIN LYMPHOMA

Normal gastric mucosa contains no lymphoid tissue.^16,17 Primary gastric lymphoma, of which MALT lymphoma is a subtype, accounts for around 5% of gastric malignancies, with an annual incidence rate of 0.5 per 100,000 people. ^18–20 Although rare, it accounts for 60% to 70% of cases of non-Hodgkin lymphoma of the gastrointestinal tract and can involve the perigastric or abdominal lymph nodes or both.^21–23 Although earlier studies suggested that its incidence was increasing, recent data indicate the incidence may be decreasing, thanks to active H pylori treatment.^24–26

Two subtypes of primary gastric non-Hodgkin lymphoma commonly described are MALT lymphoma and diffuse large B-cell (DLBC) lymphoma. In the Revised European-American Lymphoma Classification, high-grade MALT lymphoma is comparable to DLBC lymphoma and may have transformed from low-grade MALT lymphoma.^27,28 Another reported subtype, mantle cell lymphoma with MALT lymphoma features, should be considered in the differential diagnosis, although it is rare.²⁹

MALT lymphoma is linked to H pylori

H pylori infection is a factor in the development of MALT lymphoma,³⁰ as multiple lines of evidence show:

• H pylori infection has been reported in more than 90% of patients with MALT lymphoma.^31–35
• H pylori antibodies have been found in stored serum drawn from patients who subsequently developed MALT lymphoma.³⁵
• In response to H pylori antigens, T cells from MALT lymphoma proliferate and cause an increase in tumor immunoglobulin production.³⁶
• In animals experimentally infected with H pylori, around one-third develop lymphoid follicles and lymphoepithelial lesions including B cells, which are similar to human MALT lymphoma.³⁷

However, only a minority of patients with H pylori develop lymphoma, owing to a host immune response that is not well defined.

Second highlight point

• Gastric MALT lymphoma is associated with H pylori.

Associated genetic translocations

Three translocations, t(11;18), t(1;14), and t(14;18), are specifically associated with MALT lymphoma, and the genes involved have been characterized.

The t(11;18) translocation, seen in gastric and nongastric MALT lymphoma, is not seen in H pylori gastritis.³⁸ This translocation is usually associated with extension of the disease outside the stomach (ie, to regional lymph nodes or distal sites).²⁷ Most cases that do not respond to H pylori eradication involve the t(11;18) and t(1;14) translocations.²⁸

Clinical presentation of gastric MALT lymphoma

The average age at presentation with gastric MALT lymphoma is 54 to 58 years.

The most common complaint is nonspecific abdominal pain in the epigastric region, sometimes accompanied by weight loss, nausea, vomiting, and, in a quarter of cases, acute or chronic bleeding.^39–41 Weight loss is common, and its extent is associated with the location and the grade of the disease.

Most cases of MALT lymphoma are found serendipitously during endoscopy, on which the appearance of the lesions ranges from small ulcerations to polypoid masses with infiltrated, thickened folds involving predominantly the antrum or prepyloric region.^15,41

MANAGING MALT LYMPHOMA

Our patient undergoes endoscopic ultrasonography, which reveals she has stage I disease, ie, it is limited to the stomach without involving the lymph nodes (stage II), adjacent organs (stage III), or distant organs (stage IV).

3. How will you treat this patient, given the present information?

• Chemotherapy
• Radiation therapy
• Surgery
• Antibiotics with a proton pump inhibitor

Antibiotics with a proton pump inhibitor would be best. According to the Maastricht III Consensus Report,⁴²H pylori eradication is the treatment of first choice for H pylori infection in patients with stage I low-grade gastric MALT lymphoma. This therapy can induce complete histologic remission in 80% to 100% of patients with MALT lymphoma. ⁴³ Several studies have shown regression⁴⁴ or complete remission of low-grade gastric MALT lymphoma after eradication of H pylori with antibiotics, making it a reasonable initial treatment.^45–49

Several regimens are used. The first choice in populations in which the prevalence of resistance to clarithromycin (Biaxin) is less than 15% to 20% is a proton pump inhibitor, clarithromycin, and either amoxicillin or metronidazole (Flagyl). (Metronidazole is preferable to amoxicillin if the prevalence of resistance to metronidazole is less than 40%.)

