The IRS has sided with medical residents and their employers who for years have argued that they should have always been eligible for the “student exemption”—but don’t count on any money just yet.

By mid-June, the IRS expects to have contacted hospitals, universities, and individual residents who filed Social Security and Medicare payroll tax refund claims as of April 1, 2005. The date is significant because it is when the IRS ruled that employees who work 40 hours or more at a school, college, or university are eligible for student exemptions.

The IRS’ administrative decision in early March affects taxes paid before 2005.

The IRS has only taken the first step and says instructions on how to further process claims will be forthcoming. For now, the federal agency says, “employers and individuals with pending claims do not need to take any action at this time.”

Still, Joseph Ming-Wah Li, MD, SFHM, assistant professor of medicine at Harvard Medical School and director of the hospital medicine division at Beth Israel Deaconess Medical Center in Boston, urges hospitalists to pay attention to the refund; over three years of residency, it could amount to several thousand dollars per physician.

“The government ruling recently was that residents should be treated more like students instead of employees,” says Dr. Li, SHM's president-elect.

Hospitals, medical schools, and residents themselves have been filing so-called “FICA refund claims” since the 1990s. A series of legal challenges led to opposing interpretations of tax codes, leading the IRS to suspend all claims until a ruling was made.

And while pending claims will now be processed, it is too late for new claims to be filed. However, residents who did not file individual claims in what the IRS calls a “timely fashion” should check with their residency institution to determine if a claim was filed on their behalf.

Read "Dr. Hospitalist's" take on this topic in this month's issue of The Hospitalist.

For more details, visit the IRS website.

The IRS has sided with medical residents and their employers who for years have argued that they should have always been eligible for the “student exemption”—but don’t count on any money just yet.

By mid-June, the IRS expects to have contacted hospitals, universities, and individual residents who filed Social Security and Medicare payroll tax refund claims as of April 1, 2005. The date is significant because it is when the IRS ruled that employees who work 40 hours or more at a school, college, or university are eligible for student exemptions.

The IRS’ administrative decision in early March affects taxes paid before 2005.

The IRS has only taken the first step and says instructions on how to further process claims will be forthcoming. For now, the federal agency says, “employers and individuals with pending claims do not need to take any action at this time.”

Still, Joseph Ming-Wah Li, MD, SFHM, assistant professor of medicine at Harvard Medical School and director of the hospital medicine division at Beth Israel Deaconess Medical Center in Boston, urges hospitalists to pay attention to the refund; over three years of residency, it could amount to several thousand dollars per physician.

“The government ruling recently was that residents should be treated more like students instead of employees,” says Dr. Li, SHM's president-elect.

Hospitals, medical schools, and residents themselves have been filing so-called “FICA refund claims” since the 1990s. A series of legal challenges led to opposing interpretations of tax codes, leading the IRS to suspend all claims until a ruling was made.

And while pending claims will now be processed, it is too late for new claims to be filed. However, residents who did not file individual claims in what the IRS calls a “timely fashion” should check with their residency institution to determine if a claim was filed on their behalf.

Read "Dr. Hospitalist's" take on this topic in this month's issue of The Hospitalist.

For more details, visit the IRS website.

The IRS has sided with medical residents and their employers who for years have argued that they should have always been eligible for the “student exemption”—but don’t count on any money just yet.

By mid-June, the IRS expects to have contacted hospitals, universities, and individual residents who filed Social Security and Medicare payroll tax refund claims as of April 1, 2005. The date is significant because it is when the IRS ruled that employees who work 40 hours or more at a school, college, or university are eligible for student exemptions.

The IRS’ administrative decision in early March affects taxes paid before 2005.

The IRS has only taken the first step and says instructions on how to further process claims will be forthcoming. For now, the federal agency says, “employers and individuals with pending claims do not need to take any action at this time.”

Still, Joseph Ming-Wah Li, MD, SFHM, assistant professor of medicine at Harvard Medical School and director of the hospital medicine division at Beth Israel Deaconess Medical Center in Boston, urges hospitalists to pay attention to the refund; over three years of residency, it could amount to several thousand dollars per physician.

“The government ruling recently was that residents should be treated more like students instead of employees,” says Dr. Li, SHM's president-elect.

Hospitals, medical schools, and residents themselves have been filing so-called “FICA refund claims” since the 1990s. A series of legal challenges led to opposing interpretations of tax codes, leading the IRS to suspend all claims until a ruling was made.

And while pending claims will now be processed, it is too late for new claims to be filed. However, residents who did not file individual claims in what the IRS calls a “timely fashion” should check with their residency institution to determine if a claim was filed on their behalf.

Read "Dr. Hospitalist's" take on this topic in this month's issue of The Hospitalist.

For more details, visit the IRS website.

Clinical question: Does remote ICU monitoring improve mortality and length of stay?

Background: A shortage of intensivists has led to increased use of remote ICU monitoring or telemedicine technology to allow intensivists to remotely and simultaneously care for patients in multiple ICUs. Data evaluating this practice have been limited.

Study design: Pre- and postintervention observational study.

Setting: Open and closed medical-surgical ICUs in community, urban, and tertiary-care teaching U.S. hospitals.

Synopsis: This observational study in six ICUs aimed to assess the association of a telemedicine intervention with clinical outcomes. The intervention consisted of a remote office with real-time audiovisual monitoring, vital signs, early warning signals, and other electronic data. Comparing preintervention (n=2,034) and postintervention (n=2,108) groups, there were no differences in mortality, LOS, or complications.

Overall, the general limitation of the study was that integration of the tele-ICU and actual ICUs was limited. Physicians for nearly two-thirds of the patients chose “minimal delegation” to the tele-ICU physician. Tele-ICU involvement was particularly limited in “closed” units, which were already staffed by on-site intensivists. Furthermore, despite access to various real-time data, critical elements of the record such as physician order entry and progress notes were not shared in real time; notes, for example, required daily faxing.

While it is unfortunate that the study could not evaluate the full potential of the adjunctive tele-ICU, it illustrates the real-world obstacles of integrating such technology into clinical practice. In future studies, a standardized telemedicine approach might facilitate evaluation efforts.

Bottom line: While this study demonstrated no benefit of telemedicine, study limitations preclude conclusions. Further studies are needed.

Citation: Thomas EJ, Lucke JF, Wueste L, Weavind L, Patel B. Association of telemedicine for remote monitoring of intensive care patients with mortality, complications, and length of stay. JAMA. 2009;302(24):2671-2678.

Dr. Kim is a hospitalist at Brigham and Women's Hospital in Boston, and an instructor at Harvard Medical School.

For more reviews of HM-related research, visit our website.

Clinical question: Does remote ICU monitoring improve mortality and length of stay?

Background: A shortage of intensivists has led to increased use of remote ICU monitoring or telemedicine technology to allow intensivists to remotely and simultaneously care for patients in multiple ICUs. Data evaluating this practice have been limited.

Study design: Pre- and postintervention observational study.

Setting: Open and closed medical-surgical ICUs in community, urban, and tertiary-care teaching U.S. hospitals.

Synopsis: This observational study in six ICUs aimed to assess the association of a telemedicine intervention with clinical outcomes. The intervention consisted of a remote office with real-time audiovisual monitoring, vital signs, early warning signals, and other electronic data. Comparing preintervention (n=2,034) and postintervention (n=2,108) groups, there were no differences in mortality, LOS, or complications.

Overall, the general limitation of the study was that integration of the tele-ICU and actual ICUs was limited. Physicians for nearly two-thirds of the patients chose “minimal delegation” to the tele-ICU physician. Tele-ICU involvement was particularly limited in “closed” units, which were already staffed by on-site intensivists. Furthermore, despite access to various real-time data, critical elements of the record such as physician order entry and progress notes were not shared in real time; notes, for example, required daily faxing.

While it is unfortunate that the study could not evaluate the full potential of the adjunctive tele-ICU, it illustrates the real-world obstacles of integrating such technology into clinical practice. In future studies, a standardized telemedicine approach might facilitate evaluation efforts.

Bottom line: While this study demonstrated no benefit of telemedicine, study limitations preclude conclusions. Further studies are needed.

Citation: Thomas EJ, Lucke JF, Wueste L, Weavind L, Patel B. Association of telemedicine for remote monitoring of intensive care patients with mortality, complications, and length of stay. JAMA. 2009;302(24):2671-2678.

Dr. Kim is a hospitalist at Brigham and Women's Hospital in Boston, and an instructor at Harvard Medical School.

For more reviews of HM-related research, visit our website.

Clinical question: Does remote ICU monitoring improve mortality and length of stay?

Background: A shortage of intensivists has led to increased use of remote ICU monitoring or telemedicine technology to allow intensivists to remotely and simultaneously care for patients in multiple ICUs. Data evaluating this practice have been limited.

Study design: Pre- and postintervention observational study.

Setting: Open and closed medical-surgical ICUs in community, urban, and tertiary-care teaching U.S. hospitals.

Synopsis: This observational study in six ICUs aimed to assess the association of a telemedicine intervention with clinical outcomes. The intervention consisted of a remote office with real-time audiovisual monitoring, vital signs, early warning signals, and other electronic data. Comparing preintervention (n=2,034) and postintervention (n=2,108) groups, there were no differences in mortality, LOS, or complications.

Overall, the general limitation of the study was that integration of the tele-ICU and actual ICUs was limited. Physicians for nearly two-thirds of the patients chose “minimal delegation” to the tele-ICU physician. Tele-ICU involvement was particularly limited in “closed” units, which were already staffed by on-site intensivists. Furthermore, despite access to various real-time data, critical elements of the record such as physician order entry and progress notes were not shared in real time; notes, for example, required daily faxing.

While it is unfortunate that the study could not evaluate the full potential of the adjunctive tele-ICU, it illustrates the real-world obstacles of integrating such technology into clinical practice. In future studies, a standardized telemedicine approach might facilitate evaluation efforts.

Bottom line: While this study demonstrated no benefit of telemedicine, study limitations preclude conclusions. Further studies are needed.

Citation: Thomas EJ, Lucke JF, Wueste L, Weavind L, Patel B. Association of telemedicine for remote monitoring of intensive care patients with mortality, complications, and length of stay. JAMA. 2009;302(24):2671-2678.

Dr. Kim is a hospitalist at Brigham and Women's Hospital in Boston, and an instructor at Harvard Medical School.

For more reviews of HM-related research, visit our website.

When and how the national focus on reducing hospital readmissions will hit hospitals’ bottom lines is not clear, but it’s more a matter of when, not if, says Eric Coleman, MD, MPH, AGSF, FACP, director of the Care Transitions Program at the University of Colorado Denver.

Reducing readmissions “jumps off the page as an area where we could see enormous savings in national health expenditures,” Dr. Coleman told participants in an SHM webinar last month. The challenge, he said, is to align incentives with quality and safety for a moving target that also happens to be highly politicized. “We’re generally pretty good at identifying who’s at risk of readmission, but it’s harder to say who’s at modifiable risk,” he explained.

Evidence shows that hospitalists already reduce costs through improved length of stay. “Can hospitalists demonstrate the ability to reduce readmission rates as well?” Dr. Coleman asked.

Bundling payment for hospital stays with various post-hospital providers is a major focus of national efforts to reduce healthcare costs. Bundling gives providers on the healthcare continuum strong motivation to work together, Dr. Coleman said. The government won’t tell providers how to divide bundled payments, but Dr. Coleman predicts that consulting firms offering ideas for divvying up the money will emerge.

The Medicare Payment Advisory Commission (MEDPAC) has signaled its interest in changing payment incentives by reducing reimbursement for readmissions as well as several provisions that directly address readmissions in the healthcare reform package signed by President Obama in March. These include:

- A national pilot program on payment bundling;

- A hospital readmissions reduction program with financial penalties starting in October 2012 for select conditions; and

- A QI program to help hospitals with high severity-adjusted readmission rates.

When and how the national focus on reducing hospital readmissions will hit hospitals’ bottom lines is not clear, but it’s more a matter of when, not if, says Eric Coleman, MD, MPH, AGSF, FACP, director of the Care Transitions Program at the University of Colorado Denver.

Reducing readmissions “jumps off the page as an area where we could see enormous savings in national health expenditures,” Dr. Coleman told participants in an SHM webinar last month. The challenge, he said, is to align incentives with quality and safety for a moving target that also happens to be highly politicized. “We’re generally pretty good at identifying who’s at risk of readmission, but it’s harder to say who’s at modifiable risk,” he explained.

Evidence shows that hospitalists already reduce costs through improved length of stay. “Can hospitalists demonstrate the ability to reduce readmission rates as well?” Dr. Coleman asked.

Bundling payment for hospital stays with various post-hospital providers is a major focus of national efforts to reduce healthcare costs. Bundling gives providers on the healthcare continuum strong motivation to work together, Dr. Coleman said. The government won’t tell providers how to divide bundled payments, but Dr. Coleman predicts that consulting firms offering ideas for divvying up the money will emerge.

The Medicare Payment Advisory Commission (MEDPAC) has signaled its interest in changing payment incentives by reducing reimbursement for readmissions as well as several provisions that directly address readmissions in the healthcare reform package signed by President Obama in March. These include:

- A national pilot program on payment bundling;

- A hospital readmissions reduction program with financial penalties starting in October 2012 for select conditions; and

- A QI program to help hospitals with high severity-adjusted readmission rates.

When and how the national focus on reducing hospital readmissions will hit hospitals’ bottom lines is not clear, but it’s more a matter of when, not if, says Eric Coleman, MD, MPH, AGSF, FACP, director of the Care Transitions Program at the University of Colorado Denver.

Reducing readmissions “jumps off the page as an area where we could see enormous savings in national health expenditures,” Dr. Coleman told participants in an SHM webinar last month. The challenge, he said, is to align incentives with quality and safety for a moving target that also happens to be highly politicized. “We’re generally pretty good at identifying who’s at risk of readmission, but it’s harder to say who’s at modifiable risk,” he explained.

Evidence shows that hospitalists already reduce costs through improved length of stay. “Can hospitalists demonstrate the ability to reduce readmission rates as well?” Dr. Coleman asked.

Bundling payment for hospital stays with various post-hospital providers is a major focus of national efforts to reduce healthcare costs. Bundling gives providers on the healthcare continuum strong motivation to work together, Dr. Coleman said. The government won’t tell providers how to divide bundled payments, but Dr. Coleman predicts that consulting firms offering ideas for divvying up the money will emerge.

The Medicare Payment Advisory Commission (MEDPAC) has signaled its interest in changing payment incentives by reducing reimbursement for readmissions as well as several provisions that directly address readmissions in the healthcare reform package signed by President Obama in March. These include:

- A national pilot program on payment bundling;

- A hospital readmissions reduction program with financial penalties starting in October 2012 for select conditions; and

- A QI program to help hospitals with high severity-adjusted readmission rates.

HM leaders should pay close attention to the landmark decision by President Obama to extend visitation and critical-care decision rights to the partners of gay and lesbian patients, according to one hospitalist.

“The hospitalists would be the gatekeepers, in some ways, to make those calls,” says Heather Whelan, MD, an assistant professor and medical director at Mount Zion Medical Service, Division of Hospital Medicine, at the University of California at San Francisco. “I think hospitalists, group managers, and hospitals themselves are going to build this into policies and practices.”

Via a memo written in mid-April, the president mandated that all hospitals receiving federal funding must extend visitation rights to gay partners and “respect the patient’s choices about who may make critical heath-care decisions for them,” according to the Washington Post. Gay activists cheered the decisions; many conservative groups decried it.

An SHM spokesperson says the society “always expects that its hospitalists and their policies know and comply with federal, state and local regulations.”

Dr. Whelan notes that many hospitals in more progressive areas of the country—including San Francisco and New York City—already extend the rights that Obama has now codified. However, she says she has heard from physicians working elsewhere that the issue can crop up on who can be involved in critical-care meetings and decisions. The issue can be particularly sensitive in cases in which the patient is noncommunicative due to a stroke or other acute condition.

“This will standardize care,” Dr. Whelan says, adding, “It almost doesn’t matter how frequently it comes up. It’s a high-stakes event. One or two instances of it coming up are too many.”

HM leaders should pay close attention to the landmark decision by President Obama to extend visitation and critical-care decision rights to the partners of gay and lesbian patients, according to one hospitalist.

“The hospitalists would be the gatekeepers, in some ways, to make those calls,” says Heather Whelan, MD, an assistant professor and medical director at Mount Zion Medical Service, Division of Hospital Medicine, at the University of California at San Francisco. “I think hospitalists, group managers, and hospitals themselves are going to build this into policies and practices.”

Via a memo written in mid-April, the president mandated that all hospitals receiving federal funding must extend visitation rights to gay partners and “respect the patient’s choices about who may make critical heath-care decisions for them,” according to the Washington Post. Gay activists cheered the decisions; many conservative groups decried it.

