John Hickner, MD, MSc

Last month, Dr. Jeff Susman turned his final editorial into a “Dear John” letter, passing on wisdom acquired during his 9+ years as this journal’s editor-in-chief. He suggested I manage my image. So in this, my first editorial, I’m taking his advice, and letting you know who I am and what’s ahead.

One of 13 children raised in a small town, I spent the first 22 years of my career with Michigan State University College of Human Medicine—practicing, teaching, and doing research in Escanaba, a small town in the Upper Peninsula. It was the heyday of rural medical education, and a heady time for a newly minted family doc. Visitors from as far afield as China and South Africa came to see how we trained competent physicians in this rural setting.

How did a small-town family doc become editor-in-chief of The Journal of Family Practice? It turns out that the journal has a tradition of small-town family physicians as editors, including Mark Ebell (2000-2002), Jeff Susman (2003-2012), and now me. Perhaps the grounding in daily, small-town practice contributed to my sense of what FPs need to know to be competent and compassionate practitioners. I’ve also served as JFP’s associate editor for original research for more than 10 years and as an editor of the monthly PURLs column.

Today, I’m chairman of family medicine at the Cleveland Clinic, a post I’ve held since 2009. Patient care is still the most rewarding part of my work, although clinical research occupies about half of my time.

I was sidetracked into research early on, my interest piqued by tympanostomy tubes. After my first 2 children had those little grommets inserted, I wanted to know what evidence supported their use—and was taken aback to find not a single randomized trial demonstrating the benefit of ear tubes over watchful waiting. Sound familiar? Consider PSA screening, electronic fetal monitoring, and antibiotics for acute respiratory infections, to name a few.

In 1980, I established a practice-based research network in Michigan to study the common issues we confront as family physicians, and in 2000 I became the first director of the American Academy of Family Physicians’ National Research Network. There are now 136 primary care practice-based research networks nationwide, answering questions important to us and our patients.

Jeff worked tirelessly to transform JFP into a journal that’s packed with practical, evidence-based information that physicians can immediately apply to patient care. I like the journal’s look, feel, and evidence-based content, and read each issue from cover to cover. Like Jeff, I will select the best available evidence to address important clinical questions. And I hope my editorials will be as entertaining and thought-provoking as his have been.

I also hope to hear from you. Let me know what you like and what you don’t, what you would like to see more of, and what issues you face in your day-to-day practice and wish we would address.

Last month, Dr. Jeff Susman turned his final editorial into a “Dear John” letter, passing on wisdom acquired during his 9+ years as this journal’s editor-in-chief. He suggested I manage my image. So in this, my first editorial, I’m taking his advice, and letting you know who I am and what’s ahead.

One of 13 children raised in a small town, I spent the first 22 years of my career with Michigan State University College of Human Medicine—practicing, teaching, and doing research in Escanaba, a small town in the Upper Peninsula. It was the heyday of rural medical education, and a heady time for a newly minted family doc. Visitors from as far afield as China and South Africa came to see how we trained competent physicians in this rural setting.

How did a small-town family doc become editor-in-chief of The Journal of Family Practice? It turns out that the journal has a tradition of small-town family physicians as editors, including Mark Ebell (2000-2002), Jeff Susman (2003-2012), and now me. Perhaps the grounding in daily, small-town practice contributed to my sense of what FPs need to know to be competent and compassionate practitioners. I’ve also served as JFP’s associate editor for original research for more than 10 years and as an editor of the monthly PURLs column.

Today, I’m chairman of family medicine at the Cleveland Clinic, a post I’ve held since 2009. Patient care is still the most rewarding part of my work, although clinical research occupies about half of my time.

I was sidetracked into research early on, my interest piqued by tympanostomy tubes. After my first 2 children had those little grommets inserted, I wanted to know what evidence supported their use—and was taken aback to find not a single randomized trial demonstrating the benefit of ear tubes over watchful waiting. Sound familiar? Consider PSA screening, electronic fetal monitoring, and antibiotics for acute respiratory infections, to name a few.

In 1980, I established a practice-based research network in Michigan to study the common issues we confront as family physicians, and in 2000 I became the first director of the American Academy of Family Physicians’ National Research Network. There are now 136 primary care practice-based research networks nationwide, answering questions important to us and our patients.

Jeff worked tirelessly to transform JFP into a journal that’s packed with practical, evidence-based information that physicians can immediately apply to patient care. I like the journal’s look, feel, and evidence-based content, and read each issue from cover to cover. Like Jeff, I will select the best available evidence to address important clinical questions. And I hope my editorials will be as entertaining and thought-provoking as his have been.

I also hope to hear from you. Let me know what you like and what you don’t, what you would like to see more of, and what issues you face in your day-to-day practice and wish we would address.

Last month, Dr. Jeff Susman turned his final editorial into a “Dear John” letter, passing on wisdom acquired during his 9+ years as this journal’s editor-in-chief. He suggested I manage my image. So in this, my first editorial, I’m taking his advice, and letting you know who I am and what’s ahead.

One of 13 children raised in a small town, I spent the first 22 years of my career with Michigan State University College of Human Medicine—practicing, teaching, and doing research in Escanaba, a small town in the Upper Peninsula. It was the heyday of rural medical education, and a heady time for a newly minted family doc. Visitors from as far afield as China and South Africa came to see how we trained competent physicians in this rural setting.

How did a small-town family doc become editor-in-chief of The Journal of Family Practice? It turns out that the journal has a tradition of small-town family physicians as editors, including Mark Ebell (2000-2002), Jeff Susman (2003-2012), and now me. Perhaps the grounding in daily, small-town practice contributed to my sense of what FPs need to know to be competent and compassionate practitioners. I’ve also served as JFP’s associate editor for original research for more than 10 years and as an editor of the monthly PURLs column.

Today, I’m chairman of family medicine at the Cleveland Clinic, a post I’ve held since 2009. Patient care is still the most rewarding part of my work, although clinical research occupies about half of my time.

I was sidetracked into research early on, my interest piqued by tympanostomy tubes. After my first 2 children had those little grommets inserted, I wanted to know what evidence supported their use—and was taken aback to find not a single randomized trial demonstrating the benefit of ear tubes over watchful waiting. Sound familiar? Consider PSA screening, electronic fetal monitoring, and antibiotics for acute respiratory infections, to name a few.

In 1980, I established a practice-based research network in Michigan to study the common issues we confront as family physicians, and in 2000 I became the first director of the American Academy of Family Physicians’ National Research Network. There are now 136 primary care practice-based research networks nationwide, answering questions important to us and our patients.

Jeff worked tirelessly to transform JFP into a journal that’s packed with practical, evidence-based information that physicians can immediately apply to patient care. I like the journal’s look, feel, and evidence-based content, and read each issue from cover to cover. Like Jeff, I will select the best available evidence to address important clinical questions. And I hope my editorials will be as entertaining and thought-provoking as his have been.

I also hope to hear from you. Let me know what you like and what you don’t, what you would like to see more of, and what issues you face in your day-to-day practice and wish we would address.

ILLUSTRATIVE CASE

A 60-year-old African American man with type 2 diabetes comes in for a follow-up visit. He is currently taking metformin 1000 mg BID, glipizide 10 mg BID, and rosiglitazone 8 mg daily. His glucose levels are well controlled and his last hemoglobin A1c was 6.8%.

Should you discontinue the rosiglitazone?

We have been reluctant to use rosiglitazone for the treatment of type 2 diabetes since 2007, when a meta-analysis found the drug to be associated with a significant elevation in risk for myocardial infarction (MI) and a borderline significant increase in risk for cardiovascular mortality.² A US Food and Drug Administration (FDA) advisory committee reviewed the evidence in 2007, but did not recommend removing rosiglitazone (Avandia, manufactured by GlaxoSmithKline [GSK]) from the market.³ Annual US sales of the drug, which fell by more than 60% over the next 2 years, totaled $408 million in 2009.⁴

Body of evidence grows
Since then, additional evidence of the risk associated with rosiglitazone has come to light. The latest study, reviewed here, is an update of the 2007 meta-analysis.² The authors used standard methodology like that of their original study, and added an alternative methodology that enabled them to include more trials.

Two FDA safety advisories have also been issued. The first, in September 2010, notified providers and patients of plans to restrict access to rosiglitazone because of its elevated risk of cardiovascular events. An update followed in February 2011, indicating that the drug label now includes a black box warning of that risk.⁵

STUDY SUMMARY: Expanded meta-analysis highlights MI risk

The new meta-analysis included 56 trials and a total of 35,531 patients. Of these, 19,509 (55%) were randomized to receive rosiglitazone, and 16,022 (45%) were assigned to a comparator group, which could be either placebo or active treatment.

To be included in the meta-analysis, a trial had to have a randomized comparator group, the duration of treatment had to be similar for all study groups, and participants had to have >24 weeks of drug exposure.¹ Outcomes of interest were MI and cardiovascular mortality. The earlier meta-analysis included 42 studies, all of which had at least one of these outcomes.² The alternative methodology used in this study—in which smaller studies were grouped by randomization ratios and larger trials were reviewed individually—made it possible to include studies without any MIs or cardiovascular deaths.

The researchers identified 3 groups of trials for inclusion:

• The first group consisted of 5 studies that GSK submitted to the FDA in 1999 for presentation to the advisory committee, which recommended approval of rosiglitazone. In these 5 trials, 1967 patients were randomly assigned to receive rosiglitazone and 793 patients received either a comparator drug or placebo.
• The second group included 48 trials, which were primarily identified from the GSK clinical trial registry. These trials were not originally published, but a legal court settlement mandated their eventual publication,⁶ providing new data not available for the previous meta-analysis. In these 48 trials, a total of 11,231 patients were randomly assigned to receive rosiglitazone and 7473 received either a comparator drug or placebo.
• The third—and smallest—group featured 3 large prospective randomized trials that had been published in major medical journals.^7-9 A total of 6311 patients were randomly assigned to receive rosiglitazone and 7756 patients received comparator drugs.

Fifteen of the 56 trials did not report any MIs, and 30 trials did not report any cardiovascular mortality. The trials without either outcome were not part of the primary analysis, but were included in the alternative analysis.

For the 41 trials with ≥1 MI, rosiglitazone therapy significantly increased the risk of MI (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.02-1.63; P=.04), but did not affect cardiovascular mortality (OR, 1.03; 95% CI, 0.78-1.36; P=.04).

The results of the alternative analysis were very similar to the primary results, showing an increased risk for MI (OR, 1.28; 95% CI, 1.01-1.62), but no change in cardiovascular mortality (OR, 0.99; 95% CI, 0.75-1.32).

WHAT’S NEW: A stronger case for a safer alternative

We believe that this meta-analysis strengthens the case against the use of rosiglitazone for the treatment of type 2 diabetes. The number of trials and patients studied is substantial, and the alternative analytic approach allowed the researchers to include all 56 available trials, whether or not any MIs or cardiovascular deaths were reported.

At an FDA advisory committee meeting in July 2010, the recommendation to remove rosiglitazone from the market received a plurality of votes. That recommendation was not carried out, however because 4 other options—all of which involved leaving rosiglitazone on the market—taken together, received more votes.¹⁰

We think this meta-analysis provides substantial doubt about the safety of rosiglitazone. If there is a safer alternative, the decision not to use rosiglitazone becomes even easier. An important question, then, is whether the other thiazolidinedione on the market, pioglitazone (Actos), carries similar risks.

The PROACTIVE trial, a large cardiovascular outcomes study published in 2005,¹¹ and a patient-level meta-analysis of cardiovascular outcomes published in 2007,¹² assessed the risk of death, MI, and stroke in a diverse population of patients taking pioglitazone. Compared with studies of cardiovascular events associated with rosiglitazone, the PROACTIVE trial and the meta-analysis showed that pioglitazone has a significantly lower risk of death, MI, or stroke.

For patients who are doing well on rosiglitazone, a within-class switch to pioglitazone would appear to decrease coronary artery events. However, it must be noted that both drugs have a black box warning regarding congestive heart failure. (The black box warning for rosiglitazone now identifies the increased risk of MI, as well).⁵

CAVEATS: Missing data weaken analysis

The authors of the meta-analysis reported here were unable to obtain individual patient outcomes, which would have allowed them to do a more powerful analysis. However, other meta-analyses, including one from the FDA,¹³ found similar results.

CHALLENGES TO IMPLEMENTATION: Patients and physicians may be reluctant to switch

Theoretically, a switch to pioglitazone is an easy choice, as it is the same class of medication as rosiglitazone but has a lower risk of MI. The use of rosiglitazone caused about 83,000 excess MIs between 1999 and 2007, the FDA estimated.¹⁴ That number has since been downgraded to up to 6000 excess MIs annually to reflect the reduced usage of the drug.^1,14 But when patients are doing well on a particular medication, neither they nor their doctor may want to change to another drug, especially when the adverse effects of the current medication are uncommon. Nonetheless, reevaluation of their diabetic medication regimen often gives patients an opportunity to ensure that they are taking the best first-line agent—which in many cases is metformin, and not a thiazolidinedione at all.¹⁵

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 60-year-old African American man with type 2 diabetes comes in for a follow-up visit. He is currently taking metformin 1000 mg BID, glipizide 10 mg BID, and rosiglitazone 8 mg daily. His glucose levels are well controlled and his last hemoglobin A1c was 6.8%.

Should you discontinue the rosiglitazone?

We have been reluctant to use rosiglitazone for the treatment of type 2 diabetes since 2007, when a meta-analysis found the drug to be associated with a significant elevation in risk for myocardial infarction (MI) and a borderline significant increase in risk for cardiovascular mortality.² A US Food and Drug Administration (FDA) advisory committee reviewed the evidence in 2007, but did not recommend removing rosiglitazone (Avandia, manufactured by GlaxoSmithKline [GSK]) from the market.³ Annual US sales of the drug, which fell by more than 60% over the next 2 years, totaled $408 million in 2009.⁴

Body of evidence grows
Since then, additional evidence of the risk associated with rosiglitazone has come to light. The latest study, reviewed here, is an update of the 2007 meta-analysis.² The authors used standard methodology like that of their original study, and added an alternative methodology that enabled them to include more trials.

Two FDA safety advisories have also been issued. The first, in September 2010, notified providers and patients of plans to restrict access to rosiglitazone because of its elevated risk of cardiovascular events. An update followed in February 2011, indicating that the drug label now includes a black box warning of that risk.⁵

STUDY SUMMARY: Expanded meta-analysis highlights MI risk

The new meta-analysis included 56 trials and a total of 35,531 patients. Of these, 19,509 (55%) were randomized to receive rosiglitazone, and 16,022 (45%) were assigned to a comparator group, which could be either placebo or active treatment.

To be included in the meta-analysis, a trial had to have a randomized comparator group, the duration of treatment had to be similar for all study groups, and participants had to have >24 weeks of drug exposure.¹ Outcomes of interest were MI and cardiovascular mortality. The earlier meta-analysis included 42 studies, all of which had at least one of these outcomes.² The alternative methodology used in this study—in which smaller studies were grouped by randomization ratios and larger trials were reviewed individually—made it possible to include studies without any MIs or cardiovascular deaths.

The researchers identified 3 groups of trials for inclusion:

• The first group consisted of 5 studies that GSK submitted to the FDA in 1999 for presentation to the advisory committee, which recommended approval of rosiglitazone. In these 5 trials, 1967 patients were randomly assigned to receive rosiglitazone and 793 patients received either a comparator drug or placebo.
• The second group included 48 trials, which were primarily identified from the GSK clinical trial registry. These trials were not originally published, but a legal court settlement mandated their eventual publication,⁶ providing new data not available for the previous meta-analysis. In these 48 trials, a total of 11,231 patients were randomly assigned to receive rosiglitazone and 7473 received either a comparator drug or placebo.
• The third—and smallest—group featured 3 large prospective randomized trials that had been published in major medical journals.^7-9 A total of 6311 patients were randomly assigned to receive rosiglitazone and 7756 patients received comparator drugs.

Fifteen of the 56 trials did not report any MIs, and 30 trials did not report any cardiovascular mortality. The trials without either outcome were not part of the primary analysis, but were included in the alternative analysis.

For the 41 trials with ≥1 MI, rosiglitazone therapy significantly increased the risk of MI (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.02-1.63; P=.04), but did not affect cardiovascular mortality (OR, 1.03; 95% CI, 0.78-1.36; P=.04).

The results of the alternative analysis were very similar to the primary results, showing an increased risk for MI (OR, 1.28; 95% CI, 1.01-1.62), but no change in cardiovascular mortality (OR, 0.99; 95% CI, 0.75-1.32).

WHAT’S NEW: A stronger case for a safer alternative

We believe that this meta-analysis strengthens the case against the use of rosiglitazone for the treatment of type 2 diabetes. The number of trials and patients studied is substantial, and the alternative analytic approach allowed the researchers to include all 56 available trials, whether or not any MIs or cardiovascular deaths were reported.

