Cleveland Clinic Journal of Medicine

Density: The quality or state of being dense; the quantity per unit volume, unit area, or unit length; the degree of opacity of a translucent medium, or the common logarithm of the opacity.

—Merriam-Webster’s dictionary¹

For more than a decade, federal law in the United States has compelled breast imaging centers to give every mammography patient a letter explaining her result.²

See related editorial

Often, however, the first person a woman speaks to about her findings is her primary care clinician, particularly if she has had a screening mammogram at a center where films are “batch-read” and are not viewed by the radiologist at the time of the appointment. Internal medicine physicians are often called on to help women understand their findings and to order follow-up tests recommended by the radiologist—a not uncommon occurrence. Also, internists often need to address patients’ anxieties about the possibility of breast cancer and provide them with enough information to make an informed decision about an appropriate action plan.

Meanwhile, discussing mammography has become more complicated. In 2009, the United States Preventive Services Task Force stopped recommending that women under age 50 be routinely screened for breast cancer, and instead stated that the decision to begin screening these women should consider “patient context” and the patient’s personal “values”³—with the implication that women’s primary clinicians would play an important role in helping them weigh the test’s potential benefits and harms.

More and more, internists must grapple with the task of how to help women decipher the concept of “breast density,” understand their personal density results, and make an informed decision about whether to undergo additional imaging studies, such as ultrasonography and magnetic resonance imaging (MRI).

LEGISLATION REQUIRING DENSITY NOTIFICATION

The impetus for this change in practice has been spurred in large part by patient advocates, who have argued that women deserve to know their density because mammography is less sensitive in women with dense breasts. So far, at least 12 states have enacted laws requiring breast imaging centers to add information about breast density in the result notification letters they mail to patients. Legislatures in several other states are considering breast density notification laws,⁴ and federal legislation has been proposed.

Some of the state laws, such as those in Connecticut, Texas, and Virginia, require informing all mammography patients about their density findings, whether or not they have dense breast tissue. Other states, such as California, Hawaii, and New York, require informing only those found to have dense tissue. And some states, such as California, Connecticut, Hawaii, Texas, and Virginia, require specific wording in the density notification letter (Table 1).

The details of all these notification laws may differ in how they specify which patients must be notified and in how the information should be worded, but the goal is the same: to raise women’s awareness so that they can embark on an informed decision with their physician about whether to undergo further testing.

Because of liability concerns, some breast imaging centers in states that currently lack such notification laws have begun informing women about their density results.

Unfortunately, at this point clinicians have no clear guidelines for helping patients with dense breasts decide whether to undergo additional testing. In addition, the evidence is equivocal, and the tests have risks as well as benefits. The patient needs to understand all this by discussing it with her physician. And to discuss this decision effectively, the physician must be well versed in the evolving literature on breast density. Below, we present important points to keep in mind as we foster these discussions with our patients.

BREAST TISSUE DENSITY IS STILL A SUBJECTIVE MEASUREMENT

Breast density limits the sensitivity of mammography. This is widely established. Yet the interpretation of breast density today is subjective. It is determined by the interpreting radiologist based on the Breast Imaging and Reporting Data System (BI-RADS), which defines “heterogeneously dense” breasts as those containing 50% to 75% dense tissue and “dense” breasts as those with more than 75%⁵ (Figure 1). This subjective measurement is based on two-dimensional imaging, which may underestimate or overestimate the percentage of breast density because of tissue summation. Ideally, density should be measured using three-dimensional imaging with automated software,⁶ but this technology is not yet widely available.

INCREASED DETECTION OF BENIGN LESIONS

Although adding ultrasonography to mammography in patients with dense breast tissue detects additional cancers,^7,8 it also leads to a significant increase in the detection of lesions that are not malignant yet require additional workup or biopsy.

The largest study to examine this was the American College of Radiology Imaging Network Protocol 6666 (ACRIN 6666),⁷ a multi-institutional study evaluating the diagnostic yield, sensitivity, and specificity of adding ultrasonography in high-risk patients who presented with negative mammograms and had heterogeneously dense tissue in at least one quadrant.⁷ (High risk was defined as a threefold higher risk of breast cancer as determined by risk factors such as personal history of breast cancer or high-risk lesions, or elevated risk using the Gail or Claus model.) The supplemental yield was 4.2 cancers per 1,000 women (95% confidence interval 1.1 to 7.2 per 1,000) on a single prevalent screen. Of 12 cancers detected solely by ultrasonography, 11 were invasive and had a median size of 10 mm. Of those reported, 8 of 9 were node-negative. Despite this additional yield, the positive predictive value of biopsy prompted by ultrasonography was only 8.9%.⁷ Other investigators have reported similar findings.⁸

RELATIONSHIP BETWEEN DENSITY AND CANCER RISK STILL NOT CLEAR

The relationship between breast density and cancer risk is not entirely clear. Higher breast density has been associated with a higher risk of breast cancer,^9,10 presumably because cancer usually develops in parenchyma, and not fatty tissue. Yet obesity and age, which are inversely associated with density, are also risk factors for the development of breast cancer. Some prominent radiologists have cast doubt on the methodology used in these density studies, which relied on density measurements calculated by two-dimensional views of the breast, and have called for a re-evaluation of the relationship between density and cancer risk.⁶

LIMITED HEALTH LITERACY: A CHALLENGE

The term “breast density” is unfamiliar to most lay people. As physicians, we need to keep in mind that more than a third of US adults have limited health literacy and thus have difficulty processing basic health information.¹¹ But even the 1 in 10 US women with “proficient” health literacy skills may find the term “density” confusing.

As the definition at the opening of this article suggests, the word itself is nuanced and has different meanings. Anecdotally, both of the authors, a general internist (E.M.) and a breast imaging specialist (M.Y.), have encountered numerous quizzical and sometimes distrustful reactions when telling patients—including some with graduate degrees—that they have “dense” breast tissue and might benefit from additional ultrasonographic testing. Avoiding jargon is key; studies have found that terms such as “benign” can be confusing when used in a mammogram result notification letter.¹²

How can we explain the concept of breast density to our patients?

Supplemental educational materials that feature simple pictures can also be helpful in conveying complex health information,¹³ although their effect on the communication of breast density has not been studied. The American College of Radiology and the Society of Breast Imaging produce a freely available, downloadable patient brochure on breast density that includes photographs of mammograms with high and low breast density. The brochure is available from the American College of Radiology online at www.acr.org, under “Tools you can use.”

We recommend introducing women to the concept of breast density before they undergo mammography—at the time the test is ordered—and provide them with supplemental materials such as the above-mentioned brochure. About 1 out of every 10 women who undergo screening mammography has a result requiring additional testing that does not result in a cancer diagnosis. Yet a body of research suggests that many women don’t realize that mammograms don’t always yield a cut-and-dried “cancer” or “no cancer” result. In past studies, women have said they were unaware of how common it is to be called back after routine screening mammography, and they wanted to be prepared for this in advance.^12,14 Similarly, many women are unaware of the concept of breast density and don’t know that they may be told about these findings when they get their mammogram report.

Avoid causing anxiety

When explaining results to women with dense breasts, we should emphasize that there are no abnormalities on the current mammogram, and that the only reason to consider additional imaging is the breast density. But regardless of the ultimate outcome, an abnormal mammogram can trigger long-standing anxiety, ¹⁵ and it is reasonable to assume that some women will become anxious when told they have highly dense breasts. It is important that clinicians be aware of this potential anxiety and inquire about any personal cancer-related concerns at the time they discuss their findings.¹⁶

Helping the patient choose the type of additional screening

If a patient is found to have dense breasts and chooses to undergo additional screening, the decision about which test—ultrasonography or MRI—can be based on the woman’s lifetime risk of breast cancer.

The American Cancer Society recommends that patients with a lifetime risk of 20% or greater—according to a risk model such as BRCAPRO, Tyrer-Cuzick, or BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)—should be screened annually with breast MRI regardless of breast density. Patients in this category are those who carry the BRCA gene mutations and their untested first-degree relatives, and patients with Li-Fraumeni, Cowden, or Bannayan-Riley-Ruvalcaba syndrome. Also considered are women who underwent chest radiation between the ages of 10 and 30, and patients who have more than one first-degree relative with breast cancer but who do not have an identifiable genetic mutation.¹⁷

Patients with dense breasts who have an increased lifetime risk but who do not meet these criteria and those who are at average risk may be offered breast ultrasonography. If risk factors are unclear, genetic counseling can help determine the lifetime risk and thus help the patient choose the additional screening test.¹⁸

MORE WORK TO DO

Clearly, we still do not know how to explain breast density results to our patients in a way that will help them make a fully informed decision about additional screening. Research suggests that letters alone are insufficient,^13,19,20 and there is no guarantee that simply adding breast density notification language to result letters will enhance a woman’s understanding and empower her to choose a course of action that is sensitive to her personal preferences.

As more states adopt notification legislation, we must develop effective methods to improve our patients’ understanding of the meaning and implications of having dense breasts and to help them decide how to proceed. Such tools could include videos, Web sites, and pictorials, as well as specialized training for patient educators and health navigators. Otherwise, including this additional, conceptually difficult information to result notification letters could make the doctor-patient interaction even more “dense”—and could increase women’s uncertainty and anxiety about their personal risk of cancer.²¹

Density: The quality or state of being dense; the quantity per unit volume, unit area, or unit length; the degree of opacity of a translucent medium, or the common logarithm of the opacity.

—Merriam-Webster’s dictionary¹

For more than a decade, federal law in the United States has compelled breast imaging centers to give every mammography patient a letter explaining her result.²

See related editorial

Often, however, the first person a woman speaks to about her findings is her primary care clinician, particularly if she has had a screening mammogram at a center where films are “batch-read” and are not viewed by the radiologist at the time of the appointment. Internal medicine physicians are often called on to help women understand their findings and to order follow-up tests recommended by the radiologist—a not uncommon occurrence. Also, internists often need to address patients’ anxieties about the possibility of breast cancer and provide them with enough information to make an informed decision about an appropriate action plan.

Meanwhile, discussing mammography has become more complicated. In 2009, the United States Preventive Services Task Force stopped recommending that women under age 50 be routinely screened for breast cancer, and instead stated that the decision to begin screening these women should consider “patient context” and the patient’s personal “values”³—with the implication that women’s primary clinicians would play an important role in helping them weigh the test’s potential benefits and harms.

