PATIENT 1: A PERSONAL AND FAMILY HISTORY OF BREAST CANCER

A 55-year-old Ashkenazi Jewish woman presents to your clinic for her annual physical. She reports that she had been diagnosed with breast cancer 10 years ago and that it had been treated with lumpectomy. You recall that Ashkenazi Jewish ethnicity and a diagnosis of breast cancer before age 50 are red flags for a hereditary cancer syndrome, and you ask about her family history of cancer. She reports that her mother was diagnosed with breast cancer in her 60s. The patient wants to know if her daughter should start breast cancer screening.

What do you do next?

Facing increasing demands and a plethora of information to be discussed in a short time, primary care physicians may find it challenging to inform patients about the possibility of a hereditary cancer syndrome, to assess the risk, to organize genetic testing if appropriate, and to counsel patients about their management options. As our knowledge of the genetics of breast cancer continues to expand, this information will become more detailed and complex.

Nevertheless, primary care physicians can help identify patients who may have a syndrome of inherited cancer predisposition or whose family history raises concern for familial breast cancer. Patients in both groups may be candidates for genetic risk assessment, for special management options for women at high risk, or for both.

This article provides an overview of inherited conditions associated with higher breast cancer risk, and guidelines to help physicians recognize patients in their own practice for whom a genetics referral may be appropriate.

BREAST CANCER IS COMPLEX AND HETEROGENEOUS

Breast cancer is the second-leading cause of cancer deaths in women. According to the American Cancer Society, an estimated 234,340 new cases of breast cancer are expected to be diagnosed in women in the United States in 2013, and about 2,240 new cases are expected in men; 39,620 women and 410 men are expected to die of it.¹

Breast cancer is a complex and heterogeneous disease, influenced by many factors, of which female sex and increasing age are the most significant. Modifiable risk factors include obesity, use of combined hormone replacement therapy, and physical inactivity. Other risk factors include dense breast tissue, having had a breast biopsy in the past, the finding of atypical hyperplasia on biopsy, a history of high-dose chest radiation, and reproductive factors that include early menarche, late menopause, nulliparity, and birth of first child after age 30.

After female sex and age, family history of the disease is the most significant risk factor for breast cancer.² If a woman has a first-degree relative (mother, sister, daughter) with breast cancer, her risk is 1.8 times higher, and if she has a second-degree relative (aunt, grandmother) with breast cancer, her risk is 1.3 times higher.³

Hereditary cancer predisposition syndromes account for 5% to 10% of cases of breast cancer. These are caused by a germline mutation in a highly penetrant gene that considerably increases the risk of malignancies of the breast and other tissues. These conditions are inherited in an autosomal-dominant fashion, with age of onset tending to be significantly—several decades—younger than the median age of onset in the general population. The most common of these is hereditary breast and ovarian cancer syndrome, caused by germline mutations of the BRCA1 or BRCA2 gene.

Familial breast cancers account for 15% to 20% of cases. Here, the women who develop breast cancer have multiple family members who are also affected but without an obvious inheritance pattern, and the age of onset is similar to that in the general population.⁴

Sporadic forms of breast cancer account for the remaining 70% to 80% of cases. Their development can be attributed mainly to nonhereditary causes, such as the environmental and personal risk factors listed above. In general, sporadic forms of breast cancer occur at older ages, with no particular inheritance pattern and with frequency of occurrence in a family comparable to that in the general population.

IS A GENETICS CONSULTATION NEEDED?

In the case described above, the primary care physician gathered basic information about the patient’s cancer-related personal and family history. Asking a few key questions (Table  1)^5,6 can help physicians understand two important things: whether a more detailed assessment of genetic risk and counseling by a genetics professional are indicated, and whether the patient would benefit from additional cancer screening and prevention.

Table 2 summarizes the National Comprehensive Cancer Network’s recommendations for cancer genetics consultation.⁵ These red flags for a hereditary breast cancer syndrome can help primary care providers identify patients for whom a cancer genetics referral is appropriate. Of note: the maternal and paternal family histories are equally important.

Because our patient was diagnosed with breast cancer before age 50 and is of Ashkenazi Jewish ethnicity, she meets these criteria and warrants a cancer genetics consultation.

The tenets of genetic counseling, described previously in this series,⁷ are relevant to hereditary cancer syndromes. Cancer risk assessment and genetic counseling constitute the process of identifying and counseling individuals at risk of familial or hereditary cancer.⁸

As in other genetic counseling scenarios, a detailed pedigree (family tree) is taken, and this information, along with the patient’s personal medical history, allows a genetics specialist to determine if the presentation is most suggestive of sporadic, familial, or hereditary cancer.

A common misconception among patients is that there is a single genetic test for hereditary breast cancer, when in fact many highly penetrant predisposition genes have been linked to heightened risk (see below). The syndromes summarized in Table 3^5,9–18 are part of the differential diagnosis for every patient presenting with a personal or family history of breast cancer, and the detailed information from the personal and family history, ascertained during the assessment, ensures the right syndrome is explored within a family.