An SHM spokesperson says the society “always expects that its hospitalists and their policies know and comply with federal, state and local regulations.”

Dr. Whelan notes that many hospitals in more progressive areas of the country—including San Francisco and New York City—already extend the rights that Obama has now codified. However, she says she has heard from physicians working elsewhere that the issue can crop up on who can be involved in critical-care meetings and decisions. The issue can be particularly sensitive in cases in which the patient is noncommunicative due to a stroke or other acute condition.

“This will standardize care,” Dr. Whelan says, adding, “It almost doesn’t matter how frequently it comes up. It’s a high-stakes event. One or two instances of it coming up are too many.”

HM leaders should pay close attention to the landmark decision by President Obama to extend visitation and critical-care decision rights to the partners of gay and lesbian patients, according to one hospitalist.

“The hospitalists would be the gatekeepers, in some ways, to make those calls,” says Heather Whelan, MD, an assistant professor and medical director at Mount Zion Medical Service, Division of Hospital Medicine, at the University of California at San Francisco. “I think hospitalists, group managers, and hospitals themselves are going to build this into policies and practices.”

Via a memo written in mid-April, the president mandated that all hospitals receiving federal funding must extend visitation rights to gay partners and “respect the patient’s choices about who may make critical heath-care decisions for them,” according to the Washington Post. Gay activists cheered the decisions; many conservative groups decried it.

An SHM spokesperson says the society “always expects that its hospitalists and their policies know and comply with federal, state and local regulations.”

Dr. Whelan notes that many hospitals in more progressive areas of the country—including San Francisco and New York City—already extend the rights that Obama has now codified. However, she says she has heard from physicians working elsewhere that the issue can crop up on who can be involved in critical-care meetings and decisions. The issue can be particularly sensitive in cases in which the patient is noncommunicative due to a stroke or other acute condition.

“This will standardize care,” Dr. Whelan says, adding, “It almost doesn’t matter how frequently it comes up. It’s a high-stakes event. One or two instances of it coming up are too many.”

Jitendra Dassani, MD, is a hospitalist who works for Advocate Medical Group at Illinois Masonic Hospital in Chicago. He passed the American Board of Internal Medicine’s (ABIM) traditional internal-medicine Maintenance of Certification (MOC) examination in 2008. According to current guidelines, he won’t have to recertify until 2018.

But Dr. Dassani is more than a veteran hospitalist. He’s practiced hospital-based medicine for well over a decade, and is planning on a long and prosperous HM career. In fact, he’s so dedicated to the field that he is planning to recertify through ABIM’s new Focused Practice in Hospital Medicine (FPHM) MOC next year—or, at the very latest, in 2012.

“I’ve been a hospitalist for 13 years, and I think it’s important to have something that can assess your knowledge and abilities as a hospitalist,” says Dr. Dassani, one of nearly 200 hospitalists who have signed up for the FPHM pathway. The first secure exam will be administered in October. “I took the general IM exam in 2008. That’s the traditional ABIM boards; I felt some of the questions were not related to my practice. That’s why I think the [FPHM] is really good and really important.”

He’s not alone. SHM and ABIM are anxious to see where this new MOC pathway goes. SHM leaders think the FPHM offers career validation and a customized MOC process to the 30,000 hospitalists practicing nationwide. ABIM is planning an extensive research effort to analyze a focused-practice MOC, using hospitalists as the test subjects.

One area in which the FPHM varies from the traditional MOC is its every-three-year requirement to complete practice-improvement modules (PIMs). Dr. Dassani likens the higher standard to the kind of continuing education and training programs other specialized fields require.

“I think it’s a good idea. It’s more work, but I support it,” he says. “Every time you get onto a plane, you hope the pilot is certified every six months, versus no one has evaluated the pilot in two years. Your safety is in his hands. Take that same analogy to medicine.

“You will have time,” he adds. “It’s 60 points over three years. One PIM is 40 points, so it’s not overwhelming.”—JC

Jitendra Dassani, MD, is a hospitalist who works for Advocate Medical Group at Illinois Masonic Hospital in Chicago. He passed the American Board of Internal Medicine’s (ABIM) traditional internal-medicine Maintenance of Certification (MOC) examination in 2008. According to current guidelines, he won’t have to recertify until 2018.

But Dr. Dassani is more than a veteran hospitalist. He’s practiced hospital-based medicine for well over a decade, and is planning on a long and prosperous HM career. In fact, he’s so dedicated to the field that he is planning to recertify through ABIM’s new Focused Practice in Hospital Medicine (FPHM) MOC next year—or, at the very latest, in 2012.

“I’ve been a hospitalist for 13 years, and I think it’s important to have something that can assess your knowledge and abilities as a hospitalist,” says Dr. Dassani, one of nearly 200 hospitalists who have signed up for the FPHM pathway. The first secure exam will be administered in October. “I took the general IM exam in 2008. That’s the traditional ABIM boards; I felt some of the questions were not related to my practice. That’s why I think the [FPHM] is really good and really important.”

He’s not alone. SHM and ABIM are anxious to see where this new MOC pathway goes. SHM leaders think the FPHM offers career validation and a customized MOC process to the 30,000 hospitalists practicing nationwide. ABIM is planning an extensive research effort to analyze a focused-practice MOC, using hospitalists as the test subjects.

One area in which the FPHM varies from the traditional MOC is its every-three-year requirement to complete practice-improvement modules (PIMs). Dr. Dassani likens the higher standard to the kind of continuing education and training programs other specialized fields require.

“I think it’s a good idea. It’s more work, but I support it,” he says. “Every time you get onto a plane, you hope the pilot is certified every six months, versus no one has evaluated the pilot in two years. Your safety is in his hands. Take that same analogy to medicine.

“You will have time,” he adds. “It’s 60 points over three years. One PIM is 40 points, so it’s not overwhelming.”—JC

Jitendra Dassani, MD, is a hospitalist who works for Advocate Medical Group at Illinois Masonic Hospital in Chicago. He passed the American Board of Internal Medicine’s (ABIM) traditional internal-medicine Maintenance of Certification (MOC) examination in 2008. According to current guidelines, he won’t have to recertify until 2018.

But Dr. Dassani is more than a veteran hospitalist. He’s practiced hospital-based medicine for well over a decade, and is planning on a long and prosperous HM career. In fact, he’s so dedicated to the field that he is planning to recertify through ABIM’s new Focused Practice in Hospital Medicine (FPHM) MOC next year—or, at the very latest, in 2012.

“I’ve been a hospitalist for 13 years, and I think it’s important to have something that can assess your knowledge and abilities as a hospitalist,” says Dr. Dassani, one of nearly 200 hospitalists who have signed up for the FPHM pathway. The first secure exam will be administered in October. “I took the general IM exam in 2008. That’s the traditional ABIM boards; I felt some of the questions were not related to my practice. That’s why I think the [FPHM] is really good and really important.”

He’s not alone. SHM and ABIM are anxious to see where this new MOC pathway goes. SHM leaders think the FPHM offers career validation and a customized MOC process to the 30,000 hospitalists practicing nationwide. ABIM is planning an extensive research effort to analyze a focused-practice MOC, using hospitalists as the test subjects.

One area in which the FPHM varies from the traditional MOC is its every-three-year requirement to complete practice-improvement modules (PIMs). Dr. Dassani likens the higher standard to the kind of continuing education and training programs other specialized fields require.

“I think it’s a good idea. It’s more work, but I support it,” he says. “Every time you get onto a plane, you hope the pilot is certified every six months, versus no one has evaluated the pilot in two years. Your safety is in his hands. Take that same analogy to medicine.

“You will have time,” he adds. “It’s 60 points over three years. One PIM is 40 points, so it’s not overwhelming.”—JC

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New Generic

• Perindopril erbumine tablets (generic Aceon)¹

New Drugs, Indications, Dosage Forms, and Approval Recommendations

• Collagenase clostridium histolytica injection (Xiaflex) has been approved by the FDA for treating the hand disease Dupuytren’s contracture. The agent breaks down excessive collagen in the hand, allowing patients to straighten the arm and have proper use of their fingers. The agent is also being studied to treat Peyronie’s disease.²
• Dalfampridine tablets (Ampyra) have been approved by the FDA to improve walking in patients with multiple sclerosis (MS).³ Seizures might occur in patients who exceed the recommended daily dose of 10 mg twice daily, or in patients with moderate to severe kidney disease. Therefore, caution is advised in these patients.
• Iloperidone tablets (Fanapt) have been approved by the FDA for the acute treatment of schizophrenia in adults.⁴ An atypical antipsychotic, it is a mixed dopamine D2/serotonin 5HT2A receptor antagonist.
• Lamotrigine extended-release tablets (Lamictal XR) have received a new FDA-approved indication for once-daily, add-on therapy for epilepsy in patients 13 years and older, with primary, generalized tonic-clonic seizures.⁵
• Liraglutide (Victoza) has been approved by the FDA as a once-daily injection for the treatment of Type 2 diabetes mellitus.⁶ Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, which is similar to exenatide. There is a label warning related to thyroid tumors that occurred in rats and mice. It is unclear whether medullary thyroid cancer will occur in adults; therefore, the agent should not be used in patients who already have this cancer or those with a family history of thyroid cancer.
• Trazodone extended-release tablets (Oleptro) have been approved by the FDA for treating major depressive disorder in adults.⁷ This product is formulated using Labopharm’s proprietary Contramid long-acting drug delivery system. The product will be available later this year.

Safety Information

• Didanosine (Videx/Videx EC) has undergone a label change in the warning and precautions sections related to the rare but serious complication of noncirrhotic portal hypertension. The label change was added because of the potential severity of portal hypertension, including death from hemorrhaging esophageal varices. A number of well-documented, postmarketing reports of this reaction were made following exclusion of other portal hypertension causes.⁸
• Long-acting beta-agonists (LABAs), formoterol (Foradil), and salmeterol (Sereven) are required to have a risk management strategy (REMS) and a revised medication guide written specifically for patients. The goal is to educate patients about the appropriate use of LABAs. There also is a plan to educate healthcare professionals about the appropriate use of LABAs.^9,10 This update is due to continued analysis of studies that show increased risk of severe asthma exacerbations, which lead to hospitalizations in adult and pediatric patients, including deaths in some LABA-utilizing patients. To safely use LABAs, the following need to be considered:
• Single-ingredient LABAs should not be used as monotherapy; they should only be used in combination with an asthma controller;
• LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controllers;
• Use an LABA for the shortest duration required to achieve asthma control and discontinue it, if possible, once asthma control is achieved. Patients should then be maintained on an asthma controller; and
• Use a combination product containing both an inhaled corticosteroid and an LABA to enhance adherence in pediatric and adolescent patients who require both of these classes to manage their asthma.
• Olanzapine (Zyprexa) has undergone a label change related to its indications for use in adolescents ages ^13-17 for treating schizophrenia and bipolar I disorder (manic or mixed episodes).¹¹ The new label asks providers to consider alternative treatments in this patient population due to the increased potential for weight gain and hyperlipidemia. Additionally, the effectiveness and safety of this agent have not been determined in patients under 13.
• Sibutramine (Meridia), marketed for weight loss, continues to be evaluated for safety.¹² A recent review found it poses an increased risk of heart attack and stroke in patients with a history of cardiovascular disease. Although the product label already had a warning related to use in patients with cardiovascular disease, the manufacturer has added a new contraindication to the sibutramine label for patients with cardiovascular disease and a history of: 1) coronary artery disease; 2) stroke or transient ischemic attack; 3) arrhythmias; 4) congestive heart failure; 5) peripheral arterial disease; and/or 6) uncontrolled hypertension (e.g., >145/90 mmHg). Providers should monitor blood pressure and heart rate regularly. If there is an unremitting increase in blood pressure and/or heart rate, sibutramine should be discontinued. Sibutramine should also be stopped in patients who do not lose at least 5% of their baseline body weight within the first three to six months of treatment.¹³TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

References

1. Lupin receives US FDA approval for Perindopril erbumine tablets. Lupin Web site. Available at: http://www.lupinworld.com/28jan10.htm. Accessed Feb. 22, 2010.
2. US FDA approves Auxilium drug for hand disease. Reuters Web site. Available at: http://www.reuters.com/article/idUSN0211921420100203. Accessed Feb. 22, 2010.
3. Petrochko C. MS walking drug gets FDA nod. MedPage Today Web site. Available at: http://www.medpagetoday.com/Neurology/MultipleSclerosis/18112. Accessed Feb. 22, 2010.
4. Fanapt available for acute schizophrenia. Monthly Prescribing Reference Web site. Available at: http://www.empr.com/fanapt-available-for-acute-schizophrenia/article/160985/. Accessed Feb. 22, 2010.
5. FDA approves once-a-day Lamictal XR as add-on epilepsy therapy for primary generalized tonic-clonic seizures. Available at: http://www.medicalnewstoday.com/articles/177796.php. Accessed Feb. 22, 2010.
6. FDA approves new treatment for Type 2 diabetes. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm198638.htm. Accessed Feb. 22, 2010.
7. Labopharm receives FDA approval for Oleptro. PR Newswire Web site. Available at: http://www.prnewswire.com/news-releases/labopharm-receives-fda-approval-for-oleptrotm-83429037.html. Accessed Feb. 22, 2010.
8. Videx/Videx EC (didanosine): Labeling revision—risk of non-cirrhotic portal hypertension. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm199343.htm. Accessed Feb. 22, 2010.
9. Long-acting beta-agonists (LABAs): new safe use requirements. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm201003.htm. Accessed Feb. 22, 2010.
10. Gever J. FDA says LABA asthma drugs not safe for solo use. MedPage Today Web site. Available at: http://www.medpagetoday.com/tbprint.cfm?tbid=18552. Accessed Feb. 22, 2010.
11. Zyprexa (olanzapine): use in adolescents. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm198402.htm. Accessed Feb. 22, 2010.
12. Follow-up to the November 2009 early communication about an ongoing safety review of sibutramine, marketed as Meridia. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm198206.htm. Accessed Feb. 21, 2010.
13. Petrochko C. FDA adds cardio warnings to weight-loss drug. MedPage Today Web site. Available at: http://www.medpagetoday.com/tbprint.cfm?tbid=18088?. Accessed Feb. 22, 2010.

New Generic

• Perindopril erbumine tablets (generic Aceon)¹

New Drugs, Indications, Dosage Forms, and Approval Recommendations

• Collagenase clostridium histolytica injection (Xiaflex) has been approved by the FDA for treating the hand disease Dupuytren’s contracture. The agent breaks down excessive collagen in the hand, allowing patients to straighten the arm and have proper use of their fingers. The agent is also being studied to treat Peyronie’s disease.²
• Dalfampridine tablets (Ampyra) have been approved by the FDA to improve walking in patients with multiple sclerosis (MS).³ Seizures might occur in patients who exceed the recommended daily dose of 10 mg twice daily, or in patients with moderate to severe kidney disease. Therefore, caution is advised in these patients.
• Iloperidone tablets (Fanapt) have been approved by the FDA for the acute treatment of schizophrenia in adults.⁴ An atypical antipsychotic, it is a mixed dopamine D2/serotonin 5HT2A receptor antagonist.
• Lamotrigine extended-release tablets (Lamictal XR) have received a new FDA-approved indication for once-daily, add-on therapy for epilepsy in patients 13 years and older, with primary, generalized tonic-clonic seizures.⁵
• Liraglutide (Victoza) has been approved by the FDA as a once-daily injection for the treatment of Type 2 diabetes mellitus.⁶ Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, which is similar to exenatide. There is a label warning related to thyroid tumors that occurred in rats and mice. It is unclear whether medullary thyroid cancer will occur in adults; therefore, the agent should not be used in patients who already have this cancer or those with a family history of thyroid cancer.
• Trazodone extended-release tablets (Oleptro) have been approved by the FDA for treating major depressive disorder in adults.⁷ This product is formulated using Labopharm’s proprietary Contramid long-acting drug delivery system. The product will be available later this year.