More and more, internists must grapple with the task of how to help women decipher the concept of “breast density,” understand their personal density results, and make an informed decision about whether to undergo additional imaging studies, such as ultrasonography and magnetic resonance imaging (MRI).

LEGISLATION REQUIRING DENSITY NOTIFICATION

The impetus for this change in practice has been spurred in large part by patient advocates, who have argued that women deserve to know their density because mammography is less sensitive in women with dense breasts. So far, at least 12 states have enacted laws requiring breast imaging centers to add information about breast density in the result notification letters they mail to patients. Legislatures in several other states are considering breast density notification laws,⁴ and federal legislation has been proposed.

Some of the state laws, such as those in Connecticut, Texas, and Virginia, require informing all mammography patients about their density findings, whether or not they have dense breast tissue. Other states, such as California, Hawaii, and New York, require informing only those found to have dense tissue. And some states, such as California, Connecticut, Hawaii, Texas, and Virginia, require specific wording in the density notification letter (Table 1).

The details of all these notification laws may differ in how they specify which patients must be notified and in how the information should be worded, but the goal is the same: to raise women’s awareness so that they can embark on an informed decision with their physician about whether to undergo further testing.

Because of liability concerns, some breast imaging centers in states that currently lack such notification laws have begun informing women about their density results.

Unfortunately, at this point clinicians have no clear guidelines for helping patients with dense breasts decide whether to undergo additional testing. In addition, the evidence is equivocal, and the tests have risks as well as benefits. The patient needs to understand all this by discussing it with her physician. And to discuss this decision effectively, the physician must be well versed in the evolving literature on breast density. Below, we present important points to keep in mind as we foster these discussions with our patients.

BREAST TISSUE DENSITY IS STILL A SUBJECTIVE MEASUREMENT

Breast density limits the sensitivity of mammography. This is widely established. Yet the interpretation of breast density today is subjective. It is determined by the interpreting radiologist based on the Breast Imaging and Reporting Data System (BI-RADS), which defines “heterogeneously dense” breasts as those containing 50% to 75% dense tissue and “dense” breasts as those with more than 75%⁵ (Figure 1). This subjective measurement is based on two-dimensional imaging, which may underestimate or overestimate the percentage of breast density because of tissue summation. Ideally, density should be measured using three-dimensional imaging with automated software,⁶ but this technology is not yet widely available.

INCREASED DETECTION OF BENIGN LESIONS

Although adding ultrasonography to mammography in patients with dense breast tissue detects additional cancers,^7,8 it also leads to a significant increase in the detection of lesions that are not malignant yet require additional workup or biopsy.

The largest study to examine this was the American College of Radiology Imaging Network Protocol 6666 (ACRIN 6666),⁷ a multi-institutional study evaluating the diagnostic yield, sensitivity, and specificity of adding ultrasonography in high-risk patients who presented with negative mammograms and had heterogeneously dense tissue in at least one quadrant.⁷ (High risk was defined as a threefold higher risk of breast cancer as determined by risk factors such as personal history of breast cancer or high-risk lesions, or elevated risk using the Gail or Claus model.) The supplemental yield was 4.2 cancers per 1,000 women (95% confidence interval 1.1 to 7.2 per 1,000) on a single prevalent screen. Of 12 cancers detected solely by ultrasonography, 11 were invasive and had a median size of 10 mm. Of those reported, 8 of 9 were node-negative. Despite this additional yield, the positive predictive value of biopsy prompted by ultrasonography was only 8.9%.⁷ Other investigators have reported similar findings.⁸

RELATIONSHIP BETWEEN DENSITY AND CANCER RISK STILL NOT CLEAR

The relationship between breast density and cancer risk is not entirely clear. Higher breast density has been associated with a higher risk of breast cancer,^9,10 presumably because cancer usually develops in parenchyma, and not fatty tissue. Yet obesity and age, which are inversely associated with density, are also risk factors for the development of breast cancer. Some prominent radiologists have cast doubt on the methodology used in these density studies, which relied on density measurements calculated by two-dimensional views of the breast, and have called for a re-evaluation of the relationship between density and cancer risk.⁶

LIMITED HEALTH LITERACY: A CHALLENGE

The term “breast density” is unfamiliar to most lay people. As physicians, we need to keep in mind that more than a third of US adults have limited health literacy and thus have difficulty processing basic health information.¹¹ But even the 1 in 10 US women with “proficient” health literacy skills may find the term “density” confusing.

As the definition at the opening of this article suggests, the word itself is nuanced and has different meanings. Anecdotally, both of the authors, a general internist (E.M.) and a breast imaging specialist (M.Y.), have encountered numerous quizzical and sometimes distrustful reactions when telling patients—including some with graduate degrees—that they have “dense” breast tissue and might benefit from additional ultrasonographic testing. Avoiding jargon is key; studies have found that terms such as “benign” can be confusing when used in a mammogram result notification letter.¹²

How can we explain the concept of breast density to our patients?

Supplemental educational materials that feature simple pictures can also be helpful in conveying complex health information,¹³ although their effect on the communication of breast density has not been studied. The American College of Radiology and the Society of Breast Imaging produce a freely available, downloadable patient brochure on breast density that includes photographs of mammograms with high and low breast density. The brochure is available from the American College of Radiology online at www.acr.org, under “Tools you can use.”

We recommend introducing women to the concept of breast density before they undergo mammography—at the time the test is ordered—and provide them with supplemental materials such as the above-mentioned brochure. About 1 out of every 10 women who undergo screening mammography has a result requiring additional testing that does not result in a cancer diagnosis. Yet a body of research suggests that many women don’t realize that mammograms don’t always yield a cut-and-dried “cancer” or “no cancer” result. In past studies, women have said they were unaware of how common it is to be called back after routine screening mammography, and they wanted to be prepared for this in advance.^12,14 Similarly, many women are unaware of the concept of breast density and don’t know that they may be told about these findings when they get their mammogram report.

Avoid causing anxiety

When explaining results to women with dense breasts, we should emphasize that there are no abnormalities on the current mammogram, and that the only reason to consider additional imaging is the breast density. But regardless of the ultimate outcome, an abnormal mammogram can trigger long-standing anxiety, ¹⁵ and it is reasonable to assume that some women will become anxious when told they have highly dense breasts. It is important that clinicians be aware of this potential anxiety and inquire about any personal cancer-related concerns at the time they discuss their findings.¹⁶

Helping the patient choose the type of additional screening

If a patient is found to have dense breasts and chooses to undergo additional screening, the decision about which test—ultrasonography or MRI—can be based on the woman’s lifetime risk of breast cancer.

The American Cancer Society recommends that patients with a lifetime risk of 20% or greater—according to a risk model such as BRCAPRO, Tyrer-Cuzick, or BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)—should be screened annually with breast MRI regardless of breast density. Patients in this category are those who carry the BRCA gene mutations and their untested first-degree relatives, and patients with Li-Fraumeni, Cowden, or Bannayan-Riley-Ruvalcaba syndrome. Also considered are women who underwent chest radiation between the ages of 10 and 30, and patients who have more than one first-degree relative with breast cancer but who do not have an identifiable genetic mutation.¹⁷

Patients with dense breasts who have an increased lifetime risk but who do not meet these criteria and those who are at average risk may be offered breast ultrasonography. If risk factors are unclear, genetic counseling can help determine the lifetime risk and thus help the patient choose the additional screening test.¹⁸

MORE WORK TO DO

Clearly, we still do not know how to explain breast density results to our patients in a way that will help them make a fully informed decision about additional screening. Research suggests that letters alone are insufficient,^13,19,20 and there is no guarantee that simply adding breast density notification language to result letters will enhance a woman’s understanding and empower her to choose a course of action that is sensitive to her personal preferences.

As more states adopt notification legislation, we must develop effective methods to improve our patients’ understanding of the meaning and implications of having dense breasts and to help them decide how to proceed. Such tools could include videos, Web sites, and pictorials, as well as specialized training for patient educators and health navigators. Otherwise, including this additional, conceptually difficult information to result notification letters could make the doctor-patient interaction even more “dense”—and could increase women’s uncertainty and anxiety about their personal risk of cancer.²¹

Density: The quality or state of being dense; the quantity per unit volume, unit area, or unit length; the degree of opacity of a translucent medium, or the common logarithm of the opacity.

—Merriam-Webster’s dictionary¹

For more than a decade, federal law in the United States has compelled breast imaging centers to give every mammography patient a letter explaining her result.²

See related editorial

Often, however, the first person a woman speaks to about her findings is her primary care clinician, particularly if she has had a screening mammogram at a center where films are “batch-read” and are not viewed by the radiologist at the time of the appointment. Internal medicine physicians are often called on to help women understand their findings and to order follow-up tests recommended by the radiologist—a not uncommon occurrence. Also, internists often need to address patients’ anxieties about the possibility of breast cancer and provide them with enough information to make an informed decision about an appropriate action plan.

Meanwhile, discussing mammography has become more complicated. In 2009, the United States Preventive Services Task Force stopped recommending that women under age 50 be routinely screened for breast cancer, and instead stated that the decision to begin screening these women should consider “patient context” and the patient’s personal “values”³—with the implication that women’s primary clinicians would play an important role in helping them weigh the test’s potential benefits and harms.

More and more, internists must grapple with the task of how to help women decipher the concept of “breast density,” understand their personal density results, and make an informed decision about whether to undergo additional imaging studies, such as ultrasonography and magnetic resonance imaging (MRI).

LEGISLATION REQUIRING DENSITY NOTIFICATION

The impetus for this change in practice has been spurred in large part by patient advocates, who have argued that women deserve to know their density because mammography is less sensitive in women with dense breasts. So far, at least 12 states have enacted laws requiring breast imaging centers to add information about breast density in the result notification letters they mail to patients. Legislatures in several other states are considering breast density notification laws,⁴ and federal legislation has been proposed.

Some of the state laws, such as those in Connecticut, Texas, and Virginia, require informing all mammography patients about their density findings, whether or not they have dense breast tissue. Other states, such as California, Hawaii, and New York, require informing only those found to have dense tissue. And some states, such as California, Connecticut, Hawaii, Texas, and Virginia, require specific wording in the density notification letter (Table 1).

The details of all these notification laws may differ in how they specify which patients must be notified and in how the information should be worded, but the goal is the same: to raise women’s awareness so that they can embark on an informed decision with their physician about whether to undergo further testing.

Because of liability concerns, some breast imaging centers in states that currently lack such notification laws have begun informing women about their density results.