At an FDA advisory committee meeting in July 2010, the recommendation to remove rosiglitazone from the market received a plurality of votes. That recommendation was not carried out, however because 4 other options—all of which involved leaving rosiglitazone on the market—taken together, received more votes.¹⁰

We think this meta-analysis provides substantial doubt about the safety of rosiglitazone. If there is a safer alternative, the decision not to use rosiglitazone becomes even easier. An important question, then, is whether the other thiazolidinedione on the market, pioglitazone (Actos), carries similar risks.

The PROACTIVE trial, a large cardiovascular outcomes study published in 2005,¹¹ and a patient-level meta-analysis of cardiovascular outcomes published in 2007,¹² assessed the risk of death, MI, and stroke in a diverse population of patients taking pioglitazone. Compared with studies of cardiovascular events associated with rosiglitazone, the PROACTIVE trial and the meta-analysis showed that pioglitazone has a significantly lower risk of death, MI, or stroke.

For patients who are doing well on rosiglitazone, a within-class switch to pioglitazone would appear to decrease coronary artery events. However, it must be noted that both drugs have a black box warning regarding congestive heart failure. (The black box warning for rosiglitazone now identifies the increased risk of MI, as well).⁵

CAVEATS: Missing data weaken analysis

The authors of the meta-analysis reported here were unable to obtain individual patient outcomes, which would have allowed them to do a more powerful analysis. However, other meta-analyses, including one from the FDA,¹³ found similar results.

CHALLENGES TO IMPLEMENTATION: Patients and physicians may be reluctant to switch

Theoretically, a switch to pioglitazone is an easy choice, as it is the same class of medication as rosiglitazone but has a lower risk of MI. The use of rosiglitazone caused about 83,000 excess MIs between 1999 and 2007, the FDA estimated.¹⁴ That number has since been downgraded to up to 6000 excess MIs annually to reflect the reduced usage of the drug.^1,14 But when patients are doing well on a particular medication, neither they nor their doctor may want to change to another drug, especially when the adverse effects of the current medication are uncommon. Nonetheless, reevaluation of their diabetic medication regimen often gives patients an opportunity to ensure that they are taking the best first-line agent—which in many cases is metformin, and not a thiazolidinedione at all.¹⁵

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 60-year-old African American man with type 2 diabetes comes in for a follow-up visit. He is currently taking metformin 1000 mg BID, glipizide 10 mg BID, and rosiglitazone 8 mg daily. His glucose levels are well controlled and his last hemoglobin A1c was 6.8%.

Should you discontinue the rosiglitazone?

We have been reluctant to use rosiglitazone for the treatment of type 2 diabetes since 2007, when a meta-analysis found the drug to be associated with a significant elevation in risk for myocardial infarction (MI) and a borderline significant increase in risk for cardiovascular mortality.² A US Food and Drug Administration (FDA) advisory committee reviewed the evidence in 2007, but did not recommend removing rosiglitazone (Avandia, manufactured by GlaxoSmithKline [GSK]) from the market.³ Annual US sales of the drug, which fell by more than 60% over the next 2 years, totaled $408 million in 2009.⁴

Body of evidence grows
Since then, additional evidence of the risk associated with rosiglitazone has come to light. The latest study, reviewed here, is an update of the 2007 meta-analysis.² The authors used standard methodology like that of their original study, and added an alternative methodology that enabled them to include more trials.

Two FDA safety advisories have also been issued. The first, in September 2010, notified providers and patients of plans to restrict access to rosiglitazone because of its elevated risk of cardiovascular events. An update followed in February 2011, indicating that the drug label now includes a black box warning of that risk.⁵

STUDY SUMMARY: Expanded meta-analysis highlights MI risk

The new meta-analysis included 56 trials and a total of 35,531 patients. Of these, 19,509 (55%) were randomized to receive rosiglitazone, and 16,022 (45%) were assigned to a comparator group, which could be either placebo or active treatment.

To be included in the meta-analysis, a trial had to have a randomized comparator group, the duration of treatment had to be similar for all study groups, and participants had to have >24 weeks of drug exposure.¹ Outcomes of interest were MI and cardiovascular mortality. The earlier meta-analysis included 42 studies, all of which had at least one of these outcomes.² The alternative methodology used in this study—in which smaller studies were grouped by randomization ratios and larger trials were reviewed individually—made it possible to include studies without any MIs or cardiovascular deaths.

The researchers identified 3 groups of trials for inclusion:

• The first group consisted of 5 studies that GSK submitted to the FDA in 1999 for presentation to the advisory committee, which recommended approval of rosiglitazone. In these 5 trials, 1967 patients were randomly assigned to receive rosiglitazone and 793 patients received either a comparator drug or placebo.
• The second group included 48 trials, which were primarily identified from the GSK clinical trial registry. These trials were not originally published, but a legal court settlement mandated their eventual publication,⁶ providing new data not available for the previous meta-analysis. In these 48 trials, a total of 11,231 patients were randomly assigned to receive rosiglitazone and 7473 received either a comparator drug or placebo.
• The third—and smallest—group featured 3 large prospective randomized trials that had been published in major medical journals.^7-9 A total of 6311 patients were randomly assigned to receive rosiglitazone and 7756 patients received comparator drugs.

Fifteen of the 56 trials did not report any MIs, and 30 trials did not report any cardiovascular mortality. The trials without either outcome were not part of the primary analysis, but were included in the alternative analysis.

For the 41 trials with ≥1 MI, rosiglitazone therapy significantly increased the risk of MI (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.02-1.63; P=.04), but did not affect cardiovascular mortality (OR, 1.03; 95% CI, 0.78-1.36; P=.04).

The results of the alternative analysis were very similar to the primary results, showing an increased risk for MI (OR, 1.28; 95% CI, 1.01-1.62), but no change in cardiovascular mortality (OR, 0.99; 95% CI, 0.75-1.32).

WHAT’S NEW: A stronger case for a safer alternative

We believe that this meta-analysis strengthens the case against the use of rosiglitazone for the treatment of type 2 diabetes. The number of trials and patients studied is substantial, and the alternative analytic approach allowed the researchers to include all 56 available trials, whether or not any MIs or cardiovascular deaths were reported.

At an FDA advisory committee meeting in July 2010, the recommendation to remove rosiglitazone from the market received a plurality of votes. That recommendation was not carried out, however because 4 other options—all of which involved leaving rosiglitazone on the market—taken together, received more votes.¹⁰

We think this meta-analysis provides substantial doubt about the safety of rosiglitazone. If there is a safer alternative, the decision not to use rosiglitazone becomes even easier. An important question, then, is whether the other thiazolidinedione on the market, pioglitazone (Actos), carries similar risks.

The PROACTIVE trial, a large cardiovascular outcomes study published in 2005,¹¹ and a patient-level meta-analysis of cardiovascular outcomes published in 2007,¹² assessed the risk of death, MI, and stroke in a diverse population of patients taking pioglitazone. Compared with studies of cardiovascular events associated with rosiglitazone, the PROACTIVE trial and the meta-analysis showed that pioglitazone has a significantly lower risk of death, MI, or stroke.

For patients who are doing well on rosiglitazone, a within-class switch to pioglitazone would appear to decrease coronary artery events. However, it must be noted that both drugs have a black box warning regarding congestive heart failure. (The black box warning for rosiglitazone now identifies the increased risk of MI, as well).⁵

CAVEATS: Missing data weaken analysis

The authors of the meta-analysis reported here were unable to obtain individual patient outcomes, which would have allowed them to do a more powerful analysis. However, other meta-analyses, including one from the FDA,¹³ found similar results.

CHALLENGES TO IMPLEMENTATION: Patients and physicians may be reluctant to switch

Theoretically, a switch to pioglitazone is an easy choice, as it is the same class of medication as rosiglitazone but has a lower risk of MI. The use of rosiglitazone caused about 83,000 excess MIs between 1999 and 2007, the FDA estimated.¹⁴ That number has since been downgraded to up to 6000 excess MIs annually to reflect the reduced usage of the drug.^1,14 But when patients are doing well on a particular medication, neither they nor their doctor may want to change to another drug, especially when the adverse effects of the current medication are uncommon. Nonetheless, reevaluation of their diabetic medication regimen often gives patients an opportunity to ensure that they are taking the best first-line agent—which in many cases is metformin, and not a thiazolidinedione at all.¹⁵

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 75-year-old man with persistent atrial fibrillation and diabetes comes to your office for a check of his international normalized ratio (INR). It has been hard to keep his INR within the normal range of 2 to 3 in recent months, and today is no different: The patient’s INR is 1.7, although he insists he has been compliant with his warfarin regimen and has had no change in diet or other medications. What other anticoagulation options can you offer him?

Patients with atrial fibrillation have a 3% to 8% annual risk of stroke.² Both adjusted-dose warfarin and antiplatelet agents such as aspirin have been shown to be effective at reducing this risk, although warfarin is significantly more effective.³

Those who have atrial fibrillation and a previous history of thromboembolism or rheumatic mitral stenosis or more than one moderate risk factor (age ≥75 years, hypertension, heart failure, impaired left ventricular systolic function, or diabetes) have the highest stroke risk. The American College of Cardiology/American Heart Association Task Force/ European Society of Cardiology (ACC/AHA/ ESC) 2006 guidelines for the management of atrial fibrillation recommend chronic anticoagulation with an oral vitamin K antagonist, such as warfarin, for these high-risk patients.⁴

Warfarin therapy is challenging
We have all experienced the frustrations of maintaining our patients on warfarin at a therapeutic INR; the average patient is within this range only about 67% of the time, although this varies dramatically from patient to patient.⁵

Many of our patients have experienced the inconvenience and cost of repeated monitoring, as well as the morbidity associated with both major and minor bleeding related to warfarin use. And there are many potential interactions between warfarin and foods or other drugs.

Is the new oral anticoagulant a better bet?
There are anticoagulants that do not require monitoring (eg, enoxaparin), but few patients are willing to undergo daily subcutaneous injections, and the cost is often prohibitive. Now there is another alternative.

Dabigatran (Pradaxa), an oral direct thrombin inhibitor, was approved by the US Food and Drug Administration in October 2010 for the prevention of stroke and systemic embolism in patients with atrial fibrillation.⁶ Dabigatran is administered twice daily in a fixed dose. Because it has a relatively short half-life (12-17 hours), it does not require INR monitoring. Dabigatran has no known interactions with foods and minimal interactions with other medications. Its value as a warfarin alternative for patients with atrial fibrillation was addressed in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study detailed below.

STUDY SUMMARY: At higher dose, dabigatran prevents more strokes than warfarin

RE-LY included 18,113 patients from 951 facilities in 44 countries. To be eligible for the study, patients had to have atrial fibrillation documented on an electrocardiogram and at least one additional risk factor for stroke.

Participants were randomized into one of 3 groups: dabigatran 110 mg twice daily, dabigatran 150 mg twice daily (both administered in a blinded fashion), or warfarin (administered in an unblinded fashion and dosed to maintain an INR between 2 and 3). Baseline characteristics, such as age, sex, and CHADS₂ (congestive heart failure, hypertension, age, diabetes, prior stroke) score, were similar across all 3 groups. The median duration of follow-up was 2 years, and complete follow-up occurred in 99.9% of participants.

The primary outcome of the study was stroke or systemic embolism. The primary safety outcome was major hemorrhage, defined as a reduction in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of blood, or symptomatic bleeding in a critical area/organ. Other outcomes were death, myocardial infarction (MI), pulmonary embolism, transient ischemic attack, and hospitalization.

For the primary outcome of prevention of stroke or systemic embolism, the 150-mg dose of dabigatran was superior to warfarin (1.11% vs 1.69% per year, relative risk [RR], 0.66; 95% confidence interval [CI], 0.53-0.82; P<.001 for superiority). The major bleeding rates were similar for dabigatran 150 mg and warfarin, although major gastrointestinal bleeding rates were significantly higher with this dose of dabigatran compared with warfarin (TABLE). Minor bleeding was more common in the warfarin group (16.37% vs 14.84%; RR, 0.91; 95% CI, 0.85-0.97; P=.005).

The 110-mg dose of dabigatran (which is not available in the United States) was neither inferior nor superior to warfarin for the prevention of stroke or systemic embolism. This dose of dabigatran had a lower risk of major bleeding compared with warfarin.

TABLE
Dabigatran vs warfarin: A look at the evidence¹

Mortality rates are similar
Rates of death from any cause were similar among the 3 treatment groups. The rates of hemorrhagic stroke were lower in both dabigatran groups compared with the warfarin group, while rates of MI were lower in the warfarin group than in either of the dabigatran groups.

Dyspepsia was the only other adverse effect that was significantly more common among dabigatran users vs warfarin users. Rates of hepatotoxicity, which was a problem wiThearlier oral direct thrombin inhibitors, were similar for both drugs. Multiple subgroup analyses revealed no significant interaction between the treatment effect of dabigatran and variables such as sex, body mass index, creatinine clearance, CHADS₂ score, aspirin use, or previous long-term use of a vitamin K antagonist.

WHAT’S NEW: This easier-to-use oral anticoagulant is a viable option

Dabigatran gives physicians and patients with atrial fibrillation an option that is more convenient than warfarin for stroke prevention. Its 150-mg dose is more effective in preventing stroke compared with warfarin, and comparable in terms of bleeding risk.

CAVEATS: Unknown long-term effects, potential for bias

The median follow-up in the RE-LY study was 2 years. Longer-term efficacy and safety data may differ from the initial results.

The trial was funded by Boehringer Ingelheim, the manufacturer of dabigatran (Pradaxa). However, study coordination, data management, and analysis were performed independently by the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.

Patients taking dabigatran received the medication in a blinded fashion, but the warfarin group could not be blinded because of the need for INR monitoring and dosage adjustments. To decrease potential bias, the outcome events were assessed by 2 independent investigators who were blinded to the treatment assignments.

CHALLENGES TO IMPLEMENTATION: Cost of dabigatran may be a barrier

The wholesale price of dabigatran, as quoted by Boehringer Ingelheim, is $6.75 per day; the retail price for a 30-day supply is approximately $235, according to drugstore.com, Walgreens, and Walmart). In comparison, a one-month supply of warfarin is about $15. Out-of-pocket costs for many patients will likely be high until dabigatran is added to insurers’ formularies. When costs for monitoring and hospitalizations or treatment for complications associated with warfarin are factored in, however, dabigatran is cost effective, a recent study indicates.⁷

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 75-year-old man with persistent atrial fibrillation and diabetes comes to your office for a check of his international normalized ratio (INR). It has been hard to keep his INR within the normal range of 2 to 3 in recent months, and today is no different: The patient’s INR is 1.7, although he insists he has been compliant with his warfarin regimen and has had no change in diet or other medications. What other anticoagulation options can you offer him?

Patients with atrial fibrillation have a 3% to 8% annual risk of stroke.² Both adjusted-dose warfarin and antiplatelet agents such as aspirin have been shown to be effective at reducing this risk, although warfarin is significantly more effective.³

Those who have atrial fibrillation and a previous history of thromboembolism or rheumatic mitral stenosis or more than one moderate risk factor (age ≥75 years, hypertension, heart failure, impaired left ventricular systolic function, or diabetes) have the highest stroke risk. The American College of Cardiology/American Heart Association Task Force/ European Society of Cardiology (ACC/AHA/ ESC) 2006 guidelines for the management of atrial fibrillation recommend chronic anticoagulation with an oral vitamin K antagonist, such as warfarin, for these high-risk patients.⁴

Warfarin therapy is challenging
We have all experienced the frustrations of maintaining our patients on warfarin at a therapeutic INR; the average patient is within this range only about 67% of the time, although this varies dramatically from patient to patient.⁵

Many of our patients have experienced the inconvenience and cost of repeated monitoring, as well as the morbidity associated with both major and minor bleeding related to warfarin use. And there are many potential interactions between warfarin and foods or other drugs.

Is the new oral anticoagulant a better bet?
There are anticoagulants that do not require monitoring (eg, enoxaparin), but few patients are willing to undergo daily subcutaneous injections, and the cost is often prohibitive. Now there is another alternative.

Dabigatran (Pradaxa), an oral direct thrombin inhibitor, was approved by the US Food and Drug Administration in October 2010 for the prevention of stroke and systemic embolism in patients with atrial fibrillation.⁶ Dabigatran is administered twice daily in a fixed dose. Because it has a relatively short half-life (12-17 hours), it does not require INR monitoring. Dabigatran has no known interactions with foods and minimal interactions with other medications. Its value as a warfarin alternative for patients with atrial fibrillation was addressed in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study detailed below.

STUDY SUMMARY: At higher dose, dabigatran prevents more strokes than warfarin

RE-LY included 18,113 patients from 951 facilities in 44 countries. To be eligible for the study, patients had to have atrial fibrillation documented on an electrocardiogram and at least one additional risk factor for stroke.