Sequential treatment—ie, 5 days of a proton pump inhibitor plus amoxicillin followed by 5 additional days of a proton pump inhibitor plus clarithromycin plus tinidazole (Tindamax)— may be better than a 7-day course of the combination of a proton pump inhibitor, amoxicillin, and clarithromycin.^50,51

Treatment with a proton pump inhibitor, clarithromycin (500 mg twice a day), and either amoxicillin (1,000 mg twice a day) or metronidazole (400 or 500 mg twice a day) for 14 days is more effective than treatment for 7 days.⁵²

H pylori reinfection in the general population is quite rare, with an estimated yearly rate as low as 2%.⁵³ Recurrence of the infection is a risk factor for lymphoma relapse.^17,54

Several predictors of the response of MALT lymphoma to eradication therapy have been recognized: H pylori positivity, stage I, lymphoma confined to the stomach; gastric wall invasion confined to mucosa and submucosa, and the absence of the t(11;18) translocation.

The time between H pylori eradication and complete remission of primary gastric lymphoma varies and can be longer than 12 months.⁵⁵

Chemotherapy. In a single study,⁵⁶ complete remission was achieved with oral cyclophosphamide (Cytoxan) in cases of antibiotic-refractory gastric MALT lymphoma. Comparable results were achieved after radiation therapy (see below); hence, oral monotherapy with cyclophosphamide might also be a suitable second-line therapy.⁵⁷

The regimen of cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHOP) has been recommended for patients with stage III and IV disease.^41,58

Rituximab (Rituxan) has been proven effective in treating t(11;18)-positive MALT lymphoma.⁵⁹

Radiation therapy. Two studies have shown a 100% complete response rate after radiation therapy with a median dose of 30 Gy.^57,60 Tsang et al⁶¹ reported complete remission in up to 90% of patients receiving radiation therapy alone, with excellent 5-year progression-free and overall survival rates of 98% and 77%, respectively.

Although surgery, radiotherapy, and chemotherapy have been used in cases in which eradication therapy failed and in more advanced stages of MALT lymphoma, there is no consensus about their use, so therapy must be individualized.

Fourth highlight point

• Antibiotic treatment for eradication of H pylori infection is the recommended treatment only for stage I low-grade MALT lymphoma.

FOLOW-UP

4. How should you follow patients with MALT lymphoma?

• Endoscopy
• H pylori testing
• Computed tomography and magnetic resonance imaging
• No surveillance required after treatment

Endoscopy is the correct answer. As initial diagnostic biopsies do not exclude aggressive lymphoma, careful endoscopic follow-up is recommended. A recommended schedule is a breath test for H pylori every 2 months in conjunction with repeat endoscopy with biopsies every 3 to 6 months for the first 2 years, and then annually.⁶²

Although H pylori may be eradicated within 1 month of drug therapy, lymphoma may take several months to disappear histologically. In patients with stage I disease with residual lymphoma after H pylori eradication therapy, a simple wait-and-watch strategy is a suitable alternative to oncologic therapy.^63,64

Local relapse may occur after many years of complete remission; thus, patients should be followed closely long-term with endoscopy and possibly endoscopic ultrasonography. ^47–49,63

Patients who fail to attain a complete remission within 12 months should undergo radiation therapy, with or without chemotherapy. The same therapy should be started as soon as possible in patients with progressive disease after antibiotic therapy. Patients negative for H pylori, patients with stage II disease, and patients with t(11;18) translocation should receive antibiotic treatment with endoscopic surveillance every 3 months.

Fifth highlight point

• Surveillance endoscopy is recommended for follow-up of MALT lymphoma.

CASE CONTINUES: HER CONDITION IMPROVES, THEN WORSENS

Computed tomography of the chest, abdomen, and pelvis reveals no evidence of additional sites of tumor. Positron emission tomography reveals increased uptake in the left tonsillar region, for which she has undergoes an ear, nose, and throat evaluation, and no pathology is found.

Due to recurrence of her marginal zone Bcell lymphoma of MALT type of the stomach, the patient is referred to an oncology service. She is treated with radiation, receiving 15 sessions of 30 Gy localized to the stomach. Three months after radiation therapy, she undergoes endoscopy again, which shows no evidence of the previously described nodules. Repeat biopsies are negative for H pylori and MALT lymphoma.

Annual surveillance endoscopy and computed tomography for the past 3 years have been negative for any tumor recurrence.

A 61-year-old woman presents to her primary care physician because for the last 4 weeks she has had difficulty swallowing solid food and a feeling of food “getting stuck in the chest.” She also reports having nausea, mild epigastric pain, and heartburn. She denies having fevers, chills, night sweats, weight loss, vomiting, diarrhea, hematochezia, or melena.

Medical history

For the past 20 years, she has had gastroesophageal reflux disease (GERD), intermittently treated with a proton pump inhibitor. She also has arthritis, hyperlipidemia, hypertension, and asthma, and she has undergone right hip replacement for a hip fracture. She has no known allergies.