Safety Information

• Didanosine (Videx/Videx EC) has undergone a label change in the warning and precautions sections related to the rare but serious complication of noncirrhotic portal hypertension. The label change was added because of the potential severity of portal hypertension, including death from hemorrhaging esophageal varices. A number of well-documented, postmarketing reports of this reaction were made following exclusion of other portal hypertension causes.⁸
• Long-acting beta-agonists (LABAs), formoterol (Foradil), and salmeterol (Sereven) are required to have a risk management strategy (REMS) and a revised medication guide written specifically for patients. The goal is to educate patients about the appropriate use of LABAs. There also is a plan to educate healthcare professionals about the appropriate use of LABAs.^9,10 This update is due to continued analysis of studies that show increased risk of severe asthma exacerbations, which lead to hospitalizations in adult and pediatric patients, including deaths in some LABA-utilizing patients. To safely use LABAs, the following need to be considered:
• Single-ingredient LABAs should not be used as monotherapy; they should only be used in combination with an asthma controller;
• LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controllers;
• Use an LABA for the shortest duration required to achieve asthma control and discontinue it, if possible, once asthma control is achieved. Patients should then be maintained on an asthma controller; and
• Use a combination product containing both an inhaled corticosteroid and an LABA to enhance adherence in pediatric and adolescent patients who require both of these classes to manage their asthma.
• Olanzapine (Zyprexa) has undergone a label change related to its indications for use in adolescents ages ^13-17 for treating schizophrenia and bipolar I disorder (manic or mixed episodes).¹¹ The new label asks providers to consider alternative treatments in this patient population due to the increased potential for weight gain and hyperlipidemia. Additionally, the effectiveness and safety of this agent have not been determined in patients under 13.
• Sibutramine (Meridia), marketed for weight loss, continues to be evaluated for safety.¹² A recent review found it poses an increased risk of heart attack and stroke in patients with a history of cardiovascular disease. Although the product label already had a warning related to use in patients with cardiovascular disease, the manufacturer has added a new contraindication to the sibutramine label for patients with cardiovascular disease and a history of: 1) coronary artery disease; 2) stroke or transient ischemic attack; 3) arrhythmias; 4) congestive heart failure; 5) peripheral arterial disease; and/or 6) uncontrolled hypertension (e.g., >145/90 mmHg). Providers should monitor blood pressure and heart rate regularly. If there is an unremitting increase in blood pressure and/or heart rate, sibutramine should be discontinued. Sibutramine should also be stopped in patients who do not lose at least 5% of their baseline body weight within the first three to six months of treatment.¹³TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

References

1. Lupin receives US FDA approval for Perindopril erbumine tablets. Lupin Web site. Available at: http://www.lupinworld.com/28jan10.htm. Accessed Feb. 22, 2010.
2. US FDA approves Auxilium drug for hand disease. Reuters Web site. Available at: http://www.reuters.com/article/idUSN0211921420100203. Accessed Feb. 22, 2010.
3. Petrochko C. MS walking drug gets FDA nod. MedPage Today Web site. Available at: http://www.medpagetoday.com/Neurology/MultipleSclerosis/18112. Accessed Feb. 22, 2010.
4. Fanapt available for acute schizophrenia. Monthly Prescribing Reference Web site. Available at: http://www.empr.com/fanapt-available-for-acute-schizophrenia/article/160985/. Accessed Feb. 22, 2010.
5. FDA approves once-a-day Lamictal XR as add-on epilepsy therapy for primary generalized tonic-clonic seizures. Available at: http://www.medicalnewstoday.com/articles/177796.php. Accessed Feb. 22, 2010.
6. FDA approves new treatment for Type 2 diabetes. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm198638.htm. Accessed Feb. 22, 2010.
7. Labopharm receives FDA approval for Oleptro. PR Newswire Web site. Available at: http://www.prnewswire.com/news-releases/labopharm-receives-fda-approval-for-oleptrotm-83429037.html. Accessed Feb. 22, 2010.
8. Videx/Videx EC (didanosine): Labeling revision—risk of non-cirrhotic portal hypertension. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm199343.htm. Accessed Feb. 22, 2010.
9. Long-acting beta-agonists (LABAs): new safe use requirements. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm201003.htm. Accessed Feb. 22, 2010.
10. Gever J. FDA says LABA asthma drugs not safe for solo use. MedPage Today Web site. Available at: http://www.medpagetoday.com/tbprint.cfm?tbid=18552. Accessed Feb. 22, 2010.
11. Zyprexa (olanzapine): use in adolescents. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm198402.htm. Accessed Feb. 22, 2010.
12. Follow-up to the November 2009 early communication about an ongoing safety review of sibutramine, marketed as Meridia. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm198206.htm. Accessed Feb. 21, 2010.
13. Petrochko C. FDA adds cardio warnings to weight-loss drug. MedPage Today Web site. Available at: http://www.medpagetoday.com/tbprint.cfm?tbid=18088?. Accessed Feb. 22, 2010.

New Generic

• Perindopril erbumine tablets (generic Aceon)¹

New Drugs, Indications, Dosage Forms, and Approval Recommendations

• Collagenase clostridium histolytica injection (Xiaflex) has been approved by the FDA for treating the hand disease Dupuytren’s contracture. The agent breaks down excessive collagen in the hand, allowing patients to straighten the arm and have proper use of their fingers. The agent is also being studied to treat Peyronie’s disease.²
• Dalfampridine tablets (Ampyra) have been approved by the FDA to improve walking in patients with multiple sclerosis (MS).³ Seizures might occur in patients who exceed the recommended daily dose of 10 mg twice daily, or in patients with moderate to severe kidney disease. Therefore, caution is advised in these patients.
• Iloperidone tablets (Fanapt) have been approved by the FDA for the acute treatment of schizophrenia in adults.⁴ An atypical antipsychotic, it is a mixed dopamine D2/serotonin 5HT2A receptor antagonist.
• Lamotrigine extended-release tablets (Lamictal XR) have received a new FDA-approved indication for once-daily, add-on therapy for epilepsy in patients 13 years and older, with primary, generalized tonic-clonic seizures.⁵
• Liraglutide (Victoza) has been approved by the FDA as a once-daily injection for the treatment of Type 2 diabetes mellitus.⁶ Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, which is similar to exenatide. There is a label warning related to thyroid tumors that occurred in rats and mice. It is unclear whether medullary thyroid cancer will occur in adults; therefore, the agent should not be used in patients who already have this cancer or those with a family history of thyroid cancer.
• Trazodone extended-release tablets (Oleptro) have been approved by the FDA for treating major depressive disorder in adults.⁷ This product is formulated using Labopharm’s proprietary Contramid long-acting drug delivery system. The product will be available later this year.

Safety Information

• Didanosine (Videx/Videx EC) has undergone a label change in the warning and precautions sections related to the rare but serious complication of noncirrhotic portal hypertension. The label change was added because of the potential severity of portal hypertension, including death from hemorrhaging esophageal varices. A number of well-documented, postmarketing reports of this reaction were made following exclusion of other portal hypertension causes.⁸
• Long-acting beta-agonists (LABAs), formoterol (Foradil), and salmeterol (Sereven) are required to have a risk management strategy (REMS) and a revised medication guide written specifically for patients. The goal is to educate patients about the appropriate use of LABAs. There also is a plan to educate healthcare professionals about the appropriate use of LABAs.^9,10 This update is due to continued analysis of studies that show increased risk of severe asthma exacerbations, which lead to hospitalizations in adult and pediatric patients, including deaths in some LABA-utilizing patients. To safely use LABAs, the following need to be considered:
• Single-ingredient LABAs should not be used as monotherapy; they should only be used in combination with an asthma controller;
• LABAs should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controllers;
• Use an LABA for the shortest duration required to achieve asthma control and discontinue it, if possible, once asthma control is achieved. Patients should then be maintained on an asthma controller; and
• Use a combination product containing both an inhaled corticosteroid and an LABA to enhance adherence in pediatric and adolescent patients who require both of these classes to manage their asthma.
• Olanzapine (Zyprexa) has undergone a label change related to its indications for use in adolescents ages ^13-17 for treating schizophrenia and bipolar I disorder (manic or mixed episodes).¹¹ The new label asks providers to consider alternative treatments in this patient population due to the increased potential for weight gain and hyperlipidemia. Additionally, the effectiveness and safety of this agent have not been determined in patients under 13.
• Sibutramine (Meridia), marketed for weight loss, continues to be evaluated for safety.¹² A recent review found it poses an increased risk of heart attack and stroke in patients with a history of cardiovascular disease. Although the product label already had a warning related to use in patients with cardiovascular disease, the manufacturer has added a new contraindication to the sibutramine label for patients with cardiovascular disease and a history of: 1) coronary artery disease; 2) stroke or transient ischemic attack; 3) arrhythmias; 4) congestive heart failure; 5) peripheral arterial disease; and/or 6) uncontrolled hypertension (e.g., >145/90 mmHg). Providers should monitor blood pressure and heart rate regularly. If there is an unremitting increase in blood pressure and/or heart rate, sibutramine should be discontinued. Sibutramine should also be stopped in patients who do not lose at least 5% of their baseline body weight within the first three to six months of treatment.¹³TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

References

1. Lupin receives US FDA approval for Perindopril erbumine tablets. Lupin Web site. Available at: http://www.lupinworld.com/28jan10.htm. Accessed Feb. 22, 2010.
2. US FDA approves Auxilium drug for hand disease. Reuters Web site. Available at: http://www.reuters.com/article/idUSN0211921420100203. Accessed Feb. 22, 2010.
3. Petrochko C. MS walking drug gets FDA nod. MedPage Today Web site. Available at: http://www.medpagetoday.com/Neurology/MultipleSclerosis/18112. Accessed Feb. 22, 2010.
4. Fanapt available for acute schizophrenia. Monthly Prescribing Reference Web site. Available at: http://www.empr.com/fanapt-available-for-acute-schizophrenia/article/160985/. Accessed Feb. 22, 2010.
5. FDA approves once-a-day Lamictal XR as add-on epilepsy therapy for primary generalized tonic-clonic seizures. Available at: http://www.medicalnewstoday.com/articles/177796.php. Accessed Feb. 22, 2010.
6. FDA approves new treatment for Type 2 diabetes. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm198638.htm. Accessed Feb. 22, 2010.
7. Labopharm receives FDA approval for Oleptro. PR Newswire Web site. Available at: http://www.prnewswire.com/news-releases/labopharm-receives-fda-approval-for-oleptrotm-83429037.html. Accessed Feb. 22, 2010.
8. Videx/Videx EC (didanosine): Labeling revision—risk of non-cirrhotic portal hypertension. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm199343.htm. Accessed Feb. 22, 2010.
9. Long-acting beta-agonists (LABAs): new safe use requirements. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm201003.htm. Accessed Feb. 22, 2010.
10. Gever J. FDA says LABA asthma drugs not safe for solo use. MedPage Today Web site. Available at: http://www.medpagetoday.com/tbprint.cfm?tbid=18552. Accessed Feb. 22, 2010.
11. Zyprexa (olanzapine): use in adolescents. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm198402.htm. Accessed Feb. 22, 2010.
12. Follow-up to the November 2009 early communication about an ongoing safety review of sibutramine, marketed as Meridia. U.S. Food and Drug Administration Web site. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm198206.htm. Accessed Feb. 21, 2010.
13. Petrochko C. FDA adds cardio warnings to weight-loss drug. MedPage Today Web site. Available at: http://www.medpagetoday.com/tbprint.cfm?tbid=18088?. Accessed Feb. 22, 2010.

In This Edition

Literature at a Glance

A guide to this month’s studies

• ICU volume and outcomes
• Bicarbonate and contrast-induced nephropathy
• Rate of incidental findings in chest CT angiography
• Consequences of adverse-event reporting by physicians
• Hip fracture comanagement
• Niacin vs. ezetimibe in atherosclerosis
• Effect of hospital pharmacists on readmission rates
• Antibiotics in acute exacerbations of COPD

Higher Patient ICU Inflow Volumes Are Associated with Unplanned Readmissions to ICU

Clinical question: Do higher rates of unplanned ICU readmissions occur on days with high patient inflow volumes?

Background: Patients readmitted to ICUs have longer lengths of stay (LOS) and higher rates of in-hospital mortality. Previous studies suggest many ICU readmissions might be due to premature discharge, but there is little evidence evaluating the impact of patient inflow volumes on the incidence of ICU readmissions.

Study design: Retrospective, cohort study.

Setting: Large, urban, tertiary-care academic medical center in Baltimore.

Synopsis: A retrospective review of 3,233 discharges from a neurosciences critical-care unit revealed 95 unplanned readmissions to the ICU setting within 72 hours of discharge to lower level of care. The odds of one or more discharges becoming an unplanned readmission became significantly higher on days when ≥8 patients were admitted to the ICU (OR, 1.66; 95% CI, 1.03-2.68), and the odds of an unplanned readmission were almost five times higher on days when ≥10 patients were admitted, compared with days when ≤9 patients were admitted (OR, 4.99; 95% CI, 2.45-10.17).

After adjusting for patient complexity, patients discharged on days with ≥10 admissions had higher than twice the odds of becoming an unplanned readmission than patients discharged on days with ≤9 admissions (OR, 2.34; 95% CI, 1.27-4.34).

This study was limited to patients in a neurosciences critical-care unit at a single academic medical center. Further research is needed to better understand how high admission volumes lead to increased unplanned readmission rates.

Bottom line: Days with high patient inflow volumes to the ICU are associated with higher rates of unplanned readmissions to the ICU, and the rate of unplanned readmissions becomes significant once a daily threshold of eight admissions is reached.

Citation: Baker DR, Pronovost PJ, Morlock LL, Geocadin RG, Holzmueller CG. Patient flow variability and unplanned readmissions to an intensive care unit. Crit Care Med. 2009;37(11):2882-2887.

Effectiveness of Sodium Bicarbonate in Contrast-Induced Nephropathy Prevention

Clinical question: Is IV sodium bicarbonate effective for prevention of contrast-induced nephropathy (CIN) in high-risk patients?

Background: CIN is a leading cause of acute kidney injury in the hospital setting. Some studies have suggested IV sodium bicarbonate might reduce risk for CIN; other studies challenge this conclusion.

Study design: Systematic review.

Setting: Published and unpublished randomized, controlled trials performed worldwide.

Synopsis: The research examined in this study was composed of randomized, controlled trials that investigated CIN prevention and included IV sodium bicarbonate in one of the treatment groups. Nine published and 15 unpublished trials were selected for a total of 3,563 patients studied. The overall pooled relative risk of CIN in patients treated with IV sodium bicarbonate compared with normal saline was 0.62 (95% CI, 0.45-0.86), though the strength of this evidence was questioned.

Significant heterogeneity across studies was found (I²=49.1%; P=0.004), partially related to substantially greater treatment effect in published (RR 0.43, 95% CI, 0.25-0.75) versus unpublished (RR 0.78, 95% CI, 0.52-1.17) studies. Publication bias was confirmed statistically. Among the published studies, greater treatment effect favoring bicarbonate over saline tended to be reported in those published before 2008, had fewer patients (<200) and events (<15), had measured events within 48 hours, and were studies of lower quality.

No effects regarding the risk of heart failure, the need for dialysis, or mortality were found, though the studies were not specifically designed to investigate those clinical outcomes. Larger studies are needed to better assess these questions.

Bottom line: IV sodium bicarbonate for CIN prevention in high-risk patients could be less effective than previous reports have suggested.

Citation: Zoungas S, Ninomiya T, Huxley R, et al. Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. Ann Intern Med. 2009;151(9):631-638.

Incidental Findings More Frequent than PE in Chest CT Angiograms

Clinical question: What is the prevalence of incidental findings on chest-computed tomographic angiograms (CTAs) ordered by an ED to evaluate for pulmonary embolism (PE)?

Background: CTAs commonly are ordered by ED physicians to assess for PE. While CTAs might yield findings to support an alternate diagnosis to PE, incidental findings might be found that often require further radiographic or clinical followup. The workup of these incidental findings can be burdensome and low-yield.

Study design: Retrospective chart review.

Setting: Single, academic, tertiary-care hospital in North Carolina.

Synopsis: All patients who underwent CTA evaluation for PE in the ED over two enrollment periods were selected; radiographic findings were compiled and their medical records reviewed. Fifty-five of 589 CTAs (9%) were positive for PE. New incidental findings requiring radiographic or clinical followup were found in 141 cases (24%).

Overall, pulmonary nodules were most common, requiring followup in 73 (13%) cases. Adenopathy requiring followup was seen in 51 cases (9%), and new masses requiring followup were found in 12 cases (2%). Findings to support alternate diagnoses for shortness of breath, hypoxemia, or tachycardia were found in 195 patients (33%), most commonly pleural effusion (19%) and infiltrates (11%). Other incidental findings that required less-urgent clinical attention were common with 615 total findings, most frequently nonmalignant bone findings in 144 cases (24%), mild dependent atelectasis in 137 cases (23%), and emphysema in 69 cases (12%).

Bottom line: Incidental findings requiring followup were more than twice as common as PE (24% vs. 9%) in CTAs ordered to evaluate for PE in an ED.

Citation: Hall WB, Truitt SG, Scheunemann LP, et al. The prevalence of clinically relevant incidental findings on chest computed tomographic angiograms ordered to diagnose pulmonary embolism. Arch Intern Med. 2009;169(21):1961-1965.

Patients Don’t Penalize for Adverse-Outcome Disclosure

Clinical question: What patient or clinical characteristics affect the likelihood of physician reporting of an adverse outcome, and how does adverse-outcome disclosure affect patient perceptions of quality of care?

Background: Harmful adverse events (AE), injuries caused by medical management rather than by the underlying condition of the patient, are common in the U.S. Previous studies have focused on physician and provider attitudes about disclosure. Little is known about how characteristics of the AE affect disclosure, and how disclosure affects patients’ perceptions of quality of care.