Cancer-focused genetic counseling may also help a patient or family process the psychological and emotional responses that can occur when cancer risk is discussed: eg, fear of cancer and death; guilt a parent may feel for passing on a genetic predisposition; and survivor guilt experienced by family members who test negative.

Genetic counselors are trained to recognize patients who may benefit from additional counseling. Not all patients pursuing cancer-focused genetic testing need a thorough evaluation by a psychologist, unlike those with adult-onset neurodegenerative conditions such as Huntington disease. Rather, the genetic counselor discusses the psychological implications of cancer-focused genetic testing and can refer the patient to a psychologist, therapist, social worker, or others if he or she feels the patient may benefit.⁸

Some patients come to a genetic counseling session with concerns about whether their insurance will pay for testing, and about whether they will face discrimination because of the testing results. In most situations, genetic testing is deemed medically necessary and is covered by the patient’s insurance. When testing is necessary, genetic counselors are skilled at preauthorizing it and writing letters of medical necessity. They are also familiar with laws and regulations that protect patients, such as the Genetic Information Nondiscrimination Act, which protects patients from insurance and employment discrimination.

Because a cancer-focused genetic counseling session typically lasts 1 hour, the counselor has enough time to address these and any other concerns that might prevent a patient who is otherwise interested in genetic testing from pursuing it.

HOW CAN GENETIC TESTING HELP?

Genetic testing for hereditary cancer syndromes can have personal benefit for the patient and at-risk family members.

Note that the syndromes in Table 3 all increase the risk of more than one type of cancer. Patients with these syndromes frequently receive care from multiple subspecialists to mitigate those risks. Guidelines exist for each of these syndromes and, if followed, may prevent the morbidity and possibly death from the genotype-specific cancers that would otherwise be in the patient’s future. For patients found to have a hereditary cancer syndrome, medical management options include more-frequent cancer screening or surveillance, prophylactic surgery, and preventive medical treatment, which will be reviewed in a future article in this series.

Identifying the specific mutation in one family member allows at-risk relatives, both female and male, to then take advantage of predictive testing, with genetic counseling. If they test positive for the risk-increasing mutation, they too can take advantage of the management options for people at high risk. If they test negative, they can continue to undergo the same screening as recommended for the general population. Also, they may be relieved to know that their cancer risk is no greater than that in the general population.

The American Society of Clinical Oncology⁹ recommends genetic counseling and testing when all of the following are true:

• There is a personal or family history suggesting genetic cancer susceptibility
• The test can be adequately interpreted
• The results will aid in the diagnosis or influence the medical or surgical management of the patient or family at hereditary risk of cancer.

Professional society guidelines also recommend that genetic testing be done only with genetic counseling before and after.^5,6,8 The National Society of Genetic Counselors provides a list of clinical genetic counselors, organized by geographical area, at www.nsgc.org.

PATIENT 1 RECEIVES GENETIC TESTING AND COUNSELING

Let’s return to the Ashkenazi Jewish patient who has a personal and family history of breast cancer, whom you referred for cancer genetics consultation and who attends this appointment. A detailed personal and family history is gathered, and a brief physical examination is done, which reveals that the patient has macrocephaly and a history of multiple uterine fibroids.

The genetic differential diagnosis for your patient includes hereditary breast and ovarian cancer syndrome (resulting from mutations in the BRCA1 and BRCA2 genes) and Cowden syndrome (from mutations in the PTEN gene) (TABLE 3). The counselor uses BRCAPRO, a statistical risk-assessment tool that estimates a patient’s risk of harboring a BRCA1 or BRCA2 mutation based on ethnicity and personal and family history of cancer, and finds her risk to be 31%. In view of this risk, genetic testing for BRCA1 and BRCA2 is offered after a detailed discussion of the genetic differential diagnosis, the implications of a positive vs a negative test result, the possibility of finding gene changes (variants) of unknown significance, and the implications of the test results for family members.

Your patient elects to pursue BRCA1 and BRCA2 genetic testing and the results are negative—no mutations in either gene are found. PTEN testing is recommended next, which your patient elects to undergo. A mutation in the PTEN gene is found, indicating that she has Cowden syndrome. This result and its implications are discussed in a posttest genetic counseling session.

Cowden syndrome is an autosomal-dominant condition that carries a heightened risk of benign and malignant neoplasms, including a lifetime risk of breast cancer of up to 85%, with the average age at diagnosis in the 40s. Mutations in the PTEN gene also predispose to other cancer types, including nonmedullary thyroid, uterine, renal, and colorectal cancers, as well as melanoma.⁹ Multiple benign skin lesions and gastrointestinal polyposis are common.²⁰

During the appointment, medical management options for patients with PTEN mutations are presented (Table 4).⁹ Given that your patient’s breast cancer was initially treated with lumpectomy, her remaining breast tissue is at risk of a second malignancy. She has never undergone thyroid imaging, colonoscopy, or kidney imaging. She reports that lately she has had occasional abnormal uterine bleeding and pain, which she believes are caused by her uterine fibroids. Given these symptoms and in light of her PTEN mutation, hysterectomy may be presented to her as an option. The genetics team sends a detailed clinical note directly to the primary care physician so they can coordinate and “quarterback” the patient’s care.

