Suppose a new patient walks into your office for a routine physical examination. As part of your discussion, you ask about her family history. She relates that her grandmother and uncle had colon cancer.

You know that colon cancer can be hereditary, but you are unsure whether this patient’s family history is significant. You know genetic testing can be ordered, but you only have 15 minutes with the patient and you are unsure which test is appropriate and how it can be ordered. What should you do next?

With advances in genetics and genomics have come expectations that health care providers understand and apply these discoveries to patient care. Identification of a genetic diagnosis can lead to personalized treatment and intensive screening, which can reduce the patient’s risk of contracting the disease in question or dying of it.^1,2 But genetic testing may also take patients on an emotional journey as they adjust to learning new information about themselves and the health care implications such a diagnosis may have for themselves and their family members.

Genetic counseling is an important component of risk assessment and testing. With increasing demands and shorter appointment times, physicians are finding it harder to provide comprehensive risk assessment and genetic counseling.^3–5 Just as “physician extenders” have helped streamline various aspects of health care, genetic counselors can serve as partners to physicians, from helping determine which testing to consider to helping guide follow-up care after test results are received.

Genetic counselors can help not only patients who have a personal or family history of a hereditary condition, but also their physicians and family members. This article will explain the process of genetic counseling and testing, highlight complexities through case examples, and provide a brief review outlining which patients should be referred for genetic counseling.

WHAT IS GENETIC COUNSELING?

The National Society of Genetic Counselors defines genetic counseling as “the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease.”⁶ The process includes:

• Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence
• Education about inheritance, testing, management, prevention, resources, and research
• Counseling to promote informed choices and adaptation to the risk or condition.⁶

WHAT HAPPENS DURING A COUNSELING SESSION?

The goals and outcomes of a successful genetic counseling session (Table 1) reflect the need for genetic counselors to not only give patients enough information to understand what is being discussed, but also to monitor their emotional responses and respond to their needs for support.⁷ The components of a typical genetic counseling session include:

• Contracting (reviewing why the patient is here)
• Reviewing the patient’s personal medical history
• Documenting relevant diagnoses in the family history
• Educating about the condition in question and relevant basic information about genetics
• If testing is indicated, educating about what the test will and will not tell the patient
• If test results are being discussed, discussing the implications of the results for the patient’s management and the utility of testing for relatives
• Identifying additional sources of support and education for patients, such as disease-specific support groups
• Making sure the patient understands the information provided
• Monitoring the patient’s emotional and psychological reactions and responding appropriately.

Before the visit, which may last from 30 minutes to several hours, the genetic counselor reviews the patient’s available medical information, performs a literature search covering relevant topics, and prepares supporting educational resources such as visual aids. After the visit, the genetic counselor contacts the patient to discuss the results of any tests ordered, makes sure the follow-up plan is clear, and arranges return visits if these are indicated. Studies have shown that these nonbillable patient-related activities take at least as much time as the actual patient visit.^8,9

EVIDENCE THAT GENETIC COUNSELING IS BENEFICIAL

Although genetic counseling may be time-consuming, its benefits to patients have been proven in a number of studies.

Improved patient knowledge. Three controlled trials found a significant increase in knowledge about cancer genetics in patients who received genetic counseling as part of their clinical services.^10–12 Additionally, a large prospective multicenter study found a continued significant increase in cancer genetics knowledge in women who had received genetic counseling for inherited breast cancer risk 1 year earlier.¹³

More accurate perception of risk. A meta-analysis of three studies found a significant increase in the accuracy of breast cancer risk perceptions among women who had received genetic counseling.¹⁴

Improved psychosocial outcomes. Anxiety was reduced in 82% of parents who received genetic counseling after screening of their newborn was positive for hemoglobinopathy trait.¹⁵ And 1 year after genetic counseling, parents of patients with psychotic disorders reported reduced anxiety as a result of an increased understanding of accurate recurrence risks.¹⁶

Improved risk-reducing behaviors. Increased genetic counseling support led to improved communication and increased contact with genetics services for at-risk family members.¹⁷ Genetic counseling also led to higher rates of mammography, clinical breast examination, and breast self-examination.¹⁸

WHO ARE GENETIC COUNSELORS?

Genetic counselors are allied health professionals with a master’s degree and with specific expertise in identifying and educating patients at risk for inherited conditions. They are certified through the American Board of Genetic Counseling. Genetic counseling is a licensed profession in many states,¹⁹ and licensure legislation is pending in several others.

HOW GENETIC COUNSELORS FACILITATE DIFFICULT COMPONENTS OF GENETIC TESTING

Genetic counselors can serve as complementary practitioners who possess the time and expertise to discuss some of the more complex components of the genetic testing process, further discussed here.

Making sure that testing is appropriate and that the right test is ordered

Let us revisit our introductory scenario—a patient presents to your office and relates a family history of colon cancer. What would you do if she then says, “I know there’s a gene for colon cancer; I want that test today so I can know if I’m at risk.” You get the sense that the patient is anxious and determined to get this testing done today. Which of the following would you do?

• Say “OK,” enter “colon cancer gene” in your hospital’s laboratory ordering system, and pray that the results are normal.
• Remember that a representative from a genetic testing company came by your office and left sample collection kits. Say “OK,” draw the patient’s blood in the tubes provided, check off testing for “comprehensive colorectal genetics panel,” and pray the results are normal.
• Tell the patient: “Most colon cancers are not necessarily caused by an inherited syndrome. However, a detailed analysis of your family history seems warranted. There are many genes that can play a role in inherited colon cancer risk, and I want to make sure the right test is done for the right person in your family. I’m going to refer you to a genetic counselor who can take a detailed family history and discuss the risks and benefits of genetic testing with you.” You make the referral and within 1 or 2 weeks, your patient is seen for genetic counseling.

If you chose ‘colon cancer gene’ testing

The phlebotomy and laboratory personnel at your facility are likely unsure what kind of sample to draw and where it should be sent. As of this writing, at least 14 genes have been associated with a risk of colorectal cancer, and testing for these genes is available through dozens of laboratories across the country.

In this scenario, your hospital does not have sufficient information to follow through on your orders, and someone pages you to discuss it. However, you are in the midst of a busy clinic and are not able to return the page promptly, so the laboratory informs the patient that it cannot draw her blood for testing today. The patient leaves feeling angry and upset.

If you chose commercial genetic testing

You may have just ordered testing for four of the genes known to cause Lynch syndrome, an inherited condition predisposing to colon, uterine, and a few other cancer types. While testing like this may be labeled as “comprehensive,” it may not include all disorders associated with colon cancer. Such shotgun approaches to patient care without consideration of family history can often lead to ordering genetic testing that may be not only medically unnecessary, but also not reimbursable by insurance companies.

Continuing with the case above, the patient’s insurance company determines that testing is not medically necessary, and she is billed for the entire cost of more than $4,400. Her results are normal, and she feels reassured that she is not at increased risk of colon cancer.

A year later, the patient phones you to say that her uncle had genetic testing with positive results. She sends you the letter she received along with the genetic counselor’s clinic note—the uncle’s mutation is in a completely different gene from the ones you tested. While she was previously told she was at low risk, the appropriate site-specific genetic test (average cost range $185–$450) to target the specific mutation is positive, and she is at increased risk of colon cancer, but is now able to pursue increased screening to reduce her risks of developing and dying from this disease.

If the patient had not been made aware of her uncle’s results, she may not have received this screening. If she were diagnosed with later-stage colon cancer after developing symptoms, she may feel you are liable for this diagnosis based on her perception that she was not at risk according to the previously negative genetic testing results ordered by you. After learning about her family history and that the right test was not ordered for her, the patient pursues legal action.

If you chose genetic counseling

If you chose to refer the patient for genetic counseling, congratulations! Your patient is seen for risk assessment and genetic counseling.

As part of the genetic counseling session, a comprehensive family history identifies the patient’s uncle who was diagnosed with colon cancer. He was previously seen for genetics assessment and was found to have a mutation in the APC gene, predisposing him to familial adenomatous polyposis. Site-specific testing, which the genetic counselor is able to get covered by the patient’s insurance through a letter of medical necessity, reveals that your patient shares her uncle’s mutation. As indicated by national guidelines, you refer the patient to a gastroenterologist for medical management, which will significantly reduce her chances of developing and dying of colorectal cancer.

It is preferable to see the family member at highest risk for an inherited condition—usually, but not always the affected relative—for genetic consultation first. During the consultation the genetic counselor would decide which syndrome, if any, is the best fit for the family.

If the affected relative tests positive, targeted and less costly testing for the specific mutation identified (ie, site-specific testing) can then be offered to family members to provide a yes-or-no answer as to their risk status.

If the relative most likely to be gene-positive tests negative, no genetic testing would be recommended for family members, as the genetic cause of the cancer in the family is unknown. In this situation, family members may be advised to pursue the same screening measures as those with a positive gene test due to their strong family history.

INFORMED CONSENT FOR GENETIC TESTING

Genetic testing consists of much more than a simple blood draw. Obtaining informed consent for genetic testing is a crucial step in the testing process, as the results can be complex and often affect multiple family members. When predictive genetic testing is being discussed, special conversations need to take place to make sure that decisions are well informed. Genetic counselors can facilitate these discussions and guide patients and families through the decision-making process.

Example: Huntington disease

The need for genetic counseling before predictive testing is best illustrated by Huntington disease, a progressive neurodegenerative disorder with typical onset in the third or fourth decade of life. Over the disease course, patients experience decreases in motor control (leading to the aptly named “Huntington chorea”), cognitive decline, and changes in psychiatric state. Ultimately, most patients die 15 to 20 years after the onset of symptoms. Treatment is palliative and symptom-based.

Huntington disease is inherited in an autosomal dominant manner, meaning that each child of an affected person has a 50% risk of inheriting the gene change responsible for this condition and of eventually developing the disease. It is caused by an expansion within the HD gene; this expansion may grow with successive generations, leading to earlier onset of symptoms.²⁰

The availability of predictive testing—which enables people who are at risk but who are without symptoms to find out their genetic status—ultimately leads each at-risk person to ask herself or himself, Do I want to know? Studies have found that only 15% to 67% of offspring of parents with Huntington disease (offspring are at 50% risk of the disease) elected to be tested, and in one longitudinal study, this rate of “uptake” decreased over time.^21,22 However, any estimates of uptake may be falsely elevated, given the likelihood that those not wishing to consider testing may not feel the need for a clinical visit focused on this subject.

After predictive testing became available, an increased risk of suicide in persons at risk of Huntington disease was documented.^23,24 In view of this risk and the careful decision-making support that people at risk need, predictive testing guidelines were developed by a committee of medical experts and members of Huntington disease family organizations.²⁵ As part of the guidelines, a multivisit pretesting process was established that includes extensive education and counseling. Delay of testing is recommended when contraindications are identified, such as evidence of coercion or a serious psychiatric condition. Most genetic testing companies offering predictive testing require a signature from the ordering clinician verifying that pretest counseling has been completed; some also include a provision that the ordering clinician will relay results to the patient in person.

More than 15 years after these guidelines were adopted, a study of suicide risk in at-risk persons continued to find rates higher than in the general population, but lower than in earlier studies.²⁶ Whether this careful pretest counseling protocol is directly related to a possible decrease in suicide risk has yet to be established, but its successful use in patients undergoing predictive Huntington disease testing has led to its adoption in other neurodegenerative diseases such as Alzheimer disease and Parkinson disease.

EXPLAINING POSITIVE GENETIC TESTING RESULTS

If genetic testing identifies a mutation, genetic counselors can help patients understand the implications of the results for themselves and for their relatives. Some patients become quite inquisitive, and the genetic counseling session morphs into a graduate-level discussion of genes, DNA, disease pathways, genetic-environmental interactions, availability of gene therapy, and clinical trials. The genetic counselor also makes the patient aware of other resources, such as disease-specific support groups, which may be developed by patients and families to provide support and practical knowledge.

In some cases, attention turns to at-risk relatives, and the genetic counselor may role-play with the patient to rehearse ways to share information with them. Genetic counselors may give patients a letter to distribute to family members with a copy of the patient’s test results, briefly explaining the condition identified and how relatives may find a genetic counselor in their area for their own risk assessment.

WHAT ABOUT GENETIC DISCRIMINATION?

Genetic discrimination is addressed in many genetic counseling sessions.

As defined by the National Human Genome Research Institute, genetic discrimination is “prejudice directed against people who have or may have a genetic disease.”²⁷

In May 2008, the Genetic Information Nondiscrimination Act (GINA) was signed into law, providing some legal protections against genetic discrimination for patients undergoing predictive genetic testing. The law applies to most employers and health insurers but does not protect against discrimination by life or disability insurers. When discussing genetic testing, genetic counselors ensure that patients are aware of their rights and protections.

GINA would not be relevant for a patient who has a medical condition that may affect his or her insurability. For example, someone with thyroid cancer who is found to have an underlying gene mutation may still be denied any type of insurance coverage on the basis of his or her personal cancer diagnosis. However, should that person’s son who has not been diagnosed with cancer opt to undergo predictive testing, GINA would provide protection against employment and health insurance discrimination, as described above.

DIRECT-TO-CONSUMER GENETIC TESTING

As DNA technology has become increasingly complex, so has the task of understanding new tests and their clinical relevance to patients.

In the last several years, more companies have begun to offer direct-to-consumer genetic testing, which may be ordered without the involvement of a health care professional. While some companies hire or work closely with genetic counselors to conduct pretest and posttest genetic counseling, others do not, and preliminary research has found that only a minority of primary care physicians feel prepared to answer patients’ questions about direct-to-consumer genetic testing.²⁸

Genetic counselors stay abreast of emerging technologies and are prepared to answer questions from patients who are considering or have already undergone such testing and from physicians who may wonder if a patient’s direct-to-consumer genetic testing results should affect his or her management.

Direct-to-consumer genetic testing will be discussed in depth in a future article in this series.

EXPLAINING ‘NORMAL’ (NEGATIVE) GENETIC TEST RESULTS

When testing results are normal, patients are educated about the meaning of “normal” results, the residual risk, and screening that might be appropriate in each person’s situation.

Sometimes a normal result does not mean the patient is not at risk for disease—for most diseases, genetic testing is not perfect and cannot identify a mutation in every at-risk family. Patients who have a family history of certain conditions may still face a higher risk despite normal test results. In these situations it is imperative that the family continue to adhere to follow-up recommendations even with normal test results.

Example: Marfan syndrome

Marfan syndrome is an autosomal dominant connective tissue disorder that, if unrecognized, is associated with significant morbidity and mortality. People with Marfan syndrome are at increased risk of aortic aneurysms, which can rupture spontaneously, leading to sudden death.

Although at least 70% of patients with Marfan syndrome have a mutation in FBN1, other patients meeting the clinical diagnostic criteria do not. Despite a normal genetic test result, they should adhere to the same screening guidelines as a person who tests positive.²⁹

This concept—that screening should still be done despite a normal “Marfan test”—may be difficult for patients to grasp without a discussion of the imperfect sensitivity of genetic testing and of their real ongoing risks. Even more difficult to understand is the idea that the patient’s family members should also be screened as though they have the disease, given that the family’s mutation is unknown and predictive testing cannot be conducted.

Further complicating matters, other disorders such as Loeys-Dietz and vascular Ehlers-Danlos syndrome can mimic Marfan syndrome by causing aortic aneurysms, but management recommendations for them are very different.^30,31

The appropriate genetic diagnosis for patients with aortic aneurysms can be facilitated by referring them to genetic counselors, who can identify appropriate testing. In this way, physicians can personalize medical management and give screening recommendations specific to the genetic disorder present.

EXPLAINING UNCERTAIN RESULTS

There are three possible results for most genetic tests—positive (a pathogenic or disease-causing mutation was found), negative (normal), and the frustrating “variant of uncertain significance” (VUS).

A VUS result means that an abnormality was detected in the gene, but that there are insufficient data about whether the abnormality alters the function of the gene in question and, thus, leads to disease. Since some gene variants are known to be common in the general population and not linked to disease and others are known to definitely alter a gene’s function and cause disease, a VUS that is clearly unknown poses a challenge not only to patient management, but also to family members seeking personal risk assessments.

Knowledge of how or if specific variants relate to disease is emerging. In time, some variants become reclassified as either disease-causing mutations or benign polymorphisms. However, careful consideration needs to be given to how to explain the abnormal result to the patient and to at-risk family members, as well as to how to explain the clinical implications of the VUS.

Example: Hereditary breast and ovarian cancer syndrome

People with hereditary breast and ovarian cancer syndrome face a lifetime risk of breast cancer of up to 87% and a risk of ovarian cancer of up to 44%. Most families with this syndrome have an inherited change in either the BRCA1 or BRCA2 gene.^32,33 Given these risks, prophylactic mastectomy and oophorectomy are among the management options for mutation-positive patients. In the absence of clear genetic counseling, a patient with a VUS might see the “abnormal” test result and believe herself to be mutation-positive and thus at very high cancer risk.

An important role for the genetic counselor is to clarify the pathogenicity of a particular VUS. When a VUS is found, genetic counselors search for information about the variant by reviewing the medical literature, discussing it with the testing laboratory, arranging for family studies when appropriate, and contacting researchers whose work focuses on the gene in question.

Failure to properly research a particular VUS can lead to unnecessary and risky surgical procedures, as well as to falsely labelling relatives as being at risk. Until a VUS is reclassified as a disease-causing mutation, testing for it should not be offered to family members (unless through a research study), nor should medical management be based solely on the results of a particular VUS. In time, a VUS may be reclassified as either a benign polymorphism or a disease-causing mutation, and the genetic counselor will recontact the patient and physician with updated information and recommendations.

WHOM SHOULD I REFER?

Genetic counseling is available for patients and families in diverse settings within health systems. The six primary areas of practice are general, cardiovascular, cancer, preconception, prenatal, and pediatrics.

Patients with a personal or family history of a hereditary condition can benefit from genetic counseling regardless of whether they would be considered appropriate for genetic testing.³⁴

At current count, there are 4,424 genetic disorders for which the underlying cause has been identified.³⁵ Individually, each disorder is rare, but when they are considered as a whole, they affect a significant minority of the general population. It is estimated that before age 25 years, 53 (5.3%) of every 1,000 people will be diagnosed with a disease that has an important genetic component.³⁶ From 20% to 30% of infant deaths are related to a genetic disorder,^37,38 and 22% of unaffected adults have a family history of cancer significant enough to warrant a genetics referral.³⁹ See Table 2 for a list of common indications for referral.

HOW CAN I FIND GENETIC COUNSELING SERVICES?

The National Society of Genetic Counselors (www.nsgc.org) and American Board of Genetic Counseling (www.abgc.net) both provide searchable databases of registered genetic counselors.

KNOWLEDGE CONTINUES TO EXPAND

Genetic knowledge continues to expand, and testing is becoming available for a growing number of medical conditions. Appropriate identification of individuals with and at risk for genetic disorders through the use of genetic testing and screening is a cornerstone of personalized medicine, with the ultimate goal of improving patient outcomes. However, in this era of value-based medicine and fewer health care dollars, genetic testing must be used in a way that maximizes its clinical impact with a careful fiscal approach.

Genetic counselors are specially trained health care professionals with expertise in genetic and genomic medicine who work in collaboration with physicians to guide patients through the complexities of heritable conditions and emerging technologies. They are trained to personalize, interpret, and communicate complex science into data that will assure best outcomes for patients and their families. Developing a partnership with the genetic counselors in your area can provide multiple benefits to your patients as well as to your own practice.

Suppose a new patient walks into your office for a routine physical examination. As part of your discussion, you ask about her family history. She relates that her grandmother and uncle had colon cancer.

You know that colon cancer can be hereditary, but you are unsure whether this patient’s family history is significant. You know genetic testing can be ordered, but you only have 15 minutes with the patient and you are unsure which test is appropriate and how it can be ordered. What should you do next?

With advances in genetics and genomics have come expectations that health care providers understand and apply these discoveries to patient care. Identification of a genetic diagnosis can lead to personalized treatment and intensive screening, which can reduce the patient’s risk of contracting the disease in question or dying of it.^1,2 But genetic testing may also take patients on an emotional journey as they adjust to learning new information about themselves and the health care implications such a diagnosis may have for themselves and their family members.

Genetic counseling is an important component of risk assessment and testing. With increasing demands and shorter appointment times, physicians are finding it harder to provide comprehensive risk assessment and genetic counseling.^3–5 Just as “physician extenders” have helped streamline various aspects of health care, genetic counselors can serve as partners to physicians, from helping determine which testing to consider to helping guide follow-up care after test results are received.

Genetic counselors can help not only patients who have a personal or family history of a hereditary condition, but also their physicians and family members. This article will explain the process of genetic counseling and testing, highlight complexities through case examples, and provide a brief review outlining which patients should be referred for genetic counseling.

WHAT IS GENETIC COUNSELING?

The National Society of Genetic Counselors defines genetic counseling as “the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease.”⁶ The process includes:

• Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence
• Education about inheritance, testing, management, prevention, resources, and research
• Counseling to promote informed choices and adaptation to the risk or condition.⁶

WHAT HAPPENS DURING A COUNSELING SESSION?

The goals and outcomes of a successful genetic counseling session (Table 1) reflect the need for genetic counselors to not only give patients enough information to understand what is being discussed, but also to monitor their emotional responses and respond to their needs for support.⁷ The components of a typical genetic counseling session include:

• Contracting (reviewing why the patient is here)
• Reviewing the patient’s personal medical history
• Documenting relevant diagnoses in the family history
• Educating about the condition in question and relevant basic information about genetics
• If testing is indicated, educating about what the test will and will not tell the patient
• If test results are being discussed, discussing the implications of the results for the patient’s management and the utility of testing for relatives
• Identifying additional sources of support and education for patients, such as disease-specific support groups
• Making sure the patient understands the information provided
• Monitoring the patient’s emotional and psychological reactions and responding appropriately.

Before the visit, which may last from 30 minutes to several hours, the genetic counselor reviews the patient’s available medical information, performs a literature search covering relevant topics, and prepares supporting educational resources such as visual aids. After the visit, the genetic counselor contacts the patient to discuss the results of any tests ordered, makes sure the follow-up plan is clear, and arranges return visits if these are indicated. Studies have shown that these nonbillable patient-related activities take at least as much time as the actual patient visit.^8,9

EVIDENCE THAT GENETIC COUNSELING IS BENEFICIAL

Although genetic counseling may be time-consuming, its benefits to patients have been proven in a number of studies.