Study design: Retrospective cohort study.

Setting: Acute-care hospitals in Massachusetts.

Synopsis: Of 4,143 eligible patients, 2,582 (62%) agreed to a telephone interview that asked about patient experiences with adverse events during their hospital stay. Respondents reporting an AE were asked about disclosure by medical staff, effects of adverse events on their hospital course, and the quality of their hospital care.

Of the 845 AEs reported by 608 patients, only 40% were disclosed, defined as “anyone from the hospital explaining why the negative effects occurred.” The majority of the AEs were related to newly prescribed medications (40%) and surgical procedures (34%). Researchers determined that 31% of the AEs were preventable and 75% were severe. In multivariate analysis, disclosure was less likely if the AE was preventable or if patients had long-term effects from the AE. Patients with an AE were more likely to rate the quality of their hospitalization higher if there had been disclosure.

Bottom line: Disclosure of adverse events by medical personnel is low (40%) in hospitalized patients, even though disclosure of adverse events increases patients’ ratings of quality of care.

Citation: López L, Weismann JS, Schneider EC, Weingart SN, Cohen AP, Epstein AM. Disclosure of hospital adverse events and its association with patients’ ratings of the quality of care. Arch Intern Med. 2009;169(20):1888-1894.

Comanagement of Hip-Fracture Patients by Geriatricians Decreases Time to Surgery, LOS, and Complications

Clinical question: Does comanagement of hip-fracture patients by geriatricians and orthopedic surgeons improve short-term outcomes?

Background: Hip fractures in older adults are associated with considerable morbidity and mortality. A model at a single center, where hip fracture patients are comanaged by geriatricians and orthopedic surgeons, demonstrated decreased LOS, readmission rates, and mortality when compared with national data. This study compares results to a usual-care site.

Study design: Retrospective cohort study.

Setting: Community-based teaching hospital and a tertiary-care hospital in Rochester, N.Y.

Synopsis: Researchers enrolled 314 patients with hip fractures. The 193 patients in the intervention group were comanaged by geriatricians and orthopedic surgeons. The 121 patients in the usual-care group were admitted under the care of orthopedic surgeons, and hospitalists were consulted when deemed necessary. Retrospective chart reviews were performed; complications were defined a priori.

When compared with usual care, patients in the intervention group had significantly shorter times to surgery (24.1 hours vs. 37.4 hours), shorter LOS (4.6 days vs. 8.3 days), fewer complications (30.6% vs. 46.3%), including fewer postoperative infections (2.3% vs. 19.8%), cardiac complications (1.0% vs. 7.4%), cases of thromboembolism (0.5% vs. 5.0%), episodes of bleeding (0% vs. 3.3%), and episodes of hypoxia (6.7% vs. 14.1%). There was no difference in inpatient mortality or 30-day readmission rates.

Further assessment comanagement by hospitalists and comanagement by geriatricians is needed.

Bottom line: Perioperative comanagement of hip-fracture patients by geriatricians and orthopedic surgeons significantly improves short-term outcomes.

Citation: Friedman SM, Mendelson DA, Bingham KW, Kates SL. Impact of a comanaged geriatric fracture center on short-term hip fracture outcomes. Arch Intern Med. 2009;169 (18):1712-1717.

Niacin Is Superior to Ezetimibe in Causing Significant Regression of Carotid Intima-Media Thickness when Combined with a Statin

Clinical question: Is ezetimibe superior to niacin for reducing carotid intima-media thickness (CIMT) in patients with coronary artery disease (CAD) already on statin monotherapy?

Background: Statin montherapy significantly reduces the risk of cardiovascular events, and further lowering of this risk can be achieved by reducing the LDL, using statin intensification, or adding ezetimibe, or by raising the HDL levels by adding niacin therapy. This comparative-effectiveness trial compared the efficacy of these two approaches.

Study design: Prospective, randomized, parallel-group, open-label study.

Setting: Tertiary-care military medical center, and private tertiary-care hospital in Washington, D.C.

Synopsis: Three hundred sixty-three patients with known CAD or CAD equivalent were enrolled, and all of the patients were maintained on statin therapy with LDL <100 and HDL <50. Patients were randomized to ezetimibe 10 mg/day or niacin, starting at 500 mg at bedtime and titrated to 2 g/day. Primary endpoint was a mean change in CIMT after 14 months. Secondary endpoints were change in lipid levels, composite of major cardiovascular events, drug discontinuation, and quality of life.

The trial was terminated early after 208 patients had completed the trial. Although ezetimibe showed greater reduction of LDL, niacin showed significantly greater reduction in the progression of CIMT. Patients receiving niacin experienced fewer cardiovascular events (1% vs. 5%) but had higher rates of withdrawal (15% vs. 9%) due to flushing.

Limitations of the study are small sample size, short follow-up period, and use of CIMT as a surrogate marker for clinical endpoint.

Bottom line: Niacin is superior to ezetimibe in reducing CIMT and raising HDL levels and might be more efficacious in reducing cardiovascular risk.

Citation: Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361(22):2113-2122.

Pharmacist-Facilitated Hospital Discharge Program Didn’t Reduce Post-Discharge Healthcare Resource Utilization

Clinical question: Does pharmacist-facilitated hospital discharge reduce hospital readmission rates?

Background: Medication discrepancies at the time of discharge often lead to confusion, medical errors, and readmission to the hospital. Patients who are at high risk of medication errors often are on multiple medications and experience adverse drug events upon discharge.

Study design: Prospective cohort study.

Setting: Tertiary-care, academic teaching hospital in Michigan.

Synopsis: One pharmacist alternated between the resident service and hospitalist service every month. The pharmacist monitored the patients being discharged for appropriateness and accuracy of medications. The pharmacist assessed medication therapy, reconciled medications, screened for adherence concerns, counseled and educated patients, and performed post-discharge telephone follow-up.

Primary outcomes were ED visits within 72 hours and readmission rates by day 14 and day 30.

The study found high numbers of medication discrepancies in the control (33.5%) and intervention (59.6%) groups, and these discrepancies were resolved prior to discharge; however, there was no significant impact on post-discharge ED visits, or 14- and 30-day readmission rates. Post-discharge telephone calls reduced 14-day readmission rates.

Bottom line: Pharmacist-facilitated hospital discharge did not significantly reduce post-discharge ED visits or readmissions.

Citation: Walker PC, Bernstein SJ, Jones JN, et al. Impact of a pharmacist-facilitated hospital discharge program. Arch Intern Med. 2009;169(21):2003-2010.

Questionable Antibiotic Benefit for Patients with Acute COPD Exacerbations

Clinical question: Does the addition of antibiotics to systemic corticosteroids provide additional benefits for patients hospitalized with acute exacerbations of chronic obstructive pulmonary disease (AECOPD)?

Background: The role of antibiotics in the treatment of AECOPD is unclear, particularly in addition to systemic corticosteroids. Many of the studies demonstrating the benefit of antibiotics were conducted several decades before systemic steroids were used routinely for the treatment of AECOPD.

Study design: Randomized, double-blinded, placebo-controlled study.

Setting: Two academic teaching hospitals in the Netherlands.

Synopsis: Two hundred sixty-five acute exacerbations of COPD were enrolled in the study, and patients were randomized to a seven-day course of 200 mg/day of doxycycline or placebo. All patients received systemic corticosteroids, nebulized bronchodilator therapy, and physiotherapy. The study found that doxycycline was equivalent to placebo for the primary endpoint of clinical success on day 30; however, doxycycline was superior to placebo for secondary outcomes of clinical success, clinical cure, symptomatic improvement, microbiological success, and reducing open label antibiotic use on day 10, but not on day 30.

Because the population studied had low levels of advanced antimicrobial resistance, the findings might not be generalizable. Results suggested a difference of treatment effect between subgroups based on C-reactive protein values, but further research is needed.

Bottom line: Patients treated with doxycycline for acute exacerbation of COPD had improved clinical outcomes at day 10, but the benefits were not significant at day 30. Data are still equivocal regarding benefits of antibiotics in patients with acute exacerbations of COPD.

Citation: Daniels JM, Snijders D, de Graaff CS, Vlaspolder F, Jansen HM, Boersma WG. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181(2):150-157. TH

PEDIATRIC HM LITERATURE

By Mark Shen, MD

Reviewed by Pediatric Editor Mark Shen, MD, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Less Is More in the Management of Acute Gastroenteritis

Clinical question: What is the effect of a guideline-training program for pediatricians on the management of acute gastroenteritis (AGE)?

Background: Guidelines recommending oral rehydration, early refeeding, and limited interventions have been developed for AGE management, but uptake by pediatricians has been slow. While individual components of these guidelines have been shown to be effective in comparison to other resource-intensive interventions, outcomes of global guideline implementation have not been studied well.

Study design: Prospective, randomized, controlled trial.

Setting: One hundred forty-nine primary-care pediatricians in Italy.

Synopsis: Pediatricians from the Italian national healthcare system were randomized to AGE guideline training or no training (usual practice; control group). The physicians enrolled 1,309 children in the study. Parents completed daily forms documenting the interventions for, and outcomes of, each illness.

Management by the trained group of pediatricians was in full compliance with the guidelines 66% of the time, as opposed to 33% of the time in the untrained group.

Significant differences between the groups were noted for each basic tenet of the guidelines: oral rehydration use, restrictive diets, medication use, and microbiologic testing. Notably, by both intention-to-treat and per-protocol analysis, the mean duration of diarrhea was shorter in children managed by the trained group of pediatricians.

As underadherence to evidence-based guidelines remains commonplace, effective implementation will become a greater area of focus. Despite a modest effect in an ambulatory population, these investigators demonstrated a clear improvement in outcomes with a simple, two-hour training program. While not studied, it is likely that the cost of care was significantly lower in the guideline group, given the dramatic differences in medication use and testing.

Bottom line: Effective implementation of AGE guidelines will improve outcomes and reduce costs.

Citation: Albano F, Lo Vecchio A, Guarino A. The applicability and efficacy of guidelines for the management of acute gastroenteritis in outpatient children: a field-randomized trial on primary care pediatricians. J Pediatr. 2010;156(2):226-230.

In This Edition

Literature at a Glance

A guide to this month’s studies

• ICU volume and outcomes
• Bicarbonate and contrast-induced nephropathy
• Rate of incidental findings in chest CT angiography
• Consequences of adverse-event reporting by physicians
• Hip fracture comanagement
• Niacin vs. ezetimibe in atherosclerosis
• Effect of hospital pharmacists on readmission rates
• Antibiotics in acute exacerbations of COPD

Higher Patient ICU Inflow Volumes Are Associated with Unplanned Readmissions to ICU

Clinical question: Do higher rates of unplanned ICU readmissions occur on days with high patient inflow volumes?

Background: Patients readmitted to ICUs have longer lengths of stay (LOS) and higher rates of in-hospital mortality. Previous studies suggest many ICU readmissions might be due to premature discharge, but there is little evidence evaluating the impact of patient inflow volumes on the incidence of ICU readmissions.

Study design: Retrospective, cohort study.

Setting: Large, urban, tertiary-care academic medical center in Baltimore.

Synopsis: A retrospective review of 3,233 discharges from a neurosciences critical-care unit revealed 95 unplanned readmissions to the ICU setting within 72 hours of discharge to lower level of care. The odds of one or more discharges becoming an unplanned readmission became significantly higher on days when ≥8 patients were admitted to the ICU (OR, 1.66; 95% CI, 1.03-2.68), and the odds of an unplanned readmission were almost five times higher on days when ≥10 patients were admitted, compared with days when ≤9 patients were admitted (OR, 4.99; 95% CI, 2.45-10.17).

After adjusting for patient complexity, patients discharged on days with ≥10 admissions had higher than twice the odds of becoming an unplanned readmission than patients discharged on days with ≤9 admissions (OR, 2.34; 95% CI, 1.27-4.34).

This study was limited to patients in a neurosciences critical-care unit at a single academic medical center. Further research is needed to better understand how high admission volumes lead to increased unplanned readmission rates.

Bottom line: Days with high patient inflow volumes to the ICU are associated with higher rates of unplanned readmissions to the ICU, and the rate of unplanned readmissions becomes significant once a daily threshold of eight admissions is reached.

Citation: Baker DR, Pronovost PJ, Morlock LL, Geocadin RG, Holzmueller CG. Patient flow variability and unplanned readmissions to an intensive care unit. Crit Care Med. 2009;37(11):2882-2887.

Effectiveness of Sodium Bicarbonate in Contrast-Induced Nephropathy Prevention

Clinical question: Is IV sodium bicarbonate effective for prevention of contrast-induced nephropathy (CIN) in high-risk patients?

Background: CIN is a leading cause of acute kidney injury in the hospital setting. Some studies have suggested IV sodium bicarbonate might reduce risk for CIN; other studies challenge this conclusion.

Study design: Systematic review.

Setting: Published and unpublished randomized, controlled trials performed worldwide.

Synopsis: The research examined in this study was composed of randomized, controlled trials that investigated CIN prevention and included IV sodium bicarbonate in one of the treatment groups. Nine published and 15 unpublished trials were selected for a total of 3,563 patients studied. The overall pooled relative risk of CIN in patients treated with IV sodium bicarbonate compared with normal saline was 0.62 (95% CI, 0.45-0.86), though the strength of this evidence was questioned.

Significant heterogeneity across studies was found (I²=49.1%; P=0.004), partially related to substantially greater treatment effect in published (RR 0.43, 95% CI, 0.25-0.75) versus unpublished (RR 0.78, 95% CI, 0.52-1.17) studies. Publication bias was confirmed statistically. Among the published studies, greater treatment effect favoring bicarbonate over saline tended to be reported in those published before 2008, had fewer patients (<200) and events (<15), had measured events within 48 hours, and were studies of lower quality.

No effects regarding the risk of heart failure, the need for dialysis, or mortality were found, though the studies were not specifically designed to investigate those clinical outcomes. Larger studies are needed to better assess these questions.

Bottom line: IV sodium bicarbonate for CIN prevention in high-risk patients could be less effective than previous reports have suggested.

Citation: Zoungas S, Ninomiya T, Huxley R, et al. Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. Ann Intern Med. 2009;151(9):631-638.

Incidental Findings More Frequent than PE in Chest CT Angiograms

Clinical question: What is the prevalence of incidental findings on chest-computed tomographic angiograms (CTAs) ordered by an ED to evaluate for pulmonary embolism (PE)?

Background: CTAs commonly are ordered by ED physicians to assess for PE. While CTAs might yield findings to support an alternate diagnosis to PE, incidental findings might be found that often require further radiographic or clinical followup. The workup of these incidental findings can be burdensome and low-yield.

Study design: Retrospective chart review.

Setting: Single, academic, tertiary-care hospital in North Carolina.

Synopsis: All patients who underwent CTA evaluation for PE in the ED over two enrollment periods were selected; radiographic findings were compiled and their medical records reviewed. Fifty-five of 589 CTAs (9%) were positive for PE. New incidental findings requiring radiographic or clinical followup were found in 141 cases (24%).

Overall, pulmonary nodules were most common, requiring followup in 73 (13%) cases. Adenopathy requiring followup was seen in 51 cases (9%), and new masses requiring followup were found in 12 cases (2%). Findings to support alternate diagnoses for shortness of breath, hypoxemia, or tachycardia were found in 195 patients (33%), most commonly pleural effusion (19%) and infiltrates (11%). Other incidental findings that required less-urgent clinical attention were common with 615 total findings, most frequently nonmalignant bone findings in 144 cases (24%), mild dependent atelectasis in 137 cases (23%), and emphysema in 69 cases (12%).

Bottom line: Incidental findings requiring followup were more than twice as common as PE (24% vs. 9%) in CTAs ordered to evaluate for PE in an ED.

Citation: Hall WB, Truitt SG, Scheunemann LP, et al. The prevalence of clinically relevant incidental findings on chest computed tomographic angiograms ordered to diagnose pulmonary embolism. Arch Intern Med. 2009;169(21):1961-1965.

Patients Don’t Penalize for Adverse-Outcome Disclosure

Clinical question: What patient or clinical characteristics affect the likelihood of physician reporting of an adverse outcome, and how does adverse-outcome disclosure affect patient perceptions of quality of care?

Background: Harmful adverse events (AE), injuries caused by medical management rather than by the underlying condition of the patient, are common in the U.S. Previous studies have focused on physician and provider attitudes about disclosure. Little is known about how characteristics of the AE affect disclosure, and how disclosure affects patients’ perceptions of quality of care.

Study design: Retrospective cohort study.

Setting: Acute-care hospitals in Massachusetts.

Synopsis: Of 4,143 eligible patients, 2,582 (62%) agreed to a telephone interview that asked about patient experiences with adverse events during their hospital stay. Respondents reporting an AE were asked about disclosure by medical staff, effects of adverse events on their hospital course, and the quality of their hospital care.