Participants were randomized into one of 3 groups: dabigatran 110 mg twice daily, dabigatran 150 mg twice daily (both administered in a blinded fashion), or warfarin (administered in an unblinded fashion and dosed to maintain an INR between 2 and 3). Baseline characteristics, such as age, sex, and CHADS₂ (congestive heart failure, hypertension, age, diabetes, prior stroke) score, were similar across all 3 groups. The median duration of follow-up was 2 years, and complete follow-up occurred in 99.9% of participants.

The primary outcome of the study was stroke or systemic embolism. The primary safety outcome was major hemorrhage, defined as a reduction in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of blood, or symptomatic bleeding in a critical area/organ. Other outcomes were death, myocardial infarction (MI), pulmonary embolism, transient ischemic attack, and hospitalization.

For the primary outcome of prevention of stroke or systemic embolism, the 150-mg dose of dabigatran was superior to warfarin (1.11% vs 1.69% per year, relative risk [RR], 0.66; 95% confidence interval [CI], 0.53-0.82; P<.001 for superiority). The major bleeding rates were similar for dabigatran 150 mg and warfarin, although major gastrointestinal bleeding rates were significantly higher with this dose of dabigatran compared with warfarin (TABLE). Minor bleeding was more common in the warfarin group (16.37% vs 14.84%; RR, 0.91; 95% CI, 0.85-0.97; P=.005).

The 110-mg dose of dabigatran (which is not available in the United States) was neither inferior nor superior to warfarin for the prevention of stroke or systemic embolism. This dose of dabigatran had a lower risk of major bleeding compared with warfarin.

TABLE
Dabigatran vs warfarin: A look at the evidence¹

Mortality rates are similar
Rates of death from any cause were similar among the 3 treatment groups. The rates of hemorrhagic stroke were lower in both dabigatran groups compared with the warfarin group, while rates of MI were lower in the warfarin group than in either of the dabigatran groups.

Dyspepsia was the only other adverse effect that was significantly more common among dabigatran users vs warfarin users. Rates of hepatotoxicity, which was a problem wiThearlier oral direct thrombin inhibitors, were similar for both drugs. Multiple subgroup analyses revealed no significant interaction between the treatment effect of dabigatran and variables such as sex, body mass index, creatinine clearance, CHADS₂ score, aspirin use, or previous long-term use of a vitamin K antagonist.

WHAT’S NEW: This easier-to-use oral anticoagulant is a viable option

Dabigatran gives physicians and patients with atrial fibrillation an option that is more convenient than warfarin for stroke prevention. Its 150-mg dose is more effective in preventing stroke compared with warfarin, and comparable in terms of bleeding risk.

CAVEATS: Unknown long-term effects, potential for bias

The median follow-up in the RE-LY study was 2 years. Longer-term efficacy and safety data may differ from the initial results.

The trial was funded by Boehringer Ingelheim, the manufacturer of dabigatran (Pradaxa). However, study coordination, data management, and analysis were performed independently by the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.

Patients taking dabigatran received the medication in a blinded fashion, but the warfarin group could not be blinded because of the need for INR monitoring and dosage adjustments. To decrease potential bias, the outcome events were assessed by 2 independent investigators who were blinded to the treatment assignments.

CHALLENGES TO IMPLEMENTATION: Cost of dabigatran may be a barrier

The wholesale price of dabigatran, as quoted by Boehringer Ingelheim, is $6.75 per day; the retail price for a 30-day supply is approximately $235, according to drugstore.com, Walgreens, and Walmart). In comparison, a one-month supply of warfarin is about $15. Out-of-pocket costs for many patients will likely be high until dabigatran is added to insurers’ formularies. When costs for monitoring and hospitalizations or treatment for complications associated with warfarin are factored in, however, dabigatran is cost effective, a recent study indicates.⁷

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 75-year-old man with persistent atrial fibrillation and diabetes comes to your office for a check of his international normalized ratio (INR). It has been hard to keep his INR within the normal range of 2 to 3 in recent months, and today is no different: The patient’s INR is 1.7, although he insists he has been compliant with his warfarin regimen and has had no change in diet or other medications. What other anticoagulation options can you offer him?

Patients with atrial fibrillation have a 3% to 8% annual risk of stroke.² Both adjusted-dose warfarin and antiplatelet agents such as aspirin have been shown to be effective at reducing this risk, although warfarin is significantly more effective.³

Those who have atrial fibrillation and a previous history of thromboembolism or rheumatic mitral stenosis or more than one moderate risk factor (age ≥75 years, hypertension, heart failure, impaired left ventricular systolic function, or diabetes) have the highest stroke risk. The American College of Cardiology/American Heart Association Task Force/ European Society of Cardiology (ACC/AHA/ ESC) 2006 guidelines for the management of atrial fibrillation recommend chronic anticoagulation with an oral vitamin K antagonist, such as warfarin, for these high-risk patients.⁴

Warfarin therapy is challenging
We have all experienced the frustrations of maintaining our patients on warfarin at a therapeutic INR; the average patient is within this range only about 67% of the time, although this varies dramatically from patient to patient.⁵

Many of our patients have experienced the inconvenience and cost of repeated monitoring, as well as the morbidity associated with both major and minor bleeding related to warfarin use. And there are many potential interactions between warfarin and foods or other drugs.

Is the new oral anticoagulant a better bet?
There are anticoagulants that do not require monitoring (eg, enoxaparin), but few patients are willing to undergo daily subcutaneous injections, and the cost is often prohibitive. Now there is another alternative.

Dabigatran (Pradaxa), an oral direct thrombin inhibitor, was approved by the US Food and Drug Administration in October 2010 for the prevention of stroke and systemic embolism in patients with atrial fibrillation.⁶ Dabigatran is administered twice daily in a fixed dose. Because it has a relatively short half-life (12-17 hours), it does not require INR monitoring. Dabigatran has no known interactions with foods and minimal interactions with other medications. Its value as a warfarin alternative for patients with atrial fibrillation was addressed in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study detailed below.

STUDY SUMMARY: At higher dose, dabigatran prevents more strokes than warfarin

RE-LY included 18,113 patients from 951 facilities in 44 countries. To be eligible for the study, patients had to have atrial fibrillation documented on an electrocardiogram and at least one additional risk factor for stroke.

Participants were randomized into one of 3 groups: dabigatran 110 mg twice daily, dabigatran 150 mg twice daily (both administered in a blinded fashion), or warfarin (administered in an unblinded fashion and dosed to maintain an INR between 2 and 3). Baseline characteristics, such as age, sex, and CHADS₂ (congestive heart failure, hypertension, age, diabetes, prior stroke) score, were similar across all 3 groups. The median duration of follow-up was 2 years, and complete follow-up occurred in 99.9% of participants.

The primary outcome of the study was stroke or systemic embolism. The primary safety outcome was major hemorrhage, defined as a reduction in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of blood, or symptomatic bleeding in a critical area/organ. Other outcomes were death, myocardial infarction (MI), pulmonary embolism, transient ischemic attack, and hospitalization.

For the primary outcome of prevention of stroke or systemic embolism, the 150-mg dose of dabigatran was superior to warfarin (1.11% vs 1.69% per year, relative risk [RR], 0.66; 95% confidence interval [CI], 0.53-0.82; P<.001 for superiority). The major bleeding rates were similar for dabigatran 150 mg and warfarin, although major gastrointestinal bleeding rates were significantly higher with this dose of dabigatran compared with warfarin (TABLE). Minor bleeding was more common in the warfarin group (16.37% vs 14.84%; RR, 0.91; 95% CI, 0.85-0.97; P=.005).

The 110-mg dose of dabigatran (which is not available in the United States) was neither inferior nor superior to warfarin for the prevention of stroke or systemic embolism. This dose of dabigatran had a lower risk of major bleeding compared with warfarin.

TABLE
Dabigatran vs warfarin: A look at the evidence¹

Mortality rates are similar
Rates of death from any cause were similar among the 3 treatment groups. The rates of hemorrhagic stroke were lower in both dabigatran groups compared with the warfarin group, while rates of MI were lower in the warfarin group than in either of the dabigatran groups.

Dyspepsia was the only other adverse effect that was significantly more common among dabigatran users vs warfarin users. Rates of hepatotoxicity, which was a problem wiThearlier oral direct thrombin inhibitors, were similar for both drugs. Multiple subgroup analyses revealed no significant interaction between the treatment effect of dabigatran and variables such as sex, body mass index, creatinine clearance, CHADS₂ score, aspirin use, or previous long-term use of a vitamin K antagonist.

WHAT’S NEW: This easier-to-use oral anticoagulant is a viable option

Dabigatran gives physicians and patients with atrial fibrillation an option that is more convenient than warfarin for stroke prevention. Its 150-mg dose is more effective in preventing stroke compared with warfarin, and comparable in terms of bleeding risk.

CAVEATS: Unknown long-term effects, potential for bias

The median follow-up in the RE-LY study was 2 years. Longer-term efficacy and safety data may differ from the initial results.

The trial was funded by Boehringer Ingelheim, the manufacturer of dabigatran (Pradaxa). However, study coordination, data management, and analysis were performed independently by the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.

Patients taking dabigatran received the medication in a blinded fashion, but the warfarin group could not be blinded because of the need for INR monitoring and dosage adjustments. To decrease potential bias, the outcome events were assessed by 2 independent investigators who were blinded to the treatment assignments.

CHALLENGES TO IMPLEMENTATION: Cost of dabigatran may be a barrier

The wholesale price of dabigatran, as quoted by Boehringer Ingelheim, is $6.75 per day; the retail price for a 30-day supply is approximately $235, according to drugstore.com, Walgreens, and Walmart). In comparison, a one-month supply of warfarin is about $15. Out-of-pocket costs for many patients will likely be high until dabigatran is added to insurers’ formularies. When costs for monitoring and hospitalizations or treatment for complications associated with warfarin are factored in, however, dabigatran is cost effective, a recent study indicates.⁷

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 47-year-old man limps into your office complaining of ankle pain. The patient is well known to you and has a long history of dyspepsia, which is aggravated when he takes any oral nonsteroidal anti-inflammatory drug (NSAID). He injured his ankle while playing basketball. You diagnose acute ankle sprain. Would a topical NSAID be a safe option for pain relief for this patient?

Patients with tendon and ligament injuries often see their family physician for care. Rest, ice, compression, elevation (RICE) therapy is first-line treatment for these injuries.² Oral NSAIDs, such as diclofenac, piroxicam, and ibuprofen reduce swelling and lead to a more rapid return to activity than RICE alone in patients with ankle sprains,³ and relieve pain associated with muscle strains, too. Acetaminophen provides comparable pain relief and resumption of normal activities.⁴

Help for those who can’t take oral NSAIDs
Oral NSAIDs, however, are contraindicated for patients with a history of gastrointestinal bleeding and must be used cautiously in those with chronic kidney disease. Some patients can’t tolerate the adverse effects, which may include stomach upset, vomiting, and abdominal pain. Others may have medication interactions that prohibit use of oral NSAIDs.

Numerous high-quality, randomized, double-blinded placebo-controlled trials of topical NSAIDs have been conducted in recent years, involving diclofenac—the only topical NSAID available in the United States— as well as other topical agents on the market outside of this country. A recent Cochrane review, detailed below, assessed the efficacy of topical NSAIDs for patients with acute musculoskeletal injuries.

STUDY SUMMARY: Topical NSAIDs provided significant relief

This meta-analysis of 47 high-quality, randomized, double-blinded, placebo-controlled trials included 3455 patients with acute strain, sprain, sport, or overuse injuries.¹ Four of the 47 trials, with a total of 746 participants, studied topical diclofenac.

There was significant heterogeneity in the studies included in the review, but each arm of every trial had at least 10 participants >16 years of age with a painful musculoskeletal injury sustained within the previous 48 hours. To be included in the Cochrane meta-analysis, participants had to have used a topical NSAID at least once a day for ≥3 days.

The primary outcome measure was a reduction in pain ≥50% from baseline. Post-treatment data were obtained approximately 7 days after the injury. Of the patients receiving any topical NSAID, 65% (1181/1822) had successful treatment, compared with 43% (695/1633) receiving a placebo. The number needed to treat (NNT) with a topical NSAID instead of placebo was 4.5 (95% confidence interval, 3.9-5.3) to reduce pain ≥50%.

For patients using topical diclofenac, 52% (166/319) had a 50% reduction in pain, vs 25% (77/307) using a topical placebo. The NNT for topical diclofenac was 3.7, about the same as for oral NSAIDs.⁵

Adverse events were rare in the topical NSAID group: 6.3% had a local adverse event such as a skin reaction vs 5.9% in the topical placebo group. There were no systemic adverse events with topical diclofenac. While all topical NSAIDs combined showed a few minor adverse events compared with placebo, no serious systemic events were reported.

WHAT’S NEW: Topical NSAIDs are a useful alternative

Patients now have another option when seeking treatment for acute musculoskeletal pain. In addition to those who are unable to take oral NSAIDs, some patients may prefer a topical preparation because of perceived or actual side effects and safety profiles.

CAVEATS: Dosing intervals were not established

This meta-analysis included studies that examined a variety of dosing strategies and conditions, so an optimal dosing interval is not clear. However, the studies generally found evidence of benefit regardless of the acute condition and the amount and type of topical NSAID used. Diclofenac had the best results compared with other topical NSAIDs. Benzydamine, which is not sold in the United States, was the only topical NSAID not found to be statistically beneficial compared with placebo, based on 3 studies.

Topical NSAIDs have a small amount of systemic absorption, with blood concentrations about 5% of those from oral NSAIDs. However, patients with a strict contraindication to oral NSAIDs (for example, severe allergy) may also have a contraindication to topical NSAIDs. Also, all patients should be cautioned to avoid oral NSAIDs while using a topical preparation.⁶

CHALLENGES TO IMPLEMENTATION: Topical NSAIDs are costly

In the United States, topical diclofenac is available only by prescription. This may create accessibility and cost differences between oral and topical NSAIDs. The average cost of a typical 10-day acute injury treatment of an adult with oral ibuprofen would be about $3 for plain tablets ($10 for extended release and enteric coated), vs about $65 for diclofenac gel, $113 for a diclofenac patch, and $66 for a diclofenac topical solution (www.drugstore.com, accessed December 2, 2010).

Physician inertia may also interfere with implementation. Physicians may not add a new medication to current prescribing options, although there appear to be no medical barriers to topical NSAIDs. This meta-analysis shows that topical NSAIDs are safe and effective for pain relief from acute injuries.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 47-year-old man limps into your office complaining of ankle pain. The patient is well known to you and has a long history of dyspepsia, which is aggravated when he takes any oral nonsteroidal anti-inflammatory drug (NSAID). He injured his ankle while playing basketball. You diagnose acute ankle sprain. Would a topical NSAID be a safe option for pain relief for this patient?

Patients with tendon and ligament injuries often see their family physician for care. Rest, ice, compression, elevation (RICE) therapy is first-line treatment for these injuries.² Oral NSAIDs, such as diclofenac, piroxicam, and ibuprofen reduce swelling and lead to a more rapid return to activity than RICE alone in patients with ankle sprains,³ and relieve pain associated with muscle strains, too. Acetaminophen provides comparable pain relief and resumption of normal activities.⁴

Help for those who can’t take oral NSAIDs
Oral NSAIDs, however, are contraindicated for patients with a history of gastrointestinal bleeding and must be used cautiously in those with chronic kidney disease. Some patients can’t tolerate the adverse effects, which may include stomach upset, vomiting, and abdominal pain. Others may have medication interactions that prohibit use of oral NSAIDs.

Numerous high-quality, randomized, double-blinded placebo-controlled trials of topical NSAIDs have been conducted in recent years, involving diclofenac—the only topical NSAID available in the United States— as well as other topical agents on the market outside of this country. A recent Cochrane review, detailed below, assessed the efficacy of topical NSAIDs for patients with acute musculoskeletal injuries.

STUDY SUMMARY: Topical NSAIDs provided significant relief

This meta-analysis of 47 high-quality, randomized, double-blinded, placebo-controlled trials included 3455 patients with acute strain, sprain, sport, or overuse injuries.¹ Four of the 47 trials, with a total of 746 participants, studied topical diclofenac.

There was significant heterogeneity in the studies included in the review, but each arm of every trial had at least 10 participants >16 years of age with a painful musculoskeletal injury sustained within the previous 48 hours. To be included in the Cochrane meta-analysis, participants had to have used a topical NSAID at least once a day for ≥3 days.

The primary outcome measure was a reduction in pain ≥50% from baseline. Post-treatment data were obtained approximately 7 days after the injury. Of the patients receiving any topical NSAID, 65% (1181/1822) had successful treatment, compared with 43% (695/1633) receiving a placebo. The number needed to treat (NNT) with a topical NSAID instead of placebo was 4.5 (95% confidence interval, 3.9-5.3) to reduce pain ≥50%.