Improved patient knowledge. Three controlled trials found a significant increase in knowledge about cancer genetics in patients who received genetic counseling as part of their clinical services.^10–12 Additionally, a large prospective multicenter study found a continued significant increase in cancer genetics knowledge in women who had received genetic counseling for inherited breast cancer risk 1 year earlier.¹³

More accurate perception of risk. A meta-analysis of three studies found a significant increase in the accuracy of breast cancer risk perceptions among women who had received genetic counseling.¹⁴

Improved psychosocial outcomes. Anxiety was reduced in 82% of parents who received genetic counseling after screening of their newborn was positive for hemoglobinopathy trait.¹⁵ And 1 year after genetic counseling, parents of patients with psychotic disorders reported reduced anxiety as a result of an increased understanding of accurate recurrence risks.¹⁶

Improved risk-reducing behaviors. Increased genetic counseling support led to improved communication and increased contact with genetics services for at-risk family members.¹⁷ Genetic counseling also led to higher rates of mammography, clinical breast examination, and breast self-examination.¹⁸

WHO ARE GENETIC COUNSELORS?

Genetic counselors are allied health professionals with a master’s degree and with specific expertise in identifying and educating patients at risk for inherited conditions. They are certified through the American Board of Genetic Counseling. Genetic counseling is a licensed profession in many states,¹⁹ and licensure legislation is pending in several others.

HOW GENETIC COUNSELORS FACILITATE DIFFICULT COMPONENTS OF GENETIC TESTING

Genetic counselors can serve as complementary practitioners who possess the time and expertise to discuss some of the more complex components of the genetic testing process, further discussed here.

Making sure that testing is appropriate and that the right test is ordered

Let us revisit our introductory scenario—a patient presents to your office and relates a family history of colon cancer. What would you do if she then says, “I know there’s a gene for colon cancer; I want that test today so I can know if I’m at risk.” You get the sense that the patient is anxious and determined to get this testing done today. Which of the following would you do?

• Say “OK,” enter “colon cancer gene” in your hospital’s laboratory ordering system, and pray that the results are normal.
• Remember that a representative from a genetic testing company came by your office and left sample collection kits. Say “OK,” draw the patient’s blood in the tubes provided, check off testing for “comprehensive colorectal genetics panel,” and pray the results are normal.
• Tell the patient: “Most colon cancers are not necessarily caused by an inherited syndrome. However, a detailed analysis of your family history seems warranted. There are many genes that can play a role in inherited colon cancer risk, and I want to make sure the right test is done for the right person in your family. I’m going to refer you to a genetic counselor who can take a detailed family history and discuss the risks and benefits of genetic testing with you.” You make the referral and within 1 or 2 weeks, your patient is seen for genetic counseling.

If you chose ‘colon cancer gene’ testing

The phlebotomy and laboratory personnel at your facility are likely unsure what kind of sample to draw and where it should be sent. As of this writing, at least 14 genes have been associated with a risk of colorectal cancer, and testing for these genes is available through dozens of laboratories across the country.

In this scenario, your hospital does not have sufficient information to follow through on your orders, and someone pages you to discuss it. However, you are in the midst of a busy clinic and are not able to return the page promptly, so the laboratory informs the patient that it cannot draw her blood for testing today. The patient leaves feeling angry and upset.

If you chose commercial genetic testing

You may have just ordered testing for four of the genes known to cause Lynch syndrome, an inherited condition predisposing to colon, uterine, and a few other cancer types. While testing like this may be labeled as “comprehensive,” it may not include all disorders associated with colon cancer. Such shotgun approaches to patient care without consideration of family history can often lead to ordering genetic testing that may be not only medically unnecessary, but also not reimbursable by insurance companies.

Continuing with the case above, the patient’s insurance company determines that testing is not medically necessary, and she is billed for the entire cost of more than $4,400. Her results are normal, and she feels reassured that she is not at increased risk of colon cancer.

A year later, the patient phones you to say that her uncle had genetic testing with positive results. She sends you the letter she received along with the genetic counselor’s clinic note—the uncle’s mutation is in a completely different gene from the ones you tested. While she was previously told she was at low risk, the appropriate site-specific genetic test (average cost range $185–$450) to target the specific mutation is positive, and she is at increased risk of colon cancer, but is now able to pursue increased screening to reduce her risks of developing and dying from this disease.

If the patient had not been made aware of her uncle’s results, she may not have received this screening. If she were diagnosed with later-stage colon cancer after developing symptoms, she may feel you are liable for this diagnosis based on her perception that she was not at risk according to the previously negative genetic testing results ordered by you. After learning about her family history and that the right test was not ordered for her, the patient pursues legal action.

If you chose genetic counseling

If you chose to refer the patient for genetic counseling, congratulations! Your patient is seen for risk assessment and genetic counseling.

As part of the genetic counseling session, a comprehensive family history identifies the patient’s uncle who was diagnosed with colon cancer. He was previously seen for genetics assessment and was found to have a mutation in the APC gene, predisposing him to familial adenomatous polyposis. Site-specific testing, which the genetic counselor is able to get covered by the patient’s insurance through a letter of medical necessity, reveals that your patient shares her uncle’s mutation. As indicated by national guidelines, you refer the patient to a gastroenterologist for medical management, which will significantly reduce her chances of developing and dying of colorectal cancer.

It is preferable to see the family member at highest risk for an inherited condition—usually, but not always the affected relative—for genetic consultation first. During the consultation the genetic counselor would decide which syndrome, if any, is the best fit for the family.

If the affected relative tests positive, targeted and less costly testing for the specific mutation identified (ie, site-specific testing) can then be offered to family members to provide a yes-or-no answer as to their risk status.

If the relative most likely to be gene-positive tests negative, no genetic testing would be recommended for family members, as the genetic cause of the cancer in the family is unknown. In this situation, family members may be advised to pursue the same screening measures as those with a positive gene test due to their strong family history.

INFORMED CONSENT FOR GENETIC TESTING

Genetic testing consists of much more than a simple blood draw. Obtaining informed consent for genetic testing is a crucial step in the testing process, as the results can be complex and often affect multiple family members. When predictive genetic testing is being discussed, special conversations need to take place to make sure that decisions are well informed. Genetic counselors can facilitate these discussions and guide patients and families through the decision-making process.

Example: Huntington disease

The need for genetic counseling before predictive testing is best illustrated by Huntington disease, a progressive neurodegenerative disorder with typical onset in the third or fourth decade of life. Over the disease course, patients experience decreases in motor control (leading to the aptly named “Huntington chorea”), cognitive decline, and changes in psychiatric state. Ultimately, most patients die 15 to 20 years after the onset of symptoms. Treatment is palliative and symptom-based.

Huntington disease is inherited in an autosomal dominant manner, meaning that each child of an affected person has a 50% risk of inheriting the gene change responsible for this condition and of eventually developing the disease. It is caused by an expansion within the HD gene; this expansion may grow with successive generations, leading to earlier onset of symptoms.²⁰

The availability of predictive testing—which enables people who are at risk but who are without symptoms to find out their genetic status—ultimately leads each at-risk person to ask herself or himself, Do I want to know? Studies have found that only 15% to 67% of offspring of parents with Huntington disease (offspring are at 50% risk of the disease) elected to be tested, and in one longitudinal study, this rate of “uptake” decreased over time.^21,22 However, any estimates of uptake may be falsely elevated, given the likelihood that those not wishing to consider testing may not feel the need for a clinical visit focused on this subject.

After predictive testing became available, an increased risk of suicide in persons at risk of Huntington disease was documented.^23,24 In view of this risk and the careful decision-making support that people at risk need, predictive testing guidelines were developed by a committee of medical experts and members of Huntington disease family organizations.²⁵ As part of the guidelines, a multivisit pretesting process was established that includes extensive education and counseling. Delay of testing is recommended when contraindications are identified, such as evidence of coercion or a serious psychiatric condition. Most genetic testing companies offering predictive testing require a signature from the ordering clinician verifying that pretest counseling has been completed; some also include a provision that the ordering clinician will relay results to the patient in person.

More than 15 years after these guidelines were adopted, a study of suicide risk in at-risk persons continued to find rates higher than in the general population, but lower than in earlier studies.²⁶ Whether this careful pretest counseling protocol is directly related to a possible decrease in suicide risk has yet to be established, but its successful use in patients undergoing predictive Huntington disease testing has led to its adoption in other neurodegenerative diseases such as Alzheimer disease and Parkinson disease.

EXPLAINING POSITIVE GENETIC TESTING RESULTS

If genetic testing identifies a mutation, genetic counselors can help patients understand the implications of the results for themselves and for their relatives. Some patients become quite inquisitive, and the genetic counseling session morphs into a graduate-level discussion of genes, DNA, disease pathways, genetic-environmental interactions, availability of gene therapy, and clinical trials. The genetic counselor also makes the patient aware of other resources, such as disease-specific support groups, which may be developed by patients and families to provide support and practical knowledge.

In some cases, attention turns to at-risk relatives, and the genetic counselor may role-play with the patient to rehearse ways to share information with them. Genetic counselors may give patients a letter to distribute to family members with a copy of the patient’s test results, briefly explaining the condition identified and how relatives may find a genetic counselor in their area for their own risk assessment.

WHAT ABOUT GENETIC DISCRIMINATION?

Genetic discrimination is addressed in many genetic counseling sessions.

As defined by the National Human Genome Research Institute, genetic discrimination is “prejudice directed against people who have or may have a genetic disease.”²⁷

In May 2008, the Genetic Information Nondiscrimination Act (GINA) was signed into law, providing some legal protections against genetic discrimination for patients undergoing predictive genetic testing. The law applies to most employers and health insurers but does not protect against discrimination by life or disability insurers. When discussing genetic testing, genetic counselors ensure that patients are aware of their rights and protections.

GINA would not be relevant for a patient who has a medical condition that may affect his or her insurability. For example, someone with thyroid cancer who is found to have an underlying gene mutation may still be denied any type of insurance coverage on the basis of his or her personal cancer diagnosis. However, should that person’s son who has not been diagnosed with cancer opt to undergo predictive testing, GINA would provide protection against employment and health insurance discrimination, as described above.

DIRECT-TO-CONSUMER GENETIC TESTING

As DNA technology has become increasingly complex, so has the task of understanding new tests and their clinical relevance to patients.

In the last several years, more companies have begun to offer direct-to-consumer genetic testing, which may be ordered without the involvement of a health care professional. While some companies hire or work closely with genetic counselors to conduct pretest and posttest genetic counseling, others do not, and preliminary research has found that only a minority of primary care physicians feel prepared to answer patients’ questions about direct-to-consumer genetic testing.²⁸

Genetic counselors stay abreast of emerging technologies and are prepared to answer questions from patients who are considering or have already undergone such testing and from physicians who may wonder if a patient’s direct-to-consumer genetic testing results should affect his or her management.

Direct-to-consumer genetic testing will be discussed in depth in a future article in this series.

EXPLAINING ‘NORMAL’ (NEGATIVE) GENETIC TEST RESULTS

When testing results are normal, patients are educated about the meaning of “normal” results, the residual risk, and screening that might be appropriate in each person’s situation.

Sometimes a normal result does not mean the patient is not at risk for disease—for most diseases, genetic testing is not perfect and cannot identify a mutation in every at-risk family. Patients who have a family history of certain conditions may still face a higher risk despite normal test results. In these situations it is imperative that the family continue to adhere to follow-up recommendations even with normal test results.

Example: Marfan syndrome

Marfan syndrome is an autosomal dominant connective tissue disorder that, if unrecognized, is associated with significant morbidity and mortality. People with Marfan syndrome are at increased risk of aortic aneurysms, which can rupture spontaneously, leading to sudden death.

Although at least 70% of patients with Marfan syndrome have a mutation in FBN1, other patients meeting the clinical diagnostic criteria do not. Despite a normal genetic test result, they should adhere to the same screening guidelines as a person who tests positive.²⁹

This concept—that screening should still be done despite a normal “Marfan test”—may be difficult for patients to grasp without a discussion of the imperfect sensitivity of genetic testing and of their real ongoing risks. Even more difficult to understand is the idea that the patient’s family members should also be screened as though they have the disease, given that the family’s mutation is unknown and predictive testing cannot be conducted.

Further complicating matters, other disorders such as Loeys-Dietz and vascular Ehlers-Danlos syndrome can mimic Marfan syndrome by causing aortic aneurysms, but management recommendations for them are very different.^30,31

The appropriate genetic diagnosis for patients with aortic aneurysms can be facilitated by referring them to genetic counselors, who can identify appropriate testing. In this way, physicians can personalize medical management and give screening recommendations specific to the genetic disorder present.

EXPLAINING UNCERTAIN RESULTS

There are three possible results for most genetic tests—positive (a pathogenic or disease-causing mutation was found), negative (normal), and the frustrating “variant of uncertain significance” (VUS).

A VUS result means that an abnormality was detected in the gene, but that there are insufficient data about whether the abnormality alters the function of the gene in question and, thus, leads to disease. Since some gene variants are known to be common in the general population and not linked to disease and others are known to definitely alter a gene’s function and cause disease, a VUS that is clearly unknown poses a challenge not only to patient management, but also to family members seeking personal risk assessments.

Knowledge of how or if specific variants relate to disease is emerging. In time, some variants become reclassified as either disease-causing mutations or benign polymorphisms. However, careful consideration needs to be given to how to explain the abnormal result to the patient and to at-risk family members, as well as to how to explain the clinical implications of the VUS.

Example: Hereditary breast and ovarian cancer syndrome

People with hereditary breast and ovarian cancer syndrome face a lifetime risk of breast cancer of up to 87% and a risk of ovarian cancer of up to 44%. Most families with this syndrome have an inherited change in either the BRCA1 or BRCA2 gene.^32,33 Given these risks, prophylactic mastectomy and oophorectomy are among the management options for mutation-positive patients. In the absence of clear genetic counseling, a patient with a VUS might see the “abnormal” test result and believe herself to be mutation-positive and thus at very high cancer risk.

An important role for the genetic counselor is to clarify the pathogenicity of a particular VUS. When a VUS is found, genetic counselors search for information about the variant by reviewing the medical literature, discussing it with the testing laboratory, arranging for family studies when appropriate, and contacting researchers whose work focuses on the gene in question.

Failure to properly research a particular VUS can lead to unnecessary and risky surgical procedures, as well as to falsely labelling relatives as being at risk. Until a VUS is reclassified as a disease-causing mutation, testing for it should not be offered to family members (unless through a research study), nor should medical management be based solely on the results of a particular VUS. In time, a VUS may be reclassified as either a benign polymorphism or a disease-causing mutation, and the genetic counselor will recontact the patient and physician with updated information and recommendations.

WHOM SHOULD I REFER?

Genetic counseling is available for patients and families in diverse settings within health systems. The six primary areas of practice are general, cardiovascular, cancer, preconception, prenatal, and pediatrics.

Patients with a personal or family history of a hereditary condition can benefit from genetic counseling regardless of whether they would be considered appropriate for genetic testing.³⁴

At current count, there are 4,424 genetic disorders for which the underlying cause has been identified.³⁵ Individually, each disorder is rare, but when they are considered as a whole, they affect a significant minority of the general population. It is estimated that before age 25 years, 53 (5.3%) of every 1,000 people will be diagnosed with a disease that has an important genetic component.³⁶ From 20% to 30% of infant deaths are related to a genetic disorder,^37,38 and 22% of unaffected adults have a family history of cancer significant enough to warrant a genetics referral.³⁹ See Table 2 for a list of common indications for referral.

HOW CAN I FIND GENETIC COUNSELING SERVICES?

The National Society of Genetic Counselors (www.nsgc.org) and American Board of Genetic Counseling (www.abgc.net) both provide searchable databases of registered genetic counselors.

KNOWLEDGE CONTINUES TO EXPAND

Genetic knowledge continues to expand, and testing is becoming available for a growing number of medical conditions. Appropriate identification of individuals with and at risk for genetic disorders through the use of genetic testing and screening is a cornerstone of personalized medicine, with the ultimate goal of improving patient outcomes. However, in this era of value-based medicine and fewer health care dollars, genetic testing must be used in a way that maximizes its clinical impact with a careful fiscal approach.

Genetic counselors are specially trained health care professionals with expertise in genetic and genomic medicine who work in collaboration with physicians to guide patients through the complexities of heritable conditions and emerging technologies. They are trained to personalize, interpret, and communicate complex science into data that will assure best outcomes for patients and their families. Developing a partnership with the genetic counselors in your area can provide multiple benefits to your patients as well as to your own practice.

Suppose a new patient walks into your office for a routine physical examination. As part of your discussion, you ask about her family history. She relates that her grandmother and uncle had colon cancer.

You know that colon cancer can be hereditary, but you are unsure whether this patient’s family history is significant. You know genetic testing can be ordered, but you only have 15 minutes with the patient and you are unsure which test is appropriate and how it can be ordered. What should you do next?

With advances in genetics and genomics have come expectations that health care providers understand and apply these discoveries to patient care. Identification of a genetic diagnosis can lead to personalized treatment and intensive screening, which can reduce the patient’s risk of contracting the disease in question or dying of it.^1,2 But genetic testing may also take patients on an emotional journey as they adjust to learning new information about themselves and the health care implications such a diagnosis may have for themselves and their family members.

Genetic counseling is an important component of risk assessment and testing. With increasing demands and shorter appointment times, physicians are finding it harder to provide comprehensive risk assessment and genetic counseling.^3–5 Just as “physician extenders” have helped streamline various aspects of health care, genetic counselors can serve as partners to physicians, from helping determine which testing to consider to helping guide follow-up care after test results are received.

Genetic counselors can help not only patients who have a personal or family history of a hereditary condition, but also their physicians and family members. This article will explain the process of genetic counseling and testing, highlight complexities through case examples, and provide a brief review outlining which patients should be referred for genetic counseling.

WHAT IS GENETIC COUNSELING?

The National Society of Genetic Counselors defines genetic counseling as “the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease.”⁶ The process includes:

• Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence
• Education about inheritance, testing, management, prevention, resources, and research
• Counseling to promote informed choices and adaptation to the risk or condition.⁶

WHAT HAPPENS DURING A COUNSELING SESSION?

The goals and outcomes of a successful genetic counseling session (Table 1) reflect the need for genetic counselors to not only give patients enough information to understand what is being discussed, but also to monitor their emotional responses and respond to their needs for support.⁷ The components of a typical genetic counseling session include:

• Contracting (reviewing why the patient is here)
• Reviewing the patient’s personal medical history
• Documenting relevant diagnoses in the family history
• Educating about the condition in question and relevant basic information about genetics
• If testing is indicated, educating about what the test will and will not tell the patient
• If test results are being discussed, discussing the implications of the results for the patient’s management and the utility of testing for relatives
• Identifying additional sources of support and education for patients, such as disease-specific support groups
• Making sure the patient understands the information provided
• Monitoring the patient’s emotional and psychological reactions and responding appropriately.

Before the visit, which may last from 30 minutes to several hours, the genetic counselor reviews the patient’s available medical information, performs a literature search covering relevant topics, and prepares supporting educational resources such as visual aids. After the visit, the genetic counselor contacts the patient to discuss the results of any tests ordered, makes sure the follow-up plan is clear, and arranges return visits if these are indicated. Studies have shown that these nonbillable patient-related activities take at least as much time as the actual patient visit.^8,9

EVIDENCE THAT GENETIC COUNSELING IS BENEFICIAL

Although genetic counseling may be time-consuming, its benefits to patients have been proven in a number of studies.

Improved patient knowledge. Three controlled trials found a significant increase in knowledge about cancer genetics in patients who received genetic counseling as part of their clinical services.^10–12 Additionally, a large prospective multicenter study found a continued significant increase in cancer genetics knowledge in women who had received genetic counseling for inherited breast cancer risk 1 year earlier.¹³

More accurate perception of risk. A meta-analysis of three studies found a significant increase in the accuracy of breast cancer risk perceptions among women who had received genetic counseling.¹⁴

Improved psychosocial outcomes. Anxiety was reduced in 82% of parents who received genetic counseling after screening of their newborn was positive for hemoglobinopathy trait.¹⁵ And 1 year after genetic counseling, parents of patients with psychotic disorders reported reduced anxiety as a result of an increased understanding of accurate recurrence risks.¹⁶

Improved risk-reducing behaviors. Increased genetic counseling support led to improved communication and increased contact with genetics services for at-risk family members.¹⁷ Genetic counseling also led to higher rates of mammography, clinical breast examination, and breast self-examination.¹⁸

WHO ARE GENETIC COUNSELORS?

Genetic counselors are allied health professionals with a master’s degree and with specific expertise in identifying and educating patients at risk for inherited conditions. They are certified through the American Board of Genetic Counseling. Genetic counseling is a licensed profession in many states,¹⁹ and licensure legislation is pending in several others.

HOW GENETIC COUNSELORS FACILITATE DIFFICULT COMPONENTS OF GENETIC TESTING

Genetic counselors can serve as complementary practitioners who possess the time and expertise to discuss some of the more complex components of the genetic testing process, further discussed here.

Making sure that testing is appropriate and that the right test is ordered

Let us revisit our introductory scenario—a patient presents to your office and relates a family history of colon cancer. What would you do if she then says, “I know there’s a gene for colon cancer; I want that test today so I can know if I’m at risk.” You get the sense that the patient is anxious and determined to get this testing done today. Which of the following would you do?

• Say “OK,” enter “colon cancer gene” in your hospital’s laboratory ordering system, and pray that the results are normal.
• Remember that a representative from a genetic testing company came by your office and left sample collection kits. Say “OK,” draw the patient’s blood in the tubes provided, check off testing for “comprehensive colorectal genetics panel,” and pray the results are normal.
• Tell the patient: “Most colon cancers are not necessarily caused by an inherited syndrome. However, a detailed analysis of your family history seems warranted. There are many genes that can play a role in inherited colon cancer risk, and I want to make sure the right test is done for the right person in your family. I’m going to refer you to a genetic counselor who can take a detailed family history and discuss the risks and benefits of genetic testing with you.” You make the referral and within 1 or 2 weeks, your patient is seen for genetic counseling.