She lives in the Midwest region of the United States and is on disability due to her arthritis. She is divorced and has three children.

She quit smoking 3 years ago after smoking half a pack per day for 30 years. She drinks socially; she has never used recreational drugs.

She recalls that an uncle had cancer, but she does not know the specific type.

Physical examination

The patient’s temperature is 96.7°F (35.9°C), heart rate 86 per minute, blood pressure 150/92 mm Hg, respiratory rate 16 per minute, and oxygen saturation 100% on room air.

Differential diagnosis

Although the differential diagnosis at this stage is broad, a few conditions that commonly present like this are:

• Esophageal cancer
• Esophageal stricture
• Esophageal webs
• Esophagitis (infectious, inflammatory)
• Peptic ulcer disease.

WHICH TEST SHOULD BE ORDERED?

1. Which test will you order now for this patient?

• Endoscopy (esophagogastroduodenoscopy)
• Serum Helicobacter pylori antibody testing
• Wireless pH monitoring
• Barium swallow

Endoscopy would be the best test to order. Esophageal cancer and esophageal stricture must be ruled out, in view of her long history of GERD, gastritis, and smoking and her alarming symptoms of difficulty swallowing and food sticking. In this situation, endoscopy is the first test recommended. In addition to its diagnostic value, it offers an opportunity to obtain tissue samples and to perform a therapeutic intervention, if necessary.^1,2

H pyloriantibody testing is used in the “test-and-treat approach” for H pylori infection, an established management strategy for patients who have uninvestigated dyspepsia and who are younger than 55 years and have no “alarm features,” ie, red flags for cancer. The alarm features commonly described are anemia, early satiety, unexplained weight loss, bleeding, odynophagia, progressive dysphagia, unexplained vomiting, and a family history or prior history of gastrointestinal malignancy.³

Our patient’s symptoms raise the possibility of cancer, so that H pylori testing would not be the best test to order at this point.

Ambulatory wireless pH monitoring with a wireless pH capsule is useful for confirming GERD in those with persistent symptoms (whether typical or atypical) who do not have evidence of mucosal damage on initial endoscopy, particularly if a trial of acid suppression has failed.^4–6

Barium swallow is an x-ray examination of the esophagus with contrast. It can show both the anatomy and the function of the esophagus, and it would be the initial diagnostic procedure of choice for patients with dysphagia who have no alarm symptoms.⁷ However, our patient does have alarm symptoms.

First highlight point

• Endoscopy is the first test in patients with dysphagia with alarm symptoms.

CASE CONTINUES: ENDOSCOPY

Multiple biopsies of the nodules show atypical lymphoid infiltrates with small cleaved lymphocytes that are mostly positive for CD5, CD20, and CD43 and negative for CD10 and CD23 by flow cytometry. In addition, a staining test for H pylori is positive.

Comment. Our patient has had GERD for the past 20 years, intermittently treated with a proton pump inhibitor. Acid suppressive therapy with a proton pump inhibitor is the standard of care of patients with erosive esophagitis. In standard doses, these drugs control symptoms in most cases and heal esophagitis in almost 90% of cases within 4 to 8 weeks.⁹ Proton pump inhibitors are also effective for maintaining healing of esophagitis and controlling symptoms in patients who respond to an acute course of therapy for a period of 6 to 12 months.¹⁰

WHAT IS THE DIAGNOSIS?

2. Which is the most likely diagnosis for our patient?

• Fundic gland polyps
• Gastric hyperplastic polyps
• Gastric adenomas
• Mucosa-associated lymphoid tissue (MALT) lymphoma

Fundic gland polyps are small (0.1–0.8 cm), hyperemic, sessile, flat, nodular lesions that have a smooth surface. They occur exclusively in the gastric corpus and are composed of normal gastric corpus-type epithelium arranged in a disorderly or microcystic configuration. ¹¹ This pattern does not match our patient’s findings.

Gastric hyperplastic polyps are elongated, cystic, and distorted foveolar epithelium with marked regeneration. Other histologic findings are stromal inflammation, edema, and smooth muscle hyperplasia.¹² This does not match our patient’s findings.

Adenomas can be flat or polypoid and range in size from a few millimeters to several centimeters. Endoscopically, adenomatous polyps have a velvety, lobulated appearance. Most are solitary (82% of cases), located in the antrum, and less than 2 cm in diameter.¹³ This does not match our patient’s findings.