For patients using topical diclofenac, 52% (166/319) had a 50% reduction in pain, vs 25% (77/307) using a topical placebo. The NNT for topical diclofenac was 3.7, about the same as for oral NSAIDs.⁵

Adverse events were rare in the topical NSAID group: 6.3% had a local adverse event such as a skin reaction vs 5.9% in the topical placebo group. There were no systemic adverse events with topical diclofenac. While all topical NSAIDs combined showed a few minor adverse events compared with placebo, no serious systemic events were reported.

WHAT’S NEW: Topical NSAIDs are a useful alternative

Patients now have another option when seeking treatment for acute musculoskeletal pain. In addition to those who are unable to take oral NSAIDs, some patients may prefer a topical preparation because of perceived or actual side effects and safety profiles.

CAVEATS: Dosing intervals were not established

This meta-analysis included studies that examined a variety of dosing strategies and conditions, so an optimal dosing interval is not clear. However, the studies generally found evidence of benefit regardless of the acute condition and the amount and type of topical NSAID used. Diclofenac had the best results compared with other topical NSAIDs. Benzydamine, which is not sold in the United States, was the only topical NSAID not found to be statistically beneficial compared with placebo, based on 3 studies.

Topical NSAIDs have a small amount of systemic absorption, with blood concentrations about 5% of those from oral NSAIDs. However, patients with a strict contraindication to oral NSAIDs (for example, severe allergy) may also have a contraindication to topical NSAIDs. Also, all patients should be cautioned to avoid oral NSAIDs while using a topical preparation.⁶

CHALLENGES TO IMPLEMENTATION: Topical NSAIDs are costly

In the United States, topical diclofenac is available only by prescription. This may create accessibility and cost differences between oral and topical NSAIDs. The average cost of a typical 10-day acute injury treatment of an adult with oral ibuprofen would be about $3 for plain tablets ($10 for extended release and enteric coated), vs about $65 for diclofenac gel, $113 for a diclofenac patch, and $66 for a diclofenac topical solution (www.drugstore.com, accessed December 2, 2010).

Physician inertia may also interfere with implementation. Physicians may not add a new medication to current prescribing options, although there appear to be no medical barriers to topical NSAIDs. This meta-analysis shows that topical NSAIDs are safe and effective for pain relief from acute injuries.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 47-year-old man limps into your office complaining of ankle pain. The patient is well known to you and has a long history of dyspepsia, which is aggravated when he takes any oral nonsteroidal anti-inflammatory drug (NSAID). He injured his ankle while playing basketball. You diagnose acute ankle sprain. Would a topical NSAID be a safe option for pain relief for this patient?

Patients with tendon and ligament injuries often see their family physician for care. Rest, ice, compression, elevation (RICE) therapy is first-line treatment for these injuries.² Oral NSAIDs, such as diclofenac, piroxicam, and ibuprofen reduce swelling and lead to a more rapid return to activity than RICE alone in patients with ankle sprains,³ and relieve pain associated with muscle strains, too. Acetaminophen provides comparable pain relief and resumption of normal activities.⁴

Help for those who can’t take oral NSAIDs
Oral NSAIDs, however, are contraindicated for patients with a history of gastrointestinal bleeding and must be used cautiously in those with chronic kidney disease. Some patients can’t tolerate the adverse effects, which may include stomach upset, vomiting, and abdominal pain. Others may have medication interactions that prohibit use of oral NSAIDs.

Numerous high-quality, randomized, double-blinded placebo-controlled trials of topical NSAIDs have been conducted in recent years, involving diclofenac—the only topical NSAID available in the United States— as well as other topical agents on the market outside of this country. A recent Cochrane review, detailed below, assessed the efficacy of topical NSAIDs for patients with acute musculoskeletal injuries.

STUDY SUMMARY: Topical NSAIDs provided significant relief

This meta-analysis of 47 high-quality, randomized, double-blinded, placebo-controlled trials included 3455 patients with acute strain, sprain, sport, or overuse injuries.¹ Four of the 47 trials, with a total of 746 participants, studied topical diclofenac.

There was significant heterogeneity in the studies included in the review, but each arm of every trial had at least 10 participants >16 years of age with a painful musculoskeletal injury sustained within the previous 48 hours. To be included in the Cochrane meta-analysis, participants had to have used a topical NSAID at least once a day for ≥3 days.

The primary outcome measure was a reduction in pain ≥50% from baseline. Post-treatment data were obtained approximately 7 days after the injury. Of the patients receiving any topical NSAID, 65% (1181/1822) had successful treatment, compared with 43% (695/1633) receiving a placebo. The number needed to treat (NNT) with a topical NSAID instead of placebo was 4.5 (95% confidence interval, 3.9-5.3) to reduce pain ≥50%.

For patients using topical diclofenac, 52% (166/319) had a 50% reduction in pain, vs 25% (77/307) using a topical placebo. The NNT for topical diclofenac was 3.7, about the same as for oral NSAIDs.⁵

Adverse events were rare in the topical NSAID group: 6.3% had a local adverse event such as a skin reaction vs 5.9% in the topical placebo group. There were no systemic adverse events with topical diclofenac. While all topical NSAIDs combined showed a few minor adverse events compared with placebo, no serious systemic events were reported.

WHAT’S NEW: Topical NSAIDs are a useful alternative

Patients now have another option when seeking treatment for acute musculoskeletal pain. In addition to those who are unable to take oral NSAIDs, some patients may prefer a topical preparation because of perceived or actual side effects and safety profiles.

CAVEATS: Dosing intervals were not established

This meta-analysis included studies that examined a variety of dosing strategies and conditions, so an optimal dosing interval is not clear. However, the studies generally found evidence of benefit regardless of the acute condition and the amount and type of topical NSAID used. Diclofenac had the best results compared with other topical NSAIDs. Benzydamine, which is not sold in the United States, was the only topical NSAID not found to be statistically beneficial compared with placebo, based on 3 studies.

Topical NSAIDs have a small amount of systemic absorption, with blood concentrations about 5% of those from oral NSAIDs. However, patients with a strict contraindication to oral NSAIDs (for example, severe allergy) may also have a contraindication to topical NSAIDs. Also, all patients should be cautioned to avoid oral NSAIDs while using a topical preparation.⁶

CHALLENGES TO IMPLEMENTATION: Topical NSAIDs are costly

In the United States, topical diclofenac is available only by prescription. This may create accessibility and cost differences between oral and topical NSAIDs. The average cost of a typical 10-day acute injury treatment of an adult with oral ibuprofen would be about $3 for plain tablets ($10 for extended release and enteric coated), vs about $65 for diclofenac gel, $113 for a diclofenac patch, and $66 for a diclofenac topical solution (www.drugstore.com, accessed December 2, 2010).

Physician inertia may also interfere with implementation. Physicians may not add a new medication to current prescribing options, although there appear to be no medical barriers to topical NSAIDs. This meta-analysis shows that topical NSAIDs are safe and effective for pain relief from acute injuries.

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 44-year-old woman with a family history of early CHD is considering hysterectomy for painful uterine fibroids. She’s thinking about undergoing concurrent bilateral oophorectomy to prevent ovarian cancer and asks for your input. How would you advise her?

Hysterectomy is the most common gynecologic surgery in the United States. In 2003, more than 600,000 hysterectomies were performed; 89% were not associated with malignancies.²

Ovarian conservation is not the norm

Data from the University Health-System Consortium Clinical Database indicate that between 2002 and 2008, about 55% of women who had a hysterectomy that was not cancer-related underwent oophorectomy. Rates of concurrent oophorectomy included:

• 68% of women ages 65 and older
• 77% of women ages 51 to 64
• 48% of women ages 31 to 50
• 3% of women ages 18 to 30.

A recent analysis from the Centers for Disease Control and Prevention found that among women who underwent hysterectomy for any reason between 1994 and 1998, 55% also had their ovaries removed.³

Hormones and CHD: An unanswered question

Over the last several decades, there has been a great deal of interest in the relationship between hormones and CHD, much of it stemming from the controversy about hormone replacement therapy (HRT). The findings of the Women’s Health Initiative implicated combined exogenous hormones (estrogen and progestin) as a risk factor for CHD.⁴ Endogenous hormone production, however, may protect against CHD; some studies have demonstrated a decreased risk of cardiovascular death with later age of menopause.^5,6

Current oophorectomy recommendations are age-specific. The American College of Obstetricians and Gynecologists (ACOG) recommends that strong consideration be given to ovarian conservation in premenopausal women who are not at risk for ovarian cancer. For postmenopausal women, however, ACOG recommends consideration of oophorectomy as prophylaxis.⁷ These recommendations are based on expert opinion. Previous studies suggest that ovarian conservation may improve survival in specific age groups.^8,9 The large, high-quality observational study reviewed here provides further guidance about the role of ovarian conservation across all age groups.

STUDY SUMMARY: Oophorectomy increases risk of CHD and death

This observational study¹ was part of the Nurses’ Health Study. It included 29,380 women, of which 16,345 (55.6%) underwent hysterectomy with bilateral oophorectomy and 13,035 (44.4%) had hysterectomy with ovarian conservation. Women with unilateral oophorectomy were excluded, as were those who had a history of CHD or stroke, and women for whom pertinent data, such as age, were missing. A follow-up survey was sent to participants every 2 years for 24 years, with an average return rate of 90%.

Women who had undergone bilateral oophorectomy had an increased risk of CHD and all-cause mortality ( TABLE ). The authors estimated that with a postsurgical life span of approximately 35 years, every 9 oophorectomies would result in 1 additional death. The authors also pointed out there were no age exceptions: Ovarian-sparing surgery was linked to improved survival in every age group.

Oophorectomy did have a protective effect against breast cancer, ovarian cancer (number needed to treat=220), and total cancer incidence, but it was associated with an increased incidence of lung cancer (number needed to harm=190) and total cancer mortality. There was no significant difference in rates of stroke, pulmonary embolus, colorectal cancer, or hip fracture.

TABLE
Oophorectomy (vs ovarian conservation) increases key risks¹

WHAT’S NEW: Ovarian conservation: Better for all ages

The evidence is clear: Conserving the ovaries, rather than removing them, during hysterectomy is associated with a lower risk of CHD and both all-cause and cancer-related mortality.

What about the patient’s age? A 2005 analysis suggested that ovarian conservation conferred a survival benefit compared to oophorectomy in women <65 years.⁸ Similarly, a 2006 cohort study found increased mortality in women <45 years who underwent concurrent oophorectomy.⁹ But this is the first study to demonstrate that ovarian-sparing surgery is associated with improved survival in women of every age group.

CAVEATS: Study sample and HRT use could affect outcome

The average age of patients in the treatment (oophorectomy) arm was higher than that of patients in the control group; the women in the treatment group were older at the time of hysterectomy (46.8 vs 43.3 years), as well. This should not bias the results, which were adjusted by age and many other variables.

Nonrepresentative sample. This group of nurses is not representative of the general population in several important aspects, including socioeconomic status, educational level, and race (94% Caucasian). This may limit the generalizability of the findings.

Study design. The observational design and the fact that the patients themselves decided whether or not to undergo oophorectomy also raise the possibility of unmeasured confounding factors.

Cancer risk. Women with known BRCA mutations were not studied separately, but the results were adjusted for family history of breast or ovarian cancer. The authors stated that a subgroup analysis of women with a family history of ovarian cancer had similar outcomes, although the data were not included

HRT use. As might be expected, patients in the oophorectomy arm of the study were more likely to use HRT. Since the completion of the study in 2000, practice recommendations have shifted against combined HRT use. Unopposed estrogen, which is not thought to increase the incidence of cardiovascular disease, remains a treatment option for women who have undergone hysterectomy and oophorectomy. But the overall effect of unopposed estrogen on survival is still uncertain.⁴ It is unclear how the recent decline in the use of exogenous hormones would affect these results.

BARRIERS TO IMPLEMENTATION: FP-GYN communication can be difficult

This study provides important information for primary care physicians to discuss with female patients and their gynecologists. However, some doctors may not have relationships with the gynecologists in their community, or have limited (or no) influence or input into which specialists their patients see. In addition, some gynecologists may hesitate to perform hysterectomy without oophorectomy in some cases for technical reasons.¹⁰

Concern about prevention of ovarian cancer must be balanced with increased risk of mortality and CHD events. It may be helpful to tell patients who are about to undergo hysterectomy for a benign condition that women are nearly 30 times more likely to die of cardiovascular disease (CHD or stroke) than ovarian cancer (413,800/year vs 14,700/year).¹¹

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

The authors wish to acknowledge Sofia Medvedev, PhD, of the University HealthSystem Consortium in Oak Brook, Ill, for analysis of the National Ambulatory Medical Care Survey data and the UHC Clinical Database.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 44-year-old woman with a family history of early CHD is considering hysterectomy for painful uterine fibroids. She’s thinking about undergoing concurrent bilateral oophorectomy to prevent ovarian cancer and asks for your input. How would you advise her?

Hysterectomy is the most common gynecologic surgery in the United States. In 2003, more than 600,000 hysterectomies were performed; 89% were not associated with malignancies.²

Ovarian conservation is not the norm

Data from the University Health-System Consortium Clinical Database indicate that between 2002 and 2008, about 55% of women who had a hysterectomy that was not cancer-related underwent oophorectomy. Rates of concurrent oophorectomy included:

• 68% of women ages 65 and older
• 77% of women ages 51 to 64
• 48% of women ages 31 to 50
• 3% of women ages 18 to 30.

A recent analysis from the Centers for Disease Control and Prevention found that among women who underwent hysterectomy for any reason between 1994 and 1998, 55% also had their ovaries removed.³

Hormones and CHD: An unanswered question

Over the last several decades, there has been a great deal of interest in the relationship between hormones and CHD, much of it stemming from the controversy about hormone replacement therapy (HRT). The findings of the Women’s Health Initiative implicated combined exogenous hormones (estrogen and progestin) as a risk factor for CHD.⁴ Endogenous hormone production, however, may protect against CHD; some studies have demonstrated a decreased risk of cardiovascular death with later age of menopause.^5,6

Current oophorectomy recommendations are age-specific. The American College of Obstetricians and Gynecologists (ACOG) recommends that strong consideration be given to ovarian conservation in premenopausal women who are not at risk for ovarian cancer. For postmenopausal women, however, ACOG recommends consideration of oophorectomy as prophylaxis.⁷ These recommendations are based on expert opinion. Previous studies suggest that ovarian conservation may improve survival in specific age groups.^8,9 The large, high-quality observational study reviewed here provides further guidance about the role of ovarian conservation across all age groups.

STUDY SUMMARY: Oophorectomy increases risk of CHD and death

This observational study¹ was part of the Nurses’ Health Study. It included 29,380 women, of which 16,345 (55.6%) underwent hysterectomy with bilateral oophorectomy and 13,035 (44.4%) had hysterectomy with ovarian conservation. Women with unilateral oophorectomy were excluded, as were those who had a history of CHD or stroke, and women for whom pertinent data, such as age, were missing. A follow-up survey was sent to participants every 2 years for 24 years, with an average return rate of 90%.

Women who had undergone bilateral oophorectomy had an increased risk of CHD and all-cause mortality ( TABLE ). The authors estimated that with a postsurgical life span of approximately 35 years, every 9 oophorectomies would result in 1 additional death. The authors also pointed out there were no age exceptions: Ovarian-sparing surgery was linked to improved survival in every age group.

Oophorectomy did have a protective effect against breast cancer, ovarian cancer (number needed to treat=220), and total cancer incidence, but it was associated with an increased incidence of lung cancer (number needed to harm=190) and total cancer mortality. There was no significant difference in rates of stroke, pulmonary embolus, colorectal cancer, or hip fracture.

TABLE
Oophorectomy (vs ovarian conservation) increases key risks¹

WHAT’S NEW: Ovarian conservation: Better for all ages

The evidence is clear: Conserving the ovaries, rather than removing them, during hysterectomy is associated with a lower risk of CHD and both all-cause and cancer-related mortality.

What about the patient’s age? A 2005 analysis suggested that ovarian conservation conferred a survival benefit compared to oophorectomy in women <65 years.⁸ Similarly, a 2006 cohort study found increased mortality in women <45 years who underwent concurrent oophorectomy.⁹ But this is the first study to demonstrate that ovarian-sparing surgery is associated with improved survival in women of every age group.

CAVEATS: Study sample and HRT use could affect outcome

The average age of patients in the treatment (oophorectomy) arm was higher than that of patients in the control group; the women in the treatment group were older at the time of hysterectomy (46.8 vs 43.3 years), as well. This should not bias the results, which were adjusted by age and many other variables.

Nonrepresentative sample. This group of nurses is not representative of the general population in several important aspects, including socioeconomic status, educational level, and race (94% Caucasian). This may limit the generalizability of the findings.

Study design. The observational design and the fact that the patients themselves decided whether or not to undergo oophorectomy also raise the possibility of unmeasured confounding factors.