Unfortunately, at this point clinicians have no clear guidelines for helping patients with dense breasts decide whether to undergo additional testing. In addition, the evidence is equivocal, and the tests have risks as well as benefits. The patient needs to understand all this by discussing it with her physician. And to discuss this decision effectively, the physician must be well versed in the evolving literature on breast density. Below, we present important points to keep in mind as we foster these discussions with our patients.

BREAST TISSUE DENSITY IS STILL A SUBJECTIVE MEASUREMENT

Breast density limits the sensitivity of mammography. This is widely established. Yet the interpretation of breast density today is subjective. It is determined by the interpreting radiologist based on the Breast Imaging and Reporting Data System (BI-RADS), which defines “heterogeneously dense” breasts as those containing 50% to 75% dense tissue and “dense” breasts as those with more than 75%⁵ (Figure 1). This subjective measurement is based on two-dimensional imaging, which may underestimate or overestimate the percentage of breast density because of tissue summation. Ideally, density should be measured using three-dimensional imaging with automated software,⁶ but this technology is not yet widely available.

INCREASED DETECTION OF BENIGN LESIONS

Although adding ultrasonography to mammography in patients with dense breast tissue detects additional cancers,^7,8 it also leads to a significant increase in the detection of lesions that are not malignant yet require additional workup or biopsy.

The largest study to examine this was the American College of Radiology Imaging Network Protocol 6666 (ACRIN 6666),⁷ a multi-institutional study evaluating the diagnostic yield, sensitivity, and specificity of adding ultrasonography in high-risk patients who presented with negative mammograms and had heterogeneously dense tissue in at least one quadrant.⁷ (High risk was defined as a threefold higher risk of breast cancer as determined by risk factors such as personal history of breast cancer or high-risk lesions, or elevated risk using the Gail or Claus model.) The supplemental yield was 4.2 cancers per 1,000 women (95% confidence interval 1.1 to 7.2 per 1,000) on a single prevalent screen. Of 12 cancers detected solely by ultrasonography, 11 were invasive and had a median size of 10 mm. Of those reported, 8 of 9 were node-negative. Despite this additional yield, the positive predictive value of biopsy prompted by ultrasonography was only 8.9%.⁷ Other investigators have reported similar findings.⁸

RELATIONSHIP BETWEEN DENSITY AND CANCER RISK STILL NOT CLEAR

The relationship between breast density and cancer risk is not entirely clear. Higher breast density has been associated with a higher risk of breast cancer,^9,10 presumably because cancer usually develops in parenchyma, and not fatty tissue. Yet obesity and age, which are inversely associated with density, are also risk factors for the development of breast cancer. Some prominent radiologists have cast doubt on the methodology used in these density studies, which relied on density measurements calculated by two-dimensional views of the breast, and have called for a re-evaluation of the relationship between density and cancer risk.⁶

LIMITED HEALTH LITERACY: A CHALLENGE

The term “breast density” is unfamiliar to most lay people. As physicians, we need to keep in mind that more than a third of US adults have limited health literacy and thus have difficulty processing basic health information.¹¹ But even the 1 in 10 US women with “proficient” health literacy skills may find the term “density” confusing.

As the definition at the opening of this article suggests, the word itself is nuanced and has different meanings. Anecdotally, both of the authors, a general internist (E.M.) and a breast imaging specialist (M.Y.), have encountered numerous quizzical and sometimes distrustful reactions when telling patients—including some with graduate degrees—that they have “dense” breast tissue and might benefit from additional ultrasonographic testing. Avoiding jargon is key; studies have found that terms such as “benign” can be confusing when used in a mammogram result notification letter.¹²

How can we explain the concept of breast density to our patients?

Supplemental educational materials that feature simple pictures can also be helpful in conveying complex health information,¹³ although their effect on the communication of breast density has not been studied. The American College of Radiology and the Society of Breast Imaging produce a freely available, downloadable patient brochure on breast density that includes photographs of mammograms with high and low breast density. The brochure is available from the American College of Radiology online at www.acr.org, under “Tools you can use.”

We recommend introducing women to the concept of breast density before they undergo mammography—at the time the test is ordered—and provide them with supplemental materials such as the above-mentioned brochure. About 1 out of every 10 women who undergo screening mammography has a result requiring additional testing that does not result in a cancer diagnosis. Yet a body of research suggests that many women don’t realize that mammograms don’t always yield a cut-and-dried “cancer” or “no cancer” result. In past studies, women have said they were unaware of how common it is to be called back after routine screening mammography, and they wanted to be prepared for this in advance.^12,14 Similarly, many women are unaware of the concept of breast density and don’t know that they may be told about these findings when they get their mammogram report.

Avoid causing anxiety

When explaining results to women with dense breasts, we should emphasize that there are no abnormalities on the current mammogram, and that the only reason to consider additional imaging is the breast density. But regardless of the ultimate outcome, an abnormal mammogram can trigger long-standing anxiety, ¹⁵ and it is reasonable to assume that some women will become anxious when told they have highly dense breasts. It is important that clinicians be aware of this potential anxiety and inquire about any personal cancer-related concerns at the time they discuss their findings.¹⁶

Helping the patient choose the type of additional screening

If a patient is found to have dense breasts and chooses to undergo additional screening, the decision about which test—ultrasonography or MRI—can be based on the woman’s lifetime risk of breast cancer.

The American Cancer Society recommends that patients with a lifetime risk of 20% or greater—according to a risk model such as BRCAPRO, Tyrer-Cuzick, or BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)—should be screened annually with breast MRI regardless of breast density. Patients in this category are those who carry the BRCA gene mutations and their untested first-degree relatives, and patients with Li-Fraumeni, Cowden, or Bannayan-Riley-Ruvalcaba syndrome. Also considered are women who underwent chest radiation between the ages of 10 and 30, and patients who have more than one first-degree relative with breast cancer but who do not have an identifiable genetic mutation.¹⁷

Patients with dense breasts who have an increased lifetime risk but who do not meet these criteria and those who are at average risk may be offered breast ultrasonography. If risk factors are unclear, genetic counseling can help determine the lifetime risk and thus help the patient choose the additional screening test.¹⁸

MORE WORK TO DO

Clearly, we still do not know how to explain breast density results to our patients in a way that will help them make a fully informed decision about additional screening. Research suggests that letters alone are insufficient,^13,19,20 and there is no guarantee that simply adding breast density notification language to result letters will enhance a woman’s understanding and empower her to choose a course of action that is sensitive to her personal preferences.

As more states adopt notification legislation, we must develop effective methods to improve our patients’ understanding of the meaning and implications of having dense breasts and to help them decide how to proceed. Such tools could include videos, Web sites, and pictorials, as well as specialized training for patient educators and health navigators. Otherwise, including this additional, conceptually difficult information to result notification letters could make the doctor-patient interaction even more “dense”—and could increase women’s uncertainty and anxiety about their personal risk of cancer.²¹

Recently, Nevada,¹ North Carolina, and Oregon joined a number of other US states (as of this writing, nine other states) in enacting laws that require informing women if they have dense breast tissue detected on mammography.² Laws are pending in other states. Federal legislation has also been introduced in the US House of Representatives.

See related commentary

THE POWER OF ADVOCACY TO CHANGE MEDICAL PRACTICE

One such bill³ was introduced as a result of the advocacy of a single patient, Nancy Cappello, a Connecticut woman who was not informed that she had dense breasts and was later found to have node-positive breast cancer.⁴

While new medical practices are rarely credited to the efforts of single physician or researcher, these “dense-breast laws” show the power a single patient may play in health care. The evidence behind these laws and their implications bring to the forefront the role of advocacy and legislation in the practice of medicine.

Dense-breast laws are the latest chapter in how legislative action can change the practice of medicine. Proof that advocacy could use law to change medical practice emerged in the early 1990s in the wake of AIDS activism. Patient-advocacy activists lobbied for early access to investigational agents, arguing that traditional pathways of clinical testing would deprive terminally ill patients of potentially lifesaving treatments. These efforts led the US Food and Drug Administration (FDA) to create the Accelerated Approval Program, which allows new drugs to garner approval based on surrogate end-point data for terminal or neglected diseases. Accelerated approval was codified into law in 1997 in the FDA’s Modernization Act.⁵ In 2012, legislative action further broadened the ability of the FDA to approve new products based on surrogate data,⁶ with the FDA’s Safety and Innovation Act, which provides for first-time approval of a drug based on “pharmacologic” end points that are even more limited.⁶

Although proponents have declared success when legislative action lowers the bar for drug and device approval, independent analyses have been more critical. In 2009, accelerated approval underwent significant scrutiny when the Government Accountability Office issued a report summarizing 16 years of the program.⁷ Over the program’s life span, the FDA called for 144 postmarketing studies, but more than one-third of these remained incomplete. Moreover, in 13 years, the FDA never exercised its power to expedite the withdrawal of a drug from the market.

Many accelerated approvals have created considerable controversy. Bevacizumab for metastatic breast cancer was ultimately found to confer no survival benefit, and its approval was revoked.⁸ Gemtuzumab ozogamicin for acute myeloid leukemia may be effective, but not at the dose that was approved.⁹ And midodrine hydrochloride and many other drugs remain untested.¹⁰

DOES THIS INFORMATION HELP PATIENTS? WHAT WOULD THEY DO WITH IT?

The question with dense-breast laws is similar to that facing other legal efforts to change medicine: Does it actually help patents? Will the information doctors disclose lead to appropriate interventions that improve health outcomes, or, instead, lead to cascades of testing and biopsies that worsen overdiagnosis?

Like accelerated approval, mandating disclosure of breast density is an intervention with uncertain efficacy. While increased breast density has been shown to increase a woman’s risk of developing breast cancer, it is also neutral regarding a woman’s chances of dying of breast cancer.¹¹ In other words, it does not identify patients who experience aggressive disease.

Next comes the larger question of what women would do with this information. Will they simply be more compliant with existing screening recommendations, or will they seek additional testing? This is where the greatest uncertainty lies. The utility of additional testing with ultrasonography or magnetic resonance imaging (MRI) remains uncertain in this population. We will certainly find more cancers if we use MRI to screen women, but it remains unclear if this translates to improved outcomes.

A recent study shows just this.¹² In Connecticut, breast density notification is mandatory, as is insurance coverage for screening (or whole-breast) ultrasonography. Since the passage of these laws, the Yale Medical Center has screened 935 women with dense breasts using ultrasonography. Over this time, they performed roughly 16,000 mammograms; thus, the breast density law applied roughly to 1 out of 16 (6.25%) studies. Of the 935 women, biopsies were performed in 54 (5.8%). These were mostly needle biopsies (46), but 3 patients underwent surgical excision, and five cysts were aspirated. From these efforts, two sub-centimeter cancers were found and one case of ductal carcinoma in situ was found. Thus, only 3.7% of women undergoing biopsy and fewer than 1% of women undergoing ultrasonography were found to have cancer.