If you chose ‘colon cancer gene’ testing

The phlebotomy and laboratory personnel at your facility are likely unsure what kind of sample to draw and where it should be sent. As of this writing, at least 14 genes have been associated with a risk of colorectal cancer, and testing for these genes is available through dozens of laboratories across the country.

In this scenario, your hospital does not have sufficient information to follow through on your orders, and someone pages you to discuss it. However, you are in the midst of a busy clinic and are not able to return the page promptly, so the laboratory informs the patient that it cannot draw her blood for testing today. The patient leaves feeling angry and upset.

If you chose commercial genetic testing

You may have just ordered testing for four of the genes known to cause Lynch syndrome, an inherited condition predisposing to colon, uterine, and a few other cancer types. While testing like this may be labeled as “comprehensive,” it may not include all disorders associated with colon cancer. Such shotgun approaches to patient care without consideration of family history can often lead to ordering genetic testing that may be not only medically unnecessary, but also not reimbursable by insurance companies.

Continuing with the case above, the patient’s insurance company determines that testing is not medically necessary, and she is billed for the entire cost of more than $4,400. Her results are normal, and she feels reassured that she is not at increased risk of colon cancer.

A year later, the patient phones you to say that her uncle had genetic testing with positive results. She sends you the letter she received along with the genetic counselor’s clinic note—the uncle’s mutation is in a completely different gene from the ones you tested. While she was previously told she was at low risk, the appropriate site-specific genetic test (average cost range $185–$450) to target the specific mutation is positive, and she is at increased risk of colon cancer, but is now able to pursue increased screening to reduce her risks of developing and dying from this disease.

If the patient had not been made aware of her uncle’s results, she may not have received this screening. If she were diagnosed with later-stage colon cancer after developing symptoms, she may feel you are liable for this diagnosis based on her perception that she was not at risk according to the previously negative genetic testing results ordered by you. After learning about her family history and that the right test was not ordered for her, the patient pursues legal action.

If you chose genetic counseling

If you chose to refer the patient for genetic counseling, congratulations! Your patient is seen for risk assessment and genetic counseling.

As part of the genetic counseling session, a comprehensive family history identifies the patient’s uncle who was diagnosed with colon cancer. He was previously seen for genetics assessment and was found to have a mutation in the APC gene, predisposing him to familial adenomatous polyposis. Site-specific testing, which the genetic counselor is able to get covered by the patient’s insurance through a letter of medical necessity, reveals that your patient shares her uncle’s mutation. As indicated by national guidelines, you refer the patient to a gastroenterologist for medical management, which will significantly reduce her chances of developing and dying of colorectal cancer.

It is preferable to see the family member at highest risk for an inherited condition—usually, but not always the affected relative—for genetic consultation first. During the consultation the genetic counselor would decide which syndrome, if any, is the best fit for the family.

If the affected relative tests positive, targeted and less costly testing for the specific mutation identified (ie, site-specific testing) can then be offered to family members to provide a yes-or-no answer as to their risk status.

If the relative most likely to be gene-positive tests negative, no genetic testing would be recommended for family members, as the genetic cause of the cancer in the family is unknown. In this situation, family members may be advised to pursue the same screening measures as those with a positive gene test due to their strong family history.

INFORMED CONSENT FOR GENETIC TESTING

Genetic testing consists of much more than a simple blood draw. Obtaining informed consent for genetic testing is a crucial step in the testing process, as the results can be complex and often affect multiple family members. When predictive genetic testing is being discussed, special conversations need to take place to make sure that decisions are well informed. Genetic counselors can facilitate these discussions and guide patients and families through the decision-making process.

Example: Huntington disease

The need for genetic counseling before predictive testing is best illustrated by Huntington disease, a progressive neurodegenerative disorder with typical onset in the third or fourth decade of life. Over the disease course, patients experience decreases in motor control (leading to the aptly named “Huntington chorea”), cognitive decline, and changes in psychiatric state. Ultimately, most patients die 15 to 20 years after the onset of symptoms. Treatment is palliative and symptom-based.

Huntington disease is inherited in an autosomal dominant manner, meaning that each child of an affected person has a 50% risk of inheriting the gene change responsible for this condition and of eventually developing the disease. It is caused by an expansion within the HD gene; this expansion may grow with successive generations, leading to earlier onset of symptoms.²⁰

The availability of predictive testing—which enables people who are at risk but who are without symptoms to find out their genetic status—ultimately leads each at-risk person to ask herself or himself, Do I want to know? Studies have found that only 15% to 67% of offspring of parents with Huntington disease (offspring are at 50% risk of the disease) elected to be tested, and in one longitudinal study, this rate of “uptake” decreased over time.^21,22 However, any estimates of uptake may be falsely elevated, given the likelihood that those not wishing to consider testing may not feel the need for a clinical visit focused on this subject.

After predictive testing became available, an increased risk of suicide in persons at risk of Huntington disease was documented.^23,24 In view of this risk and the careful decision-making support that people at risk need, predictive testing guidelines were developed by a committee of medical experts and members of Huntington disease family organizations.²⁵ As part of the guidelines, a multivisit pretesting process was established that includes extensive education and counseling. Delay of testing is recommended when contraindications are identified, such as evidence of coercion or a serious psychiatric condition. Most genetic testing companies offering predictive testing require a signature from the ordering clinician verifying that pretest counseling has been completed; some also include a provision that the ordering clinician will relay results to the patient in person.

More than 15 years after these guidelines were adopted, a study of suicide risk in at-risk persons continued to find rates higher than in the general population, but lower than in earlier studies.²⁶ Whether this careful pretest counseling protocol is directly related to a possible decrease in suicide risk has yet to be established, but its successful use in patients undergoing predictive Huntington disease testing has led to its adoption in other neurodegenerative diseases such as Alzheimer disease and Parkinson disease.

EXPLAINING POSITIVE GENETIC TESTING RESULTS

If genetic testing identifies a mutation, genetic counselors can help patients understand the implications of the results for themselves and for their relatives. Some patients become quite inquisitive, and the genetic counseling session morphs into a graduate-level discussion of genes, DNA, disease pathways, genetic-environmental interactions, availability of gene therapy, and clinical trials. The genetic counselor also makes the patient aware of other resources, such as disease-specific support groups, which may be developed by patients and families to provide support and practical knowledge.

In some cases, attention turns to at-risk relatives, and the genetic counselor may role-play with the patient to rehearse ways to share information with them. Genetic counselors may give patients a letter to distribute to family members with a copy of the patient’s test results, briefly explaining the condition identified and how relatives may find a genetic counselor in their area for their own risk assessment.

WHAT ABOUT GENETIC DISCRIMINATION?

Genetic discrimination is addressed in many genetic counseling sessions.

As defined by the National Human Genome Research Institute, genetic discrimination is “prejudice directed against people who have or may have a genetic disease.”²⁷

In May 2008, the Genetic Information Nondiscrimination Act (GINA) was signed into law, providing some legal protections against genetic discrimination for patients undergoing predictive genetic testing. The law applies to most employers and health insurers but does not protect against discrimination by life or disability insurers. When discussing genetic testing, genetic counselors ensure that patients are aware of their rights and protections.

GINA would not be relevant for a patient who has a medical condition that may affect his or her insurability. For example, someone with thyroid cancer who is found to have an underlying gene mutation may still be denied any type of insurance coverage on the basis of his or her personal cancer diagnosis. However, should that person’s son who has not been diagnosed with cancer opt to undergo predictive testing, GINA would provide protection against employment and health insurance discrimination, as described above.

DIRECT-TO-CONSUMER GENETIC TESTING

As DNA technology has become increasingly complex, so has the task of understanding new tests and their clinical relevance to patients.

In the last several years, more companies have begun to offer direct-to-consumer genetic testing, which may be ordered without the involvement of a health care professional. While some companies hire or work closely with genetic counselors to conduct pretest and posttest genetic counseling, others do not, and preliminary research has found that only a minority of primary care physicians feel prepared to answer patients’ questions about direct-to-consumer genetic testing.²⁸

Genetic counselors stay abreast of emerging technologies and are prepared to answer questions from patients who are considering or have already undergone such testing and from physicians who may wonder if a patient’s direct-to-consumer genetic testing results should affect his or her management.

Direct-to-consumer genetic testing will be discussed in depth in a future article in this series.

EXPLAINING ‘NORMAL’ (NEGATIVE) GENETIC TEST RESULTS

When testing results are normal, patients are educated about the meaning of “normal” results, the residual risk, and screening that might be appropriate in each person’s situation.

Sometimes a normal result does not mean the patient is not at risk for disease—for most diseases, genetic testing is not perfect and cannot identify a mutation in every at-risk family. Patients who have a family history of certain conditions may still face a higher risk despite normal test results. In these situations it is imperative that the family continue to adhere to follow-up recommendations even with normal test results.

Example: Marfan syndrome

Marfan syndrome is an autosomal dominant connective tissue disorder that, if unrecognized, is associated with significant morbidity and mortality. People with Marfan syndrome are at increased risk of aortic aneurysms, which can rupture spontaneously, leading to sudden death.

Although at least 70% of patients with Marfan syndrome have a mutation in FBN1, other patients meeting the clinical diagnostic criteria do not. Despite a normal genetic test result, they should adhere to the same screening guidelines as a person who tests positive.²⁹

This concept—that screening should still be done despite a normal “Marfan test”—may be difficult for patients to grasp without a discussion of the imperfect sensitivity of genetic testing and of their real ongoing risks. Even more difficult to understand is the idea that the patient’s family members should also be screened as though they have the disease, given that the family’s mutation is unknown and predictive testing cannot be conducted.

Further complicating matters, other disorders such as Loeys-Dietz and vascular Ehlers-Danlos syndrome can mimic Marfan syndrome by causing aortic aneurysms, but management recommendations for them are very different.^30,31

The appropriate genetic diagnosis for patients with aortic aneurysms can be facilitated by referring them to genetic counselors, who can identify appropriate testing. In this way, physicians can personalize medical management and give screening recommendations specific to the genetic disorder present.

EXPLAINING UNCERTAIN RESULTS

There are three possible results for most genetic tests—positive (a pathogenic or disease-causing mutation was found), negative (normal), and the frustrating “variant of uncertain significance” (VUS).

A VUS result means that an abnormality was detected in the gene, but that there are insufficient data about whether the abnormality alters the function of the gene in question and, thus, leads to disease. Since some gene variants are known to be common in the general population and not linked to disease and others are known to definitely alter a gene’s function and cause disease, a VUS that is clearly unknown poses a challenge not only to patient management, but also to family members seeking personal risk assessments.

Knowledge of how or if specific variants relate to disease is emerging. In time, some variants become reclassified as either disease-causing mutations or benign polymorphisms. However, careful consideration needs to be given to how to explain the abnormal result to the patient and to at-risk family members, as well as to how to explain the clinical implications of the VUS.

Example: Hereditary breast and ovarian cancer syndrome

People with hereditary breast and ovarian cancer syndrome face a lifetime risk of breast cancer of up to 87% and a risk of ovarian cancer of up to 44%. Most families with this syndrome have an inherited change in either the BRCA1 or BRCA2 gene.^32,33 Given these risks, prophylactic mastectomy and oophorectomy are among the management options for mutation-positive patients. In the absence of clear genetic counseling, a patient with a VUS might see the “abnormal” test result and believe herself to be mutation-positive and thus at very high cancer risk.

An important role for the genetic counselor is to clarify the pathogenicity of a particular VUS. When a VUS is found, genetic counselors search for information about the variant by reviewing the medical literature, discussing it with the testing laboratory, arranging for family studies when appropriate, and contacting researchers whose work focuses on the gene in question.

Failure to properly research a particular VUS can lead to unnecessary and risky surgical procedures, as well as to falsely labelling relatives as being at risk. Until a VUS is reclassified as a disease-causing mutation, testing for it should not be offered to family members (unless through a research study), nor should medical management be based solely on the results of a particular VUS. In time, a VUS may be reclassified as either a benign polymorphism or a disease-causing mutation, and the genetic counselor will recontact the patient and physician with updated information and recommendations.

WHOM SHOULD I REFER?

Genetic counseling is available for patients and families in diverse settings within health systems. The six primary areas of practice are general, cardiovascular, cancer, preconception, prenatal, and pediatrics.

Patients with a personal or family history of a hereditary condition can benefit from genetic counseling regardless of whether they would be considered appropriate for genetic testing.³⁴

At current count, there are 4,424 genetic disorders for which the underlying cause has been identified.³⁵ Individually, each disorder is rare, but when they are considered as a whole, they affect a significant minority of the general population. It is estimated that before age 25 years, 53 (5.3%) of every 1,000 people will be diagnosed with a disease that has an important genetic component.³⁶ From 20% to 30% of infant deaths are related to a genetic disorder,^37,38 and 22% of unaffected adults have a family history of cancer significant enough to warrant a genetics referral.³⁹ See Table 2 for a list of common indications for referral.

HOW CAN I FIND GENETIC COUNSELING SERVICES?

The National Society of Genetic Counselors (www.nsgc.org) and American Board of Genetic Counseling (www.abgc.net) both provide searchable databases of registered genetic counselors.

KNOWLEDGE CONTINUES TO EXPAND

Genetic knowledge continues to expand, and testing is becoming available for a growing number of medical conditions. Appropriate identification of individuals with and at risk for genetic disorders through the use of genetic testing and screening is a cornerstone of personalized medicine, with the ultimate goal of improving patient outcomes. However, in this era of value-based medicine and fewer health care dollars, genetic testing must be used in a way that maximizes its clinical impact with a careful fiscal approach.

Genetic counselors are specially trained health care professionals with expertise in genetic and genomic medicine who work in collaboration with physicians to guide patients through the complexities of heritable conditions and emerging technologies. They are trained to personalize, interpret, and communicate complex science into data that will assure best outcomes for patients and their families. Developing a partnership with the genetic counselors in your area can provide multiple benefits to your patients as well as to your own practice.

More than 10% of patients labeled as having cellulitis do not have cellulitis.¹ This is unfortunate, as it leads to excessive and incorrect use of antibiotics and to delays in appropriate therapy.² However, it is not surprising, given the number of conditions that bear a striking similarity to cellulitis. A familiarity with the features of true cellulitis and with the handful of conditions that can bear a striking similarity to it is the way out of this potential diagnostic quagmire.

WHAT CELLULITIS IS—AND IS NOT

The key characteristics of cellulitis are redness, warmth, tenderness, and swelling of the skin. A history of trauma and pain in the affected area and evidence of leukocytosis³ suggest cellulitis. A symmetric or diffusely scattered pattern indicates a condition other than cellulitis, which is overwhelmingly unilateral, with smooth, indistinct borders^4,5 Other factors pointing to cellulitis are underlying immunosuppression, a more rapid progression, previous episodes, systemic symptoms (eg, fever, leukocytosis), new medications, new travel or outdoor exposure, and comorbidities such as diabetes and peripheral vascular disease. A long-standing, slowly progressive course and a history of unsuccessful treatment with antibiotics are strong indicators of a condition other than cellulitis.

Consultation with a dermatologist is recommended to narrow the differential diagnosis. The dermatologist can determine if biopsy is necessary, as many dermatoses that mimic cellulitis can be diagnosed by visual recognition alone.

STASIS DERMATITIS

The most common mimic of cellulitis is stasis dermatitis (Figure 1).² Patients can present with ill-defined, bilateral, pitting edema of the lower extremities, typically with erythema, hyperpigmentation, serous drainage, and superficial desquamation.^3,6,7

The inciting factor is chronic venous insufficiency, leading to interstitial edema, extravasation of red blood cells, and decreased tissue oxygenation. This process causes micro-vascular changes and microthrombi that up-regulate transforming growth factor beta and fibroblastic growth factor.⁷ If the process is allowed to continue, stasis dermatitis may progress to lipodermatosclerosis.

Tip: Stasis dermatitis is generally bilateral, the process will have been ongoing for years, there is often pitting edema, and the legs should be nontender.

LIPODERMATOSCLEROSIS

Lipodermatosclerosis is a sclerosing panniculitis classically described as an “inverted champagne bottle” or “inverted bowling pin” appearance of the leg, ie, the diameter of the leg is sharply narrowed directly below the calf (Figure 2).

There is an acute and a chronic phase. The acute phase is characterized by inflammation and erythema, and the chronic phase is characterized by fibrosis.⁸ The acute phase presents with severe lower-extremity pain above the medial malleolus, erythema, edema, and warmth; there is no sharp demarcation between affected and unaffected skin.^9,10 This phase can be difficult to distinguish from cellulitis, so the history plays a key role. Known venous insufficiency, cutaneous changes of stasis dermatitis, and the absence of systemic symptoms all point to lipodermatosclerosis.

The chronic phase is characterized by unilateral or bilateral, indurated, sclerotic plaques with a “bound-down” appearance (ie, they appear as if tethered—or bound—to the subcutaneous tissue) affecting the skin from below the knee to the ankle; there is a sharp demarcation between affected and unaffected skin.^9–11 The skin is often bronze or brown secondary to hemosiderin deposits. There can be prominent varicosities and scattered ulcerations depending on the course of the disease.

This condition is thought to be the result of long-standing chronic venous insufficiency.^7,8,9,11 It is proposed that venous incompetence leads to extravasation of interstitial fluid and red blood cells, decreased diffusion of oxygen to the tissues, and eventual tissue and endothelial damage. As the endothelium is damaged, microthrombi formation and infarction ensue, stimulating fibroblasts to form granulation tissue.

Tip: The history helps to distinguish acute lipodermatosclerosis from cellulitis. Chroniclipodermatoslcerosis will have been ongoing for years, the legs should be nontender, the skin will be bound-down, and the diameter of the leg will sharply decrease from knee to ankle.

CONTACT DERMATITIS

Allergic and irritant forms of contact dermatitis are often mistaken for cellulitis. Irritant contact dermatitis (Figure 3) presents with erythematous patches and plaques with well-defined borders, often in a geometric distribution where the skin was exposed to an irritant.¹² Allergic contact dermatitis is a delayed hypersensitivity dermatitis that can be secondary to something ingested, applied to the skin, or airborne (Figure 4). It presents as erythematous macules, papules, and plaques that may have serous drainage or vesiculation. Lesions of allergic contact dermatitis are usually confined to the site of contact with the allergen, but they can infrequently be found at distant sites, in which case it is considered systemic contact dermatitis.^3,5 Depending on the severity of the allergy, patients may complain of intense pain and pruritus.³

Additionally, chronic, nonhealing leg ulcers may have a confounding allergic contact dermatitis.⁷ Although patients may believe they are helping the ulcer heal by applying topical antibiotics or other lubricants, they may in fact be impeding the healing process. Always inquire as to what the patient is applying if he or she has leg ulceration with surrounding edema and erythema that has not resolved with conventional treatments.^13,14

Tip: The key to distinguishing contact dermatitis from cellulitis is the history. For example, ask about recent changes in medications, soaps, and laundry detergents, new hobbies, or recent surgeries. The involved site is often confined to the area where the allergen contacted the skin, except in cases of exposure to an airborne allergen.

LYMPHEDEMA

Lymphedema is characterized by localized edema of an affected extremity, with induration, erythema, and secondary cutaneous changes such as hyperkeratosis, dyspigmentation, and wart-like architecture (Figure 5).

Primary lymphedema appears in the setting of congenital abnormalities, whereas secondary lymphedema results from an interruption of a previously functioning lymphatic system (eg, after radical mastectomy).

Patients often present with unilateral nonpitting edema and erythema in the absence of systemic symptoms.¹² Many patients presenting with lower-extremity lymphedema are overweight or obese, as the weight they carry causes obstruction of the inguinal lymphatics.⁶

The pathophysiology is not clearly delineated but is thought to be a consequence of decreased oxygenation of tissue secondary to extravasated lymph. As the oxygen is compromised, macrophages and fibroblasts are recruited, resulting in fibrosis.⁶

Patients with lymphedema are more susceptible to superficial and deep skin infections, as the natural defense system in the epidermis and papillary dermis is compromised by impaired lymphatic drainage.¹⁵

To differentiate uncomplicated lymphedema from a secondary cutaneous infection, the clinician should take into account the presence or absence of warmth, pain, increased erythema, and systemic symptoms (Figure 6).

Tip: Primary lymphedema will most likely present in childhood with no inciting factors and will require a full workup. Obtaining a history should make secondary lymphedema a relatively straightforward diagnosis: Has the patient undergone lymph node dissection? Has the patient had an injury in the affected leg? Lymphedema is overwhelmingly unilateral and nonpitting, and is often seen in overweight people (if no precipitating factor is present).

EOSINOPHILIC CELLULITIS

Eosinophilic cellulitis, or Wells syndrome, was first described in 1971 as a granulomatous dermatitis.¹⁶ It is a recurrent hypersensitivity reaction to a drug, to a vaccine, or to an insect bite, or to a viral or fungal infection that presents on the extremities as localized erythema, edema, and induration with sharp borders and a green or gray hue (Figure 7).^17–19 The lesions commonly progress to firm, indurated plaques that resemble morphea. The plaques may take weeks or years to resolve, but they do so without scarring.^12,17,20,21

As patients tend to have recurrent bouts of eosinophilic cellulitis, they may have lesions in different stages of healing. Patients tend to report itching and burning that precedes the onset of plaques.²² The complete blood count typically shows a transient hypereosinophilia.^{12,16,17,23–25}

Tip: This diagnosis often requires biopsy for confirmation, but helpful clues are a history of recurrent episodes, the color of the lesions, and peripheral eosinophilia.