MALT lymphoma, the correct answer, is characterized by small cleaved lymphocytes positive for CD4, CD20, and CD43. Although CD5 positivity is not characteristic, rare cases of MALT lymphoma may be CD5-positive and may be more aggressive.¹⁴

Other common features of MALT lymphoma are erosions, small nodules, thickening of gastric folds—generally suggesting a benign condition—or hyperemic or even normal gastric mucosa.¹⁵ Our patient’s complaint of food sticking in her chest and difficulty swallowing was most likely related to the erosive esophagitis found on endoscopy.

A TYPE OF NON-HODGKIN LYMPHOMA

Normal gastric mucosa contains no lymphoid tissue.^16,17 Primary gastric lymphoma, of which MALT lymphoma is a subtype, accounts for around 5% of gastric malignancies, with an annual incidence rate of 0.5 per 100,000 people. ^18–20 Although rare, it accounts for 60% to 70% of cases of non-Hodgkin lymphoma of the gastrointestinal tract and can involve the perigastric or abdominal lymph nodes or both.^21–23 Although earlier studies suggested that its incidence was increasing, recent data indicate the incidence may be decreasing, thanks to active H pylori treatment.^24–26

Two subtypes of primary gastric non-Hodgkin lymphoma commonly described are MALT lymphoma and diffuse large B-cell (DLBC) lymphoma. In the Revised European-American Lymphoma Classification, high-grade MALT lymphoma is comparable to DLBC lymphoma and may have transformed from low-grade MALT lymphoma.^27,28 Another reported subtype, mantle cell lymphoma with MALT lymphoma features, should be considered in the differential diagnosis, although it is rare.²⁹

MALT lymphoma is linked to H pylori

H pylori infection is a factor in the development of MALT lymphoma,³⁰ as multiple lines of evidence show:

• H pylori infection has been reported in more than 90% of patients with MALT lymphoma.^31–35
• H pylori antibodies have been found in stored serum drawn from patients who subsequently developed MALT lymphoma.³⁵
• In response to H pylori antigens, T cells from MALT lymphoma proliferate and cause an increase in tumor immunoglobulin production.³⁶
• In animals experimentally infected with H pylori, around one-third develop lymphoid follicles and lymphoepithelial lesions including B cells, which are similar to human MALT lymphoma.³⁷

However, only a minority of patients with H pylori develop lymphoma, owing to a host immune response that is not well defined.

Second highlight point

• Gastric MALT lymphoma is associated with H pylori.

Associated genetic translocations

Three translocations, t(11;18), t(1;14), and t(14;18), are specifically associated with MALT lymphoma, and the genes involved have been characterized.

The t(11;18) translocation, seen in gastric and nongastric MALT lymphoma, is not seen in H pylori gastritis.³⁸ This translocation is usually associated with extension of the disease outside the stomach (ie, to regional lymph nodes or distal sites).²⁷ Most cases that do not respond to H pylori eradication involve the t(11;18) and t(1;14) translocations.²⁸

Clinical presentation of gastric MALT lymphoma

The average age at presentation with gastric MALT lymphoma is 54 to 58 years.

The most common complaint is nonspecific abdominal pain in the epigastric region, sometimes accompanied by weight loss, nausea, vomiting, and, in a quarter of cases, acute or chronic bleeding.^39–41 Weight loss is common, and its extent is associated with the location and the grade of the disease.

Most cases of MALT lymphoma are found serendipitously during endoscopy, on which the appearance of the lesions ranges from small ulcerations to polypoid masses with infiltrated, thickened folds involving predominantly the antrum or prepyloric region.^15,41

MANAGING MALT LYMPHOMA

Our patient undergoes endoscopic ultrasonography, which reveals she has stage I disease, ie, it is limited to the stomach without involving the lymph nodes (stage II), adjacent organs (stage III), or distant organs (stage IV).

3. How will you treat this patient, given the present information?

• Chemotherapy
• Radiation therapy
• Surgery
• Antibiotics with a proton pump inhibitor

Antibiotics with a proton pump inhibitor would be best. According to the Maastricht III Consensus Report,⁴²H pylori eradication is the treatment of first choice for H pylori infection in patients with stage I low-grade gastric MALT lymphoma. This therapy can induce complete histologic remission in 80% to 100% of patients with MALT lymphoma. ⁴³ Several studies have shown regression⁴⁴ or complete remission of low-grade gastric MALT lymphoma after eradication of H pylori with antibiotics, making it a reasonable initial treatment.^45–49

Several regimens are used. The first choice in populations in which the prevalence of resistance to clarithromycin (Biaxin) is less than 15% to 20% is a proton pump inhibitor, clarithromycin, and either amoxicillin or metronidazole (Flagyl). (Metronidazole is preferable to amoxicillin if the prevalence of resistance to metronidazole is less than 40%.)