Of the 845 AEs reported by 608 patients, only 40% were disclosed, defined as “anyone from the hospital explaining why the negative effects occurred.” The majority of the AEs were related to newly prescribed medications (40%) and surgical procedures (34%). Researchers determined that 31% of the AEs were preventable and 75% were severe. In multivariate analysis, disclosure was less likely if the AE was preventable or if patients had long-term effects from the AE. Patients with an AE were more likely to rate the quality of their hospitalization higher if there had been disclosure.

Bottom line: Disclosure of adverse events by medical personnel is low (40%) in hospitalized patients, even though disclosure of adverse events increases patients’ ratings of quality of care.

Citation: López L, Weismann JS, Schneider EC, Weingart SN, Cohen AP, Epstein AM. Disclosure of hospital adverse events and its association with patients’ ratings of the quality of care. Arch Intern Med. 2009;169(20):1888-1894.

Comanagement of Hip-Fracture Patients by Geriatricians Decreases Time to Surgery, LOS, and Complications

Clinical question: Does comanagement of hip-fracture patients by geriatricians and orthopedic surgeons improve short-term outcomes?

Background: Hip fractures in older adults are associated with considerable morbidity and mortality. A model at a single center, where hip fracture patients are comanaged by geriatricians and orthopedic surgeons, demonstrated decreased LOS, readmission rates, and mortality when compared with national data. This study compares results to a usual-care site.

Study design: Retrospective cohort study.

Setting: Community-based teaching hospital and a tertiary-care hospital in Rochester, N.Y.

Synopsis: Researchers enrolled 314 patients with hip fractures. The 193 patients in the intervention group were comanaged by geriatricians and orthopedic surgeons. The 121 patients in the usual-care group were admitted under the care of orthopedic surgeons, and hospitalists were consulted when deemed necessary. Retrospective chart reviews were performed; complications were defined a priori.

When compared with usual care, patients in the intervention group had significantly shorter times to surgery (24.1 hours vs. 37.4 hours), shorter LOS (4.6 days vs. 8.3 days), fewer complications (30.6% vs. 46.3%), including fewer postoperative infections (2.3% vs. 19.8%), cardiac complications (1.0% vs. 7.4%), cases of thromboembolism (0.5% vs. 5.0%), episodes of bleeding (0% vs. 3.3%), and episodes of hypoxia (6.7% vs. 14.1%). There was no difference in inpatient mortality or 30-day readmission rates.

Further assessment comanagement by hospitalists and comanagement by geriatricians is needed.

Bottom line: Perioperative comanagement of hip-fracture patients by geriatricians and orthopedic surgeons significantly improves short-term outcomes.

Citation: Friedman SM, Mendelson DA, Bingham KW, Kates SL. Impact of a comanaged geriatric fracture center on short-term hip fracture outcomes. Arch Intern Med. 2009;169 (18):1712-1717.

Niacin Is Superior to Ezetimibe in Causing Significant Regression of Carotid Intima-Media Thickness when Combined with a Statin

Clinical question: Is ezetimibe superior to niacin for reducing carotid intima-media thickness (CIMT) in patients with coronary artery disease (CAD) already on statin monotherapy?

Background: Statin montherapy significantly reduces the risk of cardiovascular events, and further lowering of this risk can be achieved by reducing the LDL, using statin intensification, or adding ezetimibe, or by raising the HDL levels by adding niacin therapy. This comparative-effectiveness trial compared the efficacy of these two approaches.

Study design: Prospective, randomized, parallel-group, open-label study.

Setting: Tertiary-care military medical center, and private tertiary-care hospital in Washington, D.C.

Synopsis: Three hundred sixty-three patients with known CAD or CAD equivalent were enrolled, and all of the patients were maintained on statin therapy with LDL <100 and HDL <50. Patients were randomized to ezetimibe 10 mg/day or niacin, starting at 500 mg at bedtime and titrated to 2 g/day. Primary endpoint was a mean change in CIMT after 14 months. Secondary endpoints were change in lipid levels, composite of major cardiovascular events, drug discontinuation, and quality of life.

The trial was terminated early after 208 patients had completed the trial. Although ezetimibe showed greater reduction of LDL, niacin showed significantly greater reduction in the progression of CIMT. Patients receiving niacin experienced fewer cardiovascular events (1% vs. 5%) but had higher rates of withdrawal (15% vs. 9%) due to flushing.

Limitations of the study are small sample size, short follow-up period, and use of CIMT as a surrogate marker for clinical endpoint.

Bottom line: Niacin is superior to ezetimibe in reducing CIMT and raising HDL levels and might be more efficacious in reducing cardiovascular risk.

Citation: Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361(22):2113-2122.

Pharmacist-Facilitated Hospital Discharge Program Didn’t Reduce Post-Discharge Healthcare Resource Utilization

Clinical question: Does pharmacist-facilitated hospital discharge reduce hospital readmission rates?

Background: Medication discrepancies at the time of discharge often lead to confusion, medical errors, and readmission to the hospital. Patients who are at high risk of medication errors often are on multiple medications and experience adverse drug events upon discharge.

Study design: Prospective cohort study.

Setting: Tertiary-care, academic teaching hospital in Michigan.

Synopsis: One pharmacist alternated between the resident service and hospitalist service every month. The pharmacist monitored the patients being discharged for appropriateness and accuracy of medications. The pharmacist assessed medication therapy, reconciled medications, screened for adherence concerns, counseled and educated patients, and performed post-discharge telephone follow-up.

Primary outcomes were ED visits within 72 hours and readmission rates by day 14 and day 30.

The study found high numbers of medication discrepancies in the control (33.5%) and intervention (59.6%) groups, and these discrepancies were resolved prior to discharge; however, there was no significant impact on post-discharge ED visits, or 14- and 30-day readmission rates. Post-discharge telephone calls reduced 14-day readmission rates.

Bottom line: Pharmacist-facilitated hospital discharge did not significantly reduce post-discharge ED visits or readmissions.

Citation: Walker PC, Bernstein SJ, Jones JN, et al. Impact of a pharmacist-facilitated hospital discharge program. Arch Intern Med. 2009;169(21):2003-2010.

Questionable Antibiotic Benefit for Patients with Acute COPD Exacerbations

Clinical question: Does the addition of antibiotics to systemic corticosteroids provide additional benefits for patients hospitalized with acute exacerbations of chronic obstructive pulmonary disease (AECOPD)?

Background: The role of antibiotics in the treatment of AECOPD is unclear, particularly in addition to systemic corticosteroids. Many of the studies demonstrating the benefit of antibiotics were conducted several decades before systemic steroids were used routinely for the treatment of AECOPD.

Study design: Randomized, double-blinded, placebo-controlled study.

Setting: Two academic teaching hospitals in the Netherlands.

Synopsis: Two hundred sixty-five acute exacerbations of COPD were enrolled in the study, and patients were randomized to a seven-day course of 200 mg/day of doxycycline or placebo. All patients received systemic corticosteroids, nebulized bronchodilator therapy, and physiotherapy. The study found that doxycycline was equivalent to placebo for the primary endpoint of clinical success on day 30; however, doxycycline was superior to placebo for secondary outcomes of clinical success, clinical cure, symptomatic improvement, microbiological success, and reducing open label antibiotic use on day 10, but not on day 30.

Because the population studied had low levels of advanced antimicrobial resistance, the findings might not be generalizable. Results suggested a difference of treatment effect between subgroups based on C-reactive protein values, but further research is needed.

Bottom line: Patients treated with doxycycline for acute exacerbation of COPD had improved clinical outcomes at day 10, but the benefits were not significant at day 30. Data are still equivocal regarding benefits of antibiotics in patients with acute exacerbations of COPD.

Citation: Daniels JM, Snijders D, de Graaff CS, Vlaspolder F, Jansen HM, Boersma WG. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181(2):150-157. TH

PEDIATRIC HM LITERATURE

By Mark Shen, MD

Reviewed by Pediatric Editor Mark Shen, MD, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Less Is More in the Management of Acute Gastroenteritis

Clinical question: What is the effect of a guideline-training program for pediatricians on the management of acute gastroenteritis (AGE)?

Background: Guidelines recommending oral rehydration, early refeeding, and limited interventions have been developed for AGE management, but uptake by pediatricians has been slow. While individual components of these guidelines have been shown to be effective in comparison to other resource-intensive interventions, outcomes of global guideline implementation have not been studied well.

Study design: Prospective, randomized, controlled trial.

Setting: One hundred forty-nine primary-care pediatricians in Italy.

Synopsis: Pediatricians from the Italian national healthcare system were randomized to AGE guideline training or no training (usual practice; control group). The physicians enrolled 1,309 children in the study. Parents completed daily forms documenting the interventions for, and outcomes of, each illness.

Management by the trained group of pediatricians was in full compliance with the guidelines 66% of the time, as opposed to 33% of the time in the untrained group.

Significant differences between the groups were noted for each basic tenet of the guidelines: oral rehydration use, restrictive diets, medication use, and microbiologic testing. Notably, by both intention-to-treat and per-protocol analysis, the mean duration of diarrhea was shorter in children managed by the trained group of pediatricians.

As underadherence to evidence-based guidelines remains commonplace, effective implementation will become a greater area of focus. Despite a modest effect in an ambulatory population, these investigators demonstrated a clear improvement in outcomes with a simple, two-hour training program. While not studied, it is likely that the cost of care was significantly lower in the guideline group, given the dramatic differences in medication use and testing.

Bottom line: Effective implementation of AGE guidelines will improve outcomes and reduce costs.

Citation: Albano F, Lo Vecchio A, Guarino A. The applicability and efficacy of guidelines for the management of acute gastroenteritis in outpatient children: a field-randomized trial on primary care pediatricians. J Pediatr. 2010;156(2):226-230.

In This Edition

Literature at a Glance

A guide to this month’s studies

• ICU volume and outcomes
• Bicarbonate and contrast-induced nephropathy
• Rate of incidental findings in chest CT angiography
• Consequences of adverse-event reporting by physicians
• Hip fracture comanagement
• Niacin vs. ezetimibe in atherosclerosis
• Effect of hospital pharmacists on readmission rates
• Antibiotics in acute exacerbations of COPD

Higher Patient ICU Inflow Volumes Are Associated with Unplanned Readmissions to ICU

Clinical question: Do higher rates of unplanned ICU readmissions occur on days with high patient inflow volumes?

Background: Patients readmitted to ICUs have longer lengths of stay (LOS) and higher rates of in-hospital mortality. Previous studies suggest many ICU readmissions might be due to premature discharge, but there is little evidence evaluating the impact of patient inflow volumes on the incidence of ICU readmissions.

Study design: Retrospective, cohort study.

Setting: Large, urban, tertiary-care academic medical center in Baltimore.

Synopsis: A retrospective review of 3,233 discharges from a neurosciences critical-care unit revealed 95 unplanned readmissions to the ICU setting within 72 hours of discharge to lower level of care. The odds of one or more discharges becoming an unplanned readmission became significantly higher on days when ≥8 patients were admitted to the ICU (OR, 1.66; 95% CI, 1.03-2.68), and the odds of an unplanned readmission were almost five times higher on days when ≥10 patients were admitted, compared with days when ≤9 patients were admitted (OR, 4.99; 95% CI, 2.45-10.17).

After adjusting for patient complexity, patients discharged on days with ≥10 admissions had higher than twice the odds of becoming an unplanned readmission than patients discharged on days with ≤9 admissions (OR, 2.34; 95% CI, 1.27-4.34).

This study was limited to patients in a neurosciences critical-care unit at a single academic medical center. Further research is needed to better understand how high admission volumes lead to increased unplanned readmission rates.

Bottom line: Days with high patient inflow volumes to the ICU are associated with higher rates of unplanned readmissions to the ICU, and the rate of unplanned readmissions becomes significant once a daily threshold of eight admissions is reached.

Citation: Baker DR, Pronovost PJ, Morlock LL, Geocadin RG, Holzmueller CG. Patient flow variability and unplanned readmissions to an intensive care unit. Crit Care Med. 2009;37(11):2882-2887.

Effectiveness of Sodium Bicarbonate in Contrast-Induced Nephropathy Prevention

Clinical question: Is IV sodium bicarbonate effective for prevention of contrast-induced nephropathy (CIN) in high-risk patients?

Background: CIN is a leading cause of acute kidney injury in the hospital setting. Some studies have suggested IV sodium bicarbonate might reduce risk for CIN; other studies challenge this conclusion.

Study design: Systematic review.

Setting: Published and unpublished randomized, controlled trials performed worldwide.

Synopsis: The research examined in this study was composed of randomized, controlled trials that investigated CIN prevention and included IV sodium bicarbonate in one of the treatment groups. Nine published and 15 unpublished trials were selected for a total of 3,563 patients studied. The overall pooled relative risk of CIN in patients treated with IV sodium bicarbonate compared with normal saline was 0.62 (95% CI, 0.45-0.86), though the strength of this evidence was questioned.

Significant heterogeneity across studies was found (I²=49.1%; P=0.004), partially related to substantially greater treatment effect in published (RR 0.43, 95% CI, 0.25-0.75) versus unpublished (RR 0.78, 95% CI, 0.52-1.17) studies. Publication bias was confirmed statistically. Among the published studies, greater treatment effect favoring bicarbonate over saline tended to be reported in those published before 2008, had fewer patients (<200) and events (<15), had measured events within 48 hours, and were studies of lower quality.

No effects regarding the risk of heart failure, the need for dialysis, or mortality were found, though the studies were not specifically designed to investigate those clinical outcomes. Larger studies are needed to better assess these questions.

Bottom line: IV sodium bicarbonate for CIN prevention in high-risk patients could be less effective than previous reports have suggested.

Citation: Zoungas S, Ninomiya T, Huxley R, et al. Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. Ann Intern Med. 2009;151(9):631-638.

Incidental Findings More Frequent than PE in Chest CT Angiograms

Clinical question: What is the prevalence of incidental findings on chest-computed tomographic angiograms (CTAs) ordered by an ED to evaluate for pulmonary embolism (PE)?

Background: CTAs commonly are ordered by ED physicians to assess for PE. While CTAs might yield findings to support an alternate diagnosis to PE, incidental findings might be found that often require further radiographic or clinical followup. The workup of these incidental findings can be burdensome and low-yield.

Study design: Retrospective chart review.

Setting: Single, academic, tertiary-care hospital in North Carolina.

Synopsis: All patients who underwent CTA evaluation for PE in the ED over two enrollment periods were selected; radiographic findings were compiled and their medical records reviewed. Fifty-five of 589 CTAs (9%) were positive for PE. New incidental findings requiring radiographic or clinical followup were found in 141 cases (24%).

Overall, pulmonary nodules were most common, requiring followup in 73 (13%) cases. Adenopathy requiring followup was seen in 51 cases (9%), and new masses requiring followup were found in 12 cases (2%). Findings to support alternate diagnoses for shortness of breath, hypoxemia, or tachycardia were found in 195 patients (33%), most commonly pleural effusion (19%) and infiltrates (11%). Other incidental findings that required less-urgent clinical attention were common with 615 total findings, most frequently nonmalignant bone findings in 144 cases (24%), mild dependent atelectasis in 137 cases (23%), and emphysema in 69 cases (12%).

Bottom line: Incidental findings requiring followup were more than twice as common as PE (24% vs. 9%) in CTAs ordered to evaluate for PE in an ED.

Citation: Hall WB, Truitt SG, Scheunemann LP, et al. The prevalence of clinically relevant incidental findings on chest computed tomographic angiograms ordered to diagnose pulmonary embolism. Arch Intern Med. 2009;169(21):1961-1965.

Patients Don’t Penalize for Adverse-Outcome Disclosure

Clinical question: What patient or clinical characteristics affect the likelihood of physician reporting of an adverse outcome, and how does adverse-outcome disclosure affect patient perceptions of quality of care?

Background: Harmful adverse events (AE), injuries caused by medical management rather than by the underlying condition of the patient, are common in the U.S. Previous studies have focused on physician and provider attitudes about disclosure. Little is known about how characteristics of the AE affect disclosure, and how disclosure affects patients’ perceptions of quality of care.

Study design: Retrospective cohort study.

Setting: Acute-care hospitals in Massachusetts.

Synopsis: Of 4,143 eligible patients, 2,582 (62%) agreed to a telephone interview that asked about patient experiences with adverse events during their hospital stay. Respondents reporting an AE were asked about disclosure by medical staff, effects of adverse events on their hospital course, and the quality of their hospital care.

Of the 845 AEs reported by 608 patients, only 40% were disclosed, defined as “anyone from the hospital explaining why the negative effects occurred.” The majority of the AEs were related to newly prescribed medications (40%) and surgical procedures (34%). Researchers determined that 31% of the AEs were preventable and 75% were severe. In multivariate analysis, disclosure was less likely if the AE was preventable or if patients had long-term effects from the AE. Patients with an AE were more likely to rate the quality of their hospitalization higher if there had been disclosure.