PAPULAR URTICARIA

Papular urticaria is a dermal hypersensitivity reaction to an insect bite, most commonly from a flea or mosquito.²⁶ Patients are often children, as their immune system may be hypersensitive. But children often develop tolerance before puberty.²⁷

The presentation may vary, from numerous urticarial papules near the site of a bite, to generalized, large, indurated, erythematous plaques reminiscent of cellulitis (Figure 8).^5,26 The lesions usually develop within hours of a bite and persist for an average of 1 to 2 weeks.²⁸ The areas typically affected are the head and neck or the upper or lower extremities; the palms, soles, and trunk are usually spared.²⁷

Patients most often complain of intense itching.¹² The pathogenesis is proposed to be mediated by the immune complex, and tissue biopsy study shows increased eosinophils. The eosinophils stimulate mast cells, causing release of histamine, leading to increased vascular permeability, edema, and erythema.^28,29

Tip: Biopsy may be necessary to confirm the diagnosis, though often the history may be sufficient. The patient may or may not recall a bite, so probe into recent activities such as outdoor sports or contact with a new pet. The papules and plaques are generally very pruritic but not painful.

DERMATOLOGY CONSULT

If the clinical presentation and history do not correlate, or if the skin condition has been treated with antibiotics yet has failed to respond, the possibility of other cutaneous dermatoses should be entertained. A dermatology consult can help determine the diagnosis, the need for further evaluation, and the best treatment course.

More than 10% of patients labeled as having cellulitis do not have cellulitis.¹ This is unfortunate, as it leads to excessive and incorrect use of antibiotics and to delays in appropriate therapy.² However, it is not surprising, given the number of conditions that bear a striking similarity to cellulitis. A familiarity with the features of true cellulitis and with the handful of conditions that can bear a striking similarity to it is the way out of this potential diagnostic quagmire.

WHAT CELLULITIS IS—AND IS NOT

The key characteristics of cellulitis are redness, warmth, tenderness, and swelling of the skin. A history of trauma and pain in the affected area and evidence of leukocytosis³ suggest cellulitis. A symmetric or diffusely scattered pattern indicates a condition other than cellulitis, which is overwhelmingly unilateral, with smooth, indistinct borders^4,5 Other factors pointing to cellulitis are underlying immunosuppression, a more rapid progression, previous episodes, systemic symptoms (eg, fever, leukocytosis), new medications, new travel or outdoor exposure, and comorbidities such as diabetes and peripheral vascular disease. A long-standing, slowly progressive course and a history of unsuccessful treatment with antibiotics are strong indicators of a condition other than cellulitis.

Consultation with a dermatologist is recommended to narrow the differential diagnosis. The dermatologist can determine if biopsy is necessary, as many dermatoses that mimic cellulitis can be diagnosed by visual recognition alone.

STASIS DERMATITIS

The most common mimic of cellulitis is stasis dermatitis (Figure 1).² Patients can present with ill-defined, bilateral, pitting edema of the lower extremities, typically with erythema, hyperpigmentation, serous drainage, and superficial desquamation.^3,6,7

The inciting factor is chronic venous insufficiency, leading to interstitial edema, extravasation of red blood cells, and decreased tissue oxygenation. This process causes micro-vascular changes and microthrombi that up-regulate transforming growth factor beta and fibroblastic growth factor.⁷ If the process is allowed to continue, stasis dermatitis may progress to lipodermatosclerosis.

Tip: Stasis dermatitis is generally bilateral, the process will have been ongoing for years, there is often pitting edema, and the legs should be nontender.

LIPODERMATOSCLEROSIS

Lipodermatosclerosis is a sclerosing panniculitis classically described as an “inverted champagne bottle” or “inverted bowling pin” appearance of the leg, ie, the diameter of the leg is sharply narrowed directly below the calf (Figure 2).

There is an acute and a chronic phase. The acute phase is characterized by inflammation and erythema, and the chronic phase is characterized by fibrosis.⁸ The acute phase presents with severe lower-extremity pain above the medial malleolus, erythema, edema, and warmth; there is no sharp demarcation between affected and unaffected skin.^9,10 This phase can be difficult to distinguish from cellulitis, so the history plays a key role. Known venous insufficiency, cutaneous changes of stasis dermatitis, and the absence of systemic symptoms all point to lipodermatosclerosis.

The chronic phase is characterized by unilateral or bilateral, indurated, sclerotic plaques with a “bound-down” appearance (ie, they appear as if tethered—or bound—to the subcutaneous tissue) affecting the skin from below the knee to the ankle; there is a sharp demarcation between affected and unaffected skin.^9–11 The skin is often bronze or brown secondary to hemosiderin deposits. There can be prominent varicosities and scattered ulcerations depending on the course of the disease.

This condition is thought to be the result of long-standing chronic venous insufficiency.^7,8,9,11 It is proposed that venous incompetence leads to extravasation of interstitial fluid and red blood cells, decreased diffusion of oxygen to the tissues, and eventual tissue and endothelial damage. As the endothelium is damaged, microthrombi formation and infarction ensue, stimulating fibroblasts to form granulation tissue.

Tip: The history helps to distinguish acute lipodermatosclerosis from cellulitis. Chroniclipodermatoslcerosis will have been ongoing for years, the legs should be nontender, the skin will be bound-down, and the diameter of the leg will sharply decrease from knee to ankle.

CONTACT DERMATITIS

Allergic and irritant forms of contact dermatitis are often mistaken for cellulitis. Irritant contact dermatitis (Figure 3) presents with erythematous patches and plaques with well-defined borders, often in a geometric distribution where the skin was exposed to an irritant.¹² Allergic contact dermatitis is a delayed hypersensitivity dermatitis that can be secondary to something ingested, applied to the skin, or airborne (Figure 4). It presents as erythematous macules, papules, and plaques that may have serous drainage or vesiculation. Lesions of allergic contact dermatitis are usually confined to the site of contact with the allergen, but they can infrequently be found at distant sites, in which case it is considered systemic contact dermatitis.^3,5 Depending on the severity of the allergy, patients may complain of intense pain and pruritus.³

Additionally, chronic, nonhealing leg ulcers may have a confounding allergic contact dermatitis.⁷ Although patients may believe they are helping the ulcer heal by applying topical antibiotics or other lubricants, they may in fact be impeding the healing process. Always inquire as to what the patient is applying if he or she has leg ulceration with surrounding edema and erythema that has not resolved with conventional treatments.^13,14

Tip: The key to distinguishing contact dermatitis from cellulitis is the history. For example, ask about recent changes in medications, soaps, and laundry detergents, new hobbies, or recent surgeries. The involved site is often confined to the area where the allergen contacted the skin, except in cases of exposure to an airborne allergen.

LYMPHEDEMA

Lymphedema is characterized by localized edema of an affected extremity, with induration, erythema, and secondary cutaneous changes such as hyperkeratosis, dyspigmentation, and wart-like architecture (Figure 5).

Primary lymphedema appears in the setting of congenital abnormalities, whereas secondary lymphedema results from an interruption of a previously functioning lymphatic system (eg, after radical mastectomy).

Patients often present with unilateral nonpitting edema and erythema in the absence of systemic symptoms.¹² Many patients presenting with lower-extremity lymphedema are overweight or obese, as the weight they carry causes obstruction of the inguinal lymphatics.⁶

The pathophysiology is not clearly delineated but is thought to be a consequence of decreased oxygenation of tissue secondary to extravasated lymph. As the oxygen is compromised, macrophages and fibroblasts are recruited, resulting in fibrosis.⁶

Patients with lymphedema are more susceptible to superficial and deep skin infections, as the natural defense system in the epidermis and papillary dermis is compromised by impaired lymphatic drainage.¹⁵

To differentiate uncomplicated lymphedema from a secondary cutaneous infection, the clinician should take into account the presence or absence of warmth, pain, increased erythema, and systemic symptoms (Figure 6).

Tip: Primary lymphedema will most likely present in childhood with no inciting factors and will require a full workup. Obtaining a history should make secondary lymphedema a relatively straightforward diagnosis: Has the patient undergone lymph node dissection? Has the patient had an injury in the affected leg? Lymphedema is overwhelmingly unilateral and nonpitting, and is often seen in overweight people (if no precipitating factor is present).

EOSINOPHILIC CELLULITIS

Eosinophilic cellulitis, or Wells syndrome, was first described in 1971 as a granulomatous dermatitis.¹⁶ It is a recurrent hypersensitivity reaction to a drug, to a vaccine, or to an insect bite, or to a viral or fungal infection that presents on the extremities as localized erythema, edema, and induration with sharp borders and a green or gray hue (Figure 7).^17–19 The lesions commonly progress to firm, indurated plaques that resemble morphea. The plaques may take weeks or years to resolve, but they do so without scarring.^12,17,20,21

As patients tend to have recurrent bouts of eosinophilic cellulitis, they may have lesions in different stages of healing. Patients tend to report itching and burning that precedes the onset of plaques.²² The complete blood count typically shows a transient hypereosinophilia.^{12,16,17,23–25}

Tip: This diagnosis often requires biopsy for confirmation, but helpful clues are a history of recurrent episodes, the color of the lesions, and peripheral eosinophilia.

PAPULAR URTICARIA

Papular urticaria is a dermal hypersensitivity reaction to an insect bite, most commonly from a flea or mosquito.²⁶ Patients are often children, as their immune system may be hypersensitive. But children often develop tolerance before puberty.²⁷

The presentation may vary, from numerous urticarial papules near the site of a bite, to generalized, large, indurated, erythematous plaques reminiscent of cellulitis (Figure 8).^5,26 The lesions usually develop within hours of a bite and persist for an average of 1 to 2 weeks.²⁸ The areas typically affected are the head and neck or the upper or lower extremities; the palms, soles, and trunk are usually spared.²⁷

Patients most often complain of intense itching.¹² The pathogenesis is proposed to be mediated by the immune complex, and tissue biopsy study shows increased eosinophils. The eosinophils stimulate mast cells, causing release of histamine, leading to increased vascular permeability, edema, and erythema.^28,29

Tip: Biopsy may be necessary to confirm the diagnosis, though often the history may be sufficient. The patient may or may not recall a bite, so probe into recent activities such as outdoor sports or contact with a new pet. The papules and plaques are generally very pruritic but not painful.

DERMATOLOGY CONSULT

If the clinical presentation and history do not correlate, or if the skin condition has been treated with antibiotics yet has failed to respond, the possibility of other cutaneous dermatoses should be entertained. A dermatology consult can help determine the diagnosis, the need for further evaluation, and the best treatment course.

More than 10% of patients labeled as having cellulitis do not have cellulitis.¹ This is unfortunate, as it leads to excessive and incorrect use of antibiotics and to delays in appropriate therapy.² However, it is not surprising, given the number of conditions that bear a striking similarity to cellulitis. A familiarity with the features of true cellulitis and with the handful of conditions that can bear a striking similarity to it is the way out of this potential diagnostic quagmire.

WHAT CELLULITIS IS—AND IS NOT

The key characteristics of cellulitis are redness, warmth, tenderness, and swelling of the skin. A history of trauma and pain in the affected area and evidence of leukocytosis³ suggest cellulitis. A symmetric or diffusely scattered pattern indicates a condition other than cellulitis, which is overwhelmingly unilateral, with smooth, indistinct borders^4,5 Other factors pointing to cellulitis are underlying immunosuppression, a more rapid progression, previous episodes, systemic symptoms (eg, fever, leukocytosis), new medications, new travel or outdoor exposure, and comorbidities such as diabetes and peripheral vascular disease. A long-standing, slowly progressive course and a history of unsuccessful treatment with antibiotics are strong indicators of a condition other than cellulitis.

Consultation with a dermatologist is recommended to narrow the differential diagnosis. The dermatologist can determine if biopsy is necessary, as many dermatoses that mimic cellulitis can be diagnosed by visual recognition alone.

STASIS DERMATITIS

The most common mimic of cellulitis is stasis dermatitis (Figure 1).² Patients can present with ill-defined, bilateral, pitting edema of the lower extremities, typically with erythema, hyperpigmentation, serous drainage, and superficial desquamation.^3,6,7

The inciting factor is chronic venous insufficiency, leading to interstitial edema, extravasation of red blood cells, and decreased tissue oxygenation. This process causes micro-vascular changes and microthrombi that up-regulate transforming growth factor beta and fibroblastic growth factor.⁷ If the process is allowed to continue, stasis dermatitis may progress to lipodermatosclerosis.

Tip: Stasis dermatitis is generally bilateral, the process will have been ongoing for years, there is often pitting edema, and the legs should be nontender.

LIPODERMATOSCLEROSIS

Lipodermatosclerosis is a sclerosing panniculitis classically described as an “inverted champagne bottle” or “inverted bowling pin” appearance of the leg, ie, the diameter of the leg is sharply narrowed directly below the calf (Figure 2).

There is an acute and a chronic phase. The acute phase is characterized by inflammation and erythema, and the chronic phase is characterized by fibrosis.⁸ The acute phase presents with severe lower-extremity pain above the medial malleolus, erythema, edema, and warmth; there is no sharp demarcation between affected and unaffected skin.^9,10 This phase can be difficult to distinguish from cellulitis, so the history plays a key role. Known venous insufficiency, cutaneous changes of stasis dermatitis, and the absence of systemic symptoms all point to lipodermatosclerosis.

The chronic phase is characterized by unilateral or bilateral, indurated, sclerotic plaques with a “bound-down” appearance (ie, they appear as if tethered—or bound—to the subcutaneous tissue) affecting the skin from below the knee to the ankle; there is a sharp demarcation between affected and unaffected skin.^9–11 The skin is often bronze or brown secondary to hemosiderin deposits. There can be prominent varicosities and scattered ulcerations depending on the course of the disease.

This condition is thought to be the result of long-standing chronic venous insufficiency.^7,8,9,11 It is proposed that venous incompetence leads to extravasation of interstitial fluid and red blood cells, decreased diffusion of oxygen to the tissues, and eventual tissue and endothelial damage. As the endothelium is damaged, microthrombi formation and infarction ensue, stimulating fibroblasts to form granulation tissue.

Tip: The history helps to distinguish acute lipodermatosclerosis from cellulitis. Chroniclipodermatoslcerosis will have been ongoing for years, the legs should be nontender, the skin will be bound-down, and the diameter of the leg will sharply decrease from knee to ankle.

CONTACT DERMATITIS

Allergic and irritant forms of contact dermatitis are often mistaken for cellulitis. Irritant contact dermatitis (Figure 3) presents with erythematous patches and plaques with well-defined borders, often in a geometric distribution where the skin was exposed to an irritant.¹² Allergic contact dermatitis is a delayed hypersensitivity dermatitis that can be secondary to something ingested, applied to the skin, or airborne (Figure 4). It presents as erythematous macules, papules, and plaques that may have serous drainage or vesiculation. Lesions of allergic contact dermatitis are usually confined to the site of contact with the allergen, but they can infrequently be found at distant sites, in which case it is considered systemic contact dermatitis.^3,5 Depending on the severity of the allergy, patients may complain of intense pain and pruritus.³

Additionally, chronic, nonhealing leg ulcers may have a confounding allergic contact dermatitis.⁷ Although patients may believe they are helping the ulcer heal by applying topical antibiotics or other lubricants, they may in fact be impeding the healing process. Always inquire as to what the patient is applying if he or she has leg ulceration with surrounding edema and erythema that has not resolved with conventional treatments.^13,14

Tip: The key to distinguishing contact dermatitis from cellulitis is the history. For example, ask about recent changes in medications, soaps, and laundry detergents, new hobbies, or recent surgeries. The involved site is often confined to the area where the allergen contacted the skin, except in cases of exposure to an airborne allergen.

LYMPHEDEMA

Lymphedema is characterized by localized edema of an affected extremity, with induration, erythema, and secondary cutaneous changes such as hyperkeratosis, dyspigmentation, and wart-like architecture (Figure 5).

Primary lymphedema appears in the setting of congenital abnormalities, whereas secondary lymphedema results from an interruption of a previously functioning lymphatic system (eg, after radical mastectomy).

Patients often present with unilateral nonpitting edema and erythema in the absence of systemic symptoms.¹² Many patients presenting with lower-extremity lymphedema are overweight or obese, as the weight they carry causes obstruction of the inguinal lymphatics.⁶

The pathophysiology is not clearly delineated but is thought to be a consequence of decreased oxygenation of tissue secondary to extravasated lymph. As the oxygen is compromised, macrophages and fibroblasts are recruited, resulting in fibrosis.⁶

Patients with lymphedema are more susceptible to superficial and deep skin infections, as the natural defense system in the epidermis and papillary dermis is compromised by impaired lymphatic drainage.¹⁵

To differentiate uncomplicated lymphedema from a secondary cutaneous infection, the clinician should take into account the presence or absence of warmth, pain, increased erythema, and systemic symptoms (Figure 6).

Tip: Primary lymphedema will most likely present in childhood with no inciting factors and will require a full workup. Obtaining a history should make secondary lymphedema a relatively straightforward diagnosis: Has the patient undergone lymph node dissection? Has the patient had an injury in the affected leg? Lymphedema is overwhelmingly unilateral and nonpitting, and is often seen in overweight people (if no precipitating factor is present).

EOSINOPHILIC CELLULITIS

Eosinophilic cellulitis, or Wells syndrome, was first described in 1971 as a granulomatous dermatitis.¹⁶ It is a recurrent hypersensitivity reaction to a drug, to a vaccine, or to an insect bite, or to a viral or fungal infection that presents on the extremities as localized erythema, edema, and induration with sharp borders and a green or gray hue (Figure 7).^17–19 The lesions commonly progress to firm, indurated plaques that resemble morphea. The plaques may take weeks or years to resolve, but they do so without scarring.^12,17,20,21

As patients tend to have recurrent bouts of eosinophilic cellulitis, they may have lesions in different stages of healing. Patients tend to report itching and burning that precedes the onset of plaques.²² The complete blood count typically shows a transient hypereosinophilia.^{12,16,17,23–25}

Tip: This diagnosis often requires biopsy for confirmation, but helpful clues are a history of recurrent episodes, the color of the lesions, and peripheral eosinophilia.

PAPULAR URTICARIA

Papular urticaria is a dermal hypersensitivity reaction to an insect bite, most commonly from a flea or mosquito.²⁶ Patients are often children, as their immune system may be hypersensitive. But children often develop tolerance before puberty.²⁷

The presentation may vary, from numerous urticarial papules near the site of a bite, to generalized, large, indurated, erythematous plaques reminiscent of cellulitis (Figure 8).^5,26 The lesions usually develop within hours of a bite and persist for an average of 1 to 2 weeks.²⁸ The areas typically affected are the head and neck or the upper or lower extremities; the palms, soles, and trunk are usually spared.²⁷

Patients most often complain of intense itching.¹² The pathogenesis is proposed to be mediated by the immune complex, and tissue biopsy study shows increased eosinophils. The eosinophils stimulate mast cells, causing release of histamine, leading to increased vascular permeability, edema, and erythema.^28,29

Tip: Biopsy may be necessary to confirm the diagnosis, though often the history may be sufficient. The patient may or may not recall a bite, so probe into recent activities such as outdoor sports or contact with a new pet. The papules and plaques are generally very pruritic but not painful.

DERMATOLOGY CONSULT

If the clinical presentation and history do not correlate, or if the skin condition has been treated with antibiotics yet has failed to respond, the possibility of other cutaneous dermatoses should be entertained. A dermatology consult can help determine the diagnosis, the need for further evaluation, and the best treatment course.

Bedside clinical diagnosis is an increasingly underappreciated art and skill. For example, contemporary medical students, residents, fellows, and cardiologists have been shown to lack competency in cardiac auscultation,^1,2 despite warnings from older physicians trained in an era when the physical examination was valued.^3,4

See editorial

However, echocardiography has given physicians the ability to visually evaluate cardiac function noninvasively and quickly. With advanced technology, does this modern decline in auscultatory skills matter? And specifically, can inexpert cardiac auscultation lead to the inadequate evaluation of valvular heart disease and subsequently to an incorrect recommendation for surgery?

Although the ill consequences for patient care would be difficult to prove, we strongly believe, on the basis of our experiences in a busy cardiovascular surgery clinic in a tertiary care center, that the answer to both questions is yes.

Here, we present three recent scenarios from the clinic of a senior cardiac surgeon who regards the skillful use of his stethoscope as being as important as the echocardiogram. These scenarios highlight how the clinical examination can complement echocardiography in the evaluation of valvular heart disease and how it can affect important management decisions.

SCENARIO 1: SEVERE AORTIC INSUFFICIENCY?

A 53-year-old woman with Turner syndrome (gonadal dysgenesis) suffered an acute ascending aortic dissection requiring resuspension of the aortic valve and replacement of the ascending aorta. Her postoperative course was complicated by pneumonia, respiratory failure, and prolonged mechanical ventilation requiring tracheostomy.

Three months after she completed her convalescence at a skilled nursing facility, she presented to her cardiologist with progressive shortness of breath that severely limited her activity. Echocardiography showed moderately severe aortic insufficiency, and she was referred for aortic valve replacement.

At the cardiac surgery clinic, she reported a further decline in her functional status, with dyspnea during minimal exertion. On physical examination, however, there was no evidence of significant aortic incompetence, ie, no widened pulse pressure, left ventricular heave, or diastolic murmur. A cardiologist specializing in echocardiography reviewed the echocardiogram from the referring physician and found that the appearance was more consistent with mild to moderate aortic insufficiency.

Because her profound symptoms were out of proportion with the degree of aortic insufficiency that was observed, further workup including pulmonary function testing was pursued to find another cause; she was subsequently found to have significant tracheal stenosis, likely related to her tracheostomy. Surgery to remove scar tissue resulted in marked improvement of her symptoms.

SCENARIO 2: SEVERE MITRAL REGURGITATION?

A 67-year-old man who had undergone homograft aortic valve replacement 13 years ago underwent routine echocardiography at another hospital. The test showed a large regurgitant jet and backward flow in the pulmonary veins, indicating moderate to severe mitral regurgitation. Also noted was a mildly decreased ejection fraction of 45%. Because of these findings, he was referred for consideration of mitral valve surgery.

At presentation, he had essentially no symptoms and had a very active lifestyle that included regular biking and running. A physical examination that included auscultation in the left lateral decubitus position noted only a soft systolic ejection murmur at the left upper sternal border.

In view of these findings, repeat echocardiography was ordered and revealed mild mitral regurgitation with normal left atrial and ventricular dimensions, as well as normal left ventricular systolic function. These findings were markedly different from those obtained at the other hospital. The murmur was thought to likely represent flow across the base of the homograft valve. These results confirmed our clinical suspicion that there was no indication for mitral valve surgery.

SCENARIO 3: NORMAL HEART VALVES?