Like many patients, your patient is very concerned about how this information may affect her daughter. She first expresses some guilt at having to tell her daughter that she may have “given” her a risk of cancer. However, during the course of the genetic counseling session, she accepts that she could not have prevented her daughter from possibly inheriting this mutation, and understands that sharing this information will enable her daughter to pursue testing to help her understand her own risks.

When a known mutation exists in the family, as is the case with your patient, predictive testing only for that mutation gives a 100% accurate result. During a separate genetic counseling appointment, the patient’s daughter opts to proceed with testing and is found to be negative for her mother’s PTEN mutation.

WHAT HAPPENS WHEN GENETIC TESTING IS NOT INDICATED?

Cancer genetic risk assessment and counseling provides benefits even when genetic testing is not indicated. In some situations genetic testing is not warranted, but referral for heightened surveillance for breast cancer is deemed necessary. Patients who have a personal or family history of cancer can still gain from a detailed assessment of their personal and family history and may come away relieved after learning that they or their family members are not at high risk of developing cancer. Such patients or families may be classified as demonstrating either familial or sporadic breast cancer diagnoses.

Familial breast cancer

Familial breast cancers, believed to account for 15% to 20% of all cases of breast cancer, share features with hereditary breast cancer syndromes.⁴ In affected families, the frequency of breast cancer is higher than in the general population (multiple family members may be affected), and the age of onset tends to be close to that in the general population.

Members of a family with familial breast cancer who have not yet developed the disease may be at increased risk of it. Several risk-assessment tools (the Gail, Tyrer-Cuzick, Claus, and other models)^21–25 use personal and family history to estimate breast cancer risk.

Depending on the assessed risk, additional options for screening and surveillance are available. The American Cancer Society recommends magnetic resonance imaging (MRI) in addition to annual mammography for women whose lifetime risk of breast cancer is greater than 20%. They also recommend that women at moderately increased risk (ie, 15%–20% lifetime risk) talk to their doctor about the benefits and limitations of adding MRI screening to yearly mammography.¹

Sporadic breast cancer

Sporadic forms of breast cancer account for 70% to 80% of cases of breast cancer. Sporadic breast cancers are thought to have mainly nonhereditary causes, with environment and personal risk factors playing a large role.

Women with apparently sporadic breast cancers are diagnosed at or beyond the average age at diagnosis in the general population and do not have a family history that suggests either a hereditary cancer syndrome or familial breast cancer. If they undergo a cancer risk assessment, they may be relieved to learn that other women in their family do not have a high probability of being affected, and that they themselves do not appear to be at increased risk of other malignancies.

PATIENT 2: NEGATIVE TEST RESULTS ARE SOMETIMES ‘UNINFORMATIVE’

A healthy 35-year-old woman is referred for a genetics consultation by her gynecologist because her mother developed breast cancer at age 40 and died of the disease. A detailed personal and family history and risk assessment are done. After pretest genetic counseling, testing for BRCA1 and BRCA2 mutations (hereditary breast and ovarian cancer syndrome) is ordered, and the patient’s test results are negative. Risk assessment determines that no other hereditary cancer syndrome is likely. Therefore, no other genetic testing is offered at this time.

Genetic testing is most informative when performed first on the family member at highest risk of having a mutation. For families with breast cancer, this is typically the person with cancer diagnosed at the earliest age.

Unfortunately, sometimes these family members cannot be tested because they are deceased or otherwise unavailable. In such situations, it is acceptable to offer testing to a close, unaffected relative, such as your patient. Pretest genetic counseling in these circumstances is key, highlighting the fact that negative (normal) results would be uninformative. In your case, we cannot know whether the patient’s mother would have tested positive for a BRCA1 or BRCA2 mutation and your patient is a “true negative,” or whether her mother would have tested negative as well.

In unaffected patients with uninformative genetic testing results, medical management is based on the patient’s personal risk factors and family history of cancer. For your patient, statistical risk modeling tools (the Gail, Claus, Couch, and Tyrer-Cuzick models) determine that her risk of developing breast cancer is 22% to 28.5%, qualifying her for MRI along with yearly mammography per the American Cancer Society guidelines previously discussed.

KNOWLEDGE CONTINUES TO EXPAND

Major advances in the understanding of breast cancer susceptibility were made in the last decade through genetic linkage mapping in families that have an overabundance of members with breast cancer.^26–28 Additionally, as more information is acquired, other genes predisposing to cancer or modifying cancer risk may be identified and additional knowledge gained.

With the advent of gene-panel-based testing and exome sequencing, we will incidentally discover mutations that predispose to cancer in patients in whom we were not looking for these mutations. With improving technology and value-based health care delivery, providers must continue to embrace multidisciplinary care, and genetics will become central in guiding medical management. In the event of an incidental finding suggesting susceptibility to heritable cancer, a consult to genetic counseling is recommended.