Sequential treatment—ie, 5 days of a proton pump inhibitor plus amoxicillin followed by 5 additional days of a proton pump inhibitor plus clarithromycin plus tinidazole (Tindamax)— may be better than a 7-day course of the combination of a proton pump inhibitor, amoxicillin, and clarithromycin.^50,51

Treatment with a proton pump inhibitor, clarithromycin (500 mg twice a day), and either amoxicillin (1,000 mg twice a day) or metronidazole (400 or 500 mg twice a day) for 14 days is more effective than treatment for 7 days.⁵²

H pylori reinfection in the general population is quite rare, with an estimated yearly rate as low as 2%.⁵³ Recurrence of the infection is a risk factor for lymphoma relapse.^17,54

Several predictors of the response of MALT lymphoma to eradication therapy have been recognized: H pylori positivity, stage I, lymphoma confined to the stomach; gastric wall invasion confined to mucosa and submucosa, and the absence of the t(11;18) translocation.

The time between H pylori eradication and complete remission of primary gastric lymphoma varies and can be longer than 12 months.⁵⁵

Chemotherapy. In a single study,⁵⁶ complete remission was achieved with oral cyclophosphamide (Cytoxan) in cases of antibiotic-refractory gastric MALT lymphoma. Comparable results were achieved after radiation therapy (see below); hence, oral monotherapy with cyclophosphamide might also be a suitable second-line therapy.⁵⁷

The regimen of cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHOP) has been recommended for patients with stage III and IV disease.^41,58

Rituximab (Rituxan) has been proven effective in treating t(11;18)-positive MALT lymphoma.⁵⁹

Radiation therapy. Two studies have shown a 100% complete response rate after radiation therapy with a median dose of 30 Gy.^57,60 Tsang et al⁶¹ reported complete remission in up to 90% of patients receiving radiation therapy alone, with excellent 5-year progression-free and overall survival rates of 98% and 77%, respectively.

Although surgery, radiotherapy, and chemotherapy have been used in cases in which eradication therapy failed and in more advanced stages of MALT lymphoma, there is no consensus about their use, so therapy must be individualized.

Fourth highlight point

• Antibiotic treatment for eradication of H pylori infection is the recommended treatment only for stage I low-grade MALT lymphoma.

FOLOW-UP

4. How should you follow patients with MALT lymphoma?

• Endoscopy
• H pylori testing
• Computed tomography and magnetic resonance imaging
• No surveillance required after treatment

Endoscopy is the correct answer. As initial diagnostic biopsies do not exclude aggressive lymphoma, careful endoscopic follow-up is recommended. A recommended schedule is a breath test for H pylori every 2 months in conjunction with repeat endoscopy with biopsies every 3 to 6 months for the first 2 years, and then annually.⁶²

Although H pylori may be eradicated within 1 month of drug therapy, lymphoma may take several months to disappear histologically. In patients with stage I disease with residual lymphoma after H pylori eradication therapy, a simple wait-and-watch strategy is a suitable alternative to oncologic therapy.^63,64

Local relapse may occur after many years of complete remission; thus, patients should be followed closely long-term with endoscopy and possibly endoscopic ultrasonography. ^47–49,63

Patients who fail to attain a complete remission within 12 months should undergo radiation therapy, with or without chemotherapy. The same therapy should be started as soon as possible in patients with progressive disease after antibiotic therapy. Patients negative for H pylori, patients with stage II disease, and patients with t(11;18) translocation should receive antibiotic treatment with endoscopic surveillance every 3 months.

Fifth highlight point

• Surveillance endoscopy is recommended for follow-up of MALT lymphoma.

CASE CONTINUES: HER CONDITION IMPROVES, THEN WORSENS

Computed tomography of the chest, abdomen, and pelvis reveals no evidence of additional sites of tumor. Positron emission tomography reveals increased uptake in the left tonsillar region, for which she has undergoes an ear, nose, and throat evaluation, and no pathology is found.

Due to recurrence of her marginal zone Bcell lymphoma of MALT type of the stomach, the patient is referred to an oncology service. She is treated with radiation, receiving 15 sessions of 30 Gy localized to the stomach. Three months after radiation therapy, she undergoes endoscopy again, which shows no evidence of the previously described nodules. Repeat biopsies are negative for H pylori and MALT lymphoma.

Annual surveillance endoscopy and computed tomography for the past 3 years have been negative for any tumor recurrence.

A 61-year-old woman presents to her primary care physician because for the last 4 weeks she has had difficulty swallowing solid food and a feeling of food “getting stuck in the chest.” She also reports having nausea, mild epigastric pain, and heartburn. She denies having fevers, chills, night sweats, weight loss, vomiting, diarrhea, hematochezia, or melena.