A 62-year-old woman presented to her local cardiologist with a 3-month history of worsening shortness of breath and fatigue. She had an abnormal nuclear stress test that led to left heart catheterization, which revealed a 60% to 70% stenosis of the left main coronary artery. She was promptly referred for coronary artery bypass grafting.

The report from her referring cardiologist indicated normal findings on her cardiac physical examination. However, when we examined her, we noted an accentuation of the first heart sound, with an opening snap and a low-pitched mid-diastolic rumble heard best at the apex, in addition to a systolic ejection murmur, diminished second heart sound, and late-peaking carotid upstroke. Echocardiography revealed significant mitral stenosis, with a mitral valve area of 1.05 cm², as well as moderately severe aortic stenosis. These findings were consistent with rheumatic heart disease, and upon questioning, the patient reported that she had received that diagnosis in her 30s while teaching in China.

In light of the findings on physical examination and imaging, the patient underwent mitral and aortic valve replacement in addition to the coronary bypass procedure for which she had originally been referred.

A SELF-FULFILLING PROPHECY

These vignettes illustrate the importance of a detailed physical examination—particularly cardiac auscultation—in the clinical evaluation of structural heart disease.

In the first two, there were significant inconsistencies between the auscultatory and echocardiographic findings, and information obtained from careful cardiac auscultation ultimately directed further testing and led to the correct diagnosis. The third scenario is particularly worrisome in our opinion, as it not only represents a lack of auscultatory skills, but probably a failure to listen at all. Further, in this patient’s case, failure to diagnose significant valvular disease would likely have meant a need for reoperation at a later date.

Although this is clearly unacceptable, in our experience it is not uncommon. As the skill of auscultation is lost, less and less information is obtained, and the abandonment of auscultation becomes a self-fulfilling prophecy.

AUSCULTATION SAVES MONEY

While these cases show the diagnostic capability of cardiac auscultation, they also show that auscultation has another virtue: it can save money. With skyrocketing health care costs, cost-effectiveness of care is increasingly important. In fact, the modern physician is called to the commitment of the just distribution of finite resources as a principle of medical professionalism.⁵ Physicians skilled in cardiac auscultation will be better able to distinguish patients who do not have significant disease and, therefore, will provide more appropriate care by decreasing the mindless use of expensive imaging.

Physicians, especially cardiologists, who are not worried about the loss of auscultatory skills are likely those who do not know how to properly auscultate the heart and, therefore, do not appreciate the vital information it may provide. Dependent on echocardiography, they fail to recognize its numerous limitations, particularly in a real-world setting where core echocardiography laboratories are not commonplace. Furthermore, the use of sophisticated hand-held echocardiography machines, often by inexperienced and untrained operators, is on the rise.

Echocardiography: Still an imperfect science

Many variables contribute to the echocardiographic assessment of severity in valvular heart disease. These include jet size and character, which may be affected by inappropriate gain settings, Nyquist limits, wall filters, ultrasound beam angulations, and regurgitant orifice area calculations. Other factors potentially affecting echocardiographic reproducibility include variability between machines, sonographers, and interpreters, as well as differences in medications, loading conditions, and blood pressure.^6,7 This potential for variability in echocardiography underlines the importance of auscultation, particularly at tertiary referral centers, where many patients are evaluated and treated on the basis of testing at other facilities. Although echocardiography has rightfully become the cornerstone of diagnosing valvular heart disease, we may often forget that it is an imperfect science.

Well-honed cardiac auscultatory skills are still an essential part of medical practice and are an indispensable complement to echocardiography. For this reason, medical schools and training programs in cardiology should encourage a renaissance in the art of cardiac auscultation and bedside clinical diagnosis, which we believe will ultimately improve patient care. Excellent resources are available for teaching auscultation, including Web sites and audiovisual software. And there may even be a wise old doctor still around for advice.
 

Acknowledgment: We would like to thank Jane Owenby for her assistance in the preparation of this manuscript.

Bedside clinical diagnosis is an increasingly underappreciated art and skill. For example, contemporary medical students, residents, fellows, and cardiologists have been shown to lack competency in cardiac auscultation,^1,2 despite warnings from older physicians trained in an era when the physical examination was valued.^3,4

See editorial

However, echocardiography has given physicians the ability to visually evaluate cardiac function noninvasively and quickly. With advanced technology, does this modern decline in auscultatory skills matter? And specifically, can inexpert cardiac auscultation lead to the inadequate evaluation of valvular heart disease and subsequently to an incorrect recommendation for surgery?

Although the ill consequences for patient care would be difficult to prove, we strongly believe, on the basis of our experiences in a busy cardiovascular surgery clinic in a tertiary care center, that the answer to both questions is yes.

Here, we present three recent scenarios from the clinic of a senior cardiac surgeon who regards the skillful use of his stethoscope as being as important as the echocardiogram. These scenarios highlight how the clinical examination can complement echocardiography in the evaluation of valvular heart disease and how it can affect important management decisions.

SCENARIO 1: SEVERE AORTIC INSUFFICIENCY?

A 53-year-old woman with Turner syndrome (gonadal dysgenesis) suffered an acute ascending aortic dissection requiring resuspension of the aortic valve and replacement of the ascending aorta. Her postoperative course was complicated by pneumonia, respiratory failure, and prolonged mechanical ventilation requiring tracheostomy.

Three months after she completed her convalescence at a skilled nursing facility, she presented to her cardiologist with progressive shortness of breath that severely limited her activity. Echocardiography showed moderately severe aortic insufficiency, and she was referred for aortic valve replacement.

At the cardiac surgery clinic, she reported a further decline in her functional status, with dyspnea during minimal exertion. On physical examination, however, there was no evidence of significant aortic incompetence, ie, no widened pulse pressure, left ventricular heave, or diastolic murmur. A cardiologist specializing in echocardiography reviewed the echocardiogram from the referring physician and found that the appearance was more consistent with mild to moderate aortic insufficiency.

Because her profound symptoms were out of proportion with the degree of aortic insufficiency that was observed, further workup including pulmonary function testing was pursued to find another cause; she was subsequently found to have significant tracheal stenosis, likely related to her tracheostomy. Surgery to remove scar tissue resulted in marked improvement of her symptoms.

SCENARIO 2: SEVERE MITRAL REGURGITATION?

A 67-year-old man who had undergone homograft aortic valve replacement 13 years ago underwent routine echocardiography at another hospital. The test showed a large regurgitant jet and backward flow in the pulmonary veins, indicating moderate to severe mitral regurgitation. Also noted was a mildly decreased ejection fraction of 45%. Because of these findings, he was referred for consideration of mitral valve surgery.

At presentation, he had essentially no symptoms and had a very active lifestyle that included regular biking and running. A physical examination that included auscultation in the left lateral decubitus position noted only a soft systolic ejection murmur at the left upper sternal border.

In view of these findings, repeat echocardiography was ordered and revealed mild mitral regurgitation with normal left atrial and ventricular dimensions, as well as normal left ventricular systolic function. These findings were markedly different from those obtained at the other hospital. The murmur was thought to likely represent flow across the base of the homograft valve. These results confirmed our clinical suspicion that there was no indication for mitral valve surgery.

SCENARIO 3: NORMAL HEART VALVES?

A 62-year-old woman presented to her local cardiologist with a 3-month history of worsening shortness of breath and fatigue. She had an abnormal nuclear stress test that led to left heart catheterization, which revealed a 60% to 70% stenosis of the left main coronary artery. She was promptly referred for coronary artery bypass grafting.

The report from her referring cardiologist indicated normal findings on her cardiac physical examination. However, when we examined her, we noted an accentuation of the first heart sound, with an opening snap and a low-pitched mid-diastolic rumble heard best at the apex, in addition to a systolic ejection murmur, diminished second heart sound, and late-peaking carotid upstroke. Echocardiography revealed significant mitral stenosis, with a mitral valve area of 1.05 cm², as well as moderately severe aortic stenosis. These findings were consistent with rheumatic heart disease, and upon questioning, the patient reported that she had received that diagnosis in her 30s while teaching in China.

In light of the findings on physical examination and imaging, the patient underwent mitral and aortic valve replacement in addition to the coronary bypass procedure for which she had originally been referred.

A SELF-FULFILLING PROPHECY

These vignettes illustrate the importance of a detailed physical examination—particularly cardiac auscultation—in the clinical evaluation of structural heart disease.

In the first two, there were significant inconsistencies between the auscultatory and echocardiographic findings, and information obtained from careful cardiac auscultation ultimately directed further testing and led to the correct diagnosis. The third scenario is particularly worrisome in our opinion, as it not only represents a lack of auscultatory skills, but probably a failure to listen at all. Further, in this patient’s case, failure to diagnose significant valvular disease would likely have meant a need for reoperation at a later date.

Although this is clearly unacceptable, in our experience it is not uncommon. As the skill of auscultation is lost, less and less information is obtained, and the abandonment of auscultation becomes a self-fulfilling prophecy.

AUSCULTATION SAVES MONEY

While these cases show the diagnostic capability of cardiac auscultation, they also show that auscultation has another virtue: it can save money. With skyrocketing health care costs, cost-effectiveness of care is increasingly important. In fact, the modern physician is called to the commitment of the just distribution of finite resources as a principle of medical professionalism.⁵ Physicians skilled in cardiac auscultation will be better able to distinguish patients who do not have significant disease and, therefore, will provide more appropriate care by decreasing the mindless use of expensive imaging.

Physicians, especially cardiologists, who are not worried about the loss of auscultatory skills are likely those who do not know how to properly auscultate the heart and, therefore, do not appreciate the vital information it may provide. Dependent on echocardiography, they fail to recognize its numerous limitations, particularly in a real-world setting where core echocardiography laboratories are not commonplace. Furthermore, the use of sophisticated hand-held echocardiography machines, often by inexperienced and untrained operators, is on the rise.

Echocardiography: Still an imperfect science

Many variables contribute to the echocardiographic assessment of severity in valvular heart disease. These include jet size and character, which may be affected by inappropriate gain settings, Nyquist limits, wall filters, ultrasound beam angulations, and regurgitant orifice area calculations. Other factors potentially affecting echocardiographic reproducibility include variability between machines, sonographers, and interpreters, as well as differences in medications, loading conditions, and blood pressure.^6,7 This potential for variability in echocardiography underlines the importance of auscultation, particularly at tertiary referral centers, where many patients are evaluated and treated on the basis of testing at other facilities. Although echocardiography has rightfully become the cornerstone of diagnosing valvular heart disease, we may often forget that it is an imperfect science.

Well-honed cardiac auscultatory skills are still an essential part of medical practice and are an indispensable complement to echocardiography. For this reason, medical schools and training programs in cardiology should encourage a renaissance in the art of cardiac auscultation and bedside clinical diagnosis, which we believe will ultimately improve patient care. Excellent resources are available for teaching auscultation, including Web sites and audiovisual software. And there may even be a wise old doctor still around for advice.
 

Acknowledgment: We would like to thank Jane Owenby for her assistance in the preparation of this manuscript.

Bedside clinical diagnosis is an increasingly underappreciated art and skill. For example, contemporary medical students, residents, fellows, and cardiologists have been shown to lack competency in cardiac auscultation,^1,2 despite warnings from older physicians trained in an era when the physical examination was valued.^3,4

See editorial

However, echocardiography has given physicians the ability to visually evaluate cardiac function noninvasively and quickly. With advanced technology, does this modern decline in auscultatory skills matter? And specifically, can inexpert cardiac auscultation lead to the inadequate evaluation of valvular heart disease and subsequently to an incorrect recommendation for surgery?

Although the ill consequences for patient care would be difficult to prove, we strongly believe, on the basis of our experiences in a busy cardiovascular surgery clinic in a tertiary care center, that the answer to both questions is yes.

Here, we present three recent scenarios from the clinic of a senior cardiac surgeon who regards the skillful use of his stethoscope as being as important as the echocardiogram. These scenarios highlight how the clinical examination can complement echocardiography in the evaluation of valvular heart disease and how it can affect important management decisions.

SCENARIO 1: SEVERE AORTIC INSUFFICIENCY?

A 53-year-old woman with Turner syndrome (gonadal dysgenesis) suffered an acute ascending aortic dissection requiring resuspension of the aortic valve and replacement of the ascending aorta. Her postoperative course was complicated by pneumonia, respiratory failure, and prolonged mechanical ventilation requiring tracheostomy.

Three months after she completed her convalescence at a skilled nursing facility, she presented to her cardiologist with progressive shortness of breath that severely limited her activity. Echocardiography showed moderately severe aortic insufficiency, and she was referred for aortic valve replacement.

At the cardiac surgery clinic, she reported a further decline in her functional status, with dyspnea during minimal exertion. On physical examination, however, there was no evidence of significant aortic incompetence, ie, no widened pulse pressure, left ventricular heave, or diastolic murmur. A cardiologist specializing in echocardiography reviewed the echocardiogram from the referring physician and found that the appearance was more consistent with mild to moderate aortic insufficiency.

Because her profound symptoms were out of proportion with the degree of aortic insufficiency that was observed, further workup including pulmonary function testing was pursued to find another cause; she was subsequently found to have significant tracheal stenosis, likely related to her tracheostomy. Surgery to remove scar tissue resulted in marked improvement of her symptoms.

SCENARIO 2: SEVERE MITRAL REGURGITATION?

A 67-year-old man who had undergone homograft aortic valve replacement 13 years ago underwent routine echocardiography at another hospital. The test showed a large regurgitant jet and backward flow in the pulmonary veins, indicating moderate to severe mitral regurgitation. Also noted was a mildly decreased ejection fraction of 45%. Because of these findings, he was referred for consideration of mitral valve surgery.

At presentation, he had essentially no symptoms and had a very active lifestyle that included regular biking and running. A physical examination that included auscultation in the left lateral decubitus position noted only a soft systolic ejection murmur at the left upper sternal border.

In view of these findings, repeat echocardiography was ordered and revealed mild mitral regurgitation with normal left atrial and ventricular dimensions, as well as normal left ventricular systolic function. These findings were markedly different from those obtained at the other hospital. The murmur was thought to likely represent flow across the base of the homograft valve. These results confirmed our clinical suspicion that there was no indication for mitral valve surgery.

SCENARIO 3: NORMAL HEART VALVES?

A 62-year-old woman presented to her local cardiologist with a 3-month history of worsening shortness of breath and fatigue. She had an abnormal nuclear stress test that led to left heart catheterization, which revealed a 60% to 70% stenosis of the left main coronary artery. She was promptly referred for coronary artery bypass grafting.

The report from her referring cardiologist indicated normal findings on her cardiac physical examination. However, when we examined her, we noted an accentuation of the first heart sound, with an opening snap and a low-pitched mid-diastolic rumble heard best at the apex, in addition to a systolic ejection murmur, diminished second heart sound, and late-peaking carotid upstroke. Echocardiography revealed significant mitral stenosis, with a mitral valve area of 1.05 cm², as well as moderately severe aortic stenosis. These findings were consistent with rheumatic heart disease, and upon questioning, the patient reported that she had received that diagnosis in her 30s while teaching in China.

In light of the findings on physical examination and imaging, the patient underwent mitral and aortic valve replacement in addition to the coronary bypass procedure for which she had originally been referred.

A SELF-FULFILLING PROPHECY

These vignettes illustrate the importance of a detailed physical examination—particularly cardiac auscultation—in the clinical evaluation of structural heart disease.

In the first two, there were significant inconsistencies between the auscultatory and echocardiographic findings, and information obtained from careful cardiac auscultation ultimately directed further testing and led to the correct diagnosis. The third scenario is particularly worrisome in our opinion, as it not only represents a lack of auscultatory skills, but probably a failure to listen at all. Further, in this patient’s case, failure to diagnose significant valvular disease would likely have meant a need for reoperation at a later date.

Although this is clearly unacceptable, in our experience it is not uncommon. As the skill of auscultation is lost, less and less information is obtained, and the abandonment of auscultation becomes a self-fulfilling prophecy.

AUSCULTATION SAVES MONEY

While these cases show the diagnostic capability of cardiac auscultation, they also show that auscultation has another virtue: it can save money. With skyrocketing health care costs, cost-effectiveness of care is increasingly important. In fact, the modern physician is called to the commitment of the just distribution of finite resources as a principle of medical professionalism.⁵ Physicians skilled in cardiac auscultation will be better able to distinguish patients who do not have significant disease and, therefore, will provide more appropriate care by decreasing the mindless use of expensive imaging.

Physicians, especially cardiologists, who are not worried about the loss of auscultatory skills are likely those who do not know how to properly auscultate the heart and, therefore, do not appreciate the vital information it may provide. Dependent on echocardiography, they fail to recognize its numerous limitations, particularly in a real-world setting where core echocardiography laboratories are not commonplace. Furthermore, the use of sophisticated hand-held echocardiography machines, often by inexperienced and untrained operators, is on the rise.

Echocardiography: Still an imperfect science

Many variables contribute to the echocardiographic assessment of severity in valvular heart disease. These include jet size and character, which may be affected by inappropriate gain settings, Nyquist limits, wall filters, ultrasound beam angulations, and regurgitant orifice area calculations. Other factors potentially affecting echocardiographic reproducibility include variability between machines, sonographers, and interpreters, as well as differences in medications, loading conditions, and blood pressure.^6,7 This potential for variability in echocardiography underlines the importance of auscultation, particularly at tertiary referral centers, where many patients are evaluated and treated on the basis of testing at other facilities. Although echocardiography has rightfully become the cornerstone of diagnosing valvular heart disease, we may often forget that it is an imperfect science.

Well-honed cardiac auscultatory skills are still an essential part of medical practice and are an indispensable complement to echocardiography. For this reason, medical schools and training programs in cardiology should encourage a renaissance in the art of cardiac auscultation and bedside clinical diagnosis, which we believe will ultimately improve patient care. Excellent resources are available for teaching auscultation, including Web sites and audiovisual software. And there may even be a wise old doctor still around for advice.
 

Acknowledgment: We would like to thank Jane Owenby for her assistance in the preparation of this manuscript.

“Those who advise that all stethoscopes should be ‘scrapped’ may be influenced by the fact that they do not know how to use their own.”

From Pulmonary Tuberculosis, 1921, by Sir James Kingston Fowler (1852–1934) of the Brompton Hospital, England

The commentary by Clark et al in this issue¹ is a timely reminder of an important problem in modern medicine: the demise of the bedside. My only divergence from the authors is in their conclusion, since my Mediterranean pessimism leads me to believe that theirs is just a gallant attempt at rearguard action for a battle that, unfortunately, has long been lost.

More than half a century ago, Paul Wood warned us against the “danger of losing our clinical heritage and pinning too much faith in figures thrown out by machines,” thundering that “medicine must suffer if this tendency is not checked.”² Well, that tendency was not checked, and medicine (and our wallets) have indeed suffered.

See related commentary

Still, technology is not the enemy. The misuse of technology is the problem.

Like Dr. Clark and his colleagues, I’ve seen many cases in which technology unguided by bedside skills took physicians down a path where tests begot tests and where, at the end, there was usually a surgeon, and often a lawyer. Sometimes even an undertaker. The deaths of Jonathan Larson (writer-composer of the musical Rent) and of his namesake, actor Jonathan (John) Ritter—who both succumbed to undiagnosed aortic dissection—make me wonder whether their pulses were ever checked.

Editorials have lamented the “hyposkillia” of our times,³ and the usual suspects have been already rounded up: our overreliance on tests, our ever-increasing fascination with the machine (what Erich Fromm called the necrophilia of our times),⁴ the loss of bedside teaching, and lastly, the lure of compensation. But one important player has so far gone unnoticed, despite being probably the major offender. In fact, it may even be responsible for the other disturbing trend in modern medicine: the loss of empathy.⁵

I’m referring to the disappearance of the humanities in both the undergraduate and the graduate curriculum. This is actually new. If we look, for example, at the great bedside diagnosticians of the past, we find that they were passionately interested in everything human. Most, if not all, were indeed humanists—lovers of the arts and literature, travelers and historians, poets and painters, curious of any field that could enrich the human spirit. Charcot, who single-handedly invented neurology, was not only a superb scientist, but also a talented artist who drew and painted (skills he considered fundamental for bedside observation) plus a bona-fide Beethoven fanatic who spent Thursday evenings on music, strictly forbidding any medical talk. Laënnec himself was a poet and musician who modeled his stethoscope after the flutes he made. And Charles Bell (of Bell palsy, phenomenon, and law) was a well-respected painter who soldiered with Wellington and left us incredible sketches of the Waterloo wounded and maimed. Even Osler, the pinnacle of 19th century humanistic medicine, believed so strongly in the value of a liberal education as to provide students with a list of 10 books (ranging from Plutarch and Montaigne to Marcus Aurelius and Shakespeare) to read for half an hour before going to sleep. Addressing the Classical Association just before his death, he lamented the “grievous damage” that had been done by regarding the humanities and science in any other light than complementary, while in reality they are “twin berries on one stem.”⁶

Until the 1870s, medicine was in fact a spin-off of the humanities. A solid humanistic education was deemed essential for admission to medical school. Then the German victory in the Franco-Prussian War shifted the axis from Paris to Berlin, and medicine went the German way. Never as touchy-feely as the French, and definitely more comfortable in the laboratory than at the bedside, the Germans produced giants like Koch, Virchow, and Roentgen, who gradually moved medicine away from the bedside and into the lab. In fact, medicine even adopted the uniform of the laboratory—the infamous white coat now banned by the British National Health system as a dirty carrier of bacteria.

Finding herself at a crossroads, America went the German way, mostly because of Flexner (himself the son of German immigrants), whose 1910 report totally changed the face of medical education. The “two cultures” were born—science was “in” and the humanities “out.”⁷

The result is what Lewis Thomas called the “baleful and malign” influence of the modern medical school on liberal-arts education.⁸ Michael Crichton put it even more bluntly. Explaining why he dropped out of medicine, he wrote, “My classmates [at Harvard] tended to think that literature, music, and art were irrelevant distractions. They held these “cultural” matters in the same intellectual contempt that a physicist holds astrology. Everything outside medicine was just a waste of time.”⁹

And since then, things have only worsened.¹⁰

Yet the link between humanities and the bedside remains crucial. I have had the privilege of meeting most of the clinicians who still contribute to physical diagnosis, and they are almost all humanists.