Of course, given the nature of this study, we cannot know what would have happened without referral and testing. However, empirical research suggests that detecting a breast cancer with screening does not mean a life was saved.¹³ In fact, only a minority of such women (13%) can credit screening with a survival gain.¹³

In a study¹⁴ that compared women with dense breasts who underwent annual vs biannual screening, no difference in the rate of advanced or metastatic disease was seen with more frequent screening, but the rates of false-positive results and biopsies were higher.¹⁴

Notably, dense-breast legislation comes at a time when fundamental questions have been raised about the impact of screening on breast cancer. A prominent study of trends in US breast cancer incidence and death rates over the last 30 years shows that even under the most favorable assumptions, mammography has led to a huge surplus in the diagnosis of breast cancer but little change in the breast cancer mortality rate.¹⁵ It is entirely possible that more-aggressive screening in women with dense breasts will only exacerbate this problem. Advocacy may harm rather than help these patients.

We are often told that laws such as the dense-breast bills are motivated by the public’s desire and patient advocacy. However, we are unsure if the vocal proponents of dense-breast laws represent the average women’s desires. These efforts may simply be another case of how a vocal and passionate minority can overcome a large and indifferent majority.¹⁶

LEGISLATING MEDICAL PRACTICE IS A BOLD STEP

Dense-breast laws present an additional challenge: they cannot be changed as quickly as scientific understanding. In other words, if the medical field comes to believe that notification is generally harmful because it leads to increased biopsies but not better health, can the law be changed rapidly enough to reflect this? There is a large precedent for the reversal of medical practices,^17,18 particularly those based on scant evidence, including cases of recommended screening tests (most notably, recent changes to prostate-specific antigen guidelines). But in all these other cases, law did not mandate the practice or recommendation. Laws are often slow to adapt to changes in understanding.

Legislating medical practice is a bold step, and even those who feel it is occasionally warranted must hold themselves to a rational guiding principle. We have incontrovertible evidence that flexible sigmoidoscopy can reduce the number of deaths from colorectal cancer, but no state mandates that doctors inform their patients of this fact. A patient’s ejection fraction serves as a marker of benefit for several lifesaving drugs and devices, yet no state mandates that physicians disclose this information to patients after echocardiography.

All of us in health care—physicians, researchers, nurses, practitioners, and patients—are patient advocates, and we all want policies that promote human health. However, doing so means adhering to practices grounded in evidence. Dense-breast laws serve as a reminder that good intentions and good people may be necessary—but are not sufficient—for sound policy.

Recently, Nevada,¹ North Carolina, and Oregon joined a number of other US states (as of this writing, nine other states) in enacting laws that require informing women if they have dense breast tissue detected on mammography.² Laws are pending in other states. Federal legislation has also been introduced in the US House of Representatives.

See related commentary

THE POWER OF ADVOCACY TO CHANGE MEDICAL PRACTICE

One such bill³ was introduced as a result of the advocacy of a single patient, Nancy Cappello, a Connecticut woman who was not informed that she had dense breasts and was later found to have node-positive breast cancer.⁴

While new medical practices are rarely credited to the efforts of single physician or researcher, these “dense-breast laws” show the power a single patient may play in health care. The evidence behind these laws and their implications bring to the forefront the role of advocacy and legislation in the practice of medicine.

Dense-breast laws are the latest chapter in how legislative action can change the practice of medicine. Proof that advocacy could use law to change medical practice emerged in the early 1990s in the wake of AIDS activism. Patient-advocacy activists lobbied for early access to investigational agents, arguing that traditional pathways of clinical testing would deprive terminally ill patients of potentially lifesaving treatments. These efforts led the US Food and Drug Administration (FDA) to create the Accelerated Approval Program, which allows new drugs to garner approval based on surrogate end-point data for terminal or neglected diseases. Accelerated approval was codified into law in 1997 in the FDA’s Modernization Act.⁵ In 2012, legislative action further broadened the ability of the FDA to approve new products based on surrogate data,⁶ with the FDA’s Safety and Innovation Act, which provides for first-time approval of a drug based on “pharmacologic” end points that are even more limited.⁶

Although proponents have declared success when legislative action lowers the bar for drug and device approval, independent analyses have been more critical. In 2009, accelerated approval underwent significant scrutiny when the Government Accountability Office issued a report summarizing 16 years of the program.⁷ Over the program’s life span, the FDA called for 144 postmarketing studies, but more than one-third of these remained incomplete. Moreover, in 13 years, the FDA never exercised its power to expedite the withdrawal of a drug from the market.

Many accelerated approvals have created considerable controversy. Bevacizumab for metastatic breast cancer was ultimately found to confer no survival benefit, and its approval was revoked.⁸ Gemtuzumab ozogamicin for acute myeloid leukemia may be effective, but not at the dose that was approved.⁹ And midodrine hydrochloride and many other drugs remain untested.¹⁰

DOES THIS INFORMATION HELP PATIENTS? WHAT WOULD THEY DO WITH IT?

The question with dense-breast laws is similar to that facing other legal efforts to change medicine: Does it actually help patents? Will the information doctors disclose lead to appropriate interventions that improve health outcomes, or, instead, lead to cascades of testing and biopsies that worsen overdiagnosis?

Like accelerated approval, mandating disclosure of breast density is an intervention with uncertain efficacy. While increased breast density has been shown to increase a woman’s risk of developing breast cancer, it is also neutral regarding a woman’s chances of dying of breast cancer.¹¹ In other words, it does not identify patients who experience aggressive disease.

Next comes the larger question of what women would do with this information. Will they simply be more compliant with existing screening recommendations, or will they seek additional testing? This is where the greatest uncertainty lies. The utility of additional testing with ultrasonography or magnetic resonance imaging (MRI) remains uncertain in this population. We will certainly find more cancers if we use MRI to screen women, but it remains unclear if this translates to improved outcomes.

A recent study shows just this.¹² In Connecticut, breast density notification is mandatory, as is insurance coverage for screening (or whole-breast) ultrasonography. Since the passage of these laws, the Yale Medical Center has screened 935 women with dense breasts using ultrasonography. Over this time, they performed roughly 16,000 mammograms; thus, the breast density law applied roughly to 1 out of 16 (6.25%) studies. Of the 935 women, biopsies were performed in 54 (5.8%). These were mostly needle biopsies (46), but 3 patients underwent surgical excision, and five cysts were aspirated. From these efforts, two sub-centimeter cancers were found and one case of ductal carcinoma in situ was found. Thus, only 3.7% of women undergoing biopsy and fewer than 1% of women undergoing ultrasonography were found to have cancer.

Of course, given the nature of this study, we cannot know what would have happened without referral and testing. However, empirical research suggests that detecting a breast cancer with screening does not mean a life was saved.¹³ In fact, only a minority of such women (13%) can credit screening with a survival gain.¹³

In a study¹⁴ that compared women with dense breasts who underwent annual vs biannual screening, no difference in the rate of advanced or metastatic disease was seen with more frequent screening, but the rates of false-positive results and biopsies were higher.¹⁴

Notably, dense-breast legislation comes at a time when fundamental questions have been raised about the impact of screening on breast cancer. A prominent study of trends in US breast cancer incidence and death rates over the last 30 years shows that even under the most favorable assumptions, mammography has led to a huge surplus in the diagnosis of breast cancer but little change in the breast cancer mortality rate.¹⁵ It is entirely possible that more-aggressive screening in women with dense breasts will only exacerbate this problem. Advocacy may harm rather than help these patients.

We are often told that laws such as the dense-breast bills are motivated by the public’s desire and patient advocacy. However, we are unsure if the vocal proponents of dense-breast laws represent the average women’s desires. These efforts may simply be another case of how a vocal and passionate minority can overcome a large and indifferent majority.¹⁶

LEGISLATING MEDICAL PRACTICE IS A BOLD STEP

Dense-breast laws present an additional challenge: they cannot be changed as quickly as scientific understanding. In other words, if the medical field comes to believe that notification is generally harmful because it leads to increased biopsies but not better health, can the law be changed rapidly enough to reflect this? There is a large precedent for the reversal of medical practices,^17,18 particularly those based on scant evidence, including cases of recommended screening tests (most notably, recent changes to prostate-specific antigen guidelines). But in all these other cases, law did not mandate the practice or recommendation. Laws are often slow to adapt to changes in understanding.

Legislating medical practice is a bold step, and even those who feel it is occasionally warranted must hold themselves to a rational guiding principle. We have incontrovertible evidence that flexible sigmoidoscopy can reduce the number of deaths from colorectal cancer, but no state mandates that doctors inform their patients of this fact. A patient’s ejection fraction serves as a marker of benefit for several lifesaving drugs and devices, yet no state mandates that physicians disclose this information to patients after echocardiography.

All of us in health care—physicians, researchers, nurses, practitioners, and patients—are patient advocates, and we all want policies that promote human health. However, doing so means adhering to practices grounded in evidence. Dense-breast laws serve as a reminder that good intentions and good people may be necessary—but are not sufficient—for sound policy.

Recently, Nevada,¹ North Carolina, and Oregon joined a number of other US states (as of this writing, nine other states) in enacting laws that require informing women if they have dense breast tissue detected on mammography.² Laws are pending in other states. Federal legislation has also been introduced in the US House of Representatives.

See related commentary

THE POWER OF ADVOCACY TO CHANGE MEDICAL PRACTICE

One such bill³ was introduced as a result of the advocacy of a single patient, Nancy Cappello, a Connecticut woman who was not informed that she had dense breasts and was later found to have node-positive breast cancer.⁴

While new medical practices are rarely credited to the efforts of single physician or researcher, these “dense-breast laws” show the power a single patient may play in health care. The evidence behind these laws and their implications bring to the forefront the role of advocacy and legislation in the practice of medicine.