Bottom line: Disclosure of adverse events by medical personnel is low (40%) in hospitalized patients, even though disclosure of adverse events increases patients’ ratings of quality of care.

Citation: López L, Weismann JS, Schneider EC, Weingart SN, Cohen AP, Epstein AM. Disclosure of hospital adverse events and its association with patients’ ratings of the quality of care. Arch Intern Med. 2009;169(20):1888-1894.

Comanagement of Hip-Fracture Patients by Geriatricians Decreases Time to Surgery, LOS, and Complications

Clinical question: Does comanagement of hip-fracture patients by geriatricians and orthopedic surgeons improve short-term outcomes?

Background: Hip fractures in older adults are associated with considerable morbidity and mortality. A model at a single center, where hip fracture patients are comanaged by geriatricians and orthopedic surgeons, demonstrated decreased LOS, readmission rates, and mortality when compared with national data. This study compares results to a usual-care site.

Study design: Retrospective cohort study.

Setting: Community-based teaching hospital and a tertiary-care hospital in Rochester, N.Y.

Synopsis: Researchers enrolled 314 patients with hip fractures. The 193 patients in the intervention group were comanaged by geriatricians and orthopedic surgeons. The 121 patients in the usual-care group were admitted under the care of orthopedic surgeons, and hospitalists were consulted when deemed necessary. Retrospective chart reviews were performed; complications were defined a priori.

When compared with usual care, patients in the intervention group had significantly shorter times to surgery (24.1 hours vs. 37.4 hours), shorter LOS (4.6 days vs. 8.3 days), fewer complications (30.6% vs. 46.3%), including fewer postoperative infections (2.3% vs. 19.8%), cardiac complications (1.0% vs. 7.4%), cases of thromboembolism (0.5% vs. 5.0%), episodes of bleeding (0% vs. 3.3%), and episodes of hypoxia (6.7% vs. 14.1%). There was no difference in inpatient mortality or 30-day readmission rates.

Further assessment comanagement by hospitalists and comanagement by geriatricians is needed.

Bottom line: Perioperative comanagement of hip-fracture patients by geriatricians and orthopedic surgeons significantly improves short-term outcomes.

Citation: Friedman SM, Mendelson DA, Bingham KW, Kates SL. Impact of a comanaged geriatric fracture center on short-term hip fracture outcomes. Arch Intern Med. 2009;169 (18):1712-1717.

Niacin Is Superior to Ezetimibe in Causing Significant Regression of Carotid Intima-Media Thickness when Combined with a Statin

Clinical question: Is ezetimibe superior to niacin for reducing carotid intima-media thickness (CIMT) in patients with coronary artery disease (CAD) already on statin monotherapy?

Background: Statin montherapy significantly reduces the risk of cardiovascular events, and further lowering of this risk can be achieved by reducing the LDL, using statin intensification, or adding ezetimibe, or by raising the HDL levels by adding niacin therapy. This comparative-effectiveness trial compared the efficacy of these two approaches.

Study design: Prospective, randomized, parallel-group, open-label study.

Setting: Tertiary-care military medical center, and private tertiary-care hospital in Washington, D.C.

Synopsis: Three hundred sixty-three patients with known CAD or CAD equivalent were enrolled, and all of the patients were maintained on statin therapy with LDL <100 and HDL <50. Patients were randomized to ezetimibe 10 mg/day or niacin, starting at 500 mg at bedtime and titrated to 2 g/day. Primary endpoint was a mean change in CIMT after 14 months. Secondary endpoints were change in lipid levels, composite of major cardiovascular events, drug discontinuation, and quality of life.

The trial was terminated early after 208 patients had completed the trial. Although ezetimibe showed greater reduction of LDL, niacin showed significantly greater reduction in the progression of CIMT. Patients receiving niacin experienced fewer cardiovascular events (1% vs. 5%) but had higher rates of withdrawal (15% vs. 9%) due to flushing.

Limitations of the study are small sample size, short follow-up period, and use of CIMT as a surrogate marker for clinical endpoint.

Bottom line: Niacin is superior to ezetimibe in reducing CIMT and raising HDL levels and might be more efficacious in reducing cardiovascular risk.

Citation: Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361(22):2113-2122.

Pharmacist-Facilitated Hospital Discharge Program Didn’t Reduce Post-Discharge Healthcare Resource Utilization

Clinical question: Does pharmacist-facilitated hospital discharge reduce hospital readmission rates?

Background: Medication discrepancies at the time of discharge often lead to confusion, medical errors, and readmission to the hospital. Patients who are at high risk of medication errors often are on multiple medications and experience adverse drug events upon discharge.

Study design: Prospective cohort study.

Setting: Tertiary-care, academic teaching hospital in Michigan.

Synopsis: One pharmacist alternated between the resident service and hospitalist service every month. The pharmacist monitored the patients being discharged for appropriateness and accuracy of medications. The pharmacist assessed medication therapy, reconciled medications, screened for adherence concerns, counseled and educated patients, and performed post-discharge telephone follow-up.

Primary outcomes were ED visits within 72 hours and readmission rates by day 14 and day 30.

The study found high numbers of medication discrepancies in the control (33.5%) and intervention (59.6%) groups, and these discrepancies were resolved prior to discharge; however, there was no significant impact on post-discharge ED visits, or 14- and 30-day readmission rates. Post-discharge telephone calls reduced 14-day readmission rates.

Bottom line: Pharmacist-facilitated hospital discharge did not significantly reduce post-discharge ED visits or readmissions.

Citation: Walker PC, Bernstein SJ, Jones JN, et al. Impact of a pharmacist-facilitated hospital discharge program. Arch Intern Med. 2009;169(21):2003-2010.

Questionable Antibiotic Benefit for Patients with Acute COPD Exacerbations

Clinical question: Does the addition of antibiotics to systemic corticosteroids provide additional benefits for patients hospitalized with acute exacerbations of chronic obstructive pulmonary disease (AECOPD)?

Background: The role of antibiotics in the treatment of AECOPD is unclear, particularly in addition to systemic corticosteroids. Many of the studies demonstrating the benefit of antibiotics were conducted several decades before systemic steroids were used routinely for the treatment of AECOPD.

Study design: Randomized, double-blinded, placebo-controlled study.

Setting: Two academic teaching hospitals in the Netherlands.

Synopsis: Two hundred sixty-five acute exacerbations of COPD were enrolled in the study, and patients were randomized to a seven-day course of 200 mg/day of doxycycline or placebo. All patients received systemic corticosteroids, nebulized bronchodilator therapy, and physiotherapy. The study found that doxycycline was equivalent to placebo for the primary endpoint of clinical success on day 30; however, doxycycline was superior to placebo for secondary outcomes of clinical success, clinical cure, symptomatic improvement, microbiological success, and reducing open label antibiotic use on day 10, but not on day 30.

Because the population studied had low levels of advanced antimicrobial resistance, the findings might not be generalizable. Results suggested a difference of treatment effect between subgroups based on C-reactive protein values, but further research is needed.

Bottom line: Patients treated with doxycycline for acute exacerbation of COPD had improved clinical outcomes at day 10, but the benefits were not significant at day 30. Data are still equivocal regarding benefits of antibiotics in patients with acute exacerbations of COPD.

Citation: Daniels JM, Snijders D, de Graaff CS, Vlaspolder F, Jansen HM, Boersma WG. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181(2):150-157. TH

PEDIATRIC HM LITERATURE

By Mark Shen, MD

Reviewed by Pediatric Editor Mark Shen, MD, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Less Is More in the Management of Acute Gastroenteritis

Clinical question: What is the effect of a guideline-training program for pediatricians on the management of acute gastroenteritis (AGE)?

Background: Guidelines recommending oral rehydration, early refeeding, and limited interventions have been developed for AGE management, but uptake by pediatricians has been slow. While individual components of these guidelines have been shown to be effective in comparison to other resource-intensive interventions, outcomes of global guideline implementation have not been studied well.

Study design: Prospective, randomized, controlled trial.

Setting: One hundred forty-nine primary-care pediatricians in Italy.

Synopsis: Pediatricians from the Italian national healthcare system were randomized to AGE guideline training or no training (usual practice; control group). The physicians enrolled 1,309 children in the study. Parents completed daily forms documenting the interventions for, and outcomes of, each illness.

Management by the trained group of pediatricians was in full compliance with the guidelines 66% of the time, as opposed to 33% of the time in the untrained group.

Significant differences between the groups were noted for each basic tenet of the guidelines: oral rehydration use, restrictive diets, medication use, and microbiologic testing. Notably, by both intention-to-treat and per-protocol analysis, the mean duration of diarrhea was shorter in children managed by the trained group of pediatricians.

As underadherence to evidence-based guidelines remains commonplace, effective implementation will become a greater area of focus. Despite a modest effect in an ambulatory population, these investigators demonstrated a clear improvement in outcomes with a simple, two-hour training program. While not studied, it is likely that the cost of care was significantly lower in the guideline group, given the dramatic differences in medication use and testing.

Bottom line: Effective implementation of AGE guidelines will improve outcomes and reduce costs.

Citation: Albano F, Lo Vecchio A, Guarino A. The applicability and efficacy of guidelines for the management of acute gastroenteritis in outpatient children: a field-randomized trial on primary care pediatricians. J Pediatr. 2010;156(2):226-230.

Case

A 70-year-old woman with recently diagnosed pancreatic cancer is admitted with worsening abdominal pain and new right-lower-extremity edema. A CT scan of the abdomen and pelvis reveals occlusive IVC and common iliac thromboses. A right-common-femoral DVT appears on Doppler ultrasound. A CT angiogram of her chest is negative for pulmonary emboli. What is the appropriate treatment for this patient’s thromboembolic disease?

Overview

VTE in the setting of malignancy is common, and the incidence of VTE among cancer patients is increasing for unclear reasons.^1,2,3 VTE occurs in an estimated 4% to 20% of all malignancy patients. Overall, cancer patients are at a sixfold increased risk of developing VTE compared with the general population, and these patients represent approximately 20% of all VTE cases.^4,5

VTE is a leading cause of mortality among hospitalized cancer patients; evidence of VTE exists in up to 50% of cancer patients at autopsy.^3,4 VTE complications lead to significant morbidity, including recurrent VTE, pulmonary hypertension, post-thrombophlebitic syndrome, bleeding, and decreased quality of life.^6,7

The risk is greatest for hospitalized cancer patients and those receiving active chemotherapy, particularly with such antiangiogenic agents as thalidomide and bevacizumab.^4,6 Certain malignancies are more frequently associated with VTE; these include gastrointestinal, gynecologic, brain, lung, renal, and hematologic cancers.⁴ Table 1 (p. 50) summarizes risk factors associated with VTE in cancer patients.⁴

Patients with malignancy are hypercoagulable, primarily because of tumor-related alterations in the coagulation cascade.⁸ Tumors contain cell-surface proteins (e.g., tissue factor and cancer procoagulant) that lead to activation of the clotting cascade via interactions with factors IX and/or X. In addition, tumor-released cytokines cause prothrombotic changes in the vascular endothelium.⁸

This hypercoagulability is exacerbated by cancer-associated treatment events, including immobility, central venous catheters, erythropoiesis-stimulating agents, and packed red-blood-cell and platelet transfusions.^5,9

Cancer-related therapy complications further confound VTE management. Drug interactions, chemotherapy-induced thrombocytopenia, malnutrition, bleeding risk from surgery or tumor location, and liver dysfunction make safe management of cancer-associated VTE a challenge.

Review of the Data

Low-molecular-weight heparin (LMWH) vs. vitamin K antagonists (VKA): There is significant evidence that LMWH is the preferred pharmacologic therapy for the initial and long-term treatment of cancer-related VTE. The most convincing data were published as the CLOT trial, and is supported by several smaller studies.¹⁰ Recommendations for the preferred use of LMWH are consistent among several national and international guidelines.^6,7

In the CLOT (Randomized Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) trial, six months of treatment with an oral VKA preceded by five to seven days of LMWH was compared with six months of treatment with LMWH (dalteparin). Patients with the diagnosis of acute symptomatic VTE were evaluated. After six months of treatment, 53 of 336 patients in the oral anticoagulant group had recurrent VTE, compared with 27 of 336 patients in the LMWH group—a relative risk reduction of 52% and an absolute risk reduction of 8% (P=0.002). Complication rates (major and minor bleeding) and overall mortality were similar between the two groups.^7,10

click for large version

Two smaller trials compared LMWHs with warfarin in the treatment of VTE in the setting of cancer. In one trial, seven of 67 enoxaparin-treated patients developed bleeding or recurrent VTE, compared with 15 of 71 warfarin-treated subjects; however, this reduction was not statistically significant (P=0.09).¹¹ In another trial, seven of 100 tinzaparin-treated patients developed recurrent VTE, compared with 16 of 100 warfarin-treated patients (P=0.044).¹²

Thus, LMWH is the preferred therapeutic agent for both DVT and PE in the setting of malignancy.⁵ Even so, although the clinical evidence supports LMWH use in the treatment of cancer-associated VTE, it’s worth noting that many of the authors of the cited papers received compensation from large pharmaceutical companies. In addition, the CLOT trial was funded by Pharmacia, which supplied the study drug.

Initial treatment (5-10 days): The American Society of Clinical Oncology (ASCO) guidelines advocate the use of LMWH during the initial five to 10 days following VTE diagnosis. Four other cancer research organization guidelines, National Comprehensive Cancer Network (NCCN), the Italian Association of Medical Oncology (AIOM), the European Society of Medical Oncology (ESMO), and the French National Federation of the League of Centers Against Cancer (FNCLCC), echo this approach, with unfractionated heparin (UFH) or fondaparinux as additional initial treatment depending on the clinical situation—i.e., renal failure, heparin-induced thrombocytopenia (HIT), or bleeding risk.⁶

Table 2 (below) summarizes recommendations for VTE treatment in cancer patients from all five guideline panels.⁶

Long-term treatment and duration (3-6 months): All of the panels agree LMWH is the preferred agent for long-term therapy of cancer-related VTE. ASCO supports treatment with LMWH for at least six months; oral VKAs with a targeted INR of 2 to 3 are acceptable when LMWH is not feasible. NCCN, AIOM, ESMO, and FNCLCC recommend an LMWH treatment duration from three to six months (ASCO recommends at least six months).

All of the panels, however, advocate indefinite duration of anticoagulation in patients with such continuing risk factors as active (metastatic, recurrent, or persistent) cancer or chemotherapy treatment.⁶ AIOM and ESMO specify indefinite LMWH, whereas ASCO does not specify oral VKA or LMWH use. Given the difficulties of managing VKA in the setting of advanced malignancy or chemotherapy, LMWH is the most practical choice, if it’s available and isn’t cost-prohibitive.

LMWH availability: Dalteparin, tinzaparin, and enoxaparin are LMWHs currently available in the U.S. for VTE treatment. Dalteparin is the only FDA-approved LMWH drug for long-term use to treat cancer-associated VTE, although enoxaparin and tinzaparin are used in practice. All three are supplied in prefilled syringes, which make self-administration easier and significantly reduce the risk of dosage error.⁶

LMWH vs. UFH: LMWH is safer and more efficacious than UFH. A summary of 22 clinical trials (including cancer patients and noncancer patients) by a Cochrane systematic review showed that treatment with LMWH in comparison with UFH results in decreased recurrent VTE, bleeding, mortality, HIT, and osteoporosis.^7,13

Other agents: Fondaparinux is a factor Xa inhibitor rarely associated with heparin-induced thrombocytopenia (HIT), which makes it an attractive alternate anticoagulant for HIT patients. Its use in comparison with other parenteral anticoagulants has not been established in patients with malignancy.

Fondaparinux is FDA-approved for initial VTE treatment, and is used in practice as an alternative prophylactic anticoagulant for patients with HIT history or heparin allergy.⁷ However, no randomized clinical trials have evaluated its efficacy in patients with HIT.