Medical history

For the past 20 years, she has had gastroesophageal reflux disease (GERD), intermittently treated with a proton pump inhibitor. She also has arthritis, hyperlipidemia, hypertension, and asthma, and she has undergone right hip replacement for a hip fracture. She has no known allergies.

She lives in the Midwest region of the United States and is on disability due to her arthritis. She is divorced and has three children.

She quit smoking 3 years ago after smoking half a pack per day for 30 years. She drinks socially; she has never used recreational drugs.

She recalls that an uncle had cancer, but she does not know the specific type.

Physical examination

The patient’s temperature is 96.7°F (35.9°C), heart rate 86 per minute, blood pressure 150/92 mm Hg, respiratory rate 16 per minute, and oxygen saturation 100% on room air.

Differential diagnosis

Although the differential diagnosis at this stage is broad, a few conditions that commonly present like this are:

• Esophageal cancer
• Esophageal stricture
• Esophageal webs
• Esophagitis (infectious, inflammatory)
• Peptic ulcer disease.

WHICH TEST SHOULD BE ORDERED?

1. Which test will you order now for this patient?

• Endoscopy (esophagogastroduodenoscopy)
• Serum Helicobacter pylori antibody testing
• Wireless pH monitoring
• Barium swallow

Endoscopy would be the best test to order. Esophageal cancer and esophageal stricture must be ruled out, in view of her long history of GERD, gastritis, and smoking and her alarming symptoms of difficulty swallowing and food sticking. In this situation, endoscopy is the first test recommended. In addition to its diagnostic value, it offers an opportunity to obtain tissue samples and to perform a therapeutic intervention, if necessary.^1,2

H pyloriantibody testing is used in the “test-and-treat approach” for H pylori infection, an established management strategy for patients who have uninvestigated dyspepsia and who are younger than 55 years and have no “alarm features,” ie, red flags for cancer. The alarm features commonly described are anemia, early satiety, unexplained weight loss, bleeding, odynophagia, progressive dysphagia, unexplained vomiting, and a family history or prior history of gastrointestinal malignancy.³

Our patient’s symptoms raise the possibility of cancer, so that H pylori testing would not be the best test to order at this point.

Ambulatory wireless pH monitoring with a wireless pH capsule is useful for confirming GERD in those with persistent symptoms (whether typical or atypical) who do not have evidence of mucosal damage on initial endoscopy, particularly if a trial of acid suppression has failed.^4–6

Barium swallow is an x-ray examination of the esophagus with contrast. It can show both the anatomy and the function of the esophagus, and it would be the initial diagnostic procedure of choice for patients with dysphagia who have no alarm symptoms.⁷ However, our patient does have alarm symptoms.

First highlight point

• Endoscopy is the first test in patients with dysphagia with alarm symptoms.

CASE CONTINUES: ENDOSCOPY

Multiple biopsies of the nodules show atypical lymphoid infiltrates with small cleaved lymphocytes that are mostly positive for CD5, CD20, and CD43 and negative for CD10 and CD23 by flow cytometry. In addition, a staining test for H pylori is positive.

Comment. Our patient has had GERD for the past 20 years, intermittently treated with a proton pump inhibitor. Acid suppressive therapy with a proton pump inhibitor is the standard of care of patients with erosive esophagitis. In standard doses, these drugs control symptoms in most cases and heal esophagitis in almost 90% of cases within 4 to 8 weeks.⁹ Proton pump inhibitors are also effective for maintaining healing of esophagitis and controlling symptoms in patients who respond to an acute course of therapy for a period of 6 to 12 months.¹⁰

WHAT IS THE DIAGNOSIS?

2. Which is the most likely diagnosis for our patient?

• Fundic gland polyps
• Gastric hyperplastic polyps
• Gastric adenomas
• Mucosa-associated lymphoid tissue (MALT) lymphoma

Fundic gland polyps are small (0.1–0.8 cm), hyperemic, sessile, flat, nodular lesions that have a smooth surface. They occur exclusively in the gastric corpus and are composed of normal gastric corpus-type epithelium arranged in a disorderly or microcystic configuration. ¹¹ This pattern does not match our patient’s findings.

Gastric hyperplastic polyps are elongated, cystic, and distorted foveolar epithelium with marked regeneration. Other histologic findings are stromal inflammation, edema, and smooth muscle hyperplasia.¹² This does not match our patient’s findings.

Adenomas can be flat or polypoid and range in size from a few millimeters to several centimeters. Endoscopically, adenomatous polyps have a velvety, lobulated appearance. Most are solitary (82% of cases), located in the antrum, and less than 2 cm in diameter.¹³ This does not match our patient’s findings.