Cancer risk. Women with known BRCA mutations were not studied separately, but the results were adjusted for family history of breast or ovarian cancer. The authors stated that a subgroup analysis of women with a family history of ovarian cancer had similar outcomes, although the data were not included

HRT use. As might be expected, patients in the oophorectomy arm of the study were more likely to use HRT. Since the completion of the study in 2000, practice recommendations have shifted against combined HRT use. Unopposed estrogen, which is not thought to increase the incidence of cardiovascular disease, remains a treatment option for women who have undergone hysterectomy and oophorectomy. But the overall effect of unopposed estrogen on survival is still uncertain.⁴ It is unclear how the recent decline in the use of exogenous hormones would affect these results.

BARRIERS TO IMPLEMENTATION: FP-GYN communication can be difficult

This study provides important information for primary care physicians to discuss with female patients and their gynecologists. However, some doctors may not have relationships with the gynecologists in their community, or have limited (or no) influence or input into which specialists their patients see. In addition, some gynecologists may hesitate to perform hysterectomy without oophorectomy in some cases for technical reasons.¹⁰

Concern about prevention of ovarian cancer must be balanced with increased risk of mortality and CHD events. It may be helpful to tell patients who are about to undergo hysterectomy for a benign condition that women are nearly 30 times more likely to die of cardiovascular disease (CHD or stroke) than ovarian cancer (413,800/year vs 14,700/year).¹¹

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

The authors wish to acknowledge Sofia Medvedev, PhD, of the University HealthSystem Consortium in Oak Brook, Ill, for analysis of the National Ambulatory Medical Care Survey data and the UHC Clinical Database.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 44-year-old woman with a family history of early CHD is considering hysterectomy for painful uterine fibroids. She’s thinking about undergoing concurrent bilateral oophorectomy to prevent ovarian cancer and asks for your input. How would you advise her?

Hysterectomy is the most common gynecologic surgery in the United States. In 2003, more than 600,000 hysterectomies were performed; 89% were not associated with malignancies.²

Ovarian conservation is not the norm

Data from the University Health-System Consortium Clinical Database indicate that between 2002 and 2008, about 55% of women who had a hysterectomy that was not cancer-related underwent oophorectomy. Rates of concurrent oophorectomy included:

• 68% of women ages 65 and older
• 77% of women ages 51 to 64
• 48% of women ages 31 to 50
• 3% of women ages 18 to 30.

A recent analysis from the Centers for Disease Control and Prevention found that among women who underwent hysterectomy for any reason between 1994 and 1998, 55% also had their ovaries removed.³

Hormones and CHD: An unanswered question

Over the last several decades, there has been a great deal of interest in the relationship between hormones and CHD, much of it stemming from the controversy about hormone replacement therapy (HRT). The findings of the Women’s Health Initiative implicated combined exogenous hormones (estrogen and progestin) as a risk factor for CHD.⁴ Endogenous hormone production, however, may protect against CHD; some studies have demonstrated a decreased risk of cardiovascular death with later age of menopause.^5,6

Current oophorectomy recommendations are age-specific. The American College of Obstetricians and Gynecologists (ACOG) recommends that strong consideration be given to ovarian conservation in premenopausal women who are not at risk for ovarian cancer. For postmenopausal women, however, ACOG recommends consideration of oophorectomy as prophylaxis.⁷ These recommendations are based on expert opinion. Previous studies suggest that ovarian conservation may improve survival in specific age groups.^8,9 The large, high-quality observational study reviewed here provides further guidance about the role of ovarian conservation across all age groups.

STUDY SUMMARY: Oophorectomy increases risk of CHD and death

This observational study¹ was part of the Nurses’ Health Study. It included 29,380 women, of which 16,345 (55.6%) underwent hysterectomy with bilateral oophorectomy and 13,035 (44.4%) had hysterectomy with ovarian conservation. Women with unilateral oophorectomy were excluded, as were those who had a history of CHD or stroke, and women for whom pertinent data, such as age, were missing. A follow-up survey was sent to participants every 2 years for 24 years, with an average return rate of 90%.

Women who had undergone bilateral oophorectomy had an increased risk of CHD and all-cause mortality ( TABLE ). The authors estimated that with a postsurgical life span of approximately 35 years, every 9 oophorectomies would result in 1 additional death. The authors also pointed out there were no age exceptions: Ovarian-sparing surgery was linked to improved survival in every age group.

Oophorectomy did have a protective effect against breast cancer, ovarian cancer (number needed to treat=220), and total cancer incidence, but it was associated with an increased incidence of lung cancer (number needed to harm=190) and total cancer mortality. There was no significant difference in rates of stroke, pulmonary embolus, colorectal cancer, or hip fracture.

TABLE
Oophorectomy (vs ovarian conservation) increases key risks¹

WHAT’S NEW: Ovarian conservation: Better for all ages

The evidence is clear: Conserving the ovaries, rather than removing them, during hysterectomy is associated with a lower risk of CHD and both all-cause and cancer-related mortality.

What about the patient’s age? A 2005 analysis suggested that ovarian conservation conferred a survival benefit compared to oophorectomy in women <65 years.⁸ Similarly, a 2006 cohort study found increased mortality in women <45 years who underwent concurrent oophorectomy.⁹ But this is the first study to demonstrate that ovarian-sparing surgery is associated with improved survival in women of every age group.

CAVEATS: Study sample and HRT use could affect outcome

The average age of patients in the treatment (oophorectomy) arm was higher than that of patients in the control group; the women in the treatment group were older at the time of hysterectomy (46.8 vs 43.3 years), as well. This should not bias the results, which were adjusted by age and many other variables.

Nonrepresentative sample. This group of nurses is not representative of the general population in several important aspects, including socioeconomic status, educational level, and race (94% Caucasian). This may limit the generalizability of the findings.

Study design. The observational design and the fact that the patients themselves decided whether or not to undergo oophorectomy also raise the possibility of unmeasured confounding factors.

Cancer risk. Women with known BRCA mutations were not studied separately, but the results were adjusted for family history of breast or ovarian cancer. The authors stated that a subgroup analysis of women with a family history of ovarian cancer had similar outcomes, although the data were not included

HRT use. As might be expected, patients in the oophorectomy arm of the study were more likely to use HRT. Since the completion of the study in 2000, practice recommendations have shifted against combined HRT use. Unopposed estrogen, which is not thought to increase the incidence of cardiovascular disease, remains a treatment option for women who have undergone hysterectomy and oophorectomy. But the overall effect of unopposed estrogen on survival is still uncertain.⁴ It is unclear how the recent decline in the use of exogenous hormones would affect these results.

BARRIERS TO IMPLEMENTATION: FP-GYN communication can be difficult

This study provides important information for primary care physicians to discuss with female patients and their gynecologists. However, some doctors may not have relationships with the gynecologists in their community, or have limited (or no) influence or input into which specialists their patients see. In addition, some gynecologists may hesitate to perform hysterectomy without oophorectomy in some cases for technical reasons.¹⁰

Concern about prevention of ovarian cancer must be balanced with increased risk of mortality and CHD events. It may be helpful to tell patients who are about to undergo hysterectomy for a benign condition that women are nearly 30 times more likely to die of cardiovascular disease (CHD or stroke) than ovarian cancer (413,800/year vs 14,700/year).¹¹

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

The authors wish to acknowledge Sofia Medvedev, PhD, of the University HealthSystem Consortium in Oak Brook, Ill, for analysis of the National Ambulatory Medical Care Survey data and the UHC Clinical Database.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

During a routine checkup of a 2-month-old boy, you notice that the left side of his head is slightly flatter than the right and his forehead protrudes forward more on the left than the right. His birth history and development are normal. You wonder if the asymmetry will resolve as the infant grows older or whether you should suggest immediate treatment.

The American Academy of Pediatrics recommends putting babies to sleep on their backs to reduce the risk of sudden infant death syndrome. As more parents have followed this recommendation, the incidence of positional preference and DP has increased, presumably because external pressure distorts the malleable infant cranium. Prenatal and intrapartum factors also can cause DP, but sleeping on the back likely accounts for the recent increase.^2-4

Not just a cosmetic issue
Although many clinicians consider skull deformities to be purely cosmetic,⁵ plagiocephaly is associated with auditory processing disorders, mandibular asymmetry, and visual field defects. Head deformities resulting from premature fusion of the cranial sutures (craniosynostosis) have been linked to an increased incidence of speech-language, cognitive, behavioral, and neurodevelopmental abnormalities.^6,7 Whether these associations are causal is not yet known.⁵ Many parents believe that unattractive facial features lead to adverse effects on children, such as teasing and poor self-esteem.^5,6

Conservative treatments for positional preference and DP include parental counseling, counter-positioning, simple exercises, and orthotic devices such as helmets.⁸ Scientific evidence supporting the effectiveness of these approaches is weak. The study we review in this PURL provides strong evidence of the effectiveness of 1 intervention—physical therapy (PT).

STUDY SUMMARY: Early physical therapy prevents severe DP

van Vlimmeren and colleagues conducted a prospective RCT comparing PT with usual care for preventing DP.¹ From a group of 400 infants born consecutively in the Netherlands, they identified 65 with positional preference at 7 weeks of age and randomized them to PT or a control group. Pediatric physical therapists blinded to group allocation evaluated each infant at 6 and 12 months. Babies with congenital muscular torticollis (defined as preferential posture of the head and asymmetrical cervical movements caused by a unilateral contracture of the sternocleidomastoid muscle), dysmorphisms, or congenital syndromes were excluded.

The PT and control groups were comparable at baseline. Parents of infants in the control group received a pamphlet about basic preventive measures, but no additional instructions. Infants in the intervention group received standardized pediatric PT from trained therapists who were unaware of the results of the infants’ baseline assessments.

PT consisted of 8 sessions between 7 weeks and 6 months of age. The first 4 sessions were held weekly; subsequent sessions occurred every 2 to 3 weeks. The second through fifth sessions took place at the infant’s home.

The intervention included exercises to reduce positional preference and stimulate motor development, along with parental counseling about counter-positioning, handling, nursing, and the causes of positional preference. Parents received a pamphlet describing basic measures to prevent DP. The therapists also encouraged earlier and more frequent play times in the prone position (“tummy time”). PT was discontinued when the infant no longer demonstrated positional preference while awake or asleep, parents were following advice about handling, and the baby exhibited no signs of motor developmental delay or asymmetries.

The primary outcome was severe DP, measured as an oblique diameter difference index (ODDI) score of 104% or more—a score representing asymmetry of the skull that is obviously noticeable and therefore considered clinically relevant.⁹ The secondary outcome measures were symmetry in posture and active movements, motor development, and passive range of motion of the cervical spine.

Intervention reduced DP at 6 and 12 months. By 6 months of age, the number of infants in the intervention group with severe DP had decreased significantly from 53% to 30%, compared with a decrease from 63% to 56% in the control group (relative risk [RR]=0.54; 95% confidence interval [CI], 0.30-0.98; number needed to treat [NNT]=3.85). At 12 months, the number of babies in the intervention group with severe DP had decreased further, to 24%, whereas the number in the control group remained unchanged at 56% (RR=0.43; 95% CI, 0.22-0.85; NNT=3.13).

Secondary outcomes comparable. No major differences in secondary outcomes were noted between the 2 groups. At 6 and 12 months of age, none of the infants had positional preference or differences in motor development. Passive range of motion of the cervical spine was within normal range and symmetrical in all infants at baseline and at 6 and 12 months. However, at the 6-month evaluation, parents of babies in the intervention group demonstrated greater symmetry and less left orientation in nursing, positioning, and handling of the infants.

WHAT’S NEW: Early intervention trumps conservative therapies

This is the first RCT of a pediatric PT program to treat infants with positional preference to prevent severe plagiocephaly, and the study provides strong evidence to support this practice. The study included healthy infants, much like the ones we encounter in primary care practice. If, as we suspect, many of us have been recommending conservative therapies, we have reason to consider referral for this increasingly common clinical problem.

CAVEATS: Study did not focus on serious deficits

This study excluded infants with congenital muscular torticollis, dysmorphisms, or other congenital syndromes. We need to be aware of these causes of DP, which may warrant additional referrals beyond pediatric PT. In addition, DP should be distinguished from craniosynostosis, which requires referral for surgical evaluation and treatment.

Cosmetic issues vs more serious problems. DP is the most benign of the many causes of head deformities. The outcomes of this trial mainly addressed the cosmetic issue rather than more serious deficits associated with plagiocephaly. Nevertheless, we believe that cosmetic considerations are important to parents and children. What’s more, the intervention carries no risk of adverse effects and produces notable benefit. We conclude that discussing PT referral with parents is the appropriate practice change to implement based on this study.

Infant age, length of follow-up. Because this study did not evaluate the impact of the intervention on infants older than 7 to 8 weeks, it is not clear whether PT would be as effective if begun later in infancy. The relatively short follow-up (12 months) precludes conclusions about outcomes such as social functioning and school performance.

CHALLENGES TO IMPLEMENTATION: A matter of time

The incidence of positional preference has been reported to be as high as 22% at 7 weeks, making it a relatively common problem encountered by family physicians.⁷ Most children with positional preference do not develop DP and when they do, it is typically a cosmetic problem. Ruling out torticollis, craniosynostosis, and other congenital causes is critical. Ascertaining parental preference is a major consideration in the decision to refer for PT. All of this takes time.

However, parents are often concerned about their baby’s misshapen skull. We think that addressing positional preference is time well spent, especially since we now have evidence that a noninvasive approach—PT—can effectively prevent DP.

Acknowledgments

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the university of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

During a routine checkup of a 2-month-old boy, you notice that the left side of his head is slightly flatter than the right and his forehead protrudes forward more on the left than the right. His birth history and development are normal. You wonder if the asymmetry will resolve as the infant grows older or whether you should suggest immediate treatment.

The American Academy of Pediatrics recommends putting babies to sleep on their backs to reduce the risk of sudden infant death syndrome. As more parents have followed this recommendation, the incidence of positional preference and DP has increased, presumably because external pressure distorts the malleable infant cranium. Prenatal and intrapartum factors also can cause DP, but sleeping on the back likely accounts for the recent increase.^2-4

Not just a cosmetic issue
Although many clinicians consider skull deformities to be purely cosmetic,⁵ plagiocephaly is associated with auditory processing disorders, mandibular asymmetry, and visual field defects. Head deformities resulting from premature fusion of the cranial sutures (craniosynostosis) have been linked to an increased incidence of speech-language, cognitive, behavioral, and neurodevelopmental abnormalities.^6,7 Whether these associations are causal is not yet known.⁵ Many parents believe that unattractive facial features lead to adverse effects on children, such as teasing and poor self-esteem.^5,6

Conservative treatments for positional preference and DP include parental counseling, counter-positioning, simple exercises, and orthotic devices such as helmets.⁸ Scientific evidence supporting the effectiveness of these approaches is weak. The study we review in this PURL provides strong evidence of the effectiveness of 1 intervention—physical therapy (PT).

STUDY SUMMARY: Early physical therapy prevents severe DP

van Vlimmeren and colleagues conducted a prospective RCT comparing PT with usual care for preventing DP.¹ From a group of 400 infants born consecutively in the Netherlands, they identified 65 with positional preference at 7 weeks of age and randomized them to PT or a control group. Pediatric physical therapists blinded to group allocation evaluated each infant at 6 and 12 months. Babies with congenital muscular torticollis (defined as preferential posture of the head and asymmetrical cervical movements caused by a unilateral contracture of the sternocleidomastoid muscle), dysmorphisms, or congenital syndromes were excluded.

The PT and control groups were comparable at baseline. Parents of infants in the control group received a pamphlet about basic preventive measures, but no additional instructions. Infants in the intervention group received standardized pediatric PT from trained therapists who were unaware of the results of the infants’ baseline assessments.

PT consisted of 8 sessions between 7 weeks and 6 months of age. The first 4 sessions were held weekly; subsequent sessions occurred every 2 to 3 weeks. The second through fifth sessions took place at the infant’s home.

The intervention included exercises to reduce positional preference and stimulate motor development, along with parental counseling about counter-positioning, handling, nursing, and the causes of positional preference. Parents received a pamphlet describing basic measures to prevent DP. The therapists also encouraged earlier and more frequent play times in the prone position (“tummy time”). PT was discontinued when the infant no longer demonstrated positional preference while awake or asleep, parents were following advice about handling, and the baby exhibited no signs of motor developmental delay or asymmetries.

The primary outcome was severe DP, measured as an oblique diameter difference index (ODDI) score of 104% or more—a score representing asymmetry of the skull that is obviously noticeable and therefore considered clinically relevant.⁹ The secondary outcome measures were symmetry in posture and active movements, motor development, and passive range of motion of the cervical spine.

Intervention reduced DP at 6 and 12 months. By 6 months of age, the number of infants in the intervention group with severe DP had decreased significantly from 53% to 30%, compared with a decrease from 63% to 56% in the control group (relative risk [RR]=0.54; 95% confidence interval [CI], 0.30-0.98; number needed to treat [NNT]=3.85). At 12 months, the number of babies in the intervention group with severe DP had decreased further, to 24%, whereas the number in the control group remained unchanged at 56% (RR=0.43; 95% CI, 0.22-0.85; NNT=3.13).