Many studies of the genetics of breast cancer are now focusing on known hereditary breast cancer syndromes and on possibilities for risk reduction, lifestyle modification, and identification of genetic variations that may increase or decrease cancer risk for an individual patient. The Center for Personalized Genetic Healthcare at Cleveland Clinic is collaborating in one such study. Titled “Risk Factor Analysis of Hereditary Breast and Ovarian Cancer Syndrome,” it is an international study led by a leading breast cancer researcher, Dr. Steven Narod from the Women’s College Research Institute in Toronto, ON. This study is focusing on women with a BRCA1 or BRCA2 mutation and their personal cancer risk factors, lifestyle choices, and overall development of cancer. This research group and others are also focusing on identifying genetic “modifiers” of cancer risk in these high-risk women.²⁹

For patients who do not have a hereditary cancer syndrome, research is further exploring novel genes and their relation to breast cancer risk. One such study in our laboratory has found that several genes once thought only to cause an increased risk of hereditary paraganglioma may also predispose to breast and thyroid cancer.^29,31 Additional research in this area is under way to clarify these risks.

GOOD SCIENCE, BAD MEDICINE?

Other research studies have identified a number of genes currently thought to be “moderately penetrant” for breast cancer risk, meaning that they may confer a risk of breast cancer slightly greater than that in the general population, but in some instances the risk has not been proven to be high enough to alter a patient’s management.^32,33

Although a few clinical laboratories currently offer testing for these kinds of genes, the clinical utility of this testing is questionable. Before offering testing on a clinical basis, we need clear, consistent data on the types of cancers associated with these genes and on the lifetime percentage risk of acquiring these cancers. Currently, it is difficult to understand whether a variant in a moderately penetrant gene is the true explanation behind a patient’s breast cancer diagnosis. If such a variant is identified and family members pursue testing for it, should those family members who test negative be considered to have the same risk of cancer as the general population? And should family members testing positive be offered prophylactic surgical options?

Without more data these questions cannot be answered, and until such data are gathered, we believe that testing for moderately penetrant genes should not be performed outside of a research study. The Center for Personalized Genetic Healthcare in Cleveland Clinic’s Genomic Medicine Institute can assist in educating and coordinating patients’ enrollment in such research studies.

PUTTING IT ALL TOGETHER

Primary care physicians are the first-line providers to individuals and families, many of whom have a personal or family history of breast cancer. Identifying patients at risk of breast cancer and hereditary cancer syndromes can be challenging in this era of shortened appointment times and patients with complex medical histories.

Reviewing an individual’s personal and cancer family history is a necessary first step in considering appropriate medical management recommendations for cancer screening and prevention, the cornerstone of personalized health care. Patients with hereditary breast cancer syndromes and those with familial breast cancer can benefit from high-risk breast cancer surveillance.

Cancer genetics risk assessment ensures that the correct genetic testing is offered to the most appropriate patients, with personalized interpretation of results and provision of future management recommendations based on the individual patient’s personal and family history. Genetic counselors empower patients to make educated and informed decisions about genetic testing, cancer screening, and prevention.

As health care continues to focus more on prevention in this new era of genomic medicine and value-based delivery of health care, genetic counselors will serve as powerful allies to physicians.³⁴

Acknowledgments: We would like to thank Dr. Colleen Clayton and Dr. Lynn Pattimakiel of the Medicine Institute, Cleveland Clinic, for their critical review of and thoughtful feedback on this manuscript.

PATIENT 1: A PERSONAL AND FAMILY HISTORY OF BREAST CANCER

A 55-year-old Ashkenazi Jewish woman presents to your clinic for her annual physical. She reports that she had been diagnosed with breast cancer 10 years ago and that it had been treated with lumpectomy. You recall that Ashkenazi Jewish ethnicity and a diagnosis of breast cancer before age 50 are red flags for a hereditary cancer syndrome, and you ask about her family history of cancer. She reports that her mother was diagnosed with breast cancer in her 60s. The patient wants to know if her daughter should start breast cancer screening.

What do you do next?

Facing increasing demands and a plethora of information to be discussed in a short time, primary care physicians may find it challenging to inform patients about the possibility of a hereditary cancer syndrome, to assess the risk, to organize genetic testing if appropriate, and to counsel patients about their management options. As our knowledge of the genetics of breast cancer continues to expand, this information will become more detailed and complex.

Nevertheless, primary care physicians can help identify patients who may have a syndrome of inherited cancer predisposition or whose family history raises concern for familial breast cancer. Patients in both groups may be candidates for genetic risk assessment, for special management options for women at high risk, or for both.

This article provides an overview of inherited conditions associated with higher breast cancer risk, and guidelines to help physicians recognize patients in their own practice for whom a genetics referral may be appropriate.