MALT lymphoma, the correct answer, is characterized by small cleaved lymphocytes positive for CD4, CD20, and CD43. Although CD5 positivity is not characteristic, rare cases of MALT lymphoma may be CD5-positive and may be more aggressive.¹⁴

Other common features of MALT lymphoma are erosions, small nodules, thickening of gastric folds—generally suggesting a benign condition—or hyperemic or even normal gastric mucosa.¹⁵ Our patient’s complaint of food sticking in her chest and difficulty swallowing was most likely related to the erosive esophagitis found on endoscopy.

A TYPE OF NON-HODGKIN LYMPHOMA

Normal gastric mucosa contains no lymphoid tissue.^16,17 Primary gastric lymphoma, of which MALT lymphoma is a subtype, accounts for around 5% of gastric malignancies, with an annual incidence rate of 0.5 per 100,000 people. ^18–20 Although rare, it accounts for 60% to 70% of cases of non-Hodgkin lymphoma of the gastrointestinal tract and can involve the perigastric or abdominal lymph nodes or both.^21–23 Although earlier studies suggested that its incidence was increasing, recent data indicate the incidence may be decreasing, thanks to active H pylori treatment.^24–26

Two subtypes of primary gastric non-Hodgkin lymphoma commonly described are MALT lymphoma and diffuse large B-cell (DLBC) lymphoma. In the Revised European-American Lymphoma Classification, high-grade MALT lymphoma is comparable to DLBC lymphoma and may have transformed from low-grade MALT lymphoma.^27,28 Another reported subtype, mantle cell lymphoma with MALT lymphoma features, should be considered in the differential diagnosis, although it is rare.²⁹

MALT lymphoma is linked to H pylori

H pylori infection is a factor in the development of MALT lymphoma,³⁰ as multiple lines of evidence show:

• H pylori infection has been reported in more than 90% of patients with MALT lymphoma.^31–35
• H pylori antibodies have been found in stored serum drawn from patients who subsequently developed MALT lymphoma.³⁵
• In response to H pylori antigens, T cells from MALT lymphoma proliferate and cause an increase in tumor immunoglobulin production.³⁶
• In animals experimentally infected with H pylori, around one-third develop lymphoid follicles and lymphoepithelial lesions including B cells, which are similar to human MALT lymphoma.³⁷

However, only a minority of patients with H pylori develop lymphoma, owing to a host immune response that is not well defined.

Second highlight point

• Gastric MALT lymphoma is associated with H pylori.

Associated genetic translocations

Three translocations, t(11;18), t(1;14), and t(14;18), are specifically associated with MALT lymphoma, and the genes involved have been characterized.

The t(11;18) translocation, seen in gastric and nongastric MALT lymphoma, is not seen in H pylori gastritis.³⁸ This translocation is usually associated with extension of the disease outside the stomach (ie, to regional lymph nodes or distal sites).²⁷ Most cases that do not respond to H pylori eradication involve the t(11;18) and t(1;14) translocations.²⁸

Clinical presentation of gastric MALT lymphoma

The average age at presentation with gastric MALT lymphoma is 54 to 58 years.

The most common complaint is nonspecific abdominal pain in the epigastric region, sometimes accompanied by weight loss, nausea, vomiting, and, in a quarter of cases, acute or chronic bleeding.^39–41 Weight loss is common, and its extent is associated with the location and the grade of the disease.

Most cases of MALT lymphoma are found serendipitously during endoscopy, on which the appearance of the lesions ranges from small ulcerations to polypoid masses with infiltrated, thickened folds involving predominantly the antrum or prepyloric region.^15,41

MANAGING MALT LYMPHOMA

Our patient undergoes endoscopic ultrasonography, which reveals she has stage I disease, ie, it is limited to the stomach without involving the lymph nodes (stage II), adjacent organs (stage III), or distant organs (stage IV).

3. How will you treat this patient, given the present information?

• Chemotherapy
• Radiation therapy
• Surgery
• Antibiotics with a proton pump inhibitor

Antibiotics with a proton pump inhibitor would be best. According to the Maastricht III Consensus Report,⁴²H pylori eradication is the treatment of first choice for H pylori infection in patients with stage I low-grade gastric MALT lymphoma. This therapy can induce complete histologic remission in 80% to 100% of patients with MALT lymphoma. ⁴³ Several studies have shown regression⁴⁴ or complete remission of low-grade gastric MALT lymphoma after eradication of H pylori with antibiotics, making it a reasonable initial treatment.^45–49

Several regimens are used. The first choice in populations in which the prevalence of resistance to clarithromycin (Biaxin) is less than 15% to 20% is a proton pump inhibitor, clarithromycin, and either amoxicillin or metronidazole (Flagyl). (Metronidazole is preferable to amoxicillin if the prevalence of resistance to metronidazole is less than 40%.)