So why should the humanities nurture the bedside? For one, they may increase our tolerance of ambiguity, a trait sorely lacking in modern medicine. This makes sense, since decoding feeble sounds emanating from chests, palpating indistinct organs, and detecting bedside nuances are all painful reminders of the ambiguous in our craft, not to mention in life. And if unprepared by a humanistic education to deal with the uncertain, students may easily opt for the “certainties” of the laboratory or radiology suite.¹¹ Once again, Osler comes to our rescue.

“A distressing feature in the life which you are about to enter” he told the graduating class of the University of Pennsylvania in 1889, “is the uncertainty which pertains not alone to our science and arts but to the very hopes and fears which make us men. In seeking absolute truth we aim at the unattainable, and must be content with finding broken portions.”¹²

The stethoscope is too closely bound with the doctor’s image not to be a metaphor for something larger. To me, it’s a metaphor for medicine as both an art and a science, wherein the humanities are—and of right ought to be—a fundamental part of the education. Hence, if we want to rekindle the bedside, we must rekindle the humanities. After all, this is what both Lewis Thomas⁸ and Sherwin Nuland¹³ have urged us to do. My hunch is that this would need to be done sooner rather than later, because if it is possible to make a scientist out of a humanist (it was done for centuries), it might be considerably harder to make a humanist out of a scientist. The experience of the past few decades seems to support this conclusion.

The alternative is a future full of tricorders and technicians, but sorely lacking in healers.

“Those who advise that all stethoscopes should be ‘scrapped’ may be influenced by the fact that they do not know how to use their own.”

From Pulmonary Tuberculosis, 1921, by Sir James Kingston Fowler (1852–1934) of the Brompton Hospital, England

The commentary by Clark et al in this issue¹ is a timely reminder of an important problem in modern medicine: the demise of the bedside. My only divergence from the authors is in their conclusion, since my Mediterranean pessimism leads me to believe that theirs is just a gallant attempt at rearguard action for a battle that, unfortunately, has long been lost.

More than half a century ago, Paul Wood warned us against the “danger of losing our clinical heritage and pinning too much faith in figures thrown out by machines,” thundering that “medicine must suffer if this tendency is not checked.”² Well, that tendency was not checked, and medicine (and our wallets) have indeed suffered.

See related commentary

Still, technology is not the enemy. The misuse of technology is the problem.

Like Dr. Clark and his colleagues, I’ve seen many cases in which technology unguided by bedside skills took physicians down a path where tests begot tests and where, at the end, there was usually a surgeon, and often a lawyer. Sometimes even an undertaker. The deaths of Jonathan Larson (writer-composer of the musical Rent) and of his namesake, actor Jonathan (John) Ritter—who both succumbed to undiagnosed aortic dissection—make me wonder whether their pulses were ever checked.

Editorials have lamented the “hyposkillia” of our times,³ and the usual suspects have been already rounded up: our overreliance on tests, our ever-increasing fascination with the machine (what Erich Fromm called the necrophilia of our times),⁴ the loss of bedside teaching, and lastly, the lure of compensation. But one important player has so far gone unnoticed, despite being probably the major offender. In fact, it may even be responsible for the other disturbing trend in modern medicine: the loss of empathy.⁵

I’m referring to the disappearance of the humanities in both the undergraduate and the graduate curriculum. This is actually new. If we look, for example, at the great bedside diagnosticians of the past, we find that they were passionately interested in everything human. Most, if not all, were indeed humanists—lovers of the arts and literature, travelers and historians, poets and painters, curious of any field that could enrich the human spirit. Charcot, who single-handedly invented neurology, was not only a superb scientist, but also a talented artist who drew and painted (skills he considered fundamental for bedside observation) plus a bona-fide Beethoven fanatic who spent Thursday evenings on music, strictly forbidding any medical talk. Laënnec himself was a poet and musician who modeled his stethoscope after the flutes he made. And Charles Bell (of Bell palsy, phenomenon, and law) was a well-respected painter who soldiered with Wellington and left us incredible sketches of the Waterloo wounded and maimed. Even Osler, the pinnacle of 19th century humanistic medicine, believed so strongly in the value of a liberal education as to provide students with a list of 10 books (ranging from Plutarch and Montaigne to Marcus Aurelius and Shakespeare) to read for half an hour before going to sleep. Addressing the Classical Association just before his death, he lamented the “grievous damage” that had been done by regarding the humanities and science in any other light than complementary, while in reality they are “twin berries on one stem.”⁶

Until the 1870s, medicine was in fact a spin-off of the humanities. A solid humanistic education was deemed essential for admission to medical school. Then the German victory in the Franco-Prussian War shifted the axis from Paris to Berlin, and medicine went the German way. Never as touchy-feely as the French, and definitely more comfortable in the laboratory than at the bedside, the Germans produced giants like Koch, Virchow, and Roentgen, who gradually moved medicine away from the bedside and into the lab. In fact, medicine even adopted the uniform of the laboratory—the infamous white coat now banned by the British National Health system as a dirty carrier of bacteria.

Finding herself at a crossroads, America went the German way, mostly because of Flexner (himself the son of German immigrants), whose 1910 report totally changed the face of medical education. The “two cultures” were born—science was “in” and the humanities “out.”⁷

The result is what Lewis Thomas called the “baleful and malign” influence of the modern medical school on liberal-arts education.⁸ Michael Crichton put it even more bluntly. Explaining why he dropped out of medicine, he wrote, “My classmates [at Harvard] tended to think that literature, music, and art were irrelevant distractions. They held these “cultural” matters in the same intellectual contempt that a physicist holds astrology. Everything outside medicine was just a waste of time.”⁹

And since then, things have only worsened.¹⁰

Yet the link between humanities and the bedside remains crucial. I have had the privilege of meeting most of the clinicians who still contribute to physical diagnosis, and they are almost all humanists.

So why should the humanities nurture the bedside? For one, they may increase our tolerance of ambiguity, a trait sorely lacking in modern medicine. This makes sense, since decoding feeble sounds emanating from chests, palpating indistinct organs, and detecting bedside nuances are all painful reminders of the ambiguous in our craft, not to mention in life. And if unprepared by a humanistic education to deal with the uncertain, students may easily opt for the “certainties” of the laboratory or radiology suite.¹¹ Once again, Osler comes to our rescue.

“A distressing feature in the life which you are about to enter” he told the graduating class of the University of Pennsylvania in 1889, “is the uncertainty which pertains not alone to our science and arts but to the very hopes and fears which make us men. In seeking absolute truth we aim at the unattainable, and must be content with finding broken portions.”¹²

The stethoscope is too closely bound with the doctor’s image not to be a metaphor for something larger. To me, it’s a metaphor for medicine as both an art and a science, wherein the humanities are—and of right ought to be—a fundamental part of the education. Hence, if we want to rekindle the bedside, we must rekindle the humanities. After all, this is what both Lewis Thomas⁸ and Sherwin Nuland¹³ have urged us to do. My hunch is that this would need to be done sooner rather than later, because if it is possible to make a scientist out of a humanist (it was done for centuries), it might be considerably harder to make a humanist out of a scientist. The experience of the past few decades seems to support this conclusion.

The alternative is a future full of tricorders and technicians, but sorely lacking in healers.

“Those who advise that all stethoscopes should be ‘scrapped’ may be influenced by the fact that they do not know how to use their own.”

From Pulmonary Tuberculosis, 1921, by Sir James Kingston Fowler (1852–1934) of the Brompton Hospital, England

The commentary by Clark et al in this issue¹ is a timely reminder of an important problem in modern medicine: the demise of the bedside. My only divergence from the authors is in their conclusion, since my Mediterranean pessimism leads me to believe that theirs is just a gallant attempt at rearguard action for a battle that, unfortunately, has long been lost.

More than half a century ago, Paul Wood warned us against the “danger of losing our clinical heritage and pinning too much faith in figures thrown out by machines,” thundering that “medicine must suffer if this tendency is not checked.”² Well, that tendency was not checked, and medicine (and our wallets) have indeed suffered.

See related commentary

Still, technology is not the enemy. The misuse of technology is the problem.

Like Dr. Clark and his colleagues, I’ve seen many cases in which technology unguided by bedside skills took physicians down a path where tests begot tests and where, at the end, there was usually a surgeon, and often a lawyer. Sometimes even an undertaker. The deaths of Jonathan Larson (writer-composer of the musical Rent) and of his namesake, actor Jonathan (John) Ritter—who both succumbed to undiagnosed aortic dissection—make me wonder whether their pulses were ever checked.

Editorials have lamented the “hyposkillia” of our times,³ and the usual suspects have been already rounded up: our overreliance on tests, our ever-increasing fascination with the machine (what Erich Fromm called the necrophilia of our times),⁴ the loss of bedside teaching, and lastly, the lure of compensation. But one important player has so far gone unnoticed, despite being probably the major offender. In fact, it may even be responsible for the other disturbing trend in modern medicine: the loss of empathy.⁵

I’m referring to the disappearance of the humanities in both the undergraduate and the graduate curriculum. This is actually new. If we look, for example, at the great bedside diagnosticians of the past, we find that they were passionately interested in everything human. Most, if not all, were indeed humanists—lovers of the arts and literature, travelers and historians, poets and painters, curious of any field that could enrich the human spirit. Charcot, who single-handedly invented neurology, was not only a superb scientist, but also a talented artist who drew and painted (skills he considered fundamental for bedside observation) plus a bona-fide Beethoven fanatic who spent Thursday evenings on music, strictly forbidding any medical talk. Laënnec himself was a poet and musician who modeled his stethoscope after the flutes he made. And Charles Bell (of Bell palsy, phenomenon, and law) was a well-respected painter who soldiered with Wellington and left us incredible sketches of the Waterloo wounded and maimed. Even Osler, the pinnacle of 19th century humanistic medicine, believed so strongly in the value of a liberal education as to provide students with a list of 10 books (ranging from Plutarch and Montaigne to Marcus Aurelius and Shakespeare) to read for half an hour before going to sleep. Addressing the Classical Association just before his death, he lamented the “grievous damage” that had been done by regarding the humanities and science in any other light than complementary, while in reality they are “twin berries on one stem.”⁶

Until the 1870s, medicine was in fact a spin-off of the humanities. A solid humanistic education was deemed essential for admission to medical school. Then the German victory in the Franco-Prussian War shifted the axis from Paris to Berlin, and medicine went the German way. Never as touchy-feely as the French, and definitely more comfortable in the laboratory than at the bedside, the Germans produced giants like Koch, Virchow, and Roentgen, who gradually moved medicine away from the bedside and into the lab. In fact, medicine even adopted the uniform of the laboratory—the infamous white coat now banned by the British National Health system as a dirty carrier of bacteria.

Finding herself at a crossroads, America went the German way, mostly because of Flexner (himself the son of German immigrants), whose 1910 report totally changed the face of medical education. The “two cultures” were born—science was “in” and the humanities “out.”⁷

The result is what Lewis Thomas called the “baleful and malign” influence of the modern medical school on liberal-arts education.⁸ Michael Crichton put it even more bluntly. Explaining why he dropped out of medicine, he wrote, “My classmates [at Harvard] tended to think that literature, music, and art were irrelevant distractions. They held these “cultural” matters in the same intellectual contempt that a physicist holds astrology. Everything outside medicine was just a waste of time.”⁹

And since then, things have only worsened.¹⁰

Yet the link between humanities and the bedside remains crucial. I have had the privilege of meeting most of the clinicians who still contribute to physical diagnosis, and they are almost all humanists.

So why should the humanities nurture the bedside? For one, they may increase our tolerance of ambiguity, a trait sorely lacking in modern medicine. This makes sense, since decoding feeble sounds emanating from chests, palpating indistinct organs, and detecting bedside nuances are all painful reminders of the ambiguous in our craft, not to mention in life. And if unprepared by a humanistic education to deal with the uncertain, students may easily opt for the “certainties” of the laboratory or radiology suite.¹¹ Once again, Osler comes to our rescue.

“A distressing feature in the life which you are about to enter” he told the graduating class of the University of Pennsylvania in 1889, “is the uncertainty which pertains not alone to our science and arts but to the very hopes and fears which make us men. In seeking absolute truth we aim at the unattainable, and must be content with finding broken portions.”¹²

The stethoscope is too closely bound with the doctor’s image not to be a metaphor for something larger. To me, it’s a metaphor for medicine as both an art and a science, wherein the humanities are—and of right ought to be—a fundamental part of the education. Hence, if we want to rekindle the bedside, we must rekindle the humanities. After all, this is what both Lewis Thomas⁸ and Sherwin Nuland¹³ have urged us to do. My hunch is that this would need to be done sooner rather than later, because if it is possible to make a scientist out of a humanist (it was done for centuries), it might be considerably harder to make a humanist out of a scientist. The experience of the past few decades seems to support this conclusion.

The alternative is a future full of tricorders and technicians, but sorely lacking in healers.

Atrial fibrillation is the most common chronic rapid arrhythmia requiring the attention of internists and cardiologists. Patients with this arrhythmia have higher rates of morbidity and death than similar patients with normal sinus rhythm, and they do so for a number of reasons.

Patients with atrial fibrillation have a slew of comorbidities, including hypertensive and ischemic heart disease. Patients undergoing cardiac surgery have a dramatically higher risk of a postoperative bout of atrial fibrillation. The main concerns are the risk of stroke and the symptoms of heart failure and fatigue (often with exercise intolerance).

Information from registries of patients with atrial fibrillation has permitted the development of prognosticators of stroke risk. The CHADS₂ score (congestive heart failure, hypertension, age > 75, diabetes, and prior stroke or transient ischemic attack) is an amazingly simple way to identify patients with atrial fibrillation who are at highest risk of stroke. This in turn has allowed stratification of patients for entrance into various anticoagulation studies. And perhaps surprisingly, when many factors are considered, nothing turns out to be dramatically better than warfarin (Coumadin)—if the international normalized ratio (INR) can be appropriately controlled.

Not many options are available to prevent atrial fibrillation. Postoperative atrial fibrillation may be prevented with high-dose steroids or colchicine (Colcrys), but this is often a self-limited, situational event. Chronic or recurrent intermittent atrial fibrillation is not readily prevented in most patients, and many symptomatic patients, as discussed by Dr. Bruce Lindsay in this issue, may benefit from drug therapy or radiofrequency ablation.

Studies suggest that trying to convert atrial fibrillation to normal sinus rhythm (vs controlling the rate) may not be worth the effort and the risk in many patients with asymptomatic atrial fibrillation. Furthermore, in patients with symptomatic atrial fibrillation, determining the cause of symptoms is difficult. For example, it may not always be easily determined if fatigue in an elderly patient with chronic atrial fibrillation is due to mild rate-related congestive heart failure, decreased left ventricular output due to the loss of the atrial “kick,” chronic ischemia, or the sedating effect of a beta-blocker given in an effort to control the tachycardia.

Despite many large, well-done studies comparing antiarrhythmic drugs, ablation techniques, and anticoagulants, patients will still benefit most from an experienced clinician’s reflective, individualized assessment before embarking on algorithm-driven long-term therapy. We have more choices, more data, and more management algorithms, but there is still no panacea for patients with atrial fibrillation.

Atrial fibrillation is the most common chronic rapid arrhythmia requiring the attention of internists and cardiologists. Patients with this arrhythmia have higher rates of morbidity and death than similar patients with normal sinus rhythm, and they do so for a number of reasons.

Patients with atrial fibrillation have a slew of comorbidities, including hypertensive and ischemic heart disease. Patients undergoing cardiac surgery have a dramatically higher risk of a postoperative bout of atrial fibrillation. The main concerns are the risk of stroke and the symptoms of heart failure and fatigue (often with exercise intolerance).

Information from registries of patients with atrial fibrillation has permitted the development of prognosticators of stroke risk. The CHADS₂ score (congestive heart failure, hypertension, age > 75, diabetes, and prior stroke or transient ischemic attack) is an amazingly simple way to identify patients with atrial fibrillation who are at highest risk of stroke. This in turn has allowed stratification of patients for entrance into various anticoagulation studies. And perhaps surprisingly, when many factors are considered, nothing turns out to be dramatically better than warfarin (Coumadin)—if the international normalized ratio (INR) can be appropriately controlled.

Not many options are available to prevent atrial fibrillation. Postoperative atrial fibrillation may be prevented with high-dose steroids or colchicine (Colcrys), but this is often a self-limited, situational event. Chronic or recurrent intermittent atrial fibrillation is not readily prevented in most patients, and many symptomatic patients, as discussed by Dr. Bruce Lindsay in this issue, may benefit from drug therapy or radiofrequency ablation.

Studies suggest that trying to convert atrial fibrillation to normal sinus rhythm (vs controlling the rate) may not be worth the effort and the risk in many patients with asymptomatic atrial fibrillation. Furthermore, in patients with symptomatic atrial fibrillation, determining the cause of symptoms is difficult. For example, it may not always be easily determined if fatigue in an elderly patient with chronic atrial fibrillation is due to mild rate-related congestive heart failure, decreased left ventricular output due to the loss of the atrial “kick,” chronic ischemia, or the sedating effect of a beta-blocker given in an effort to control the tachycardia.

Despite many large, well-done studies comparing antiarrhythmic drugs, ablation techniques, and anticoagulants, patients will still benefit most from an experienced clinician’s reflective, individualized assessment before embarking on algorithm-driven long-term therapy. We have more choices, more data, and more management algorithms, but there is still no panacea for patients with atrial fibrillation.

Atrial fibrillation is the most common chronic rapid arrhythmia requiring the attention of internists and cardiologists. Patients with this arrhythmia have higher rates of morbidity and death than similar patients with normal sinus rhythm, and they do so for a number of reasons.

Patients with atrial fibrillation have a slew of comorbidities, including hypertensive and ischemic heart disease. Patients undergoing cardiac surgery have a dramatically higher risk of a postoperative bout of atrial fibrillation. The main concerns are the risk of stroke and the symptoms of heart failure and fatigue (often with exercise intolerance).

Information from registries of patients with atrial fibrillation has permitted the development of prognosticators of stroke risk. The CHADS₂ score (congestive heart failure, hypertension, age > 75, diabetes, and prior stroke or transient ischemic attack) is an amazingly simple way to identify patients with atrial fibrillation who are at highest risk of stroke. This in turn has allowed stratification of patients for entrance into various anticoagulation studies. And perhaps surprisingly, when many factors are considered, nothing turns out to be dramatically better than warfarin (Coumadin)—if the international normalized ratio (INR) can be appropriately controlled.

Not many options are available to prevent atrial fibrillation. Postoperative atrial fibrillation may be prevented with high-dose steroids or colchicine (Colcrys), but this is often a self-limited, situational event. Chronic or recurrent intermittent atrial fibrillation is not readily prevented in most patients, and many symptomatic patients, as discussed by Dr. Bruce Lindsay in this issue, may benefit from drug therapy or radiofrequency ablation.

Studies suggest that trying to convert atrial fibrillation to normal sinus rhythm (vs controlling the rate) may not be worth the effort and the risk in many patients with asymptomatic atrial fibrillation. Furthermore, in patients with symptomatic atrial fibrillation, determining the cause of symptoms is difficult. For example, it may not always be easily determined if fatigue in an elderly patient with chronic atrial fibrillation is due to mild rate-related congestive heart failure, decreased left ventricular output due to the loss of the atrial “kick,” chronic ischemia, or the sedating effect of a beta-blocker given in an effort to control the tachycardia.

Despite many large, well-done studies comparing antiarrhythmic drugs, ablation techniques, and anticoagulants, patients will still benefit most from an experienced clinician’s reflective, individualized assessment before embarking on algorithm-driven long-term therapy. We have more choices, more data, and more management algorithms, but there is still no panacea for patients with atrial fibrillation.

Although many developments have occurred in the last decade for managing atrial fibrillation, challenges remain. New and emerging alternatives to warfarin (Coumadin) for anticoagulation therapy prevent stroke marginally better and pose slightly less risk of hemorrhage, but they have important drawbacks.

The antiarrhythmic drug dronedarone (Multaq) has been found to offer only temporary benefit for persistent atrial fibrillation, and significant risks have emerged.

Radiofrequency ablation is gaining prominence, but repeat procedures are sometimes necessary.

An investigational device can be implanted via percutaneous catheter in the left atrial appendage to prevent embolization. It is too soon to know its eventual role in clinical practice.

This article reviews the results of clinical trials of these new treatments and discusses their role in clinical practice.

CHALLENGES OF ANTICOAGULATION

The main focus of managing atrial fibrillation is on alleviating symptoms, by either rate control or rhythm control. The other focus is on preventing stroke—a devastating outcome—with anticoagulation therapy.

For deciding whether to give warfarin to patients with atrial fibrillation, the six-point CHADS₂ score is a crude but effective way of assessing the risk of stroke based on the following risk factors: congestive heart failure, hypertension, age 75 years or older, and diabetes (1 point each); or a history of stroke or transient ischemic attack (2 points).¹ Warfarin is given if patients have a score of at least 2 points.

Warfarin has a narrow therapeutic window, with a higher risk of ischemic stroke if the international normalized ratio (INR) is less than 2.0,² and a higher risk of intracranial hemorrhage if the INR is more than 3.0.³ Keeping the INR in the therapeutic range is difficult because of variations in diet, concurrent medications, and other factors.

The percent of time that the INR is within the therapeutic range predicts the risk of adverse events. Connolly et al⁴ showed that the cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death was no better with warfarin than with clopidogrel (Plavix) plus aspirin if the INR was in the therapeutic range less than 65% of the time, but the risk was significantly less if the INR was in the therapeutic range more than 65% of the time.

Also, comparing warfarin with the combination of aspirin and clopidogrel, Verheugt⁵ found that the rates of stroke of any kind, of disabling and fatal stroke, and of stroke per major bleed were lower in patients taking warfarin. Although many physicians prefer aspirin plus clopidogrel because of concerns about bleeding with warfarin, the rates of major bleeding were about the same in the two groups.

In a trial in patients for whom warfarin was “unsuitable,”⁶ the combination of aspirin plus clopidogrel was associated with a lower rate of stroke than aspirin alone (2.4% per year vs 3.3% per year, relative risk 0.762) but a higher rate of major bleeding events (2.0% per year vs 1.3% per year, relative risk 1.57).