BREAST CANCER IS COMPLEX AND HETEROGENEOUS

Breast cancer is the second-leading cause of cancer deaths in women. According to the American Cancer Society, an estimated 234,340 new cases of breast cancer are expected to be diagnosed in women in the United States in 2013, and about 2,240 new cases are expected in men; 39,620 women and 410 men are expected to die of it.¹

Breast cancer is a complex and heterogeneous disease, influenced by many factors, of which female sex and increasing age are the most significant. Modifiable risk factors include obesity, use of combined hormone replacement therapy, and physical inactivity. Other risk factors include dense breast tissue, having had a breast biopsy in the past, the finding of atypical hyperplasia on biopsy, a history of high-dose chest radiation, and reproductive factors that include early menarche, late menopause, nulliparity, and birth of first child after age 30.

After female sex and age, family history of the disease is the most significant risk factor for breast cancer.² If a woman has a first-degree relative (mother, sister, daughter) with breast cancer, her risk is 1.8 times higher, and if she has a second-degree relative (aunt, grandmother) with breast cancer, her risk is 1.3 times higher.³

Hereditary cancer predisposition syndromes account for 5% to 10% of cases of breast cancer. These are caused by a germline mutation in a highly penetrant gene that considerably increases the risk of malignancies of the breast and other tissues. These conditions are inherited in an autosomal-dominant fashion, with age of onset tending to be significantly—several decades—younger than the median age of onset in the general population. The most common of these is hereditary breast and ovarian cancer syndrome, caused by germline mutations of the BRCA1 or BRCA2 gene.

Familial breast cancers account for 15% to 20% of cases. Here, the women who develop breast cancer have multiple family members who are also affected but without an obvious inheritance pattern, and the age of onset is similar to that in the general population.⁴

Sporadic forms of breast cancer account for the remaining 70% to 80% of cases. Their development can be attributed mainly to nonhereditary causes, such as the environmental and personal risk factors listed above. In general, sporadic forms of breast cancer occur at older ages, with no particular inheritance pattern and with frequency of occurrence in a family comparable to that in the general population.

IS A GENETICS CONSULTATION NEEDED?

In the case described above, the primary care physician gathered basic information about the patient’s cancer-related personal and family history. Asking a few key questions (Table  1)^5,6 can help physicians understand two important things: whether a more detailed assessment of genetic risk and counseling by a genetics professional are indicated, and whether the patient would benefit from additional cancer screening and prevention.

Table 2 summarizes the National Comprehensive Cancer Network’s recommendations for cancer genetics consultation.⁵ These red flags for a hereditary breast cancer syndrome can help primary care providers identify patients for whom a cancer genetics referral is appropriate. Of note: the maternal and paternal family histories are equally important.

Because our patient was diagnosed with breast cancer before age 50 and is of Ashkenazi Jewish ethnicity, she meets these criteria and warrants a cancer genetics consultation.

The tenets of genetic counseling, described previously in this series,⁷ are relevant to hereditary cancer syndromes. Cancer risk assessment and genetic counseling constitute the process of identifying and counseling individuals at risk of familial or hereditary cancer.⁸

As in other genetic counseling scenarios, a detailed pedigree (family tree) is taken, and this information, along with the patient’s personal medical history, allows a genetics specialist to determine if the presentation is most suggestive of sporadic, familial, or hereditary cancer.

A common misconception among patients is that there is a single genetic test for hereditary breast cancer, when in fact many highly penetrant predisposition genes have been linked to heightened risk (see below). The syndromes summarized in Table 3^5,9–18 are part of the differential diagnosis for every patient presenting with a personal or family history of breast cancer, and the detailed information from the personal and family history, ascertained during the assessment, ensures the right syndrome is explored within a family.

Cancer-focused genetic counseling may also help a patient or family process the psychological and emotional responses that can occur when cancer risk is discussed: eg, fear of cancer and death; guilt a parent may feel for passing on a genetic predisposition; and survivor guilt experienced by family members who test negative.

Genetic counselors are trained to recognize patients who may benefit from additional counseling. Not all patients pursuing cancer-focused genetic testing need a thorough evaluation by a psychologist, unlike those with adult-onset neurodegenerative conditions such as Huntington disease. Rather, the genetic counselor discusses the psychological implications of cancer-focused genetic testing and can refer the patient to a psychologist, therapist, social worker, or others if he or she feels the patient may benefit.⁸

Some patients come to a genetic counseling session with concerns about whether their insurance will pay for testing, and about whether they will face discrimination because of the testing results. In most situations, genetic testing is deemed medically necessary and is covered by the patient’s insurance. When testing is necessary, genetic counselors are skilled at preauthorizing it and writing letters of medical necessity. They are also familiar with laws and regulations that protect patients, such as the Genetic Information Nondiscrimination Act, which protects patients from insurance and employment discrimination.

Because a cancer-focused genetic counseling session typically lasts 1 hour, the counselor has enough time to address these and any other concerns that might prevent a patient who is otherwise interested in genetic testing from pursuing it.

HOW CAN GENETIC TESTING HELP?

Genetic testing for hereditary cancer syndromes can have personal benefit for the patient and at-risk family members.