Dense-breast laws are the latest chapter in how legislative action can change the practice of medicine. Proof that advocacy could use law to change medical practice emerged in the early 1990s in the wake of AIDS activism. Patient-advocacy activists lobbied for early access to investigational agents, arguing that traditional pathways of clinical testing would deprive terminally ill patients of potentially lifesaving treatments. These efforts led the US Food and Drug Administration (FDA) to create the Accelerated Approval Program, which allows new drugs to garner approval based on surrogate end-point data for terminal or neglected diseases. Accelerated approval was codified into law in 1997 in the FDA’s Modernization Act.⁵ In 2012, legislative action further broadened the ability of the FDA to approve new products based on surrogate data,⁶ with the FDA’s Safety and Innovation Act, which provides for first-time approval of a drug based on “pharmacologic” end points that are even more limited.⁶

Although proponents have declared success when legislative action lowers the bar for drug and device approval, independent analyses have been more critical. In 2009, accelerated approval underwent significant scrutiny when the Government Accountability Office issued a report summarizing 16 years of the program.⁷ Over the program’s life span, the FDA called for 144 postmarketing studies, but more than one-third of these remained incomplete. Moreover, in 13 years, the FDA never exercised its power to expedite the withdrawal of a drug from the market.

Many accelerated approvals have created considerable controversy. Bevacizumab for metastatic breast cancer was ultimately found to confer no survival benefit, and its approval was revoked.⁸ Gemtuzumab ozogamicin for acute myeloid leukemia may be effective, but not at the dose that was approved.⁹ And midodrine hydrochloride and many other drugs remain untested.¹⁰

DOES THIS INFORMATION HELP PATIENTS? WHAT WOULD THEY DO WITH IT?

The question with dense-breast laws is similar to that facing other legal efforts to change medicine: Does it actually help patents? Will the information doctors disclose lead to appropriate interventions that improve health outcomes, or, instead, lead to cascades of testing and biopsies that worsen overdiagnosis?

Like accelerated approval, mandating disclosure of breast density is an intervention with uncertain efficacy. While increased breast density has been shown to increase a woman’s risk of developing breast cancer, it is also neutral regarding a woman’s chances of dying of breast cancer.¹¹ In other words, it does not identify patients who experience aggressive disease.

Next comes the larger question of what women would do with this information. Will they simply be more compliant with existing screening recommendations, or will they seek additional testing? This is where the greatest uncertainty lies. The utility of additional testing with ultrasonography or magnetic resonance imaging (MRI) remains uncertain in this population. We will certainly find more cancers if we use MRI to screen women, but it remains unclear if this translates to improved outcomes.

A recent study shows just this.¹² In Connecticut, breast density notification is mandatory, as is insurance coverage for screening (or whole-breast) ultrasonography. Since the passage of these laws, the Yale Medical Center has screened 935 women with dense breasts using ultrasonography. Over this time, they performed roughly 16,000 mammograms; thus, the breast density law applied roughly to 1 out of 16 (6.25%) studies. Of the 935 women, biopsies were performed in 54 (5.8%). These were mostly needle biopsies (46), but 3 patients underwent surgical excision, and five cysts were aspirated. From these efforts, two sub-centimeter cancers were found and one case of ductal carcinoma in situ was found. Thus, only 3.7% of women undergoing biopsy and fewer than 1% of women undergoing ultrasonography were found to have cancer.

Of course, given the nature of this study, we cannot know what would have happened without referral and testing. However, empirical research suggests that detecting a breast cancer with screening does not mean a life was saved.¹³ In fact, only a minority of such women (13%) can credit screening with a survival gain.¹³

In a study¹⁴ that compared women with dense breasts who underwent annual vs biannual screening, no difference in the rate of advanced or metastatic disease was seen with more frequent screening, but the rates of false-positive results and biopsies were higher.¹⁴

Notably, dense-breast legislation comes at a time when fundamental questions have been raised about the impact of screening on breast cancer. A prominent study of trends in US breast cancer incidence and death rates over the last 30 years shows that even under the most favorable assumptions, mammography has led to a huge surplus in the diagnosis of breast cancer but little change in the breast cancer mortality rate.¹⁵ It is entirely possible that more-aggressive screening in women with dense breasts will only exacerbate this problem. Advocacy may harm rather than help these patients.

We are often told that laws such as the dense-breast bills are motivated by the public’s desire and patient advocacy. However, we are unsure if the vocal proponents of dense-breast laws represent the average women’s desires. These efforts may simply be another case of how a vocal and passionate minority can overcome a large and indifferent majority.¹⁶

LEGISLATING MEDICAL PRACTICE IS A BOLD STEP

Dense-breast laws present an additional challenge: they cannot be changed as quickly as scientific understanding. In other words, if the medical field comes to believe that notification is generally harmful because it leads to increased biopsies but not better health, can the law be changed rapidly enough to reflect this? There is a large precedent for the reversal of medical practices,^17,18 particularly those based on scant evidence, including cases of recommended screening tests (most notably, recent changes to prostate-specific antigen guidelines). But in all these other cases, law did not mandate the practice or recommendation. Laws are often slow to adapt to changes in understanding.

Legislating medical practice is a bold step, and even those who feel it is occasionally warranted must hold themselves to a rational guiding principle. We have incontrovertible evidence that flexible sigmoidoscopy can reduce the number of deaths from colorectal cancer, but no state mandates that doctors inform their patients of this fact. A patient’s ejection fraction serves as a marker of benefit for several lifesaving drugs and devices, yet no state mandates that physicians disclose this information to patients after echocardiography.

All of us in health care—physicians, researchers, nurses, practitioners, and patients—are patient advocates, and we all want policies that promote human health. However, doing so means adhering to practices grounded in evidence. Dense-breast laws serve as a reminder that good intentions and good people may be necessary—but are not sufficient—for sound policy.

Current evidence suggests no absolute contraindication to angiotensin receptor blockers (ARBs) in patients who have had angioedema attributable to an angiotensin-converting enzyme (ACE) inhibitor. However, since ARBs can also cause angioedema, they should be prescribed with extreme caution after a thorough risk-benefit analysis and after educating the patient to watch for signs of angioedema while taking the drug.

A GROWING PROBLEM

Angioedema is a potentially life-threatening swelling of the skin and subcutaneous tissues, often affecting the lips and tongue (Figure 1), and in some cases interfering with breathing and requiring tracheostomy.¹ The incidence rate of angioedema in patients taking ACE inhibitors ranges from 0.1% to 0.7%.^2–4 Although this rate may seem low, the widespread and growing use of ACE inhibitors and ARBs in patients with diabetes, diabetic nephropathy, and congestive heart failure⁵ makes angioedema fairly common in clinical practice.

ACE inhibitor-induced angioedema most commonly occurs within days of initiating therapy, but it also may occur weeks, months, or even years after the start of treatment.¹ Patients who are over age 65, black, or female are at higher risk, as are renal transplant recipients taking mTOR inhibitors such as sirolimus. Diabetes appears to be associated with a lower risk.^4,6,7 This adverse reaction to ACE inhibitors is thought to be a class side effect, and the future use of this class of drugs would be contraindicated.^8,9

ACE inhibitors cause angioedema by direct interference with the degradation of bradykinin, thereby increasing bradykinin levels and potentiating its biologic effect, leading to increased vascular permeability, inflammation, and activation of nociceptors.⁸

EVIDENCE TO SUPPORT THE USE OF ARBs

ACE inhibitors and ARBs both block the renin-angiotensin-aldosterone pathway and confer similar advantages in patients with congestive heart failure, renal failure, and diabetes. But since ARBs directly inhibit the angiotensin receptor and do not interfere with bradykinin degradation, how they cause angioedema is unclear, and clinicians have questioned whether these agents might be used safely in patients who have had angioedema on an ACE inhibitor.

In a large meta-analysis of randomized clinical trials, Makani et al² investigated the risk of angioedema with ARB use in 35,479 patients and compared this with other commonly used antihypertensive drugs. The weighted incidence of angioedema was 0.30% with an ACE inhibitor, 0.11% with an ARB, and 0.07% with placebo.² In seven trials included in this study that compared ARBs with placebo, there was no significant difference in the risk of angioedema. Even in such a large study, the event rate was small, making definite conclusions difficult.

In a retrospective observational study of 4 million patients by Toh et al,³ patients on beta-blockers were used as a reference, and propensity scoring was used to estimate the hazard ratio of angioedema separately for drugs targeting the renin-angiotensin-aldosterone system, including ACE inhibitors and ARBs. The risk of angioedema, as measured by the cumulative incidence and incidence rate, was highest for ACE inhibitors and was similar between ARBs and beta-blockers. The risk of serious angioedema was three times higher with ACE inhibitors than with beta-blockers, and there was no higher risk of serious angioedema with ARBs than with beta-blockers.³

Looking specifically at the use of ARBs in patients who developed angioedema on an ACE inhibitor, Haymore et al¹⁰ performed a meta-analysis evaluating only three studies that showed the estimated risk of angioedema with an ARB was between 3.5% and 9.4% in patients with a history of ACE inhibitor-induced angioedema. Later, when the results of the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease trial¹¹ were published, the previous meta-analysis was updated¹²: the risk of angioedema with an ARB was only 2.5% (95% confidence interval 0%–6.6%), and there was no statistically significant difference in the odds (odds ratio 1.1; 95% confidence interval 0.07–17) of angioedema between ARBs and placebo.^10,12 Again, these results should be interpreted with caution, as only two patients in the ARB (telmisartan) group and three patients in the placebo group developed angioedema.

In another review, Beavers et al¹³ advised that the prescribing practitioner should carefully perform a risk-benefit analysis before substituting an ARB in patients with ACE inhibitor-induced angioedema. They concluded that an ARB could be considered in patients who are likely to have a large clinical benefit from an ARB, such as those with heart failure. They also suggested that angioedema related to ARBs was less severe and occurred earlier than with that linked to ACE inhibitors.

No large clinical trial has yet been specifically designed to address the use of ARBs in patients with a history of ACE inhibitor-induced angioedema. The package insert for the ARB losartan mentions that the risk of this adverse reaction might be higher in patients who have had angioedema on an ACE inhibitor. However, the issue of recurrent angioedema is not further addressed for this or other commonly used ARBs.

GENERAL RECOMMENDATIONS

The mechanisms of ARB-induced angioedema are yet unknown. However, studies have shown that the incidence of angioedema while on an ARB is low and is probably comparable to that of placebo.^2,3,12–14 And since ARBs share many of the cardiac and renal protective effects of ACE inhibitors, ARBs may be beneficial for patients who discontinue an ACE inhibitor because of adverse effects including angioedema.^9,15,16 Based on the discussion above, there is no clear evidence to suggest that ARBs are contraindicated in such patients, especially if there is a compelling indication for an ARB.