Several new oral anticoagulants, including direct thrombin and factor Xa inhibitors, are being investigated; efficacy has not been established in cancer patients.⁷

Inferior vena cava (IVC) filters: Limited data surround the use of IVC filters, and most consensus guidelines recommend their use only in specific settings. One randomized controlled study (not limited to patients with cancer) showed no difference in overall short-term or long-term survival among patients receiving IVC filters for VTE treatment. However, there was a decrease in symptomatic PE in the filter group 12 days after placement. The tradeoff was significantly more recurrent DVTs at two years’ followup. The authors concluded that systematic use of IVC filters is not recommended.¹⁴

Because all of the study participants in this trial were receiving concomitant anticoagulation, it is difficult to generalize results to patients who have contraindications to anticoagulation. Nonetheless, ASCO, NCCN, and several other guideline panels recommend IVC filters only for patients with contraindications to anticoagulation or failure of long-term anticoagulation. NCCN broadens these recommendations for IVC filter placement to include patients with severe cardiac or pulmonary dysfunction.⁶ However, this recommendation is controversial, given the lack of supporting data, cost, and invasiveness of the procedure.⁷

click for large version

All patients with IVC filters without contraindication to anticoagulation should be anticoagulated.⁹

Prophylaxis: The importance of VTE prophylaxis in all hospitalized patients, including patients with cancer, is under close scrutiny in an attempt to improve patient safety and quality. The Centers for Medicare & Medicaid Services (CMS), in conjunction with the Joint Commission, has added VTE to its list of conditions that are reasonably preventable, and hospitals will no longer be reimbursed for the cost of treatment if acquired during a hospital stay. This rule currently is in effect for knee and hip replacements.¹⁵

The need for improvement in aggressive and appropriate prophylaxis of hospitalized patients was demonstrated by a single study in which just one-third of hospitalized patients received appropriate prophylaxis, according to American College of Chest Physicians (ACCP) guidelines.¹⁶

Despite a lack of robust data regarding VTE prophylaxis in patients with malignancy, strong data exist for VTE prophylaxis in hospitalized patients. All patients with cancer, and without contraindications to anticoagulation, should receive pharmacologic VTE prophylaxis while hospitalized. In the absence of supporting data, guidelines do not suggest VTE prophylaxis for ambulatory patients with cancer, except in certain multiple myeloma patients.⁶

Intracranial malignancies: Patients with intracranial malignancies are at risk for VTE, and the presence of intracranial tumors or metastases are not absolute contraindications to anticoagulation. However, data are sparse regarding VTE therapy in this subgroup. Active intracranial bleeding is an absolute contraindication to anticoagulation, and it should be avoided in patients with recent intracranial surgery or thrombocytopenia (e.g., platelet count < 50 x 10⁹).⁴ In general, the presence of intracranial lesions without high-risk features should not deter the use of prophylactic anticoagulation.

Thrombocytopenia: Cancer patients frequently have chemotherapy-induced cytopenias, including thrombocytopenia. There is a paucity of data regarding anticoagulation in the setting of thrombocytopenia. In a recent review of VTE in the setting of cancer, Lee suggests dose reduction of LMWH by half in patients with platelet counts between 20 and 50 x 109/L.⁷ At our institution, hematologists suggest halving treatment-dose LMWH at platelet counts between 30 and 50 x 10⁹/L, and discontinuing pharmacologic prophylaxis at platelet counts of less than 50 x 10⁹/L—although there are little data to support these recommendations. Anticoagulation should be discontinued in patients with platelet counts below 20-30 x 10⁹/L, as the risk of bleeding becomes too high.⁷

Thrombolytic therapy: Catheter-directed thrombolysis or systemic thrombolytic therapy might be appropriate treatment options for acute VTE. Presence of extensive proximal DVT, symptom duration of less than two weeks, life expectancy of greater than one year, good functional status, and low bleeding risk are prerequisites. Anticoagulation recommendations do not change following thrombolytic therapy.¹⁷

In the setting of PE, hemodynamic instability is the primary indication for thrombolysis. ACCP does not recommend thrombolytic therapy for the majority of VTE patients.¹⁷

Back to the Case

Our patient’s lower-extremity ultrasound and CT of the abdomen and pelvis both revealed extensive clot burden, which likely is related to her underlying pancreatic cancer. She should be started on an LMWH. Given the low likelihood of cure from her cancer, anticoagulation should be continued indefinitely, and an LMWH should be given for at least the first six months. Whether she should be switched to an oral VKA after six months depends on several factors: cost considerations, nutritional status, chemotherapy, presence of cytopenias, and bleeding risk.

IVC filter placement is not indicated at this time, as the patient does not have any contraindications to anticoagulation, has not failed anticoagulation, and does not have impending cardiac or pulmonary compromise. She is not a candidate for thrombolytic therapy due to her poor functional status and limited life expectancy.

Bottom Line

Cancer-associated VTE is increasingly common, and optimally is treated with LMWH for at least six months—indefinitely in the setting of active cancer or treatment. IVC filters have limited and specific indications in the setting of cancer-associated VTE, and should be reserved for situations when anticoagulation is contraindicated. TH

Dr. Weaver is an instructor in the division of hospital medicine at Northwestern University’s Feinberg School of Medicine in Chicago. Dr. Barsuk is an assistant professor in the division of hospital medicine at Feinberg.

References

1. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer. 2007;110(10): 2339-2346.
2. Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olsen RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med. 2006(1);119:60-68.
3. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5(3):632-634.
4. Lyman GA, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25(34):5490-5505.
5. Lyman GH, Khorana AA. Cancer, clots and consensus: new understanding of an old problem. J Clin Oncol. 2009;27(29):4821-4826.
6. Khorana AA, Streiff MB, Farge D, et al. Venous thromboembolism prophylaxis and treatment in cancer: a consensus statement of major guidelines panels and call to action. J Clin Oncol. 2009;27(29):4919-4926.
7. Lee, AY. Anticoagulation in the treatment of established venous thromboembolism in patients with cancer. J Clin Oncol. 2009;27(29):4895-4901.
8. Kuderer NM, Ortel TL, Francis CW. Impact of venous thromboembolism and anticoagulation on cancer and cancer survival. J Clin Oncol. 2009;27(29):4902-4911.
9. Prandoni, P. How I treat venous thromboembolism in patients with cancer. Blood. 2005;106(13):4027-4033.
10. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-153.
11. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002;162(15):1729-1735.
12. Hull RD, Pineo GF, Brant RF, et al. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006;119(12):1062-1072.
13. Van Dongen CJ, van den Belt AG, Prins MH, Lensing AW. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2004:18(4);CD001100.
14. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7): 409-415.
15. Amin AN, Deitelzweig SB. Optimizing the prevention of venous thromboembolism: recent quality initiatives and strategies to drive improvement. Jt Comm J Qual Patient Saf. 2009;35(11):558-564.
16. Amin A, Stemkowski S, Lin J, Yang G. Thromboprophylaxis rates in US medical centers: success or failure? J Thromb Haemost. 2007;5(8):1610-1616.
17. Hirsch J, Guyatt G, Albers W, et al. Executive summary: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed.). Chest. 2008:133(6 Suppl);71S-105S.

Case

A 70-year-old woman with recently diagnosed pancreatic cancer is admitted with worsening abdominal pain and new right-lower-extremity edema. A CT scan of the abdomen and pelvis reveals occlusive IVC and common iliac thromboses. A right-common-femoral DVT appears on Doppler ultrasound. A CT angiogram of her chest is negative for pulmonary emboli. What is the appropriate treatment for this patient’s thromboembolic disease?

Overview

VTE in the setting of malignancy is common, and the incidence of VTE among cancer patients is increasing for unclear reasons.^1,2,3 VTE occurs in an estimated 4% to 20% of all malignancy patients. Overall, cancer patients are at a sixfold increased risk of developing VTE compared with the general population, and these patients represent approximately 20% of all VTE cases.^4,5

VTE is a leading cause of mortality among hospitalized cancer patients; evidence of VTE exists in up to 50% of cancer patients at autopsy.^3,4 VTE complications lead to significant morbidity, including recurrent VTE, pulmonary hypertension, post-thrombophlebitic syndrome, bleeding, and decreased quality of life.^6,7

The risk is greatest for hospitalized cancer patients and those receiving active chemotherapy, particularly with such antiangiogenic agents as thalidomide and bevacizumab.^4,6 Certain malignancies are more frequently associated with VTE; these include gastrointestinal, gynecologic, brain, lung, renal, and hematologic cancers.⁴ Table 1 (p. 50) summarizes risk factors associated with VTE in cancer patients.⁴

Patients with malignancy are hypercoagulable, primarily because of tumor-related alterations in the coagulation cascade.⁸ Tumors contain cell-surface proteins (e.g., tissue factor and cancer procoagulant) that lead to activation of the clotting cascade via interactions with factors IX and/or X. In addition, tumor-released cytokines cause prothrombotic changes in the vascular endothelium.⁸

This hypercoagulability is exacerbated by cancer-associated treatment events, including immobility, central venous catheters, erythropoiesis-stimulating agents, and packed red-blood-cell and platelet transfusions.^5,9

Cancer-related therapy complications further confound VTE management. Drug interactions, chemotherapy-induced thrombocytopenia, malnutrition, bleeding risk from surgery or tumor location, and liver dysfunction make safe management of cancer-associated VTE a challenge.

Review of the Data

Low-molecular-weight heparin (LMWH) vs. vitamin K antagonists (VKA): There is significant evidence that LMWH is the preferred pharmacologic therapy for the initial and long-term treatment of cancer-related VTE. The most convincing data were published as the CLOT trial, and is supported by several smaller studies.¹⁰ Recommendations for the preferred use of LMWH are consistent among several national and international guidelines.^6,7

In the CLOT (Randomized Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) trial, six months of treatment with an oral VKA preceded by five to seven days of LMWH was compared with six months of treatment with LMWH (dalteparin). Patients with the diagnosis of acute symptomatic VTE were evaluated. After six months of treatment, 53 of 336 patients in the oral anticoagulant group had recurrent VTE, compared with 27 of 336 patients in the LMWH group—a relative risk reduction of 52% and an absolute risk reduction of 8% (P=0.002). Complication rates (major and minor bleeding) and overall mortality were similar between the two groups.^7,10

click for large version

Two smaller trials compared LMWHs with warfarin in the treatment of VTE in the setting of cancer. In one trial, seven of 67 enoxaparin-treated patients developed bleeding or recurrent VTE, compared with 15 of 71 warfarin-treated subjects; however, this reduction was not statistically significant (P=0.09).¹¹ In another trial, seven of 100 tinzaparin-treated patients developed recurrent VTE, compared with 16 of 100 warfarin-treated patients (P=0.044).¹²

Thus, LMWH is the preferred therapeutic agent for both DVT and PE in the setting of malignancy.⁵ Even so, although the clinical evidence supports LMWH use in the treatment of cancer-associated VTE, it’s worth noting that many of the authors of the cited papers received compensation from large pharmaceutical companies. In addition, the CLOT trial was funded by Pharmacia, which supplied the study drug.

Initial treatment (5-10 days): The American Society of Clinical Oncology (ASCO) guidelines advocate the use of LMWH during the initial five to 10 days following VTE diagnosis. Four other cancer research organization guidelines, National Comprehensive Cancer Network (NCCN), the Italian Association of Medical Oncology (AIOM), the European Society of Medical Oncology (ESMO), and the French National Federation of the League of Centers Against Cancer (FNCLCC), echo this approach, with unfractionated heparin (UFH) or fondaparinux as additional initial treatment depending on the clinical situation—i.e., renal failure, heparin-induced thrombocytopenia (HIT), or bleeding risk.⁶

Table 2 (below) summarizes recommendations for VTE treatment in cancer patients from all five guideline panels.⁶

Long-term treatment and duration (3-6 months): All of the panels agree LMWH is the preferred agent for long-term therapy of cancer-related VTE. ASCO supports treatment with LMWH for at least six months; oral VKAs with a targeted INR of 2 to 3 are acceptable when LMWH is not feasible. NCCN, AIOM, ESMO, and FNCLCC recommend an LMWH treatment duration from three to six months (ASCO recommends at least six months).

All of the panels, however, advocate indefinite duration of anticoagulation in patients with such continuing risk factors as active (metastatic, recurrent, or persistent) cancer or chemotherapy treatment.⁶ AIOM and ESMO specify indefinite LMWH, whereas ASCO does not specify oral VKA or LMWH use. Given the difficulties of managing VKA in the setting of advanced malignancy or chemotherapy, LMWH is the most practical choice, if it’s available and isn’t cost-prohibitive.

LMWH availability: Dalteparin, tinzaparin, and enoxaparin are LMWHs currently available in the U.S. for VTE treatment. Dalteparin is the only FDA-approved LMWH drug for long-term use to treat cancer-associated VTE, although enoxaparin and tinzaparin are used in practice. All three are supplied in prefilled syringes, which make self-administration easier and significantly reduce the risk of dosage error.⁶

LMWH vs. UFH: LMWH is safer and more efficacious than UFH. A summary of 22 clinical trials (including cancer patients and noncancer patients) by a Cochrane systematic review showed that treatment with LMWH in comparison with UFH results in decreased recurrent VTE, bleeding, mortality, HIT, and osteoporosis.^7,13

Other agents: Fondaparinux is a factor Xa inhibitor rarely associated with heparin-induced thrombocytopenia (HIT), which makes it an attractive alternate anticoagulant for HIT patients. Its use in comparison with other parenteral anticoagulants has not been established in patients with malignancy.

Fondaparinux is FDA-approved for initial VTE treatment, and is used in practice as an alternative prophylactic anticoagulant for patients with HIT history or heparin allergy.⁷ However, no randomized clinical trials have evaluated its efficacy in patients with HIT.

Several new oral anticoagulants, including direct thrombin and factor Xa inhibitors, are being investigated; efficacy has not been established in cancer patients.⁷

Inferior vena cava (IVC) filters: Limited data surround the use of IVC filters, and most consensus guidelines recommend their use only in specific settings. One randomized controlled study (not limited to patients with cancer) showed no difference in overall short-term or long-term survival among patients receiving IVC filters for VTE treatment. However, there was a decrease in symptomatic PE in the filter group 12 days after placement. The tradeoff was significantly more recurrent DVTs at two years’ followup. The authors concluded that systematic use of IVC filters is not recommended.¹⁴

Because all of the study participants in this trial were receiving concomitant anticoagulation, it is difficult to generalize results to patients who have contraindications to anticoagulation. Nonetheless, ASCO, NCCN, and several other guideline panels recommend IVC filters only for patients with contraindications to anticoagulation or failure of long-term anticoagulation. NCCN broadens these recommendations for IVC filter placement to include patients with severe cardiac or pulmonary dysfunction.⁶ However, this recommendation is controversial, given the lack of supporting data, cost, and invasiveness of the procedure.⁷

click for large version

All patients with IVC filters without contraindication to anticoagulation should be anticoagulated.⁹

Prophylaxis: The importance of VTE prophylaxis in all hospitalized patients, including patients with cancer, is under close scrutiny in an attempt to improve patient safety and quality. The Centers for Medicare & Medicaid Services (CMS), in conjunction with the Joint Commission, has added VTE to its list of conditions that are reasonably preventable, and hospitals will no longer be reimbursed for the cost of treatment if acquired during a hospital stay. This rule currently is in effect for knee and hip replacements.¹⁵

The need for improvement in aggressive and appropriate prophylaxis of hospitalized patients was demonstrated by a single study in which just one-third of hospitalized patients received appropriate prophylaxis, according to American College of Chest Physicians (ACCP) guidelines.¹⁶

Despite a lack of robust data regarding VTE prophylaxis in patients with malignancy, strong data exist for VTE prophylaxis in hospitalized patients. All patients with cancer, and without contraindications to anticoagulation, should receive pharmacologic VTE prophylaxis while hospitalized. In the absence of supporting data, guidelines do not suggest VTE prophylaxis for ambulatory patients with cancer, except in certain multiple myeloma patients.⁶

Intracranial malignancies: Patients with intracranial malignancies are at risk for VTE, and the presence of intracranial tumors or metastases are not absolute contraindications to anticoagulation. However, data are sparse regarding VTE therapy in this subgroup. Active intracranial bleeding is an absolute contraindication to anticoagulation, and it should be avoided in patients with recent intracranial surgery or thrombocytopenia (e.g., platelet count < 50 x 10⁹).⁴ In general, the presence of intracranial lesions without high-risk features should not deter the use of prophylactic anticoagulation.

Thrombocytopenia: Cancer patients frequently have chemotherapy-induced cytopenias, including thrombocytopenia. There is a paucity of data regarding anticoagulation in the setting of thrombocytopenia. In a recent review of VTE in the setting of cancer, Lee suggests dose reduction of LMWH by half in patients with platelet counts between 20 and 50 x 109/L.⁷ At our institution, hematologists suggest halving treatment-dose LMWH at platelet counts between 30 and 50 x 10⁹/L, and discontinuing pharmacologic prophylaxis at platelet counts of less than 50 x 10⁹/L—although there are little data to support these recommendations. Anticoagulation should be discontinued in patients with platelet counts below 20-30 x 10⁹/L, as the risk of bleeding becomes too high.⁷

Thrombolytic therapy: Catheter-directed thrombolysis or systemic thrombolytic therapy might be appropriate treatment options for acute VTE. Presence of extensive proximal DVT, symptom duration of less than two weeks, life expectancy of greater than one year, good functional status, and low bleeding risk are prerequisites. Anticoagulation recommendations do not change following thrombolytic therapy.¹⁷

In the setting of PE, hemodynamic instability is the primary indication for thrombolysis. ACCP does not recommend thrombolytic therapy for the majority of VTE patients.¹⁷

Back to the Case

Our patient’s lower-extremity ultrasound and CT of the abdomen and pelvis both revealed extensive clot burden, which likely is related to her underlying pancreatic cancer. She should be started on an LMWH. Given the low likelihood of cure from her cancer, anticoagulation should be continued indefinitely, and an LMWH should be given for at least the first six months. Whether she should be switched to an oral VKA after six months depends on several factors: cost considerations, nutritional status, chemotherapy, presence of cytopenias, and bleeding risk.