Secondary outcomes comparable. No major differences in secondary outcomes were noted between the 2 groups. At 6 and 12 months of age, none of the infants had positional preference or differences in motor development. Passive range of motion of the cervical spine was within normal range and symmetrical in all infants at baseline and at 6 and 12 months. However, at the 6-month evaluation, parents of babies in the intervention group demonstrated greater symmetry and less left orientation in nursing, positioning, and handling of the infants.

WHAT’S NEW: Early intervention trumps conservative therapies

This is the first RCT of a pediatric PT program to treat infants with positional preference to prevent severe plagiocephaly, and the study provides strong evidence to support this practice. The study included healthy infants, much like the ones we encounter in primary care practice. If, as we suspect, many of us have been recommending conservative therapies, we have reason to consider referral for this increasingly common clinical problem.

CAVEATS: Study did not focus on serious deficits

This study excluded infants with congenital muscular torticollis, dysmorphisms, or other congenital syndromes. We need to be aware of these causes of DP, which may warrant additional referrals beyond pediatric PT. In addition, DP should be distinguished from craniosynostosis, which requires referral for surgical evaluation and treatment.

Cosmetic issues vs more serious problems. DP is the most benign of the many causes of head deformities. The outcomes of this trial mainly addressed the cosmetic issue rather than more serious deficits associated with plagiocephaly. Nevertheless, we believe that cosmetic considerations are important to parents and children. What’s more, the intervention carries no risk of adverse effects and produces notable benefit. We conclude that discussing PT referral with parents is the appropriate practice change to implement based on this study.

Infant age, length of follow-up. Because this study did not evaluate the impact of the intervention on infants older than 7 to 8 weeks, it is not clear whether PT would be as effective if begun later in infancy. The relatively short follow-up (12 months) precludes conclusions about outcomes such as social functioning and school performance.

CHALLENGES TO IMPLEMENTATION: A matter of time

The incidence of positional preference has been reported to be as high as 22% at 7 weeks, making it a relatively common problem encountered by family physicians.⁷ Most children with positional preference do not develop DP and when they do, it is typically a cosmetic problem. Ruling out torticollis, craniosynostosis, and other congenital causes is critical. Ascertaining parental preference is a major consideration in the decision to refer for PT. All of this takes time.

However, parents are often concerned about their baby’s misshapen skull. We think that addressing positional preference is time well spent, especially since we now have evidence that a noninvasive approach—PT—can effectively prevent DP.

Acknowledgments

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the university of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

During a routine checkup of a 2-month-old boy, you notice that the left side of his head is slightly flatter than the right and his forehead protrudes forward more on the left than the right. His birth history and development are normal. You wonder if the asymmetry will resolve as the infant grows older or whether you should suggest immediate treatment.

The American Academy of Pediatrics recommends putting babies to sleep on their backs to reduce the risk of sudden infant death syndrome. As more parents have followed this recommendation, the incidence of positional preference and DP has increased, presumably because external pressure distorts the malleable infant cranium. Prenatal and intrapartum factors also can cause DP, but sleeping on the back likely accounts for the recent increase.^2-4

Not just a cosmetic issue
Although many clinicians consider skull deformities to be purely cosmetic,⁵ plagiocephaly is associated with auditory processing disorders, mandibular asymmetry, and visual field defects. Head deformities resulting from premature fusion of the cranial sutures (craniosynostosis) have been linked to an increased incidence of speech-language, cognitive, behavioral, and neurodevelopmental abnormalities.^6,7 Whether these associations are causal is not yet known.⁵ Many parents believe that unattractive facial features lead to adverse effects on children, such as teasing and poor self-esteem.^5,6

Conservative treatments for positional preference and DP include parental counseling, counter-positioning, simple exercises, and orthotic devices such as helmets.⁸ Scientific evidence supporting the effectiveness of these approaches is weak. The study we review in this PURL provides strong evidence of the effectiveness of 1 intervention—physical therapy (PT).

STUDY SUMMARY: Early physical therapy prevents severe DP

van Vlimmeren and colleagues conducted a prospective RCT comparing PT with usual care for preventing DP.¹ From a group of 400 infants born consecutively in the Netherlands, they identified 65 with positional preference at 7 weeks of age and randomized them to PT or a control group. Pediatric physical therapists blinded to group allocation evaluated each infant at 6 and 12 months. Babies with congenital muscular torticollis (defined as preferential posture of the head and asymmetrical cervical movements caused by a unilateral contracture of the sternocleidomastoid muscle), dysmorphisms, or congenital syndromes were excluded.

The PT and control groups were comparable at baseline. Parents of infants in the control group received a pamphlet about basic preventive measures, but no additional instructions. Infants in the intervention group received standardized pediatric PT from trained therapists who were unaware of the results of the infants’ baseline assessments.

PT consisted of 8 sessions between 7 weeks and 6 months of age. The first 4 sessions were held weekly; subsequent sessions occurred every 2 to 3 weeks. The second through fifth sessions took place at the infant’s home.

The intervention included exercises to reduce positional preference and stimulate motor development, along with parental counseling about counter-positioning, handling, nursing, and the causes of positional preference. Parents received a pamphlet describing basic measures to prevent DP. The therapists also encouraged earlier and more frequent play times in the prone position (“tummy time”). PT was discontinued when the infant no longer demonstrated positional preference while awake or asleep, parents were following advice about handling, and the baby exhibited no signs of motor developmental delay or asymmetries.

The primary outcome was severe DP, measured as an oblique diameter difference index (ODDI) score of 104% or more—a score representing asymmetry of the skull that is obviously noticeable and therefore considered clinically relevant.⁹ The secondary outcome measures were symmetry in posture and active movements, motor development, and passive range of motion of the cervical spine.

Intervention reduced DP at 6 and 12 months. By 6 months of age, the number of infants in the intervention group with severe DP had decreased significantly from 53% to 30%, compared with a decrease from 63% to 56% in the control group (relative risk [RR]=0.54; 95% confidence interval [CI], 0.30-0.98; number needed to treat [NNT]=3.85). At 12 months, the number of babies in the intervention group with severe DP had decreased further, to 24%, whereas the number in the control group remained unchanged at 56% (RR=0.43; 95% CI, 0.22-0.85; NNT=3.13).

Secondary outcomes comparable. No major differences in secondary outcomes were noted between the 2 groups. At 6 and 12 months of age, none of the infants had positional preference or differences in motor development. Passive range of motion of the cervical spine was within normal range and symmetrical in all infants at baseline and at 6 and 12 months. However, at the 6-month evaluation, parents of babies in the intervention group demonstrated greater symmetry and less left orientation in nursing, positioning, and handling of the infants.

WHAT’S NEW: Early intervention trumps conservative therapies

This is the first RCT of a pediatric PT program to treat infants with positional preference to prevent severe plagiocephaly, and the study provides strong evidence to support this practice. The study included healthy infants, much like the ones we encounter in primary care practice. If, as we suspect, many of us have been recommending conservative therapies, we have reason to consider referral for this increasingly common clinical problem.

CAVEATS: Study did not focus on serious deficits

This study excluded infants with congenital muscular torticollis, dysmorphisms, or other congenital syndromes. We need to be aware of these causes of DP, which may warrant additional referrals beyond pediatric PT. In addition, DP should be distinguished from craniosynostosis, which requires referral for surgical evaluation and treatment.

Cosmetic issues vs more serious problems. DP is the most benign of the many causes of head deformities. The outcomes of this trial mainly addressed the cosmetic issue rather than more serious deficits associated with plagiocephaly. Nevertheless, we believe that cosmetic considerations are important to parents and children. What’s more, the intervention carries no risk of adverse effects and produces notable benefit. We conclude that discussing PT referral with parents is the appropriate practice change to implement based on this study.

Infant age, length of follow-up. Because this study did not evaluate the impact of the intervention on infants older than 7 to 8 weeks, it is not clear whether PT would be as effective if begun later in infancy. The relatively short follow-up (12 months) precludes conclusions about outcomes such as social functioning and school performance.

CHALLENGES TO IMPLEMENTATION: A matter of time

The incidence of positional preference has been reported to be as high as 22% at 7 weeks, making it a relatively common problem encountered by family physicians.⁷ Most children with positional preference do not develop DP and when they do, it is typically a cosmetic problem. Ruling out torticollis, craniosynostosis, and other congenital causes is critical. Ascertaining parental preference is a major consideration in the decision to refer for PT. All of this takes time.

However, parents are often concerned about their baby’s misshapen skull. We think that addressing positional preference is time well spent, especially since we now have evidence that a noninvasive approach—PT—can effectively prevent DP.

Acknowledgments

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the university of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 23-year-old patient with a body mass index (BMI) of 18 tells you she’s fat and she’s afraid of gaining weight. Further questioning reveals that your patient binges on cookies and potato chips about once a week, then compensates for overeating by taking laxatives or exercising excessively—a practice she’s been following since she started college several years ago. The eating disorder she describes does not meet the criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) for bulimia or anorexia nervosa, although it has elements of both. Rather, it fits the diagnostic criteria for eating disorder NOS. You’re aware that CBT is the first-line behavioral treatment for bulimia, and wonder whether it would be helpful for your patient.

Eating disorders often go undetected and untreated in primary care practices,³ as many patients don’t volunteer information about their weight or behaviors related to food, and physicians often fail to ask. Overall, as few as 10% of those with eating disorders receive any form of treatment.¹

Would you recognize this loosely defined disorder?

In the United States, the lifetime prevalence of eating disorders is 0.6% for anorexia nervosa (0.3% for men and 0.9% for women), 1.0% for bulimia (0.5% for men and 1.5% for women), and 2.8% for binge-eating disorder (2.0% for men, 3.5% for women).⁴ Eating disorder NOS, which encompasses subthreshold cases of anorexia or bulimia, patients with elements of both anorexia and bulimia, and patients with binge-eating disorder, accounts for 50% to 80% of eating disorder diagnoses in outpatient settings. Yet there have been few studies of the treatment of these patients.^2,5,6

A review of DSM-IV criteria

The diagnostic criteria for anorexia nervosa include a refusal to maintain a weight of at least 85% of normal body weight (or having a BMI ≤17.5), intense fear of gaining weight, disturbance in the way one’s body shape is experienced, and amenorrhea in females who are post-menarche.

Criteria for bulimia include recurrent episodes of binge eating (consuming a large amount of food with a sense of lack of control over eating) and recurrent inappropriate compensatory behaviors to prevent weight gain (self-induced vomiting, excessive exercise, fasting, laxatives, diuretics, or enemas) at least twice weekly for 3 months; and self-evaluation that is unduly influenced by body shape and weight.⁷ Most patients with eating disorder NOS have clinical features of both anorexia and bulimia.⁶

APA guidelines are silent on NOS

CBT has consistently proven to be the most useful behavioral treatment for patients with bulimia.¹ Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine—the only medication with Food and Drug Administration approval for the treatment of an eating disorder⁸ —are about as effective as CBT, and the combination of CBT and an SSRI is superior to either treatment alone.⁹ CBT has also been found to be somewhat effective in treating binge-eating disorder.¹⁰

Anorexia nervosa, the most deadly eating disorder (the mortality rate is 6.6%¹¹ ) and the most difficult to treat, is the exception. Several studies have assessed CBT for treating anorexia, but it has not been found to be very effective.^10,12,13

The 2006 American Psychiatric Association practice guidelines for the treatment of patients with eating disorders feature recommendations for anorexia, bulimia, and binge-eating disorder, but do not address eating disorder NOS.¹⁰ The National Institute for Clinical Excellence (NICE) in the United Kingdom issued guidelines for the treatment of eating disorders in 2004. In response to the lack of evidence for treating eating disorder NOS, NICE recommended basing treatment on the form of eating disorder that most closely resembles the patient’s presentation.¹⁴ Fairburn et al addressed the lack of evidence for treatment of eating disorder NOS with the study summarized here.

STUDY SUMMARY: Both broad and focused CBT delivered results

Conducted at 2 eating disorder centers in the United Kingdom, this RCT included 154 patients, 18 to 65 years of age, who met DSM-IV criteria for either bulimia or eating disorder NOS. Exclusion criteria included prior treatment with CBT or other evidence-based treatment for the same eating disorder, and a BMI ≤17.5.

Most of the patients were female (95.5%) and white (90.3%), with a median age of 26 years and a median duration of eating disorder of 8.6 years. Sixty-two percent of the patients had a diagnosis of eating disorder NOS, and 38% were diagnosed with bulimia. Half of the patients had another current psychiatric diagnosis—a major depressive disorder, an anxiety disorder, or substance abuse.

The patients were randomized into 4 groups: Two received immediate treatment, and the other 2, referred to as waiting list controls, waited 8 weeks before beginning treatment. Treatment consisted of 1 of 2 forms of CBT-E, an enhanced form of CBT used to treat adult outpatients with eating disorders. Patients either received CBT-Ef, a focused form of CBT that exclusively targets eating disorder psychopathology, or CBT-Eb, a broader form of therapy that also addresses other problems that are common in patients with eating disorders, such as perfectionism and low self-esteem.

Both types of CBT-E featured a 90-minute preparatory session, 20 50-minute sessions, and 1 review session 20 weeks after completion of treatment. In the first 4 sessions, CBT-Ef and CBT-Eb were identical—addressing the eating disorder exclusively. CBT-Ef continued to focus on the eating disorder for the rest of the sessions, while subsequent CBT-Eb sessions also dealt with mood intolerance, interpersonal difficulties, and related issues. Five therapists—4 psychologists and 1 nurse-therapist—conducted the treatments.

Patients were weaned from ongoing psychiatric therapy during the study, but those who were on antidepressant therapy (n=76) were able to continue it. Patients were assessed before treatment, at the end of the waiting period for those in the control groups, after 8 weeks of treatment, at the end of treatment, and 20, 40, and 60 weeks after completion of treatment. (Twenty-two percent of the enrollees did not complete treatment.)

Primary outcomes were based on the Eating Disorder Examination (EDE), administered by assessors who were not involved in the treatment and were blinded to the patients’ group assignment. Change in severity of eating disorder features was measured by the global EDE score (0-6) and attaining a global EDE score <1.74 (<1 standard deviation above the community mean).

No treatment vs CBT. The waiting period left little doubt of the short-term efficacy of CBT: After 8 weeks, there was significant improvement in eating disorder behaviors and overall severity in both the CBT-Ef and CBT-Eb groups (EDE scores fell from 4.15 at baseline to 3.26 and from 4.04 to 2.89, respectively). In the same time period, scores for the waiting list control groups remained flat (from 4.08 at baseline to 3.99).

At the end of treatment and at the 60-week follow-up, patients in both forms of CBT-E showed significant improvement across all measures, with no significant difference between treatments. By the end of treatment, 66.4% of those who completed all of the CBT sessions had global EDE scores <1.74 (considered clinically significant).

Subgroup analysis offers opportunity for fine-tuning

When analyzed separately, the patients with bulimia and those with eating disorder NOS did equally well at the end of treatment: 52.7% of those with bulimia and 53.3% of those with eating disorder NOS had global EDE scores <1.74. At the 60-week follow-up, the patients with bulimia maintained their improvement slightly more: 61.4% had global EDE scores <1.74, compared with 45.7% of the patients with eating disorder NOS.

The researchers also compared the outcomes of patients with the most complex additional psychopathology with those of patients with less complex problems. Greater complexity was defined as moderate ratings in at least 2 of the following domains: mood intolerance, clinical perfectionism, low self-esteem, and interpersonal difficulties.

Broad focus more effective for high complexity. Overall, those in the more complex subgroup did not respond as well; 48% had global EDE scores <1.74, vs 60% of those in the less complex group. However, those in the more complex subgroup did better with the broad form of CBT (at 60-week follow up, 60% had scores <1.74 with CBT-Eb, compared with 40% in the CBT-Ef treatment arm), while the less complex subgroup did better with the more tightly focused CBT-Ef. ²

WHAT’S NEW: Evidence supports CBT for NOS diagnosis

The most recent (2004) Cochrane review of “psychotherapy for bulimia nervosa and binging” included 40 RCTs of patients with bulimia, binge-eating disorder, and eating disorder NOS with recurrent binge-eating episodes (included in 7 studies). While the review confirmed that CBT is effective for bulimia and “similar syndromes,” it identified a need for larger and higher quality trials of CBT, particularly in patients with eating disorder NOS.¹ The study reviewed in this PURL—the first large, high-quality trial to include a number of patients with eating disorder NOS—provides strong evidence that CBT is effective for this group of patients.²

CAVEATS: Limited wait time leaves unanswered questions

One limitation of this study is the lack of a control group beyond the 8-week waiting period. Prior studies of CBT for bulimia that delayed therapy for those in the control groups for a longer duration have consistently shown that patients receiving CBT did significantly better than those in the control group.⁹ While a “no treatment” group would have made the results more robust in this case, it would not have been ethical to withhold treatment for the entire length of the study.