Note that the syndromes in Table 3 all increase the risk of more than one type of cancer. Patients with these syndromes frequently receive care from multiple subspecialists to mitigate those risks. Guidelines exist for each of these syndromes and, if followed, may prevent the morbidity and possibly death from the genotype-specific cancers that would otherwise be in the patient’s future. For patients found to have a hereditary cancer syndrome, medical management options include more-frequent cancer screening or surveillance, prophylactic surgery, and preventive medical treatment, which will be reviewed in a future article in this series.

Identifying the specific mutation in one family member allows at-risk relatives, both female and male, to then take advantage of predictive testing, with genetic counseling. If they test positive for the risk-increasing mutation, they too can take advantage of the management options for people at high risk. If they test negative, they can continue to undergo the same screening as recommended for the general population. Also, they may be relieved to know that their cancer risk is no greater than that in the general population.

The American Society of Clinical Oncology⁹ recommends genetic counseling and testing when all of the following are true:

• There is a personal or family history suggesting genetic cancer susceptibility
• The test can be adequately interpreted
• The results will aid in the diagnosis or influence the medical or surgical management of the patient or family at hereditary risk of cancer.

Professional society guidelines also recommend that genetic testing be done only with genetic counseling before and after.^5,6,8 The National Society of Genetic Counselors provides a list of clinical genetic counselors, organized by geographical area, at www.nsgc.org.

PATIENT 1 RECEIVES GENETIC TESTING AND COUNSELING

Let’s return to the Ashkenazi Jewish patient who has a personal and family history of breast cancer, whom you referred for cancer genetics consultation and who attends this appointment. A detailed personal and family history is gathered, and a brief physical examination is done, which reveals that the patient has macrocephaly and a history of multiple uterine fibroids.

The genetic differential diagnosis for your patient includes hereditary breast and ovarian cancer syndrome (resulting from mutations in the BRCA1 and BRCA2 genes) and Cowden syndrome (from mutations in the PTEN gene) (TABLE 3). The counselor uses BRCAPRO, a statistical risk-assessment tool that estimates a patient’s risk of harboring a BRCA1 or BRCA2 mutation based on ethnicity and personal and family history of cancer, and finds her risk to be 31%. In view of this risk, genetic testing for BRCA1 and BRCA2 is offered after a detailed discussion of the genetic differential diagnosis, the implications of a positive vs a negative test result, the possibility of finding gene changes (variants) of unknown significance, and the implications of the test results for family members.

Your patient elects to pursue BRCA1 and BRCA2 genetic testing and the results are negative—no mutations in either gene are found. PTEN testing is recommended next, which your patient elects to undergo. A mutation in the PTEN gene is found, indicating that she has Cowden syndrome. This result and its implications are discussed in a posttest genetic counseling session.

Cowden syndrome is an autosomal-dominant condition that carries a heightened risk of benign and malignant neoplasms, including a lifetime risk of breast cancer of up to 85%, with the average age at diagnosis in the 40s. Mutations in the PTEN gene also predispose to other cancer types, including nonmedullary thyroid, uterine, renal, and colorectal cancers, as well as melanoma.⁹ Multiple benign skin lesions and gastrointestinal polyposis are common.²⁰

During the appointment, medical management options for patients with PTEN mutations are presented (Table 4).⁹ Given that your patient’s breast cancer was initially treated with lumpectomy, her remaining breast tissue is at risk of a second malignancy. She has never undergone thyroid imaging, colonoscopy, or kidney imaging. She reports that lately she has had occasional abnormal uterine bleeding and pain, which she believes are caused by her uterine fibroids. Given these symptoms and in light of her PTEN mutation, hysterectomy may be presented to her as an option. The genetics team sends a detailed clinical note directly to the primary care physician so they can coordinate and “quarterback” the patient’s care.

Like many patients, your patient is very concerned about how this information may affect her daughter. She first expresses some guilt at having to tell her daughter that she may have “given” her a risk of cancer. However, during the course of the genetic counseling session, she accepts that she could not have prevented her daughter from possibly inheriting this mutation, and understands that sharing this information will enable her daughter to pursue testing to help her understand her own risks.

When a known mutation exists in the family, as is the case with your patient, predictive testing only for that mutation gives a 100% accurate result. During a separate genetic counseling appointment, the patient’s daughter opts to proceed with testing and is found to be negative for her mother’s PTEN mutation.

WHAT HAPPENS WHEN GENETIC TESTING IS NOT INDICATED?

Cancer genetic risk assessment and counseling provides benefits even when genetic testing is not indicated. In some situations genetic testing is not warranted, but referral for heightened surveillance for breast cancer is deemed necessary. Patients who have a personal or family history of cancer can still gain from a detailed assessment of their personal and family history and may come away relieved after learning that they or their family members are not at high risk of developing cancer. Such patients or families may be classified as demonstrating either familial or sporadic breast cancer diagnoses.