NEW ALTERNATIVES TO WARFARIN

Because of the problems with warfarin, alternatives have been sought for many years. Several new oral anticoagulants are available or are being developed,⁷ including the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis) and the direct factor II (thrombin) inhibitor dabigatran (Pradaxa) (Table 1).

Dabigatran’s advantages and drawbacks

Dabigatran has been on the market for more than a year and has gained rapid acceptance. The dosage is 150 mg twice a day, or 75 mg twice a day if renal function is impaired. Cleared by the kidneys, it has a half-life of 12 to 17 hours; 75% is cleared within 24 hours. For a patient who needs surgery that poses a low risk of bleeding, the general recommendation is to stop dabigatran the night before the surgical procedure. For operations with a greater risk of bleeding, many surgeons recommend stopping the drug 3 or 4 days before.

Advantages of dabigatran include that it is not influenced by diet and that the onset of therapeutic benefit is within 1 hour. Although some drugs affect dabigatran, drug interactions are more troublesome with warfarin.

A serious concern about dabigatran and the other new agents is that if a bleeding problem arises, the effects of these drugs are not reversible by administration of fresh frozen plasma. Dabigatran is reversible by dialysis; however, if a patient is also hypotensive, dialysis is not an option, and simply waiting for the drug to clear is the only choice.

Another drawback is that therapeutic levels cannot be monitored. If a patient taking warfarin requires cardioversion, the INR is carefully monitored for several weeks beforehand to reduce the risk of stroke. With dabigatran, there is no way to know if a patient is actually taking the drug as prescribed.

 

 

Clinical trials show that alternatives are marginally better than warfarin

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,⁸ dabigatran was associated with a significantly lower incidence of intracranial hemorrhage, combined strokes, and systemic embolization than warfarin. The incidence of major bleeds was slightly lower with dabigatran. Although dabigatran performed better, the differences were small and would not require patients to change from warfarin if they are already doing well.

Apixaban and rivaroxaban are other alternatives to warfarin, with different mechanisms of action and metabolism. Although rivaroxaban’s half-life is similar to that of apixaban and dabigatran, it is being marketed as allowing once-daily dosing instead of twice-daily.

Recent randomized controlled clinical trials of the new drugs include:

• The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial,⁹ which compared apixaban and aspirin
• The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban and warfarin¹⁰
• The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF),¹¹ comparing rivaroxaban and warfarin
• RE-LY,⁸ comparing dabigatran and warfarin.

In the ARISTOTLE,¹⁰ ROCKET AF,¹¹ and RE-LY trials,⁸ the time that the warfarin patients’ INRs were in the therapeutic range varied from 55% to 68%. This seems low and is a problem when trying to compare therapies, but is probably about as high as one can expect in the real world.

In AVERROES,⁹ the combined rate of stroke and embolism was higher with aspirin than with apixaban. In the other trials, the rates were slightly better with the new drugs than with warfarin, and the rates of major hemorrhage and hemorrhagic stroke were only slightly higher with warfarin than with the new drugs. Because the differences in benefits and risks are so small, the main advantage of the newer drugs will probably be for patients who have difficulty staying in the therapeutic INR range on warfarin.

RATE CONTROL VS RESTORATION OF SINUS RHYTHM

Evidence is insufficient to determine the risk of very-long-term asymptomatic atrial fibrillation in patients on appropriate anticoagulation. Rate control is an option for asymptomatic patients but provides no change in quality of life and no definitive reduction in the risk of stroke. The main argument for restoring normal sinus rhythm in patients with mild to moderate symptoms is that it improves exercise capacity. The need for anticoagulation persists when patients are converted to sinus rhythm because the risk of recurrent atrial fibrillation remains high.

For patients with symptomatic atrial fibrillation, rate control is sometimes achieved with beta-blockers or calcium channel blockers. Rate control may be augmented with the addition of digoxin, but when used alone digoxin generally does not control the rate of atrial fibrillation. However, in many cases of atrial fibrillation, symptoms are not rate-related, and cardioversion to normal sinus rhythm should be attempted. In such cases, the symptoms may be attributable to a loss of atrial transport function.

Patients with the following risk factors should be admitted to the hospital to start antiarrhythmic drugs:

• Borderline or a long QTc interval at baseline (> 450 msec)
• Treatment with dofetilide (Tikosyn) because of its effects on the QT interval
• Heart failure or poor left-ventricular function
• Sinus node dysfunction
• Significant atrioventricular conduction disease.

Selecting an antiarrhythmic drug

Any of the antiarrhythmic drugs listed in Table 2 can be used for a patient with lone atrial fibrillation (ie, not caused by underlying heart disease). The choice of drug should be determined by whether coronary artery disease or renal failure is present as well. Liver disease or chronic obstructive pulmonary disease also may affect this decision.

Benefits of dronedarone are mixed

In a randomized trial of dronedarone vs placebo in patients with atrial fibrillation, the rate of death and the rate of first hospitalization due to a cardiovascular event at 21 months were significantly lower with dronedarone.¹² No difference was found between the two groups in the rate of death from all causes, but fewer people died of cardiovascular causes in the dronedarone group. More patients taking dronedarone developed bradycardia, QT-interval prolongation, nausea, diarrhea, rash, or a higher serum creatinine level. Gastrointestinal side effects are often a problem with dronedarone: 20% to 30% of patients cannot tolerate the drug.

Dronedarone may cause a small rise in creatinine, and although this effect should be monitored, by itself it should not be interpreted as impairment of renal function. In a study in healthy people,¹³ dronedarone caused a 10% to 15% increase in serum creatinine, but the glomerular filtration rate was unchanged, as were renal plasma flow and anion secretion.

Another trial, in patients with severe heart failure, found that patients taking dronedarone had higher rates of hospitalization and overall mortality, raising serious concern about the safety of this drug in patients with advanced heart failure.¹⁴

Singh et al¹⁵ pooled the data from two multicenter, randomized trials that compared dronedarone with placebo for maintaining sinus rhythm in patients with atrial fibrillation or flutter. The mean time to the recurrence of atrial fibrillation was 116 days with dronedarone and 53 days with placebo. Other trials also showed longer times to recurrence and lower recurrence rates with dronedarone. Although the differences were statistically significant, they may not be clinically meaningful for patients.

Dronedarone is structurally similar to amiodarone (Cordarone), but the two drugs work differently. A meta-analysis of clinical trials¹⁶ found that amiodarone recipients had a lower rate of recurrence of atrial fibrillation than did those receiving dronedarone.

Two safety warnings for dronedarone

In January 2011, the US Food and Drug Administration (FDA) issued an alert about cases of rare but severe liver injury in patients treated with dronedarone, including two cases of acute liver failure leading to liver transplantation.¹⁷

The Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)¹⁸ compared dronedarone and placebo in patients with permanent atrial fibrillation. More people died or had serious cardiovascular adverse events in the dronedarone group. The study was stopped early after data monitoring showed that rates of death, stroke, and hospitalization for heart failure were two times higher in patients receiving dronedarone. This prompted the FDA to issue another safety alert in July 2011.

Interestingly, the PALLAS study did not set out to determine whether dronedarone controls atrial fibrillation, as the study patients had long-standing, persistent atrial fibrillation. The study was designed only to determine if the drug reduces the rate of adverse events; it clearly does not, and the study shows that dronedarone should not be used to control the heart rate in patients with persistent atrial fibrillation. Instead, its use is best restricted to patients with paroxysmal atrial fibrillation without significant cardiovascular disease.

ABLATION OF ATRIAL FIBRILLATION

Another way to try to restore sinus rhythm is to destroy or isolate the area that is generating the abnormal beats via a catheter-based procedure.

Radiofrequency ablation is generally tried in patients in whom one or two drugs have failed to control atrial fibrillation. Direct comparisons show that ablation is superior to drug therapy and is effective in about 75% of patients with paroxysmal atrial fibrillation vs 20% to 40% of patients on drug therapy. Ablation plus drug therapy is often more effective than either treatment alone.

Mechanisms of atrial fibrillation and ablation

In many cases, atrial fibrillation is stimulated by vagal and sympathetic inputs to the atrium that enter around the pulmonary veins and trigger electrical activations in the area, generating spiraling, reentering circuits. Focal atrial fibrillation also originates predominantly in the pulmonary veins. Ablation of tissue widely circumscribing the mouth of the pulmonary veins prevents the electrical signal from exiting into the atrium.

In about 11% to 37% of cases, atrial fibrillation originates elsewhere, eg, in the left atrium, in the superior vena cava, or in the vein of Marshall. Techniques have evolved to also ablate these regions.

Anticoagulation therapy is recommended before the procedure, and patients at low risk should continue it for a minimum of 2 months afterward. Patients with a higher CHADS₂ score should receive anticoagulation therapy for at least 1 year. The consensus statement by the Heart Rhythm Society¹⁹ recommends that patients remain on warfarin or one of the newer anticoagulants if their CHADS₂ score is 2 or higher. This is because patients have a significant risk of recurrence of atrial fibrillation after radiofrequency ablation, so if their stroke risk is high they should remain on anticoagulant therapy.

Ablation is usually effective, but it carries rare but serious risks

The efficacy of a single radiofrequency ablation procedure is in the range of 60% to 80% for paroxysmal atrial fibrillation and 40% to 60% for persistent atrial fibrillation. The Second International Ablation Registry²⁰ shows a success rate of about 75% in patients with paroxysmal atrial fibrillation and about 65% in patients with persistent and permanent atrial fibrillation. Registry data are often more favorable because reporting is optional, but these results are consistent with those from experienced medical centers. Rates of suppression of atrial fibrillation are higher in patients who also take antiarrhythmic drugs, making a “hybrid” approach useful when ablation alone fails.

According to a worldwide survey, the risk of serious complications is 4.5%. These include stroke (0.23%), tamponade (1.3%), and pulmonary vein stenosis (< 0.29%). The esophagus lies just behind the right atrium, and burning through and creating a fistula between them occurs in about 0.04% of cases and is almost uniformly fatal.²⁰

A second ablation procedure is sometimes indicated for the recurrence of atrial fibrillation, which is almost always caused by recovery of the pulmonary veins. Bhargava et al²¹ found that the success rate at Cleveland Clinic for a single procedure for paroxysmal atrial fibrillation was 77%, and that it was 92% after a repeat procedure. For persistent atrial fibrillation, success rates were 76% after the first procedure and 90% after the second. Even for long-standing persistent atrial fibrillation (ie, lasting more than 1 year), 80% success was achieved after two procedures. Patients who are less likely to have a successful ablation procedure are those with long-standing atrial fibrillation and coexisting heart disease, including severe valvular disease, although mitral regurgitation sometimes improves if sinus rhythm can be maintained.

The need for a second procedure

After ablation, patients should be closely monitored for a recurrence of atrial fibrillation. Continuous monitoring with implantable cardiac monitor loop recorders can detect unrecognized episodes of arrhythmia. Long-term follow-up is also required to track outcomes and quality of life.

According to the Heart Rhythm Society Task Force on Catheter and Surgical Ablation of Atrial Fibrillation,¹⁹ atrial fibrillation recurs after ablation in about 35% to 60% of patients in the first 3 months, with recurrence rates after 1 year ranging from 5% to 16%. The rate of success is determined by the skill of the surgeon, underlying heart disease, attention to follow-up, and how success is defined.

Freedom from recurrence early on is a good predictor that late recurrence is unlikely. Patients who only have a very early recurrence (within the first 4 weeks) are more likely to have long-term freedom from atrial fibrillation tha those who have recurrences after that time.²²

In a study of 831 patients, Hussein et al²³ found recurrence rates of 24% between months 3 to 13 following ablation and 9% after 12 months. At 55 months, 79% were free from atrial fibrillation without drugs, 11% were free of atrial fibrillation with medications, and 5% had refractory atrial fibrillation.

Recurrence—whether early or late—was more likely to occur in people with persistent vs paroxysmal atrial fibrillation. Other risk factors for late recurrence included older age and larger left atrial size (which is also a risk factor for recurrence on drug therapy). Although recurrent arrhythmia was most often atrial fibrillation, atrial flutter also occurred frequently (in 27% of patients with late recurrence). Three patients (4% of patients with late recurrence) developed atrial tachycardia.²³

In patients with early recurrence, 81% underwent repeat ablation, all of whom had recovery of one or more pulmonary veins. After the second ablation, 21% had recurrence, 65% of whom were controlled by medications.²³

Whether a patient should undergo subsequent ablation procedures depends on the severity of symptoms, the likelihood of success (based on an educated guess), and the patient’s willingness to undergo another procedure.

ATRIAL APPENDAGE OCCLUSION DEVICE UNDER INVESTIGATION

New devices are being investigated that occlude the left atrial appendage to try to prevent embolization.

The Watchman device, resembling an umbrella, is implanted via a percutaneous catheter in the left atrial appendage, closing it off to preclude a thrombus from forming in the appendage and embolizing to the body. Clinical trials showed that patients who received a device had a slightly lower risk of stroke than otherwise seen in clinical practice.²⁴ Safety and efficacy are still being determined.

The device cannot be deployed in a patient with an existing thrombus because of the danger of dislodging the thrombus, allowing it to embolize.

Although many developments have occurred in the last decade for managing atrial fibrillation, challenges remain. New and emerging alternatives to warfarin (Coumadin) for anticoagulation therapy prevent stroke marginally better and pose slightly less risk of hemorrhage, but they have important drawbacks.

The antiarrhythmic drug dronedarone (Multaq) has been found to offer only temporary benefit for persistent atrial fibrillation, and significant risks have emerged.

Radiofrequency ablation is gaining prominence, but repeat procedures are sometimes necessary.

An investigational device can be implanted via percutaneous catheter in the left atrial appendage to prevent embolization. It is too soon to know its eventual role in clinical practice.

This article reviews the results of clinical trials of these new treatments and discusses their role in clinical practice.

CHALLENGES OF ANTICOAGULATION

The main focus of managing atrial fibrillation is on alleviating symptoms, by either rate control or rhythm control. The other focus is on preventing stroke—a devastating outcome—with anticoagulation therapy.

For deciding whether to give warfarin to patients with atrial fibrillation, the six-point CHADS₂ score is a crude but effective way of assessing the risk of stroke based on the following risk factors: congestive heart failure, hypertension, age 75 years or older, and diabetes (1 point each); or a history of stroke or transient ischemic attack (2 points).¹ Warfarin is given if patients have a score of at least 2 points.

Warfarin has a narrow therapeutic window, with a higher risk of ischemic stroke if the international normalized ratio (INR) is less than 2.0,² and a higher risk of intracranial hemorrhage if the INR is more than 3.0.³ Keeping the INR in the therapeutic range is difficult because of variations in diet, concurrent medications, and other factors.

The percent of time that the INR is within the therapeutic range predicts the risk of adverse events. Connolly et al⁴ showed that the cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death was no better with warfarin than with clopidogrel (Plavix) plus aspirin if the INR was in the therapeutic range less than 65% of the time, but the risk was significantly less if the INR was in the therapeutic range more than 65% of the time.

Also, comparing warfarin with the combination of aspirin and clopidogrel, Verheugt⁵ found that the rates of stroke of any kind, of disabling and fatal stroke, and of stroke per major bleed were lower in patients taking warfarin. Although many physicians prefer aspirin plus clopidogrel because of concerns about bleeding with warfarin, the rates of major bleeding were about the same in the two groups.

In a trial in patients for whom warfarin was “unsuitable,”⁶ the combination of aspirin plus clopidogrel was associated with a lower rate of stroke than aspirin alone (2.4% per year vs 3.3% per year, relative risk 0.762) but a higher rate of major bleeding events (2.0% per year vs 1.3% per year, relative risk 1.57).

NEW ALTERNATIVES TO WARFARIN

Because of the problems with warfarin, alternatives have been sought for many years. Several new oral anticoagulants are available or are being developed,⁷ including the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis) and the direct factor II (thrombin) inhibitor dabigatran (Pradaxa) (Table 1).

Dabigatran’s advantages and drawbacks

Dabigatran has been on the market for more than a year and has gained rapid acceptance. The dosage is 150 mg twice a day, or 75 mg twice a day if renal function is impaired. Cleared by the kidneys, it has a half-life of 12 to 17 hours; 75% is cleared within 24 hours. For a patient who needs surgery that poses a low risk of bleeding, the general recommendation is to stop dabigatran the night before the surgical procedure. For operations with a greater risk of bleeding, many surgeons recommend stopping the drug 3 or 4 days before.

Advantages of dabigatran include that it is not influenced by diet and that the onset of therapeutic benefit is within 1 hour. Although some drugs affect dabigatran, drug interactions are more troublesome with warfarin.

A serious concern about dabigatran and the other new agents is that if a bleeding problem arises, the effects of these drugs are not reversible by administration of fresh frozen plasma. Dabigatran is reversible by dialysis; however, if a patient is also hypotensive, dialysis is not an option, and simply waiting for the drug to clear is the only choice.

Another drawback is that therapeutic levels cannot be monitored. If a patient taking warfarin requires cardioversion, the INR is carefully monitored for several weeks beforehand to reduce the risk of stroke. With dabigatran, there is no way to know if a patient is actually taking the drug as prescribed.

 

 

Clinical trials show that alternatives are marginally better than warfarin

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,⁸ dabigatran was associated with a significantly lower incidence of intracranial hemorrhage, combined strokes, and systemic embolization than warfarin. The incidence of major bleeds was slightly lower with dabigatran. Although dabigatran performed better, the differences were small and would not require patients to change from warfarin if they are already doing well.

Apixaban and rivaroxaban are other alternatives to warfarin, with different mechanisms of action and metabolism. Although rivaroxaban’s half-life is similar to that of apixaban and dabigatran, it is being marketed as allowing once-daily dosing instead of twice-daily.

Recent randomized controlled clinical trials of the new drugs include:

• The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial,⁹ which compared apixaban and aspirin
• The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban and warfarin¹⁰
• The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF),¹¹ comparing rivaroxaban and warfarin
• RE-LY,⁸ comparing dabigatran and warfarin.

In the ARISTOTLE,¹⁰ ROCKET AF,¹¹ and RE-LY trials,⁸ the time that the warfarin patients’ INRs were in the therapeutic range varied from 55% to 68%. This seems low and is a problem when trying to compare therapies, but is probably about as high as one can expect in the real world.

In AVERROES,⁹ the combined rate of stroke and embolism was higher with aspirin than with apixaban. In the other trials, the rates were slightly better with the new drugs than with warfarin, and the rates of major hemorrhage and hemorrhagic stroke were only slightly higher with warfarin than with the new drugs. Because the differences in benefits and risks are so small, the main advantage of the newer drugs will probably be for patients who have difficulty staying in the therapeutic INR range on warfarin.

RATE CONTROL VS RESTORATION OF SINUS RHYTHM

Evidence is insufficient to determine the risk of very-long-term asymptomatic atrial fibrillation in patients on appropriate anticoagulation. Rate control is an option for asymptomatic patients but provides no change in quality of life and no definitive reduction in the risk of stroke. The main argument for restoring normal sinus rhythm in patients with mild to moderate symptoms is that it improves exercise capacity. The need for anticoagulation persists when patients are converted to sinus rhythm because the risk of recurrent atrial fibrillation remains high.

For patients with symptomatic atrial fibrillation, rate control is sometimes achieved with beta-blockers or calcium channel blockers. Rate control may be augmented with the addition of digoxin, but when used alone digoxin generally does not control the rate of atrial fibrillation. However, in many cases of atrial fibrillation, symptoms are not rate-related, and cardioversion to normal sinus rhythm should be attempted. In such cases, the symptoms may be attributable to a loss of atrial transport function.

Patients with the following risk factors should be admitted to the hospital to start antiarrhythmic drugs:

• Borderline or a long QTc interval at baseline (> 450 msec)
• Treatment with dofetilide (Tikosyn) because of its effects on the QT interval
• Heart failure or poor left-ventricular function
• Sinus node dysfunction
• Significant atrioventricular conduction disease.

Selecting an antiarrhythmic drug

Any of the antiarrhythmic drugs listed in Table 2 can be used for a patient with lone atrial fibrillation (ie, not caused by underlying heart disease). The choice of drug should be determined by whether coronary artery disease or renal failure is present as well. Liver disease or chronic obstructive pulmonary disease also may affect this decision.

Benefits of dronedarone are mixed

In a randomized trial of dronedarone vs placebo in patients with atrial fibrillation, the rate of death and the rate of first hospitalization due to a cardiovascular event at 21 months were significantly lower with dronedarone.¹² No difference was found between the two groups in the rate of death from all causes, but fewer people died of cardiovascular causes in the dronedarone group. More patients taking dronedarone developed bradycardia, QT-interval prolongation, nausea, diarrhea, rash, or a higher serum creatinine level. Gastrointestinal side effects are often a problem with dronedarone: 20% to 30% of patients cannot tolerate the drug.

Dronedarone may cause a small rise in creatinine, and although this effect should be monitored, by itself it should not be interpreted as impairment of renal function. In a study in healthy people,¹³ dronedarone caused a 10% to 15% increase in serum creatinine, but the glomerular filtration rate was unchanged, as were renal plasma flow and anion secretion.

Another trial, in patients with severe heart failure, found that patients taking dronedarone had higher rates of hospitalization and overall mortality, raising serious concern about the safety of this drug in patients with advanced heart failure.¹⁴

Singh et al¹⁵ pooled the data from two multicenter, randomized trials that compared dronedarone with placebo for maintaining sinus rhythm in patients with atrial fibrillation or flutter. The mean time to the recurrence of atrial fibrillation was 116 days with dronedarone and 53 days with placebo. Other trials also showed longer times to recurrence and lower recurrence rates with dronedarone. Although the differences were statistically significant, they may not be clinically meaningful for patients.

Dronedarone is structurally similar to amiodarone (Cordarone), but the two drugs work differently. A meta-analysis of clinical trials¹⁶ found that amiodarone recipients had a lower rate of recurrence of atrial fibrillation than did those receiving dronedarone.