Sequential treatment—ie, 5 days of a proton pump inhibitor plus amoxicillin followed by 5 additional days of a proton pump inhibitor plus clarithromycin plus tinidazole (Tindamax)— may be better than a 7-day course of the combination of a proton pump inhibitor, amoxicillin, and clarithromycin.^50,51

Treatment with a proton pump inhibitor, clarithromycin (500 mg twice a day), and either amoxicillin (1,000 mg twice a day) or metronidazole (400 or 500 mg twice a day) for 14 days is more effective than treatment for 7 days.⁵²

H pylori reinfection in the general population is quite rare, with an estimated yearly rate as low as 2%.⁵³ Recurrence of the infection is a risk factor for lymphoma relapse.^17,54

Several predictors of the response of MALT lymphoma to eradication therapy have been recognized: H pylori positivity, stage I, lymphoma confined to the stomach; gastric wall invasion confined to mucosa and submucosa, and the absence of the t(11;18) translocation.

The time between H pylori eradication and complete remission of primary gastric lymphoma varies and can be longer than 12 months.⁵⁵

Chemotherapy. In a single study,⁵⁶ complete remission was achieved with oral cyclophosphamide (Cytoxan) in cases of antibiotic-refractory gastric MALT lymphoma. Comparable results were achieved after radiation therapy (see below); hence, oral monotherapy with cyclophosphamide might also be a suitable second-line therapy.⁵⁷

The regimen of cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHOP) has been recommended for patients with stage III and IV disease.^41,58

Rituximab (Rituxan) has been proven effective in treating t(11;18)-positive MALT lymphoma.⁵⁹

Radiation therapy. Two studies have shown a 100% complete response rate after radiation therapy with a median dose of 30 Gy.^57,60 Tsang et al⁶¹ reported complete remission in up to 90% of patients receiving radiation therapy alone, with excellent 5-year progression-free and overall survival rates of 98% and 77%, respectively.

Although surgery, radiotherapy, and chemotherapy have been used in cases in which eradication therapy failed and in more advanced stages of MALT lymphoma, there is no consensus about their use, so therapy must be individualized.

Fourth highlight point

• Antibiotic treatment for eradication of H pylori infection is the recommended treatment only for stage I low-grade MALT lymphoma.

FOLOW-UP

4. How should you follow patients with MALT lymphoma?

• Endoscopy
• H pylori testing
• Computed tomography and magnetic resonance imaging
• No surveillance required after treatment

Endoscopy is the correct answer. As initial diagnostic biopsies do not exclude aggressive lymphoma, careful endoscopic follow-up is recommended. A recommended schedule is a breath test for H pylori every 2 months in conjunction with repeat endoscopy with biopsies every 3 to 6 months for the first 2 years, and then annually.⁶²

Although H pylori may be eradicated within 1 month of drug therapy, lymphoma may take several months to disappear histologically. In patients with stage I disease with residual lymphoma after H pylori eradication therapy, a simple wait-and-watch strategy is a suitable alternative to oncologic therapy.^63,64

Local relapse may occur after many years of complete remission; thus, patients should be followed closely long-term with endoscopy and possibly endoscopic ultrasonography. ^47–49,63

Patients who fail to attain a complete remission within 12 months should undergo radiation therapy, with or without chemotherapy. The same therapy should be started as soon as possible in patients with progressive disease after antibiotic therapy. Patients negative for H pylori, patients with stage II disease, and patients with t(11;18) translocation should receive antibiotic treatment with endoscopic surveillance every 3 months.

Fifth highlight point

• Surveillance endoscopy is recommended for follow-up of MALT lymphoma.

CASE CONTINUES: HER CONDITION IMPROVES, THEN WORSENS

Computed tomography of the chest, abdomen, and pelvis reveals no evidence of additional sites of tumor. Positron emission tomography reveals increased uptake in the left tonsillar region, for which she has undergoes an ear, nose, and throat evaluation, and no pathology is found.

Due to recurrence of her marginal zone Bcell lymphoma of MALT type of the stomach, the patient is referred to an oncology service. She is treated with radiation, receiving 15 sessions of 30 Gy localized to the stomach. Three months after radiation therapy, she undergoes endoscopy again, which shows no evidence of the previously described nodules. Repeat biopsies are negative for H pylori and MALT lymphoma.

Annual surveillance endoscopy and computed tomography for the past 3 years have been negative for any tumor recurrence.