Familial breast cancer

Familial breast cancers, believed to account for 15% to 20% of all cases of breast cancer, share features with hereditary breast cancer syndromes.⁴ In affected families, the frequency of breast cancer is higher than in the general population (multiple family members may be affected), and the age of onset tends to be close to that in the general population.

Members of a family with familial breast cancer who have not yet developed the disease may be at increased risk of it. Several risk-assessment tools (the Gail, Tyrer-Cuzick, Claus, and other models)^21–25 use personal and family history to estimate breast cancer risk.

Depending on the assessed risk, additional options for screening and surveillance are available. The American Cancer Society recommends magnetic resonance imaging (MRI) in addition to annual mammography for women whose lifetime risk of breast cancer is greater than 20%. They also recommend that women at moderately increased risk (ie, 15%–20% lifetime risk) talk to their doctor about the benefits and limitations of adding MRI screening to yearly mammography.¹

Sporadic breast cancer

Sporadic forms of breast cancer account for 70% to 80% of cases of breast cancer. Sporadic breast cancers are thought to have mainly nonhereditary causes, with environment and personal risk factors playing a large role.

Women with apparently sporadic breast cancers are diagnosed at or beyond the average age at diagnosis in the general population and do not have a family history that suggests either a hereditary cancer syndrome or familial breast cancer. If they undergo a cancer risk assessment, they may be relieved to learn that other women in their family do not have a high probability of being affected, and that they themselves do not appear to be at increased risk of other malignancies.

PATIENT 2: NEGATIVE TEST RESULTS ARE SOMETIMES ‘UNINFORMATIVE’

A healthy 35-year-old woman is referred for a genetics consultation by her gynecologist because her mother developed breast cancer at age 40 and died of the disease. A detailed personal and family history and risk assessment are done. After pretest genetic counseling, testing for BRCA1 and BRCA2 mutations (hereditary breast and ovarian cancer syndrome) is ordered, and the patient’s test results are negative. Risk assessment determines that no other hereditary cancer syndrome is likely. Therefore, no other genetic testing is offered at this time.

Genetic testing is most informative when performed first on the family member at highest risk of having a mutation. For families with breast cancer, this is typically the person with cancer diagnosed at the earliest age.

Unfortunately, sometimes these family members cannot be tested because they are deceased or otherwise unavailable. In such situations, it is acceptable to offer testing to a close, unaffected relative, such as your patient. Pretest genetic counseling in these circumstances is key, highlighting the fact that negative (normal) results would be uninformative. In your case, we cannot know whether the patient’s mother would have tested positive for a BRCA1 or BRCA2 mutation and your patient is a “true negative,” or whether her mother would have tested negative as well.

In unaffected patients with uninformative genetic testing results, medical management is based on the patient’s personal risk factors and family history of cancer. For your patient, statistical risk modeling tools (the Gail, Claus, Couch, and Tyrer-Cuzick models) determine that her risk of developing breast cancer is 22% to 28.5%, qualifying her for MRI along with yearly mammography per the American Cancer Society guidelines previously discussed.

KNOWLEDGE CONTINUES TO EXPAND

Major advances in the understanding of breast cancer susceptibility were made in the last decade through genetic linkage mapping in families that have an overabundance of members with breast cancer.^26–28 Additionally, as more information is acquired, other genes predisposing to cancer or modifying cancer risk may be identified and additional knowledge gained.

With the advent of gene-panel-based testing and exome sequencing, we will incidentally discover mutations that predispose to cancer in patients in whom we were not looking for these mutations. With improving technology and value-based health care delivery, providers must continue to embrace multidisciplinary care, and genetics will become central in guiding medical management. In the event of an incidental finding suggesting susceptibility to heritable cancer, a consult to genetic counseling is recommended.

Many studies of the genetics of breast cancer are now focusing on known hereditary breast cancer syndromes and on possibilities for risk reduction, lifestyle modification, and identification of genetic variations that may increase or decrease cancer risk for an individual patient. The Center for Personalized Genetic Healthcare at Cleveland Clinic is collaborating in one such study. Titled “Risk Factor Analysis of Hereditary Breast and Ovarian Cancer Syndrome,” it is an international study led by a leading breast cancer researcher, Dr. Steven Narod from the Women’s College Research Institute in Toronto, ON. This study is focusing on women with a BRCA1 or BRCA2 mutation and their personal cancer risk factors, lifestyle choices, and overall development of cancer. This research group and others are also focusing on identifying genetic “modifiers” of cancer risk in these high-risk women.²⁹

For patients who do not have a hereditary cancer syndrome, research is further exploring novel genes and their relation to breast cancer risk. One such study in our laboratory has found that several genes once thought only to cause an increased risk of hereditary paraganglioma may also predispose to breast and thyroid cancer.^29,31 Additional research in this area is under way to clarify these risks.

GOOD SCIENCE, BAD MEDICINE?