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines on hypertension in chronic kidney disease recommend caution when substituting an ARB for an ACE inhibitor after angioedema.¹⁵ The joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA) for the diagnosis and management of heart failure in adults advise “extreme caution.”^9,16

The risks and benefits of ARB therapy in this setting should be analyzed by the prescribing physician and discussed with the patient. The patient should be closely monitored for the recurrence of angioedema and should be given a clear plan of action should symptoms recur.

OUR ADVICE

In patients with ACE inhibitor-induced angioedema, we recommend the following:

• Determine that the patient truly has one of the evidence-based, compelling indications for an ARB. Carefully weigh the risks and benefits for the individual patient, and discuss the risk of angioedema based on age, race, sex, and medical history, and the availability of immediate medical care should angioedema occur.
• If there is an evidence-based indication for an ARB that outweighs the risk of angioedema, an ARB may be started with caution.
• Specifically discuss with the patient the possibility of recurrence of angioedema while on an ARB, and provide instructions on how to proceed if this should occur.

Current evidence suggests no absolute contraindication to angiotensin receptor blockers (ARBs) in patients who have had angioedema attributable to an angiotensin-converting enzyme (ACE) inhibitor. However, since ARBs can also cause angioedema, they should be prescribed with extreme caution after a thorough risk-benefit analysis and after educating the patient to watch for signs of angioedema while taking the drug.

A GROWING PROBLEM

Angioedema is a potentially life-threatening swelling of the skin and subcutaneous tissues, often affecting the lips and tongue (Figure 1), and in some cases interfering with breathing and requiring tracheostomy.¹ The incidence rate of angioedema in patients taking ACE inhibitors ranges from 0.1% to 0.7%.^2–4 Although this rate may seem low, the widespread and growing use of ACE inhibitors and ARBs in patients with diabetes, diabetic nephropathy, and congestive heart failure⁵ makes angioedema fairly common in clinical practice.

ACE inhibitor-induced angioedema most commonly occurs within days of initiating therapy, but it also may occur weeks, months, or even years after the start of treatment.¹ Patients who are over age 65, black, or female are at higher risk, as are renal transplant recipients taking mTOR inhibitors such as sirolimus. Diabetes appears to be associated with a lower risk.^4,6,7 This adverse reaction to ACE inhibitors is thought to be a class side effect, and the future use of this class of drugs would be contraindicated.^8,9

ACE inhibitors cause angioedema by direct interference with the degradation of bradykinin, thereby increasing bradykinin levels and potentiating its biologic effect, leading to increased vascular permeability, inflammation, and activation of nociceptors.⁸

EVIDENCE TO SUPPORT THE USE OF ARBs

ACE inhibitors and ARBs both block the renin-angiotensin-aldosterone pathway and confer similar advantages in patients with congestive heart failure, renal failure, and diabetes. But since ARBs directly inhibit the angiotensin receptor and do not interfere with bradykinin degradation, how they cause angioedema is unclear, and clinicians have questioned whether these agents might be used safely in patients who have had angioedema on an ACE inhibitor.

In a large meta-analysis of randomized clinical trials, Makani et al² investigated the risk of angioedema with ARB use in 35,479 patients and compared this with other commonly used antihypertensive drugs. The weighted incidence of angioedema was 0.30% with an ACE inhibitor, 0.11% with an ARB, and 0.07% with placebo.² In seven trials included in this study that compared ARBs with placebo, there was no significant difference in the risk of angioedema. Even in such a large study, the event rate was small, making definite conclusions difficult.

In a retrospective observational study of 4 million patients by Toh et al,³ patients on beta-blockers were used as a reference, and propensity scoring was used to estimate the hazard ratio of angioedema separately for drugs targeting the renin-angiotensin-aldosterone system, including ACE inhibitors and ARBs. The risk of angioedema, as measured by the cumulative incidence and incidence rate, was highest for ACE inhibitors and was similar between ARBs and beta-blockers. The risk of serious angioedema was three times higher with ACE inhibitors than with beta-blockers, and there was no higher risk of serious angioedema with ARBs than with beta-blockers.³

Looking specifically at the use of ARBs in patients who developed angioedema on an ACE inhibitor, Haymore et al¹⁰ performed a meta-analysis evaluating only three studies that showed the estimated risk of angioedema with an ARB was between 3.5% and 9.4% in patients with a history of ACE inhibitor-induced angioedema. Later, when the results of the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease trial¹¹ were published, the previous meta-analysis was updated¹²: the risk of angioedema with an ARB was only 2.5% (95% confidence interval 0%–6.6%), and there was no statistically significant difference in the odds (odds ratio 1.1; 95% confidence interval 0.07–17) of angioedema between ARBs and placebo.^10,12 Again, these results should be interpreted with caution, as only two patients in the ARB (telmisartan) group and three patients in the placebo group developed angioedema.

In another review, Beavers et al¹³ advised that the prescribing practitioner should carefully perform a risk-benefit analysis before substituting an ARB in patients with ACE inhibitor-induced angioedema. They concluded that an ARB could be considered in patients who are likely to have a large clinical benefit from an ARB, such as those with heart failure. They also suggested that angioedema related to ARBs was less severe and occurred earlier than with that linked to ACE inhibitors.

No large clinical trial has yet been specifically designed to address the use of ARBs in patients with a history of ACE inhibitor-induced angioedema. The package insert for the ARB losartan mentions that the risk of this adverse reaction might be higher in patients who have had angioedema on an ACE inhibitor. However, the issue of recurrent angioedema is not further addressed for this or other commonly used ARBs.

GENERAL RECOMMENDATIONS

The mechanisms of ARB-induced angioedema are yet unknown. However, studies have shown that the incidence of angioedema while on an ARB is low and is probably comparable to that of placebo.^2,3,12–14 And since ARBs share many of the cardiac and renal protective effects of ACE inhibitors, ARBs may be beneficial for patients who discontinue an ACE inhibitor because of adverse effects including angioedema.^9,15,16 Based on the discussion above, there is no clear evidence to suggest that ARBs are contraindicated in such patients, especially if there is a compelling indication for an ARB.

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines on hypertension in chronic kidney disease recommend caution when substituting an ARB for an ACE inhibitor after angioedema.¹⁵ The joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA) for the diagnosis and management of heart failure in adults advise “extreme caution.”^9,16

The risks and benefits of ARB therapy in this setting should be analyzed by the prescribing physician and discussed with the patient. The patient should be closely monitored for the recurrence of angioedema and should be given a clear plan of action should symptoms recur.

OUR ADVICE

In patients with ACE inhibitor-induced angioedema, we recommend the following:

• Determine that the patient truly has one of the evidence-based, compelling indications for an ARB. Carefully weigh the risks and benefits for the individual patient, and discuss the risk of angioedema based on age, race, sex, and medical history, and the availability of immediate medical care should angioedema occur.
• If there is an evidence-based indication for an ARB that outweighs the risk of angioedema, an ARB may be started with caution.
• Specifically discuss with the patient the possibility of recurrence of angioedema while on an ARB, and provide instructions on how to proceed if this should occur.

Current evidence suggests no absolute contraindication to angiotensin receptor blockers (ARBs) in patients who have had angioedema attributable to an angiotensin-converting enzyme (ACE) inhibitor. However, since ARBs can also cause angioedema, they should be prescribed with extreme caution after a thorough risk-benefit analysis and after educating the patient to watch for signs of angioedema while taking the drug.

A GROWING PROBLEM

Angioedema is a potentially life-threatening swelling of the skin and subcutaneous tissues, often affecting the lips and tongue (Figure 1), and in some cases interfering with breathing and requiring tracheostomy.¹ The incidence rate of angioedema in patients taking ACE inhibitors ranges from 0.1% to 0.7%.^2–4 Although this rate may seem low, the widespread and growing use of ACE inhibitors and ARBs in patients with diabetes, diabetic nephropathy, and congestive heart failure⁵ makes angioedema fairly common in clinical practice.

ACE inhibitor-induced angioedema most commonly occurs within days of initiating therapy, but it also may occur weeks, months, or even years after the start of treatment.¹ Patients who are over age 65, black, or female are at higher risk, as are renal transplant recipients taking mTOR inhibitors such as sirolimus. Diabetes appears to be associated with a lower risk.^4,6,7 This adverse reaction to ACE inhibitors is thought to be a class side effect, and the future use of this class of drugs would be contraindicated.^8,9

ACE inhibitors cause angioedema by direct interference with the degradation of bradykinin, thereby increasing bradykinin levels and potentiating its biologic effect, leading to increased vascular permeability, inflammation, and activation of nociceptors.⁸

EVIDENCE TO SUPPORT THE USE OF ARBs

ACE inhibitors and ARBs both block the renin-angiotensin-aldosterone pathway and confer similar advantages in patients with congestive heart failure, renal failure, and diabetes. But since ARBs directly inhibit the angiotensin receptor and do not interfere with bradykinin degradation, how they cause angioedema is unclear, and clinicians have questioned whether these agents might be used safely in patients who have had angioedema on an ACE inhibitor.

In a large meta-analysis of randomized clinical trials, Makani et al² investigated the risk of angioedema with ARB use in 35,479 patients and compared this with other commonly used antihypertensive drugs. The weighted incidence of angioedema was 0.30% with an ACE inhibitor, 0.11% with an ARB, and 0.07% with placebo.² In seven trials included in this study that compared ARBs with placebo, there was no significant difference in the risk of angioedema. Even in such a large study, the event rate was small, making definite conclusions difficult.

In a retrospective observational study of 4 million patients by Toh et al,³ patients on beta-blockers were used as a reference, and propensity scoring was used to estimate the hazard ratio of angioedema separately for drugs targeting the renin-angiotensin-aldosterone system, including ACE inhibitors and ARBs. The risk of angioedema, as measured by the cumulative incidence and incidence rate, was highest for ACE inhibitors and was similar between ARBs and beta-blockers. The risk of serious angioedema was three times higher with ACE inhibitors than with beta-blockers, and there was no higher risk of serious angioedema with ARBs than with beta-blockers.³

Looking specifically at the use of ARBs in patients who developed angioedema on an ACE inhibitor, Haymore et al¹⁰ performed a meta-analysis evaluating only three studies that showed the estimated risk of angioedema with an ARB was between 3.5% and 9.4% in patients with a history of ACE inhibitor-induced angioedema. Later, when the results of the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease trial¹¹ were published, the previous meta-analysis was updated¹²: the risk of angioedema with an ARB was only 2.5% (95% confidence interval 0%–6.6%), and there was no statistically significant difference in the odds (odds ratio 1.1; 95% confidence interval 0.07–17) of angioedema between ARBs and placebo.^10,12 Again, these results should be interpreted with caution, as only two patients in the ARB (telmisartan) group and three patients in the placebo group developed angioedema.