It is noteworthy, too, that this study only included patients with a BMI >17.5. Patients with a diagnosis of anorexia nervosa, who by definition have a lower BMI, will need other treatments, including hospitalization in some cases.

CHALLENGES TO IMPLEMENTATION: Identifying patients and therapists

The primary challenge is to determine which of your patients have eating disorders. When discussing diet, adding a simple question such as, “Are you happy with your current weight?” can help you identify those who meet the criteria for an eating disorder or are at high risk.³

Identifying local mental health providers who are trained to provide CBT for patients with eating disorders is another concern. Insurance coverage for this intensive treatment may also be a limiting factor in some cases.

Many studies support the use of fluoxetine for patients with bulimia, and combined treatment with SSRIs and CBT has been shown to be superior to either treatment alone.^8,10,14 Consider starting the patient on an antidepressant while she (or he) awaits the start of CBT.

Acknowledgements

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURLs) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 23-year-old patient with a body mass index (BMI) of 18 tells you she’s fat and she’s afraid of gaining weight. Further questioning reveals that your patient binges on cookies and potato chips about once a week, then compensates for overeating by taking laxatives or exercising excessively—a practice she’s been following since she started college several years ago. The eating disorder she describes does not meet the criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) for bulimia or anorexia nervosa, although it has elements of both. Rather, it fits the diagnostic criteria for eating disorder NOS. You’re aware that CBT is the first-line behavioral treatment for bulimia, and wonder whether it would be helpful for your patient.

Eating disorders often go undetected and untreated in primary care practices,³ as many patients don’t volunteer information about their weight or behaviors related to food, and physicians often fail to ask. Overall, as few as 10% of those with eating disorders receive any form of treatment.¹

Would you recognize this loosely defined disorder?

In the United States, the lifetime prevalence of eating disorders is 0.6% for anorexia nervosa (0.3% for men and 0.9% for women), 1.0% for bulimia (0.5% for men and 1.5% for women), and 2.8% for binge-eating disorder (2.0% for men, 3.5% for women).⁴ Eating disorder NOS, which encompasses subthreshold cases of anorexia or bulimia, patients with elements of both anorexia and bulimia, and patients with binge-eating disorder, accounts for 50% to 80% of eating disorder diagnoses in outpatient settings. Yet there have been few studies of the treatment of these patients.^2,5,6

A review of DSM-IV criteria

The diagnostic criteria for anorexia nervosa include a refusal to maintain a weight of at least 85% of normal body weight (or having a BMI ≤17.5), intense fear of gaining weight, disturbance in the way one’s body shape is experienced, and amenorrhea in females who are post-menarche.

Criteria for bulimia include recurrent episodes of binge eating (consuming a large amount of food with a sense of lack of control over eating) and recurrent inappropriate compensatory behaviors to prevent weight gain (self-induced vomiting, excessive exercise, fasting, laxatives, diuretics, or enemas) at least twice weekly for 3 months; and self-evaluation that is unduly influenced by body shape and weight.⁷ Most patients with eating disorder NOS have clinical features of both anorexia and bulimia.⁶

APA guidelines are silent on NOS

CBT has consistently proven to be the most useful behavioral treatment for patients with bulimia.¹ Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine—the only medication with Food and Drug Administration approval for the treatment of an eating disorder⁸ —are about as effective as CBT, and the combination of CBT and an SSRI is superior to either treatment alone.⁹ CBT has also been found to be somewhat effective in treating binge-eating disorder.¹⁰

Anorexia nervosa, the most deadly eating disorder (the mortality rate is 6.6%¹¹ ) and the most difficult to treat, is the exception. Several studies have assessed CBT for treating anorexia, but it has not been found to be very effective.^10,12,13

The 2006 American Psychiatric Association practice guidelines for the treatment of patients with eating disorders feature recommendations for anorexia, bulimia, and binge-eating disorder, but do not address eating disorder NOS.¹⁰ The National Institute for Clinical Excellence (NICE) in the United Kingdom issued guidelines for the treatment of eating disorders in 2004. In response to the lack of evidence for treating eating disorder NOS, NICE recommended basing treatment on the form of eating disorder that most closely resembles the patient’s presentation.¹⁴ Fairburn et al addressed the lack of evidence for treatment of eating disorder NOS with the study summarized here.

STUDY SUMMARY: Both broad and focused CBT delivered results

Conducted at 2 eating disorder centers in the United Kingdom, this RCT included 154 patients, 18 to 65 years of age, who met DSM-IV criteria for either bulimia or eating disorder NOS. Exclusion criteria included prior treatment with CBT or other evidence-based treatment for the same eating disorder, and a BMI ≤17.5.

Most of the patients were female (95.5%) and white (90.3%), with a median age of 26 years and a median duration of eating disorder of 8.6 years. Sixty-two percent of the patients had a diagnosis of eating disorder NOS, and 38% were diagnosed with bulimia. Half of the patients had another current psychiatric diagnosis—a major depressive disorder, an anxiety disorder, or substance abuse.

The patients were randomized into 4 groups: Two received immediate treatment, and the other 2, referred to as waiting list controls, waited 8 weeks before beginning treatment. Treatment consisted of 1 of 2 forms of CBT-E, an enhanced form of CBT used to treat adult outpatients with eating disorders. Patients either received CBT-Ef, a focused form of CBT that exclusively targets eating disorder psychopathology, or CBT-Eb, a broader form of therapy that also addresses other problems that are common in patients with eating disorders, such as perfectionism and low self-esteem.

Both types of CBT-E featured a 90-minute preparatory session, 20 50-minute sessions, and 1 review session 20 weeks after completion of treatment. In the first 4 sessions, CBT-Ef and CBT-Eb were identical—addressing the eating disorder exclusively. CBT-Ef continued to focus on the eating disorder for the rest of the sessions, while subsequent CBT-Eb sessions also dealt with mood intolerance, interpersonal difficulties, and related issues. Five therapists—4 psychologists and 1 nurse-therapist—conducted the treatments.

Patients were weaned from ongoing psychiatric therapy during the study, but those who were on antidepressant therapy (n=76) were able to continue it. Patients were assessed before treatment, at the end of the waiting period for those in the control groups, after 8 weeks of treatment, at the end of treatment, and 20, 40, and 60 weeks after completion of treatment. (Twenty-two percent of the enrollees did not complete treatment.)

Primary outcomes were based on the Eating Disorder Examination (EDE), administered by assessors who were not involved in the treatment and were blinded to the patients’ group assignment. Change in severity of eating disorder features was measured by the global EDE score (0-6) and attaining a global EDE score <1.74 (<1 standard deviation above the community mean).

No treatment vs CBT. The waiting period left little doubt of the short-term efficacy of CBT: After 8 weeks, there was significant improvement in eating disorder behaviors and overall severity in both the CBT-Ef and CBT-Eb groups (EDE scores fell from 4.15 at baseline to 3.26 and from 4.04 to 2.89, respectively). In the same time period, scores for the waiting list control groups remained flat (from 4.08 at baseline to 3.99).

At the end of treatment and at the 60-week follow-up, patients in both forms of CBT-E showed significant improvement across all measures, with no significant difference between treatments. By the end of treatment, 66.4% of those who completed all of the CBT sessions had global EDE scores <1.74 (considered clinically significant).

Subgroup analysis offers opportunity for fine-tuning

When analyzed separately, the patients with bulimia and those with eating disorder NOS did equally well at the end of treatment: 52.7% of those with bulimia and 53.3% of those with eating disorder NOS had global EDE scores <1.74. At the 60-week follow-up, the patients with bulimia maintained their improvement slightly more: 61.4% had global EDE scores <1.74, compared with 45.7% of the patients with eating disorder NOS.

The researchers also compared the outcomes of patients with the most complex additional psychopathology with those of patients with less complex problems. Greater complexity was defined as moderate ratings in at least 2 of the following domains: mood intolerance, clinical perfectionism, low self-esteem, and interpersonal difficulties.

Broad focus more effective for high complexity. Overall, those in the more complex subgroup did not respond as well; 48% had global EDE scores <1.74, vs 60% of those in the less complex group. However, those in the more complex subgroup did better with the broad form of CBT (at 60-week follow up, 60% had scores <1.74 with CBT-Eb, compared with 40% in the CBT-Ef treatment arm), while the less complex subgroup did better with the more tightly focused CBT-Ef. ²

WHAT’S NEW: Evidence supports CBT for NOS diagnosis

The most recent (2004) Cochrane review of “psychotherapy for bulimia nervosa and binging” included 40 RCTs of patients with bulimia, binge-eating disorder, and eating disorder NOS with recurrent binge-eating episodes (included in 7 studies). While the review confirmed that CBT is effective for bulimia and “similar syndromes,” it identified a need for larger and higher quality trials of CBT, particularly in patients with eating disorder NOS.¹ The study reviewed in this PURL—the first large, high-quality trial to include a number of patients with eating disorder NOS—provides strong evidence that CBT is effective for this group of patients.²

CAVEATS: Limited wait time leaves unanswered questions

One limitation of this study is the lack of a control group beyond the 8-week waiting period. Prior studies of CBT for bulimia that delayed therapy for those in the control groups for a longer duration have consistently shown that patients receiving CBT did significantly better than those in the control group.⁹ While a “no treatment” group would have made the results more robust in this case, it would not have been ethical to withhold treatment for the entire length of the study.

It is noteworthy, too, that this study only included patients with a BMI >17.5. Patients with a diagnosis of anorexia nervosa, who by definition have a lower BMI, will need other treatments, including hospitalization in some cases.

CHALLENGES TO IMPLEMENTATION: Identifying patients and therapists

The primary challenge is to determine which of your patients have eating disorders. When discussing diet, adding a simple question such as, “Are you happy with your current weight?” can help you identify those who meet the criteria for an eating disorder or are at high risk.³

Identifying local mental health providers who are trained to provide CBT for patients with eating disorders is another concern. Insurance coverage for this intensive treatment may also be a limiting factor in some cases.

Many studies support the use of fluoxetine for patients with bulimia, and combined treatment with SSRIs and CBT has been shown to be superior to either treatment alone.^8,10,14 Consider starting the patient on an antidepressant while she (or he) awaits the start of CBT.

Acknowledgements

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURLs) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 23-year-old patient with a body mass index (BMI) of 18 tells you she’s fat and she’s afraid of gaining weight. Further questioning reveals that your patient binges on cookies and potato chips about once a week, then compensates for overeating by taking laxatives or exercising excessively—a practice she’s been following since she started college several years ago. The eating disorder she describes does not meet the criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) for bulimia or anorexia nervosa, although it has elements of both. Rather, it fits the diagnostic criteria for eating disorder NOS. You’re aware that CBT is the first-line behavioral treatment for bulimia, and wonder whether it would be helpful for your patient.

Eating disorders often go undetected and untreated in primary care practices,³ as many patients don’t volunteer information about their weight or behaviors related to food, and physicians often fail to ask. Overall, as few as 10% of those with eating disorders receive any form of treatment.¹

Would you recognize this loosely defined disorder?

In the United States, the lifetime prevalence of eating disorders is 0.6% for anorexia nervosa (0.3% for men and 0.9% for women), 1.0% for bulimia (0.5% for men and 1.5% for women), and 2.8% for binge-eating disorder (2.0% for men, 3.5% for women).⁴ Eating disorder NOS, which encompasses subthreshold cases of anorexia or bulimia, patients with elements of both anorexia and bulimia, and patients with binge-eating disorder, accounts for 50% to 80% of eating disorder diagnoses in outpatient settings. Yet there have been few studies of the treatment of these patients.^2,5,6

A review of DSM-IV criteria

The diagnostic criteria for anorexia nervosa include a refusal to maintain a weight of at least 85% of normal body weight (or having a BMI ≤17.5), intense fear of gaining weight, disturbance in the way one’s body shape is experienced, and amenorrhea in females who are post-menarche.

Criteria for bulimia include recurrent episodes of binge eating (consuming a large amount of food with a sense of lack of control over eating) and recurrent inappropriate compensatory behaviors to prevent weight gain (self-induced vomiting, excessive exercise, fasting, laxatives, diuretics, or enemas) at least twice weekly for 3 months; and self-evaluation that is unduly influenced by body shape and weight.⁷ Most patients with eating disorder NOS have clinical features of both anorexia and bulimia.⁶

APA guidelines are silent on NOS

CBT has consistently proven to be the most useful behavioral treatment for patients with bulimia.¹ Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine—the only medication with Food and Drug Administration approval for the treatment of an eating disorder⁸ —are about as effective as CBT, and the combination of CBT and an SSRI is superior to either treatment alone.⁹ CBT has also been found to be somewhat effective in treating binge-eating disorder.¹⁰

Anorexia nervosa, the most deadly eating disorder (the mortality rate is 6.6%¹¹ ) and the most difficult to treat, is the exception. Several studies have assessed CBT for treating anorexia, but it has not been found to be very effective.^10,12,13

The 2006 American Psychiatric Association practice guidelines for the treatment of patients with eating disorders feature recommendations for anorexia, bulimia, and binge-eating disorder, but do not address eating disorder NOS.¹⁰ The National Institute for Clinical Excellence (NICE) in the United Kingdom issued guidelines for the treatment of eating disorders in 2004. In response to the lack of evidence for treating eating disorder NOS, NICE recommended basing treatment on the form of eating disorder that most closely resembles the patient’s presentation.¹⁴ Fairburn et al addressed the lack of evidence for treatment of eating disorder NOS with the study summarized here.

STUDY SUMMARY: Both broad and focused CBT delivered results

Conducted at 2 eating disorder centers in the United Kingdom, this RCT included 154 patients, 18 to 65 years of age, who met DSM-IV criteria for either bulimia or eating disorder NOS. Exclusion criteria included prior treatment with CBT or other evidence-based treatment for the same eating disorder, and a BMI ≤17.5.

Most of the patients were female (95.5%) and white (90.3%), with a median age of 26 years and a median duration of eating disorder of 8.6 years. Sixty-two percent of the patients had a diagnosis of eating disorder NOS, and 38% were diagnosed with bulimia. Half of the patients had another current psychiatric diagnosis—a major depressive disorder, an anxiety disorder, or substance abuse.

The patients were randomized into 4 groups: Two received immediate treatment, and the other 2, referred to as waiting list controls, waited 8 weeks before beginning treatment. Treatment consisted of 1 of 2 forms of CBT-E, an enhanced form of CBT used to treat adult outpatients with eating disorders. Patients either received CBT-Ef, a focused form of CBT that exclusively targets eating disorder psychopathology, or CBT-Eb, a broader form of therapy that also addresses other problems that are common in patients with eating disorders, such as perfectionism and low self-esteem.

Both types of CBT-E featured a 90-minute preparatory session, 20 50-minute sessions, and 1 review session 20 weeks after completion of treatment. In the first 4 sessions, CBT-Ef and CBT-Eb were identical—addressing the eating disorder exclusively. CBT-Ef continued to focus on the eating disorder for the rest of the sessions, while subsequent CBT-Eb sessions also dealt with mood intolerance, interpersonal difficulties, and related issues. Five therapists—4 psychologists and 1 nurse-therapist—conducted the treatments.

Patients were weaned from ongoing psychiatric therapy during the study, but those who were on antidepressant therapy (n=76) were able to continue it. Patients were assessed before treatment, at the end of the waiting period for those in the control groups, after 8 weeks of treatment, at the end of treatment, and 20, 40, and 60 weeks after completion of treatment. (Twenty-two percent of the enrollees did not complete treatment.)

Primary outcomes were based on the Eating Disorder Examination (EDE), administered by assessors who were not involved in the treatment and were blinded to the patients’ group assignment. Change in severity of eating disorder features was measured by the global EDE score (0-6) and attaining a global EDE score <1.74 (<1 standard deviation above the community mean).

No treatment vs CBT. The waiting period left little doubt of the short-term efficacy of CBT: After 8 weeks, there was significant improvement in eating disorder behaviors and overall severity in both the CBT-Ef and CBT-Eb groups (EDE scores fell from 4.15 at baseline to 3.26 and from 4.04 to 2.89, respectively). In the same time period, scores for the waiting list control groups remained flat (from 4.08 at baseline to 3.99).

At the end of treatment and at the 60-week follow-up, patients in both forms of CBT-E showed significant improvement across all measures, with no significant difference between treatments. By the end of treatment, 66.4% of those who completed all of the CBT sessions had global EDE scores <1.74 (considered clinically significant).

Subgroup analysis offers opportunity for fine-tuning

When analyzed separately, the patients with bulimia and those with eating disorder NOS did equally well at the end of treatment: 52.7% of those with bulimia and 53.3% of those with eating disorder NOS had global EDE scores <1.74. At the 60-week follow-up, the patients with bulimia maintained their improvement slightly more: 61.4% had global EDE scores <1.74, compared with 45.7% of the patients with eating disorder NOS.

The researchers also compared the outcomes of patients with the most complex additional psychopathology with those of patients with less complex problems. Greater complexity was defined as moderate ratings in at least 2 of the following domains: mood intolerance, clinical perfectionism, low self-esteem, and interpersonal difficulties.