IVC filter placement is not indicated at this time, as the patient does not have any contraindications to anticoagulation, has not failed anticoagulation, and does not have impending cardiac or pulmonary compromise. She is not a candidate for thrombolytic therapy due to her poor functional status and limited life expectancy.

Bottom Line

Cancer-associated VTE is increasingly common, and optimally is treated with LMWH for at least six months—indefinitely in the setting of active cancer or treatment. IVC filters have limited and specific indications in the setting of cancer-associated VTE, and should be reserved for situations when anticoagulation is contraindicated. TH

Dr. Weaver is an instructor in the division of hospital medicine at Northwestern University’s Feinberg School of Medicine in Chicago. Dr. Barsuk is an assistant professor in the division of hospital medicine at Feinberg.

References

1. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer. 2007;110(10): 2339-2346.
2. Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olsen RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med. 2006(1);119:60-68.
3. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5(3):632-634.
4. Lyman GA, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25(34):5490-5505.
5. Lyman GH, Khorana AA. Cancer, clots and consensus: new understanding of an old problem. J Clin Oncol. 2009;27(29):4821-4826.
6. Khorana AA, Streiff MB, Farge D, et al. Venous thromboembolism prophylaxis and treatment in cancer: a consensus statement of major guidelines panels and call to action. J Clin Oncol. 2009;27(29):4919-4926.
7. Lee, AY. Anticoagulation in the treatment of established venous thromboembolism in patients with cancer. J Clin Oncol. 2009;27(29):4895-4901.
8. Kuderer NM, Ortel TL, Francis CW. Impact of venous thromboembolism and anticoagulation on cancer and cancer survival. J Clin Oncol. 2009;27(29):4902-4911.
9. Prandoni, P. How I treat venous thromboembolism in patients with cancer. Blood. 2005;106(13):4027-4033.
10. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-153.
11. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002;162(15):1729-1735.
12. Hull RD, Pineo GF, Brant RF, et al. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006;119(12):1062-1072.
13. Van Dongen CJ, van den Belt AG, Prins MH, Lensing AW. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2004:18(4);CD001100.
14. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7): 409-415.
15. Amin AN, Deitelzweig SB. Optimizing the prevention of venous thromboembolism: recent quality initiatives and strategies to drive improvement. Jt Comm J Qual Patient Saf. 2009;35(11):558-564.
16. Amin A, Stemkowski S, Lin J, Yang G. Thromboprophylaxis rates in US medical centers: success or failure? J Thromb Haemost. 2007;5(8):1610-1616.
17. Hirsch J, Guyatt G, Albers W, et al. Executive summary: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed.). Chest. 2008:133(6 Suppl);71S-105S.

Case

A 70-year-old woman with recently diagnosed pancreatic cancer is admitted with worsening abdominal pain and new right-lower-extremity edema. A CT scan of the abdomen and pelvis reveals occlusive IVC and common iliac thromboses. A right-common-femoral DVT appears on Doppler ultrasound. A CT angiogram of her chest is negative for pulmonary emboli. What is the appropriate treatment for this patient’s thromboembolic disease?

Overview

VTE in the setting of malignancy is common, and the incidence of VTE among cancer patients is increasing for unclear reasons.^1,2,3 VTE occurs in an estimated 4% to 20% of all malignancy patients. Overall, cancer patients are at a sixfold increased risk of developing VTE compared with the general population, and these patients represent approximately 20% of all VTE cases.^4,5

VTE is a leading cause of mortality among hospitalized cancer patients; evidence of VTE exists in up to 50% of cancer patients at autopsy.^3,4 VTE complications lead to significant morbidity, including recurrent VTE, pulmonary hypertension, post-thrombophlebitic syndrome, bleeding, and decreased quality of life.^6,7

The risk is greatest for hospitalized cancer patients and those receiving active chemotherapy, particularly with such antiangiogenic agents as thalidomide and bevacizumab.^4,6 Certain malignancies are more frequently associated with VTE; these include gastrointestinal, gynecologic, brain, lung, renal, and hematologic cancers.⁴ Table 1 (p. 50) summarizes risk factors associated with VTE in cancer patients.⁴

Patients with malignancy are hypercoagulable, primarily because of tumor-related alterations in the coagulation cascade.⁸ Tumors contain cell-surface proteins (e.g., tissue factor and cancer procoagulant) that lead to activation of the clotting cascade via interactions with factors IX and/or X. In addition, tumor-released cytokines cause prothrombotic changes in the vascular endothelium.⁸

This hypercoagulability is exacerbated by cancer-associated treatment events, including immobility, central venous catheters, erythropoiesis-stimulating agents, and packed red-blood-cell and platelet transfusions.^5,9

Cancer-related therapy complications further confound VTE management. Drug interactions, chemotherapy-induced thrombocytopenia, malnutrition, bleeding risk from surgery or tumor location, and liver dysfunction make safe management of cancer-associated VTE a challenge.

Review of the Data

Low-molecular-weight heparin (LMWH) vs. vitamin K antagonists (VKA): There is significant evidence that LMWH is the preferred pharmacologic therapy for the initial and long-term treatment of cancer-related VTE. The most convincing data were published as the CLOT trial, and is supported by several smaller studies.¹⁰ Recommendations for the preferred use of LMWH are consistent among several national and international guidelines.^6,7

In the CLOT (Randomized Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) trial, six months of treatment with an oral VKA preceded by five to seven days of LMWH was compared with six months of treatment with LMWH (dalteparin). Patients with the diagnosis of acute symptomatic VTE were evaluated. After six months of treatment, 53 of 336 patients in the oral anticoagulant group had recurrent VTE, compared with 27 of 336 patients in the LMWH group—a relative risk reduction of 52% and an absolute risk reduction of 8% (P=0.002). Complication rates (major and minor bleeding) and overall mortality were similar between the two groups.^7,10

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Two smaller trials compared LMWHs with warfarin in the treatment of VTE in the setting of cancer. In one trial, seven of 67 enoxaparin-treated patients developed bleeding or recurrent VTE, compared with 15 of 71 warfarin-treated subjects; however, this reduction was not statistically significant (P=0.09).¹¹ In another trial, seven of 100 tinzaparin-treated patients developed recurrent VTE, compared with 16 of 100 warfarin-treated patients (P=0.044).¹²

Thus, LMWH is the preferred therapeutic agent for both DVT and PE in the setting of malignancy.⁵ Even so, although the clinical evidence supports LMWH use in the treatment of cancer-associated VTE, it’s worth noting that many of the authors of the cited papers received compensation from large pharmaceutical companies. In addition, the CLOT trial was funded by Pharmacia, which supplied the study drug.

Initial treatment (5-10 days): The American Society of Clinical Oncology (ASCO) guidelines advocate the use of LMWH during the initial five to 10 days following VTE diagnosis. Four other cancer research organization guidelines, National Comprehensive Cancer Network (NCCN), the Italian Association of Medical Oncology (AIOM), the European Society of Medical Oncology (ESMO), and the French National Federation of the League of Centers Against Cancer (FNCLCC), echo this approach, with unfractionated heparin (UFH) or fondaparinux as additional initial treatment depending on the clinical situation—i.e., renal failure, heparin-induced thrombocytopenia (HIT), or bleeding risk.⁶

Table 2 (below) summarizes recommendations for VTE treatment in cancer patients from all five guideline panels.⁶

Long-term treatment and duration (3-6 months): All of the panels agree LMWH is the preferred agent for long-term therapy of cancer-related VTE. ASCO supports treatment with LMWH for at least six months; oral VKAs with a targeted INR of 2 to 3 are acceptable when LMWH is not feasible. NCCN, AIOM, ESMO, and FNCLCC recommend an LMWH treatment duration from three to six months (ASCO recommends at least six months).

All of the panels, however, advocate indefinite duration of anticoagulation in patients with such continuing risk factors as active (metastatic, recurrent, or persistent) cancer or chemotherapy treatment.⁶ AIOM and ESMO specify indefinite LMWH, whereas ASCO does not specify oral VKA or LMWH use. Given the difficulties of managing VKA in the setting of advanced malignancy or chemotherapy, LMWH is the most practical choice, if it’s available and isn’t cost-prohibitive.

LMWH availability: Dalteparin, tinzaparin, and enoxaparin are LMWHs currently available in the U.S. for VTE treatment. Dalteparin is the only FDA-approved LMWH drug for long-term use to treat cancer-associated VTE, although enoxaparin and tinzaparin are used in practice. All three are supplied in prefilled syringes, which make self-administration easier and significantly reduce the risk of dosage error.⁶

LMWH vs. UFH: LMWH is safer and more efficacious than UFH. A summary of 22 clinical trials (including cancer patients and noncancer patients) by a Cochrane systematic review showed that treatment with LMWH in comparison with UFH results in decreased recurrent VTE, bleeding, mortality, HIT, and osteoporosis.^7,13

Other agents: Fondaparinux is a factor Xa inhibitor rarely associated with heparin-induced thrombocytopenia (HIT), which makes it an attractive alternate anticoagulant for HIT patients. Its use in comparison with other parenteral anticoagulants has not been established in patients with malignancy.

Fondaparinux is FDA-approved for initial VTE treatment, and is used in practice as an alternative prophylactic anticoagulant for patients with HIT history or heparin allergy.⁷ However, no randomized clinical trials have evaluated its efficacy in patients with HIT.

Several new oral anticoagulants, including direct thrombin and factor Xa inhibitors, are being investigated; efficacy has not been established in cancer patients.⁷

Inferior vena cava (IVC) filters: Limited data surround the use of IVC filters, and most consensus guidelines recommend their use only in specific settings. One randomized controlled study (not limited to patients with cancer) showed no difference in overall short-term or long-term survival among patients receiving IVC filters for VTE treatment. However, there was a decrease in symptomatic PE in the filter group 12 days after placement. The tradeoff was significantly more recurrent DVTs at two years’ followup. The authors concluded that systematic use of IVC filters is not recommended.¹⁴

Because all of the study participants in this trial were receiving concomitant anticoagulation, it is difficult to generalize results to patients who have contraindications to anticoagulation. Nonetheless, ASCO, NCCN, and several other guideline panels recommend IVC filters only for patients with contraindications to anticoagulation or failure of long-term anticoagulation. NCCN broadens these recommendations for IVC filter placement to include patients with severe cardiac or pulmonary dysfunction.⁶ However, this recommendation is controversial, given the lack of supporting data, cost, and invasiveness of the procedure.⁷

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All patients with IVC filters without contraindication to anticoagulation should be anticoagulated.⁹

Prophylaxis: The importance of VTE prophylaxis in all hospitalized patients, including patients with cancer, is under close scrutiny in an attempt to improve patient safety and quality. The Centers for Medicare & Medicaid Services (CMS), in conjunction with the Joint Commission, has added VTE to its list of conditions that are reasonably preventable, and hospitals will no longer be reimbursed for the cost of treatment if acquired during a hospital stay. This rule currently is in effect for knee and hip replacements.¹⁵

The need for improvement in aggressive and appropriate prophylaxis of hospitalized patients was demonstrated by a single study in which just one-third of hospitalized patients received appropriate prophylaxis, according to American College of Chest Physicians (ACCP) guidelines.¹⁶

Despite a lack of robust data regarding VTE prophylaxis in patients with malignancy, strong data exist for VTE prophylaxis in hospitalized patients. All patients with cancer, and without contraindications to anticoagulation, should receive pharmacologic VTE prophylaxis while hospitalized. In the absence of supporting data, guidelines do not suggest VTE prophylaxis for ambulatory patients with cancer, except in certain multiple myeloma patients.⁶

Intracranial malignancies: Patients with intracranial malignancies are at risk for VTE, and the presence of intracranial tumors or metastases are not absolute contraindications to anticoagulation. However, data are sparse regarding VTE therapy in this subgroup. Active intracranial bleeding is an absolute contraindication to anticoagulation, and it should be avoided in patients with recent intracranial surgery or thrombocytopenia (e.g., platelet count < 50 x 10⁹).⁴ In general, the presence of intracranial lesions without high-risk features should not deter the use of prophylactic anticoagulation.

Thrombocytopenia: Cancer patients frequently have chemotherapy-induced cytopenias, including thrombocytopenia. There is a paucity of data regarding anticoagulation in the setting of thrombocytopenia. In a recent review of VTE in the setting of cancer, Lee suggests dose reduction of LMWH by half in patients with platelet counts between 20 and 50 x 109/L.⁷ At our institution, hematologists suggest halving treatment-dose LMWH at platelet counts between 30 and 50 x 10⁹/L, and discontinuing pharmacologic prophylaxis at platelet counts of less than 50 x 10⁹/L—although there are little data to support these recommendations. Anticoagulation should be discontinued in patients with platelet counts below 20-30 x 10⁹/L, as the risk of bleeding becomes too high.⁷

Thrombolytic therapy: Catheter-directed thrombolysis or systemic thrombolytic therapy might be appropriate treatment options for acute VTE. Presence of extensive proximal DVT, symptom duration of less than two weeks, life expectancy of greater than one year, good functional status, and low bleeding risk are prerequisites. Anticoagulation recommendations do not change following thrombolytic therapy.¹⁷

In the setting of PE, hemodynamic instability is the primary indication for thrombolysis. ACCP does not recommend thrombolytic therapy for the majority of VTE patients.¹⁷

Back to the Case

Our patient’s lower-extremity ultrasound and CT of the abdomen and pelvis both revealed extensive clot burden, which likely is related to her underlying pancreatic cancer. She should be started on an LMWH. Given the low likelihood of cure from her cancer, anticoagulation should be continued indefinitely, and an LMWH should be given for at least the first six months. Whether she should be switched to an oral VKA after six months depends on several factors: cost considerations, nutritional status, chemotherapy, presence of cytopenias, and bleeding risk.

IVC filter placement is not indicated at this time, as the patient does not have any contraindications to anticoagulation, has not failed anticoagulation, and does not have impending cardiac or pulmonary compromise. She is not a candidate for thrombolytic therapy due to her poor functional status and limited life expectancy.

Bottom Line

Cancer-associated VTE is increasingly common, and optimally is treated with LMWH for at least six months—indefinitely in the setting of active cancer or treatment. IVC filters have limited and specific indications in the setting of cancer-associated VTE, and should be reserved for situations when anticoagulation is contraindicated. TH

Dr. Weaver is an instructor in the division of hospital medicine at Northwestern University’s Feinberg School of Medicine in Chicago. Dr. Barsuk is an assistant professor in the division of hospital medicine at Feinberg.

References

1. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer. 2007;110(10): 2339-2346.
2. Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olsen RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med. 2006(1);119:60-68.
3. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5(3):632-634.
4. Lyman GA, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25(34):5490-5505.
5. Lyman GH, Khorana AA. Cancer, clots and consensus: new understanding of an old problem. J Clin Oncol. 2009;27(29):4821-4826.
6. Khorana AA, Streiff MB, Farge D, et al. Venous thromboembolism prophylaxis and treatment in cancer: a consensus statement of major guidelines panels and call to action. J Clin Oncol. 2009;27(29):4919-4926.
7. Lee, AY. Anticoagulation in the treatment of established venous thromboembolism in patients with cancer. J Clin Oncol. 2009;27(29):4895-4901.
8. Kuderer NM, Ortel TL, Francis CW. Impact of venous thromboembolism and anticoagulation on cancer and cancer survival. J Clin Oncol. 2009;27(29):4902-4911.
9. Prandoni, P. How I treat venous thromboembolism in patients with cancer. Blood. 2005;106(13):4027-4033.
10. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-153.
11. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002;162(15):1729-1735.
12. Hull RD, Pineo GF, Brant RF, et al. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006;119(12):1062-1072.
13. Van Dongen CJ, van den Belt AG, Prins MH, Lensing AW. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2004:18(4);CD001100.
14. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7): 409-415.
15. Amin AN, Deitelzweig SB. Optimizing the prevention of venous thromboembolism: recent quality initiatives and strategies to drive improvement. Jt Comm J Qual Patient Saf. 2009;35(11):558-564.
16. Amin A, Stemkowski S, Lin J, Yang G. Thromboprophylaxis rates in US medical centers: success or failure? J Thromb Haemost. 2007;5(8):1610-1616.
17. Hirsch J, Guyatt G, Albers W, et al. Executive summary: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed.). Chest. 2008:133(6 Suppl);71S-105S.