In another review, Beavers et al¹³ advised that the prescribing practitioner should carefully perform a risk-benefit analysis before substituting an ARB in patients with ACE inhibitor-induced angioedema. They concluded that an ARB could be considered in patients who are likely to have a large clinical benefit from an ARB, such as those with heart failure. They also suggested that angioedema related to ARBs was less severe and occurred earlier than with that linked to ACE inhibitors.

No large clinical trial has yet been specifically designed to address the use of ARBs in patients with a history of ACE inhibitor-induced angioedema. The package insert for the ARB losartan mentions that the risk of this adverse reaction might be higher in patients who have had angioedema on an ACE inhibitor. However, the issue of recurrent angioedema is not further addressed for this or other commonly used ARBs.

GENERAL RECOMMENDATIONS

The mechanisms of ARB-induced angioedema are yet unknown. However, studies have shown that the incidence of angioedema while on an ARB is low and is probably comparable to that of placebo.^2,3,12–14 And since ARBs share many of the cardiac and renal protective effects of ACE inhibitors, ARBs may be beneficial for patients who discontinue an ACE inhibitor because of adverse effects including angioedema.^9,15,16 Based on the discussion above, there is no clear evidence to suggest that ARBs are contraindicated in such patients, especially if there is a compelling indication for an ARB.

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines on hypertension in chronic kidney disease recommend caution when substituting an ARB for an ACE inhibitor after angioedema.¹⁵ The joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA) for the diagnosis and management of heart failure in adults advise “extreme caution.”^9,16

The risks and benefits of ARB therapy in this setting should be analyzed by the prescribing physician and discussed with the patient. The patient should be closely monitored for the recurrence of angioedema and should be given a clear plan of action should symptoms recur.

OUR ADVICE

In patients with ACE inhibitor-induced angioedema, we recommend the following:

• Determine that the patient truly has one of the evidence-based, compelling indications for an ARB. Carefully weigh the risks and benefits for the individual patient, and discuss the risk of angioedema based on age, race, sex, and medical history, and the availability of immediate medical care should angioedema occur.
• If there is an evidence-based indication for an ARB that outweighs the risk of angioedema, an ARB may be started with caution.
• Specifically discuss with the patient the possibility of recurrence of angioedema while on an ARB, and provide instructions on how to proceed if this should occur.

Phil Canuto, the executive editor of the Cleveland Clinic Journal of Medicine for almost 20 years, is retiring. Known to relatively few of our authors and peer reviewers, Phil has been the invisible force behind the current print and digital face and body of CCJM.

Few medical journals have a persona that connects with their readers, relating in ways that lead to a bonding between reader and journal that extends beyond the content of the monthly articles. We have strived to attain such a relationship with you, our readers, and I will take the liberty of assuming we have to some extent succeeded. I devote my space this month to talking with you about Phil and his relationship with the Journal.

I have frequently described our journalistic mission as publishing articles for our readers—not for our authors. Phil helped translate this concept into reality by insisting that articles be readable and understandable and always have a clearly stated “bottom-line” message.

Phil joined the CCJM in 1995. He came with genuine journalistic and writing skills and a conviction that medical writing for and by physicians could and should have the same clarity that provides effective information transfer in other venues. He had previously worked as a reporter and medical writer at The Akron Beacon Journal newspaper, and prior to that had been the public information officer for the USDA Food and Nutrition Service. He holds a master’s degree from Medill School of Journalism at Northwestern University.

Phil incorporated basic and sound principles of writing into CCJM, something still not uniformly done in medical journals. He pushed for each article to tell a story and clearly communicate a message to the practicing clinician that could translate into improved patient care. Bright and experienced expert clinicians were coaxed to translate their complex topics and opinions into educational messages that were accurate, relevant, and accessible. Based on unsolicited feedback from our readers and the results of standard media industry surveys, he was right on target: clarity is not the antithesis of erudition (although not all authors have shared this perspective).

He was no publishing Luddite. Phil was the driver behind continuously upgrading our open-access CCJM website—enhancing CME options, creating apps for other media, incorporating an online manuscript-tracking system, and tracking and cataloguing patterns of reader use in order to link growth to the needs of our readers. He enabled CCJM to become an early routine user of plagiarism-detection software. With all of this forward positioning, he also found time to champion the electronic archiving of all 81 years of the Journal (which you can now freely access on the Journal’s website).

These very tangible and significant contributions pale in comparison with his impact on the internal operations of the Journal and on my own maturation as editor in chief (and I speak here as well on behalf of previous physician editors). He has been a constant voice of reason, somehow able to recognize potential controversies and develop strategies to ameliorate the personal conflict while not minimizing valid intellectual differences.

A product of the publication pressures of daily newspapers, he would overlook no opportunity to remind me to move manuscripts along and think of potential topics that we should discuss—his admonition to “feed the beast” is stenciled indelibly in my brain. And he never excused himself from equal responsibility for the feeding. He regularly perused subspecialty journals looking for advances in treatment and diagnosis and through many (fortunately well-weathered) medical adventures, few of his physicians have escaped his probing question, “What’s coming that internists should know about, and who can write about it?”

We will miss his equipoise in dealing with the multiple challenges that frequently arise in the running of a monthly journal. We will miss his many skills, and his enthusiasm and commitment to the Journal’s success in achieving our mission. And I will miss his advice, his creativity, his balanced counsel and support, and his willingness to edit and provide honest feedback on whatever writings I sent his way.

From all of us at CCJM, thank you, Phil, for being you, and for a job very well done. Sleep late and read the newspaper.

PS: Phil—Please note that although too wordy, I at least introduced the “story line” in the first sentence.

Phil Canuto, the executive editor of the Cleveland Clinic Journal of Medicine for almost 20 years, is retiring. Known to relatively few of our authors and peer reviewers, Phil has been the invisible force behind the current print and digital face and body of CCJM.

Few medical journals have a persona that connects with their readers, relating in ways that lead to a bonding between reader and journal that extends beyond the content of the monthly articles. We have strived to attain such a relationship with you, our readers, and I will take the liberty of assuming we have to some extent succeeded. I devote my space this month to talking with you about Phil and his relationship with the Journal.

I have frequently described our journalistic mission as publishing articles for our readers—not for our authors. Phil helped translate this concept into reality by insisting that articles be readable and understandable and always have a clearly stated “bottom-line” message.

Phil joined the CCJM in 1995. He came with genuine journalistic and writing skills and a conviction that medical writing for and by physicians could and should have the same clarity that provides effective information transfer in other venues. He had previously worked as a reporter and medical writer at The Akron Beacon Journal newspaper, and prior to that had been the public information officer for the USDA Food and Nutrition Service. He holds a master’s degree from Medill School of Journalism at Northwestern University.

Phil incorporated basic and sound principles of writing into CCJM, something still not uniformly done in medical journals. He pushed for each article to tell a story and clearly communicate a message to the practicing clinician that could translate into improved patient care. Bright and experienced expert clinicians were coaxed to translate their complex topics and opinions into educational messages that were accurate, relevant, and accessible. Based on unsolicited feedback from our readers and the results of standard media industry surveys, he was right on target: clarity is not the antithesis of erudition (although not all authors have shared this perspective).

He was no publishing Luddite. Phil was the driver behind continuously upgrading our open-access CCJM website—enhancing CME options, creating apps for other media, incorporating an online manuscript-tracking system, and tracking and cataloguing patterns of reader use in order to link growth to the needs of our readers. He enabled CCJM to become an early routine user of plagiarism-detection software. With all of this forward positioning, he also found time to champion the electronic archiving of all 81 years of the Journal (which you can now freely access on the Journal’s website).

These very tangible and significant contributions pale in comparison with his impact on the internal operations of the Journal and on my own maturation as editor in chief (and I speak here as well on behalf of previous physician editors). He has been a constant voice of reason, somehow able to recognize potential controversies and develop strategies to ameliorate the personal conflict while not minimizing valid intellectual differences.

A product of the publication pressures of daily newspapers, he would overlook no opportunity to remind me to move manuscripts along and think of potential topics that we should discuss—his admonition to “feed the beast” is stenciled indelibly in my brain. And he never excused himself from equal responsibility for the feeding. He regularly perused subspecialty journals looking for advances in treatment and diagnosis and through many (fortunately well-weathered) medical adventures, few of his physicians have escaped his probing question, “What’s coming that internists should know about, and who can write about it?”

We will miss his equipoise in dealing with the multiple challenges that frequently arise in the running of a monthly journal. We will miss his many skills, and his enthusiasm and commitment to the Journal’s success in achieving our mission. And I will miss his advice, his creativity, his balanced counsel and support, and his willingness to edit and provide honest feedback on whatever writings I sent his way.

From all of us at CCJM, thank you, Phil, for being you, and for a job very well done. Sleep late and read the newspaper.

PS: Phil—Please note that although too wordy, I at least introduced the “story line” in the first sentence.

Phil Canuto, the executive editor of the Cleveland Clinic Journal of Medicine for almost 20 years, is retiring. Known to relatively few of our authors and peer reviewers, Phil has been the invisible force behind the current print and digital face and body of CCJM.

Few medical journals have a persona that connects with their readers, relating in ways that lead to a bonding between reader and journal that extends beyond the content of the monthly articles. We have strived to attain such a relationship with you, our readers, and I will take the liberty of assuming we have to some extent succeeded. I devote my space this month to talking with you about Phil and his relationship with the Journal.

I have frequently described our journalistic mission as publishing articles for our readers—not for our authors. Phil helped translate this concept into reality by insisting that articles be readable and understandable and always have a clearly stated “bottom-line” message.

Phil joined the CCJM in 1995. He came with genuine journalistic and writing skills and a conviction that medical writing for and by physicians could and should have the same clarity that provides effective information transfer in other venues. He had previously worked as a reporter and medical writer at The Akron Beacon Journal newspaper, and prior to that had been the public information officer for the USDA Food and Nutrition Service. He holds a master’s degree from Medill School of Journalism at Northwestern University.