Broad focus more effective for high complexity. Overall, those in the more complex subgroup did not respond as well; 48% had global EDE scores <1.74, vs 60% of those in the less complex group. However, those in the more complex subgroup did better with the broad form of CBT (at 60-week follow up, 60% had scores <1.74 with CBT-Eb, compared with 40% in the CBT-Ef treatment arm), while the less complex subgroup did better with the more tightly focused CBT-Ef. ²

WHAT’S NEW: Evidence supports CBT for NOS diagnosis

The most recent (2004) Cochrane review of “psychotherapy for bulimia nervosa and binging” included 40 RCTs of patients with bulimia, binge-eating disorder, and eating disorder NOS with recurrent binge-eating episodes (included in 7 studies). While the review confirmed that CBT is effective for bulimia and “similar syndromes,” it identified a need for larger and higher quality trials of CBT, particularly in patients with eating disorder NOS.¹ The study reviewed in this PURL—the first large, high-quality trial to include a number of patients with eating disorder NOS—provides strong evidence that CBT is effective for this group of patients.²

CAVEATS: Limited wait time leaves unanswered questions

One limitation of this study is the lack of a control group beyond the 8-week waiting period. Prior studies of CBT for bulimia that delayed therapy for those in the control groups for a longer duration have consistently shown that patients receiving CBT did significantly better than those in the control group.⁹ While a “no treatment” group would have made the results more robust in this case, it would not have been ethical to withhold treatment for the entire length of the study.

It is noteworthy, too, that this study only included patients with a BMI >17.5. Patients with a diagnosis of anorexia nervosa, who by definition have a lower BMI, will need other treatments, including hospitalization in some cases.

CHALLENGES TO IMPLEMENTATION: Identifying patients and therapists

The primary challenge is to determine which of your patients have eating disorders. When discussing diet, adding a simple question such as, “Are you happy with your current weight?” can help you identify those who meet the criteria for an eating disorder or are at high risk.³

Identifying local mental health providers who are trained to provide CBT for patients with eating disorders is another concern. Insurance coverage for this intensive treatment may also be a limiting factor in some cases.

Many studies support the use of fluoxetine for patients with bulimia, and combined treatment with SSRIs and CBT has been shown to be superior to either treatment alone.^8,10,14 Consider starting the patient on an antidepressant while she (or he) awaits the start of CBT.

Acknowledgements

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURLs) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

John M, a 50-year-old patient, recently had a routine colonoscopy and was diagnosed with diverticulosis. Concerned because a friend has had multiple bouts of diverticulitis and a partial colectomy, John schedules an appointment to discuss management of diverticulosis. His friend has told John he’ll have to follow a strict diet and avoid nuts, corn, and popcorn altogether. Anxious to avoid the complications his friend has experienced, John turns to you for dietary advice. Would you know what dietary advice is best?

Diverticulosis affects one-third of the US population by age 60; by the age of 85, two-thirds are affected.^2,3 This common digestive disorder has been associated with a diet high in refined carbohydrates, and is less prevalent among people who follow a vegetarian diet.^4-6 Up to 35% of patients with diverticulosis develop complications, including diverticulitis and diverticular bleeding, that frequently require hospitalization and invasive procedures.^7,8

Nuts or no nuts? In search of evidence

Biological mechanisms responsible for the development of diverticular complications are poorly understood.^1,4 But luminal trauma has been suggested as a contributory factor and nuts, corn, popcorn, and seeds have long been viewed as likely culprits.⁸ Thus, physicians have historically advised patients with diverticular disease to avoid these foods.^8-12

That recommendation, however, had little evidence to support it. Until the study by Strate et al that we report on here, no studies had assessed the consumption of nuts, corn, popcorn, or seeds as a risk factor for diverticulitis or diverticular complications.^1,13 Conversely, there was a growing body of evidence that a diet rich in nuts may provide protection against many common disorders, including coronary heart disease, diabetes, colon and prostate cancers, and gall bladder disease.^14-19 The research by Strate et al settles the matter, but it also provides an interesting twist.

STUDY SUMMARY: Nuts and popcorn linked to lower risk

The Strate trial is part of the Health Professionals Follow-up Study, a prospective cohort study that followed male health professionals in the United States from 1986 to 2004.²⁰ A counterpart to the all-female Nurses’ Health Study, this long-running study allowed investigators to evaluate the relationship between nutritional factors and the incidence of serious illnesses such as cancer, heart disease, and other vascular diseases. The study population was comprised of 47,228 men between the ages of 40 and 75 years who completed periodic self-administered medical and dietary questionnaires.

At baseline, all the men were free of diverticulosis or related complications, as well as cancer and inflammatory bowel disease. During the 18 years of follow-up, 801 incident cases of diverticulitis and 383 cases of diverticular bleeding occurred. After analyzing the data, the researchers reported that, not only was the consumption of nuts and/or popcorn not associated with an increased risk of diverticulitis, it had a protective effect. The hazard ratios for men with the highest intake of nuts and/or popcorn (at least twice a week) compared with men with the lowest intake (less than once a month) were 0.80 (95% confidence interval [CI], 0.63-1.01) for nuts and 0.72 (95% CI, 0.56-0.92) for popcorn. The researchers found no association, positive or negative, between corn consumption and diverticulitis, nor between nut, corn, or popcorn consumption and diverticular bleeding or the development of uncomplicated diverticulosis.¹

FIGURE
Colonoscopy reveals diverticular disease

WHAT’S NEW?: A long-standing belief gets debunked

This study—the first to examine the relationship between a diet rich in nuts, corn, or popcorn and diverticular disease—showed that these foods did not increase the risk of developing diverticulosis, diverticulitis, or diverticular bleeding. Moreover, it found an association between a diet rich in nuts or popcorn and a decreased risk of diverticulitis. Although we can’t characterize this as a cause-and-effect relationship based on this study, the evidence convinces us that, at the least, nuts, corn, and popcorn do not increase the risk of diverticular disease. We think we can confidently tell patients to enjoy these foods.

CAVEATS: Protective effect of nuts is tough to explain

As with all cohort studies, there is a possibility of unmeasured confounding variables which, in this case, could account for the protective effect of nuts and popcorn suggested by the decreased risk of diverticulitis. Although this was a large and carefully conducted prospective cohort study involving health professionals, we are not aware of any proven pathophysiologic mechanism by which nuts, corn, and popcorn may either increase or decrease the risk of diverticular disease or its complications.

A randomized controlled trial addressing this dietary issue is unlikely—and probably unnecessary. This study provides the strongest evidence on this topic by far. We think many patients have been unnecessarily deprived of these foods.

The study did not enroll young patients or women. However, diverticulosis is rare before the age of 40.^2,9 And, because no clear sex difference has been observed in diverticular disease, we see no reason why this evidence should not apply equally to female patients.^2,13

Also of note: This study did not assess total seed intake, per se. Rather, it assessed the consumption of strawberries and blueberries, the source of the seeds. The researchers found no association between strawberries and blueberries and diverticular complications, and we see no reason to tell patients to avoid them.

CHALLENGES TO IMPLEMENTATION: There are no obstacles to implementation

Dietary advice is an integral part of primary care practice. We see no challenges to implementing this practice changer, which should come as welcome news to patients at risk of diverticular disease or its complications.

Acknowledgements

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

John M, a 50-year-old patient, recently had a routine colonoscopy and was diagnosed with diverticulosis. Concerned because a friend has had multiple bouts of diverticulitis and a partial colectomy, John schedules an appointment to discuss management of diverticulosis. His friend has told John he’ll have to follow a strict diet and avoid nuts, corn, and popcorn altogether. Anxious to avoid the complications his friend has experienced, John turns to you for dietary advice. Would you know what dietary advice is best?

Diverticulosis affects one-third of the US population by age 60; by the age of 85, two-thirds are affected.^2,3 This common digestive disorder has been associated with a diet high in refined carbohydrates, and is less prevalent among people who follow a vegetarian diet.^4-6 Up to 35% of patients with diverticulosis develop complications, including diverticulitis and diverticular bleeding, that frequently require hospitalization and invasive procedures.^7,8

Nuts or no nuts? In search of evidence

Biological mechanisms responsible for the development of diverticular complications are poorly understood.^1,4 But luminal trauma has been suggested as a contributory factor and nuts, corn, popcorn, and seeds have long been viewed as likely culprits.⁸ Thus, physicians have historically advised patients with diverticular disease to avoid these foods.^8-12

That recommendation, however, had little evidence to support it. Until the study by Strate et al that we report on here, no studies had assessed the consumption of nuts, corn, popcorn, or seeds as a risk factor for diverticulitis or diverticular complications.^1,13 Conversely, there was a growing body of evidence that a diet rich in nuts may provide protection against many common disorders, including coronary heart disease, diabetes, colon and prostate cancers, and gall bladder disease.^14-19 The research by Strate et al settles the matter, but it also provides an interesting twist.

STUDY SUMMARY: Nuts and popcorn linked to lower risk

The Strate trial is part of the Health Professionals Follow-up Study, a prospective cohort study that followed male health professionals in the United States from 1986 to 2004.²⁰ A counterpart to the all-female Nurses’ Health Study, this long-running study allowed investigators to evaluate the relationship between nutritional factors and the incidence of serious illnesses such as cancer, heart disease, and other vascular diseases. The study population was comprised of 47,228 men between the ages of 40 and 75 years who completed periodic self-administered medical and dietary questionnaires.

At baseline, all the men were free of diverticulosis or related complications, as well as cancer and inflammatory bowel disease. During the 18 years of follow-up, 801 incident cases of diverticulitis and 383 cases of diverticular bleeding occurred. After analyzing the data, the researchers reported that, not only was the consumption of nuts and/or popcorn not associated with an increased risk of diverticulitis, it had a protective effect. The hazard ratios for men with the highest intake of nuts and/or popcorn (at least twice a week) compared with men with the lowest intake (less than once a month) were 0.80 (95% confidence interval [CI], 0.63-1.01) for nuts and 0.72 (95% CI, 0.56-0.92) for popcorn. The researchers found no association, positive or negative, between corn consumption and diverticulitis, nor between nut, corn, or popcorn consumption and diverticular bleeding or the development of uncomplicated diverticulosis.¹

FIGURE
Colonoscopy reveals diverticular disease

WHAT’S NEW?: A long-standing belief gets debunked

This study—the first to examine the relationship between a diet rich in nuts, corn, or popcorn and diverticular disease—showed that these foods did not increase the risk of developing diverticulosis, diverticulitis, or diverticular bleeding. Moreover, it found an association between a diet rich in nuts or popcorn and a decreased risk of diverticulitis. Although we can’t characterize this as a cause-and-effect relationship based on this study, the evidence convinces us that, at the least, nuts, corn, and popcorn do not increase the risk of diverticular disease. We think we can confidently tell patients to enjoy these foods.

CAVEATS: Protective effect of nuts is tough to explain

As with all cohort studies, there is a possibility of unmeasured confounding variables which, in this case, could account for the protective effect of nuts and popcorn suggested by the decreased risk of diverticulitis. Although this was a large and carefully conducted prospective cohort study involving health professionals, we are not aware of any proven pathophysiologic mechanism by which nuts, corn, and popcorn may either increase or decrease the risk of diverticular disease or its complications.

A randomized controlled trial addressing this dietary issue is unlikely—and probably unnecessary. This study provides the strongest evidence on this topic by far. We think many patients have been unnecessarily deprived of these foods.

The study did not enroll young patients or women. However, diverticulosis is rare before the age of 40.^2,9 And, because no clear sex difference has been observed in diverticular disease, we see no reason why this evidence should not apply equally to female patients.^2,13

Also of note: This study did not assess total seed intake, per se. Rather, it assessed the consumption of strawberries and blueberries, the source of the seeds. The researchers found no association between strawberries and blueberries and diverticular complications, and we see no reason to tell patients to avoid them.

CHALLENGES TO IMPLEMENTATION: There are no obstacles to implementation

Dietary advice is an integral part of primary care practice. We see no challenges to implementing this practice changer, which should come as welcome news to patients at risk of diverticular disease or its complications.

Acknowledgements

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

John M, a 50-year-old patient, recently had a routine colonoscopy and was diagnosed with diverticulosis. Concerned because a friend has had multiple bouts of diverticulitis and a partial colectomy, John schedules an appointment to discuss management of diverticulosis. His friend has told John he’ll have to follow a strict diet and avoid nuts, corn, and popcorn altogether. Anxious to avoid the complications his friend has experienced, John turns to you for dietary advice. Would you know what dietary advice is best?

Diverticulosis affects one-third of the US population by age 60; by the age of 85, two-thirds are affected.^2,3 This common digestive disorder has been associated with a diet high in refined carbohydrates, and is less prevalent among people who follow a vegetarian diet.^4-6 Up to 35% of patients with diverticulosis develop complications, including diverticulitis and diverticular bleeding, that frequently require hospitalization and invasive procedures.^7,8

Nuts or no nuts? In search of evidence

Biological mechanisms responsible for the development of diverticular complications are poorly understood.^1,4 But luminal trauma has been suggested as a contributory factor and nuts, corn, popcorn, and seeds have long been viewed as likely culprits.⁸ Thus, physicians have historically advised patients with diverticular disease to avoid these foods.^8-12

That recommendation, however, had little evidence to support it. Until the study by Strate et al that we report on here, no studies had assessed the consumption of nuts, corn, popcorn, or seeds as a risk factor for diverticulitis or diverticular complications.^1,13 Conversely, there was a growing body of evidence that a diet rich in nuts may provide protection against many common disorders, including coronary heart disease, diabetes, colon and prostate cancers, and gall bladder disease.^14-19 The research by Strate et al settles the matter, but it also provides an interesting twist.

STUDY SUMMARY: Nuts and popcorn linked to lower risk

The Strate trial is part of the Health Professionals Follow-up Study, a prospective cohort study that followed male health professionals in the United States from 1986 to 2004.²⁰ A counterpart to the all-female Nurses’ Health Study, this long-running study allowed investigators to evaluate the relationship between nutritional factors and the incidence of serious illnesses such as cancer, heart disease, and other vascular diseases. The study population was comprised of 47,228 men between the ages of 40 and 75 years who completed periodic self-administered medical and dietary questionnaires.

At baseline, all the men were free of diverticulosis or related complications, as well as cancer and inflammatory bowel disease. During the 18 years of follow-up, 801 incident cases of diverticulitis and 383 cases of diverticular bleeding occurred. After analyzing the data, the researchers reported that, not only was the consumption of nuts and/or popcorn not associated with an increased risk of diverticulitis, it had a protective effect. The hazard ratios for men with the highest intake of nuts and/or popcorn (at least twice a week) compared with men with the lowest intake (less than once a month) were 0.80 (95% confidence interval [CI], 0.63-1.01) for nuts and 0.72 (95% CI, 0.56-0.92) for popcorn. The researchers found no association, positive or negative, between corn consumption and diverticulitis, nor between nut, corn, or popcorn consumption and diverticular bleeding or the development of uncomplicated diverticulosis.¹

FIGURE
Colonoscopy reveals diverticular disease

WHAT’S NEW?: A long-standing belief gets debunked

This study—the first to examine the relationship between a diet rich in nuts, corn, or popcorn and diverticular disease—showed that these foods did not increase the risk of developing diverticulosis, diverticulitis, or diverticular bleeding. Moreover, it found an association between a diet rich in nuts or popcorn and a decreased risk of diverticulitis. Although we can’t characterize this as a cause-and-effect relationship based on this study, the evidence convinces us that, at the least, nuts, corn, and popcorn do not increase the risk of diverticular disease. We think we can confidently tell patients to enjoy these foods.

CAVEATS: Protective effect of nuts is tough to explain

As with all cohort studies, there is a possibility of unmeasured confounding variables which, in this case, could account for the protective effect of nuts and popcorn suggested by the decreased risk of diverticulitis. Although this was a large and carefully conducted prospective cohort study involving health professionals, we are not aware of any proven pathophysiologic mechanism by which nuts, corn, and popcorn may either increase or decrease the risk of diverticular disease or its complications.

A randomized controlled trial addressing this dietary issue is unlikely—and probably unnecessary. This study provides the strongest evidence on this topic by far. We think many patients have been unnecessarily deprived of these foods.

The study did not enroll young patients or women. However, diverticulosis is rare before the age of 40.^2,9 And, because no clear sex difference has been observed in diverticular disease, we see no reason why this evidence should not apply equally to female patients.^2,13

Also of note: This study did not assess total seed intake, per se. Rather, it assessed the consumption of strawberries and blueberries, the source of the seeds. The researchers found no association between strawberries and blueberries and diverticular complications, and we see no reason to tell patients to avoid them.

CHALLENGES TO IMPLEMENTATION: There are no obstacles to implementation

Dietary advice is an integral part of primary care practice. We see no challenges to implementing this practice changer, which should come as welcome news to patients at risk of diverticular disease or its complications.

Acknowledgements

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.