Two safety warnings for dronedarone

In January 2011, the US Food and Drug Administration (FDA) issued an alert about cases of rare but severe liver injury in patients treated with dronedarone, including two cases of acute liver failure leading to liver transplantation.¹⁷

The Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)¹⁸ compared dronedarone and placebo in patients with permanent atrial fibrillation. More people died or had serious cardiovascular adverse events in the dronedarone group. The study was stopped early after data monitoring showed that rates of death, stroke, and hospitalization for heart failure were two times higher in patients receiving dronedarone. This prompted the FDA to issue another safety alert in July 2011.

Interestingly, the PALLAS study did not set out to determine whether dronedarone controls atrial fibrillation, as the study patients had long-standing, persistent atrial fibrillation. The study was designed only to determine if the drug reduces the rate of adverse events; it clearly does not, and the study shows that dronedarone should not be used to control the heart rate in patients with persistent atrial fibrillation. Instead, its use is best restricted to patients with paroxysmal atrial fibrillation without significant cardiovascular disease.

ABLATION OF ATRIAL FIBRILLATION

Another way to try to restore sinus rhythm is to destroy or isolate the area that is generating the abnormal beats via a catheter-based procedure.

Radiofrequency ablation is generally tried in patients in whom one or two drugs have failed to control atrial fibrillation. Direct comparisons show that ablation is superior to drug therapy and is effective in about 75% of patients with paroxysmal atrial fibrillation vs 20% to 40% of patients on drug therapy. Ablation plus drug therapy is often more effective than either treatment alone.

Mechanisms of atrial fibrillation and ablation

In many cases, atrial fibrillation is stimulated by vagal and sympathetic inputs to the atrium that enter around the pulmonary veins and trigger electrical activations in the area, generating spiraling, reentering circuits. Focal atrial fibrillation also originates predominantly in the pulmonary veins. Ablation of tissue widely circumscribing the mouth of the pulmonary veins prevents the electrical signal from exiting into the atrium.

In about 11% to 37% of cases, atrial fibrillation originates elsewhere, eg, in the left atrium, in the superior vena cava, or in the vein of Marshall. Techniques have evolved to also ablate these regions.

Anticoagulation therapy is recommended before the procedure, and patients at low risk should continue it for a minimum of 2 months afterward. Patients with a higher CHADS₂ score should receive anticoagulation therapy for at least 1 year. The consensus statement by the Heart Rhythm Society¹⁹ recommends that patients remain on warfarin or one of the newer anticoagulants if their CHADS₂ score is 2 or higher. This is because patients have a significant risk of recurrence of atrial fibrillation after radiofrequency ablation, so if their stroke risk is high they should remain on anticoagulant therapy.

Ablation is usually effective, but it carries rare but serious risks

The efficacy of a single radiofrequency ablation procedure is in the range of 60% to 80% for paroxysmal atrial fibrillation and 40% to 60% for persistent atrial fibrillation. The Second International Ablation Registry²⁰ shows a success rate of about 75% in patients with paroxysmal atrial fibrillation and about 65% in patients with persistent and permanent atrial fibrillation. Registry data are often more favorable because reporting is optional, but these results are consistent with those from experienced medical centers. Rates of suppression of atrial fibrillation are higher in patients who also take antiarrhythmic drugs, making a “hybrid” approach useful when ablation alone fails.

According to a worldwide survey, the risk of serious complications is 4.5%. These include stroke (0.23%), tamponade (1.3%), and pulmonary vein stenosis (< 0.29%). The esophagus lies just behind the right atrium, and burning through and creating a fistula between them occurs in about 0.04% of cases and is almost uniformly fatal.²⁰

A second ablation procedure is sometimes indicated for the recurrence of atrial fibrillation, which is almost always caused by recovery of the pulmonary veins. Bhargava et al²¹ found that the success rate at Cleveland Clinic for a single procedure for paroxysmal atrial fibrillation was 77%, and that it was 92% after a repeat procedure. For persistent atrial fibrillation, success rates were 76% after the first procedure and 90% after the second. Even for long-standing persistent atrial fibrillation (ie, lasting more than 1 year), 80% success was achieved after two procedures. Patients who are less likely to have a successful ablation procedure are those with long-standing atrial fibrillation and coexisting heart disease, including severe valvular disease, although mitral regurgitation sometimes improves if sinus rhythm can be maintained.

The need for a second procedure

After ablation, patients should be closely monitored for a recurrence of atrial fibrillation. Continuous monitoring with implantable cardiac monitor loop recorders can detect unrecognized episodes of arrhythmia. Long-term follow-up is also required to track outcomes and quality of life.

According to the Heart Rhythm Society Task Force on Catheter and Surgical Ablation of Atrial Fibrillation,¹⁹ atrial fibrillation recurs after ablation in about 35% to 60% of patients in the first 3 months, with recurrence rates after 1 year ranging from 5% to 16%. The rate of success is determined by the skill of the surgeon, underlying heart disease, attention to follow-up, and how success is defined.

Freedom from recurrence early on is a good predictor that late recurrence is unlikely. Patients who only have a very early recurrence (within the first 4 weeks) are more likely to have long-term freedom from atrial fibrillation tha those who have recurrences after that time.²²

In a study of 831 patients, Hussein et al²³ found recurrence rates of 24% between months 3 to 13 following ablation and 9% after 12 months. At 55 months, 79% were free from atrial fibrillation without drugs, 11% were free of atrial fibrillation with medications, and 5% had refractory atrial fibrillation.

Recurrence—whether early or late—was more likely to occur in people with persistent vs paroxysmal atrial fibrillation. Other risk factors for late recurrence included older age and larger left atrial size (which is also a risk factor for recurrence on drug therapy). Although recurrent arrhythmia was most often atrial fibrillation, atrial flutter also occurred frequently (in 27% of patients with late recurrence). Three patients (4% of patients with late recurrence) developed atrial tachycardia.²³

In patients with early recurrence, 81% underwent repeat ablation, all of whom had recovery of one or more pulmonary veins. After the second ablation, 21% had recurrence, 65% of whom were controlled by medications.²³

Whether a patient should undergo subsequent ablation procedures depends on the severity of symptoms, the likelihood of success (based on an educated guess), and the patient’s willingness to undergo another procedure.

ATRIAL APPENDAGE OCCLUSION DEVICE UNDER INVESTIGATION

New devices are being investigated that occlude the left atrial appendage to try to prevent embolization.

The Watchman device, resembling an umbrella, is implanted via a percutaneous catheter in the left atrial appendage, closing it off to preclude a thrombus from forming in the appendage and embolizing to the body. Clinical trials showed that patients who received a device had a slightly lower risk of stroke than otherwise seen in clinical practice.²⁴ Safety and efficacy are still being determined.

The device cannot be deployed in a patient with an existing thrombus because of the danger of dislodging the thrombus, allowing it to embolize.

Although many developments have occurred in the last decade for managing atrial fibrillation, challenges remain. New and emerging alternatives to warfarin (Coumadin) for anticoagulation therapy prevent stroke marginally better and pose slightly less risk of hemorrhage, but they have important drawbacks.

The antiarrhythmic drug dronedarone (Multaq) has been found to offer only temporary benefit for persistent atrial fibrillation, and significant risks have emerged.

Radiofrequency ablation is gaining prominence, but repeat procedures are sometimes necessary.

An investigational device can be implanted via percutaneous catheter in the left atrial appendage to prevent embolization. It is too soon to know its eventual role in clinical practice.

This article reviews the results of clinical trials of these new treatments and discusses their role in clinical practice.

CHALLENGES OF ANTICOAGULATION

The main focus of managing atrial fibrillation is on alleviating symptoms, by either rate control or rhythm control. The other focus is on preventing stroke—a devastating outcome—with anticoagulation therapy.

For deciding whether to give warfarin to patients with atrial fibrillation, the six-point CHADS₂ score is a crude but effective way of assessing the risk of stroke based on the following risk factors: congestive heart failure, hypertension, age 75 years or older, and diabetes (1 point each); or a history of stroke or transient ischemic attack (2 points).¹ Warfarin is given if patients have a score of at least 2 points.

Warfarin has a narrow therapeutic window, with a higher risk of ischemic stroke if the international normalized ratio (INR) is less than 2.0,² and a higher risk of intracranial hemorrhage if the INR is more than 3.0.³ Keeping the INR in the therapeutic range is difficult because of variations in diet, concurrent medications, and other factors.

The percent of time that the INR is within the therapeutic range predicts the risk of adverse events. Connolly et al⁴ showed that the cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death was no better with warfarin than with clopidogrel (Plavix) plus aspirin if the INR was in the therapeutic range less than 65% of the time, but the risk was significantly less if the INR was in the therapeutic range more than 65% of the time.

Also, comparing warfarin with the combination of aspirin and clopidogrel, Verheugt⁵ found that the rates of stroke of any kind, of disabling and fatal stroke, and of stroke per major bleed were lower in patients taking warfarin. Although many physicians prefer aspirin plus clopidogrel because of concerns about bleeding with warfarin, the rates of major bleeding were about the same in the two groups.

In a trial in patients for whom warfarin was “unsuitable,”⁶ the combination of aspirin plus clopidogrel was associated with a lower rate of stroke than aspirin alone (2.4% per year vs 3.3% per year, relative risk 0.762) but a higher rate of major bleeding events (2.0% per year vs 1.3% per year, relative risk 1.57).

NEW ALTERNATIVES TO WARFARIN

Because of the problems with warfarin, alternatives have been sought for many years. Several new oral anticoagulants are available or are being developed,⁷ including the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis) and the direct factor II (thrombin) inhibitor dabigatran (Pradaxa) (Table 1).

Dabigatran’s advantages and drawbacks

Dabigatran has been on the market for more than a year and has gained rapid acceptance. The dosage is 150 mg twice a day, or 75 mg twice a day if renal function is impaired. Cleared by the kidneys, it has a half-life of 12 to 17 hours; 75% is cleared within 24 hours. For a patient who needs surgery that poses a low risk of bleeding, the general recommendation is to stop dabigatran the night before the surgical procedure. For operations with a greater risk of bleeding, many surgeons recommend stopping the drug 3 or 4 days before.

Advantages of dabigatran include that it is not influenced by diet and that the onset of therapeutic benefit is within 1 hour. Although some drugs affect dabigatran, drug interactions are more troublesome with warfarin.

A serious concern about dabigatran and the other new agents is that if a bleeding problem arises, the effects of these drugs are not reversible by administration of fresh frozen plasma. Dabigatran is reversible by dialysis; however, if a patient is also hypotensive, dialysis is not an option, and simply waiting for the drug to clear is the only choice.

Another drawback is that therapeutic levels cannot be monitored. If a patient taking warfarin requires cardioversion, the INR is carefully monitored for several weeks beforehand to reduce the risk of stroke. With dabigatran, there is no way to know if a patient is actually taking the drug as prescribed.

 

 

Clinical trials show that alternatives are marginally better than warfarin

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,⁸ dabigatran was associated with a significantly lower incidence of intracranial hemorrhage, combined strokes, and systemic embolization than warfarin. The incidence of major bleeds was slightly lower with dabigatran. Although dabigatran performed better, the differences were small and would not require patients to change from warfarin if they are already doing well.

Apixaban and rivaroxaban are other alternatives to warfarin, with different mechanisms of action and metabolism. Although rivaroxaban’s half-life is similar to that of apixaban and dabigatran, it is being marketed as allowing once-daily dosing instead of twice-daily.

Recent randomized controlled clinical trials of the new drugs include:

• The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial,⁹ which compared apixaban and aspirin
• The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban and warfarin¹⁰
• The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF),¹¹ comparing rivaroxaban and warfarin
• RE-LY,⁸ comparing dabigatran and warfarin.

In the ARISTOTLE,¹⁰ ROCKET AF,¹¹ and RE-LY trials,⁸ the time that the warfarin patients’ INRs were in the therapeutic range varied from 55% to 68%. This seems low and is a problem when trying to compare therapies, but is probably about as high as one can expect in the real world.

In AVERROES,⁹ the combined rate of stroke and embolism was higher with aspirin than with apixaban. In the other trials, the rates were slightly better with the new drugs than with warfarin, and the rates of major hemorrhage and hemorrhagic stroke were only slightly higher with warfarin than with the new drugs. Because the differences in benefits and risks are so small, the main advantage of the newer drugs will probably be for patients who have difficulty staying in the therapeutic INR range on warfarin.

RATE CONTROL VS RESTORATION OF SINUS RHYTHM

Evidence is insufficient to determine the risk of very-long-term asymptomatic atrial fibrillation in patients on appropriate anticoagulation. Rate control is an option for asymptomatic patients but provides no change in quality of life and no definitive reduction in the risk of stroke. The main argument for restoring normal sinus rhythm in patients with mild to moderate symptoms is that it improves exercise capacity. The need for anticoagulation persists when patients are converted to sinus rhythm because the risk of recurrent atrial fibrillation remains high.

For patients with symptomatic atrial fibrillation, rate control is sometimes achieved with beta-blockers or calcium channel blockers. Rate control may be augmented with the addition of digoxin, but when used alone digoxin generally does not control the rate of atrial fibrillation. However, in many cases of atrial fibrillation, symptoms are not rate-related, and cardioversion to normal sinus rhythm should be attempted. In such cases, the symptoms may be attributable to a loss of atrial transport function.

Patients with the following risk factors should be admitted to the hospital to start antiarrhythmic drugs:

• Borderline or a long QTc interval at baseline (> 450 msec)
• Treatment with dofetilide (Tikosyn) because of its effects on the QT interval
• Heart failure or poor left-ventricular function
• Sinus node dysfunction
• Significant atrioventricular conduction disease.

Selecting an antiarrhythmic drug

Any of the antiarrhythmic drugs listed in Table 2 can be used for a patient with lone atrial fibrillation (ie, not caused by underlying heart disease). The choice of drug should be determined by whether coronary artery disease or renal failure is present as well. Liver disease or chronic obstructive pulmonary disease also may affect this decision.

Benefits of dronedarone are mixed

In a randomized trial of dronedarone vs placebo in patients with atrial fibrillation, the rate of death and the rate of first hospitalization due to a cardiovascular event at 21 months were significantly lower with dronedarone.¹² No difference was found between the two groups in the rate of death from all causes, but fewer people died of cardiovascular causes in the dronedarone group. More patients taking dronedarone developed bradycardia, QT-interval prolongation, nausea, diarrhea, rash, or a higher serum creatinine level. Gastrointestinal side effects are often a problem with dronedarone: 20% to 30% of patients cannot tolerate the drug.

Dronedarone may cause a small rise in creatinine, and although this effect should be monitored, by itself it should not be interpreted as impairment of renal function. In a study in healthy people,¹³ dronedarone caused a 10% to 15% increase in serum creatinine, but the glomerular filtration rate was unchanged, as were renal plasma flow and anion secretion.

Another trial, in patients with severe heart failure, found that patients taking dronedarone had higher rates of hospitalization and overall mortality, raising serious concern about the safety of this drug in patients with advanced heart failure.¹⁴

Singh et al¹⁵ pooled the data from two multicenter, randomized trials that compared dronedarone with placebo for maintaining sinus rhythm in patients with atrial fibrillation or flutter. The mean time to the recurrence of atrial fibrillation was 116 days with dronedarone and 53 days with placebo. Other trials also showed longer times to recurrence and lower recurrence rates with dronedarone. Although the differences were statistically significant, they may not be clinically meaningful for patients.

Dronedarone is structurally similar to amiodarone (Cordarone), but the two drugs work differently. A meta-analysis of clinical trials¹⁶ found that amiodarone recipients had a lower rate of recurrence of atrial fibrillation than did those receiving dronedarone.

Two safety warnings for dronedarone

In January 2011, the US Food and Drug Administration (FDA) issued an alert about cases of rare but severe liver injury in patients treated with dronedarone, including two cases of acute liver failure leading to liver transplantation.¹⁷

The Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)¹⁸ compared dronedarone and placebo in patients with permanent atrial fibrillation. More people died or had serious cardiovascular adverse events in the dronedarone group. The study was stopped early after data monitoring showed that rates of death, stroke, and hospitalization for heart failure were two times higher in patients receiving dronedarone. This prompted the FDA to issue another safety alert in July 2011.

Interestingly, the PALLAS study did not set out to determine whether dronedarone controls atrial fibrillation, as the study patients had long-standing, persistent atrial fibrillation. The study was designed only to determine if the drug reduces the rate of adverse events; it clearly does not, and the study shows that dronedarone should not be used to control the heart rate in patients with persistent atrial fibrillation. Instead, its use is best restricted to patients with paroxysmal atrial fibrillation without significant cardiovascular disease.

ABLATION OF ATRIAL FIBRILLATION

Another way to try to restore sinus rhythm is to destroy or isolate the area that is generating the abnormal beats via a catheter-based procedure.

Radiofrequency ablation is generally tried in patients in whom one or two drugs have failed to control atrial fibrillation. Direct comparisons show that ablation is superior to drug therapy and is effective in about 75% of patients with paroxysmal atrial fibrillation vs 20% to 40% of patients on drug therapy. Ablation plus drug therapy is often more effective than either treatment alone.

Mechanisms of atrial fibrillation and ablation

In many cases, atrial fibrillation is stimulated by vagal and sympathetic inputs to the atrium that enter around the pulmonary veins and trigger electrical activations in the area, generating spiraling, reentering circuits. Focal atrial fibrillation also originates predominantly in the pulmonary veins. Ablation of tissue widely circumscribing the mouth of the pulmonary veins prevents the electrical signal from exiting into the atrium.

In about 11% to 37% of cases, atrial fibrillation originates elsewhere, eg, in the left atrium, in the superior vena cava, or in the vein of Marshall. Techniques have evolved to also ablate these regions.

Anticoagulation therapy is recommended before the procedure, and patients at low risk should continue it for a minimum of 2 months afterward. Patients with a higher CHADS₂ score should receive anticoagulation therapy for at least 1 year. The consensus statement by the Heart Rhythm Society¹⁹ recommends that patients remain on warfarin or one of the newer anticoagulants if their CHADS₂ score is 2 or higher. This is because patients have a significant risk of recurrence of atrial fibrillation after radiofrequency ablation, so if their stroke risk is high they should remain on anticoagulant therapy.

Ablation is usually effective, but it carries rare but serious risks

The efficacy of a single radiofrequency ablation procedure is in the range of 60% to 80% for paroxysmal atrial fibrillation and 40% to 60% for persistent atrial fibrillation. The Second International Ablation Registry²⁰ shows a success rate of about 75% in patients with paroxysmal atrial fibrillation and about 65% in patients with persistent and permanent atrial fibrillation. Registry data are often more favorable because reporting is optional, but these results are consistent with those from experienced medical centers. Rates of suppression of atrial fibrillation are higher in patients who also take antiarrhythmic drugs, making a “hybrid” approach useful when ablation alone fails.

According to a worldwide survey, the risk of serious complications is 4.5%. These include stroke (0.23%), tamponade (1.3%), and pulmonary vein stenosis (< 0.29%). The esophagus lies just behind the right atrium, and burning through and creating a fistula between them occurs in about 0.04% of cases and is almost uniformly fatal.²⁰

A second ablation procedure is sometimes indicated for the recurrence of atrial fibrillation, which is almost always caused by recovery of the pulmonary veins. Bhargava et al²¹ found that the success rate at Cleveland Clinic for a single procedure for paroxysmal atrial fibrillation was 77%, and that it was 92% after a repeat procedure. For persistent atrial fibrillation, success rates were 76% after the first procedure and 90% after the second. Even for long-standing persistent atrial fibrillation (ie, lasting more than 1 year), 80% success was achieved after two procedures. Patients who are less likely to have a successful ablation procedure are those with long-standing atrial fibrillation and coexisting heart disease, including severe valvular disease, although mitral regurgitation sometimes improves if sinus rhythm can be maintained.

The need for a second procedure

After ablation, patients should be closely monitored for a recurrence of atrial fibrillation. Continuous monitoring with implantable cardiac monitor loop recorders can detect unrecognized episodes of arrhythmia. Long-term follow-up is also required to track outcomes and quality of life.

According to the Heart Rhythm Society Task Force on Catheter and Surgical Ablation of Atrial Fibrillation,¹⁹ atrial fibrillation recurs after ablation in about 35% to 60% of patients in the first 3 months, with recurrence rates after 1 year ranging from 5% to 16%. The rate of success is determined by the skill of the surgeon, underlying heart disease, attention to follow-up, and how success is defined.

Freedom from recurrence early on is a good predictor that late recurrence is unlikely. Patients who only have a very early recurrence (within the first 4 weeks) are more likely to have long-term freedom from atrial fibrillation tha those who have recurrences after that time.²²

In a study of 831 patients, Hussein et al²³ found recurrence rates of 24% between months 3 to 13 following ablation and 9% after 12 months. At 55 months, 79% were free from atrial fibrillation without drugs, 11% were free of atrial fibrillation with medications, and 5% had refractory atrial fibrillation.

Recurrence—whether early or late—was more likely to occur in people with persistent vs paroxysmal atrial fibrillation. Other risk factors for late recurrence included older age and larger left atrial size (which is also a risk factor for recurrence on drug therapy). Although recurrent arrhythmia was most often atrial fibrillation, atrial flutter also occurred frequently (in 27% of patients with late recurrence). Three patients (4% of patients with late recurrence) developed atrial tachycardia.²³

In patients with early recurrence, 81% underwent repeat ablation, all of whom had recovery of one or more pulmonary veins. After the second ablation, 21% had recurrence, 65% of whom were controlled by medications.²³

Whether a patient should undergo subsequent ablation procedures depends on the severity of symptoms, the likelihood of success (based on an educated guess), and the patient’s willingness to undergo another procedure.

ATRIAL APPENDAGE OCCLUSION DEVICE UNDER INVESTIGATION

New devices are being investigated that occlude the left atrial appendage to try to prevent embolization.

The Watchman device, resembling an umbrella, is implanted via a percutaneous catheter in the left atrial appendage, closing it off to preclude a thrombus from forming in the appendage and embolizing to the body. Clinical trials showed that patients who received a device had a slightly lower risk of stroke than otherwise seen in clinical practice.²⁴ Safety and efficacy are still being determined.

The device cannot be deployed in a patient with an existing thrombus because of the danger of dislodging the thrombus, allowing it to embolize.