Phil incorporated basic and sound principles of writing into CCJM, something still not uniformly done in medical journals. He pushed for each article to tell a story and clearly communicate a message to the practicing clinician that could translate into improved patient care. Bright and experienced expert clinicians were coaxed to translate their complex topics and opinions into educational messages that were accurate, relevant, and accessible. Based on unsolicited feedback from our readers and the results of standard media industry surveys, he was right on target: clarity is not the antithesis of erudition (although not all authors have shared this perspective).

He was no publishing Luddite. Phil was the driver behind continuously upgrading our open-access CCJM website—enhancing CME options, creating apps for other media, incorporating an online manuscript-tracking system, and tracking and cataloguing patterns of reader use in order to link growth to the needs of our readers. He enabled CCJM to become an early routine user of plagiarism-detection software. With all of this forward positioning, he also found time to champion the electronic archiving of all 81 years of the Journal (which you can now freely access on the Journal’s website).

These very tangible and significant contributions pale in comparison with his impact on the internal operations of the Journal and on my own maturation as editor in chief (and I speak here as well on behalf of previous physician editors). He has been a constant voice of reason, somehow able to recognize potential controversies and develop strategies to ameliorate the personal conflict while not minimizing valid intellectual differences.

A product of the publication pressures of daily newspapers, he would overlook no opportunity to remind me to move manuscripts along and think of potential topics that we should discuss—his admonition to “feed the beast” is stenciled indelibly in my brain. And he never excused himself from equal responsibility for the feeding. He regularly perused subspecialty journals looking for advances in treatment and diagnosis and through many (fortunately well-weathered) medical adventures, few of his physicians have escaped his probing question, “What’s coming that internists should know about, and who can write about it?”

We will miss his equipoise in dealing with the multiple challenges that frequently arise in the running of a monthly journal. We will miss his many skills, and his enthusiasm and commitment to the Journal’s success in achieving our mission. And I will miss his advice, his creativity, his balanced counsel and support, and his willingness to edit and provide honest feedback on whatever writings I sent his way.

From all of us at CCJM, thank you, Phil, for being you, and for a job very well done. Sleep late and read the newspaper.

PS: Phil—Please note that although too wordy, I at least introduced the “story line” in the first sentence.

To the Editor: I read with interest the review of the new oral anticoagulants by Fawole et al¹ and agree with their comments on the prevention of bleeding and the importance of monitoring renal function in managing patients on the new classes of oral anticoagulants. However, no specifics were given on how to proceed. Thus, I recommend that renal risk stratification be done before and 1 week after starting these new drugs.

Originally, the US Food and Drug Administration approved dabigatran (Pradaxa) at a dose of 150 mg orally twice daily in patients with a creatinine clearance of 15 to 30 mL/min/1.73 m². This dosing corresponded to the estimated glomerular filtration rate (eGFR) in patients with stage 4 chronic kidney disease, but this dosing is contraindicated in other guidelines worldwide (Canada, Europe, the United Kingdom, Japan, Australia, and New Zealand).² Not unexpectedly, 3,781 serious adverse effects were noted in the 2011 US postmarketing experience with dabigatran. These included death (542 cases), hemorrhage (2,367 cases), acute renal failure (291 cases), stroke (644 cases), and suspected liver failure (15 cases).³ Thirteen months after dabigatran’s approval in the United States, Boehringer Ingelheim changed the dosage and product guidelines.^2–4 The new dosage⁴ is 75 mg twice daily for patients with a creatinine clearance of 15 to 30 mL/min/1.73 m².

Therefore, I suggest a nephrologic “way out”⁵ when using the new oral anticoagulants to avoid the problems with dabigatran noted above.

First, if these drugs are to be used in nonvalvular atrial fibrillation, risk factors should be determined using the CHADS2 or the CHADS2-VASc score. Special attention should be given to patients age 75 and older, women, and patients with a history of stroke, transient ischemic attack, or systemic embolism. All of these have been noted to be major risk factors.^6,7

Second, renal risk stratification⁸ should be done using a comprehensive metabolic panel before and 1 week after starting new oral anticoagulants, or if there is a change in the patient’s clinical condition. Most US laboratories now provide an eGFR and the stage of chronic kidney disease.^3,5 For example (Table 1), if dabigatran is used, one should follow current dosing guidelines for chronic kidney disease stages 1 through 3, ie, 150 mg twice daily. If stage 4 chronic kidney disease is detected (creatinine clearance 15–29 mL/min/1.73 m²), the updated recommended dosage is 75 mg twice daily. If stage 5 is noted (eGFR ≤ 15 mL/min/1.73 m²), dabigatran is not indicated. Similar steps can be done using current guidelines for the other new oral anticoagulants.

This simple renal risk stratification guideline should help avoid some of the problems noted in the dabigatran postmarketing experience, which were aggravated by the lack of approval of a 110-mg dose and by misleading advertising, claiming that no blood monitoring was required.^2–5 Thus, the new oral anticoagulants should be a welcome addition to our armamentarium in patients who need them, and we hope to avoid the risks, morbidity, mortality, and expense of trying to reverse adverse effects.

To the Editor: I read with interest the review of the new oral anticoagulants by Fawole et al¹ and agree with their comments on the prevention of bleeding and the importance of monitoring renal function in managing patients on the new classes of oral anticoagulants. However, no specifics were given on how to proceed. Thus, I recommend that renal risk stratification be done before and 1 week after starting these new drugs.

Originally, the US Food and Drug Administration approved dabigatran (Pradaxa) at a dose of 150 mg orally twice daily in patients with a creatinine clearance of 15 to 30 mL/min/1.73 m². This dosing corresponded to the estimated glomerular filtration rate (eGFR) in patients with stage 4 chronic kidney disease, but this dosing is contraindicated in other guidelines worldwide (Canada, Europe, the United Kingdom, Japan, Australia, and New Zealand).² Not unexpectedly, 3,781 serious adverse effects were noted in the 2011 US postmarketing experience with dabigatran. These included death (542 cases), hemorrhage (2,367 cases), acute renal failure (291 cases), stroke (644 cases), and suspected liver failure (15 cases).³ Thirteen months after dabigatran’s approval in the United States, Boehringer Ingelheim changed the dosage and product guidelines.^2–4 The new dosage⁴ is 75 mg twice daily for patients with a creatinine clearance of 15 to 30 mL/min/1.73 m².

Therefore, I suggest a nephrologic “way out”⁵ when using the new oral anticoagulants to avoid the problems with dabigatran noted above.

First, if these drugs are to be used in nonvalvular atrial fibrillation, risk factors should be determined using the CHADS2 or the CHADS2-VASc score. Special attention should be given to patients age 75 and older, women, and patients with a history of stroke, transient ischemic attack, or systemic embolism. All of these have been noted to be major risk factors.^6,7

Second, renal risk stratification⁸ should be done using a comprehensive metabolic panel before and 1 week after starting new oral anticoagulants, or if there is a change in the patient’s clinical condition. Most US laboratories now provide an eGFR and the stage of chronic kidney disease.^3,5 For example (Table 1), if dabigatran is used, one should follow current dosing guidelines for chronic kidney disease stages 1 through 3, ie, 150 mg twice daily. If stage 4 chronic kidney disease is detected (creatinine clearance 15–29 mL/min/1.73 m²), the updated recommended dosage is 75 mg twice daily. If stage 5 is noted (eGFR ≤ 15 mL/min/1.73 m²), dabigatran is not indicated. Similar steps can be done using current guidelines for the other new oral anticoagulants.

This simple renal risk stratification guideline should help avoid some of the problems noted in the dabigatran postmarketing experience, which were aggravated by the lack of approval of a 110-mg dose and by misleading advertising, claiming that no blood monitoring was required.^2–5 Thus, the new oral anticoagulants should be a welcome addition to our armamentarium in patients who need them, and we hope to avoid the risks, morbidity, mortality, and expense of trying to reverse adverse effects.

To the Editor: I read with interest the review of the new oral anticoagulants by Fawole et al¹ and agree with their comments on the prevention of bleeding and the importance of monitoring renal function in managing patients on the new classes of oral anticoagulants. However, no specifics were given on how to proceed. Thus, I recommend that renal risk stratification be done before and 1 week after starting these new drugs.

Originally, the US Food and Drug Administration approved dabigatran (Pradaxa) at a dose of 150 mg orally twice daily in patients with a creatinine clearance of 15 to 30 mL/min/1.73 m². This dosing corresponded to the estimated glomerular filtration rate (eGFR) in patients with stage 4 chronic kidney disease, but this dosing is contraindicated in other guidelines worldwide (Canada, Europe, the United Kingdom, Japan, Australia, and New Zealand).² Not unexpectedly, 3,781 serious adverse effects were noted in the 2011 US postmarketing experience with dabigatran. These included death (542 cases), hemorrhage (2,367 cases), acute renal failure (291 cases), stroke (644 cases), and suspected liver failure (15 cases).³ Thirteen months after dabigatran’s approval in the United States, Boehringer Ingelheim changed the dosage and product guidelines.^2–4 The new dosage⁴ is 75 mg twice daily for patients with a creatinine clearance of 15 to 30 mL/min/1.73 m².

Therefore, I suggest a nephrologic “way out”⁵ when using the new oral anticoagulants to avoid the problems with dabigatran noted above.

First, if these drugs are to be used in nonvalvular atrial fibrillation, risk factors should be determined using the CHADS2 or the CHADS2-VASc score. Special attention should be given to patients age 75 and older, women, and patients with a history of stroke, transient ischemic attack, or systemic embolism. All of these have been noted to be major risk factors.^6,7

Second, renal risk stratification⁸ should be done using a comprehensive metabolic panel before and 1 week after starting new oral anticoagulants, or if there is a change in the patient’s clinical condition. Most US laboratories now provide an eGFR and the stage of chronic kidney disease.^3,5 For example (Table 1), if dabigatran is used, one should follow current dosing guidelines for chronic kidney disease stages 1 through 3, ie, 150 mg twice daily. If stage 4 chronic kidney disease is detected (creatinine clearance 15–29 mL/min/1.73 m²), the updated recommended dosage is 75 mg twice daily. If stage 5 is noted (eGFR ≤ 15 mL/min/1.73 m²), dabigatran is not indicated. Similar steps can be done using current guidelines for the other new oral anticoagulants.

This simple renal risk stratification guideline should help avoid some of the problems noted in the dabigatran postmarketing experience, which were aggravated by the lack of approval of a 110-mg dose and by misleading advertising, claiming that no blood monitoring was required.^2–5 Thus, the new oral anticoagulants should be a welcome addition to our armamentarium in patients who need them, and we hope to avoid the risks, morbidity, mortality, and expense of trying to reverse adverse effects.