Other research studies have identified a number of genes currently thought to be “moderately penetrant” for breast cancer risk, meaning that they may confer a risk of breast cancer slightly greater than that in the general population, but in some instances the risk has not been proven to be high enough to alter a patient’s management.^32,33

Although a few clinical laboratories currently offer testing for these kinds of genes, the clinical utility of this testing is questionable. Before offering testing on a clinical basis, we need clear, consistent data on the types of cancers associated with these genes and on the lifetime percentage risk of acquiring these cancers. Currently, it is difficult to understand whether a variant in a moderately penetrant gene is the true explanation behind a patient’s breast cancer diagnosis. If such a variant is identified and family members pursue testing for it, should those family members who test negative be considered to have the same risk of cancer as the general population? And should family members testing positive be offered prophylactic surgical options?

Without more data these questions cannot be answered, and until such data are gathered, we believe that testing for moderately penetrant genes should not be performed outside of a research study. The Center for Personalized Genetic Healthcare in Cleveland Clinic’s Genomic Medicine Institute can assist in educating and coordinating patients’ enrollment in such research studies.

PUTTING IT ALL TOGETHER

Primary care physicians are the first-line providers to individuals and families, many of whom have a personal or family history of breast cancer. Identifying patients at risk of breast cancer and hereditary cancer syndromes can be challenging in this era of shortened appointment times and patients with complex medical histories.

Reviewing an individual’s personal and cancer family history is a necessary first step in considering appropriate medical management recommendations for cancer screening and prevention, the cornerstone of personalized health care. Patients with hereditary breast cancer syndromes and those with familial breast cancer can benefit from high-risk breast cancer surveillance.

Cancer genetics risk assessment ensures that the correct genetic testing is offered to the most appropriate patients, with personalized interpretation of results and provision of future management recommendations based on the individual patient’s personal and family history. Genetic counselors empower patients to make educated and informed decisions about genetic testing, cancer screening, and prevention.

As health care continues to focus more on prevention in this new era of genomic medicine and value-based delivery of health care, genetic counselors will serve as powerful allies to physicians.³⁴

Acknowledgments: We would like to thank Dr. Colleen Clayton and Dr. Lynn Pattimakiel of the Medicine Institute, Cleveland Clinic, for their critical review of and thoughtful feedback on this manuscript.

PATIENT 1: A PERSONAL AND FAMILY HISTORY OF BREAST CANCER

A 55-year-old Ashkenazi Jewish woman presents to your clinic for her annual physical. She reports that she had been diagnosed with breast cancer 10 years ago and that it had been treated with lumpectomy. You recall that Ashkenazi Jewish ethnicity and a diagnosis of breast cancer before age 50 are red flags for a hereditary cancer syndrome, and you ask about her family history of cancer. She reports that her mother was diagnosed with breast cancer in her 60s. The patient wants to know if her daughter should start breast cancer screening.

What do you do next?

Facing increasing demands and a plethora of information to be discussed in a short time, primary care physicians may find it challenging to inform patients about the possibility of a hereditary cancer syndrome, to assess the risk, to organize genetic testing if appropriate, and to counsel patients about their management options. As our knowledge of the genetics of breast cancer continues to expand, this information will become more detailed and complex.

Nevertheless, primary care physicians can help identify patients who may have a syndrome of inherited cancer predisposition or whose family history raises concern for familial breast cancer. Patients in both groups may be candidates for genetic risk assessment, for special management options for women at high risk, or for both.

This article provides an overview of inherited conditions associated with higher breast cancer risk, and guidelines to help physicians recognize patients in their own practice for whom a genetics referral may be appropriate.

BREAST CANCER IS COMPLEX AND HETEROGENEOUS

Breast cancer is the second-leading cause of cancer deaths in women. According to the American Cancer Society, an estimated 234,340 new cases of breast cancer are expected to be diagnosed in women in the United States in 2013, and about 2,240 new cases are expected in men; 39,620 women and 410 men are expected to die of it.¹

Breast cancer is a complex and heterogeneous disease, influenced by many factors, of which female sex and increasing age are the most significant. Modifiable risk factors include obesity, use of combined hormone replacement therapy, and physical inactivity. Other risk factors include dense breast tissue, having had a breast biopsy in the past, the finding of atypical hyperplasia on biopsy, a history of high-dose chest radiation, and reproductive factors that include early menarche, late menopause, nulliparity, and birth of first child after age 30.

After female sex and age, family history of the disease is the most significant risk factor for breast cancer.² If a woman has a first-degree relative (mother, sister, daughter) with breast cancer, her risk is 1.8 times higher, and if she has a second-degree relative (aunt, grandmother) with breast cancer, her risk is 1.3 times higher.³

Hereditary cancer predisposition syndromes account for 5% to 10% of cases of breast cancer. These are caused by a germline mutation in a highly penetrant gene that considerably increases the risk of malignancies of the breast and other tissues. These conditions are inherited in an autosomal-dominant fashion, with age of onset tending to be significantly—several decades—younger than the median age of onset in the general population. The most common of these is hereditary breast and ovarian cancer syndrome, caused by germline mutations of the BRCA1 or BRCA2 gene.

Familial breast cancers account for 15% to 20% of cases. Here, the women who develop breast cancer have multiple family members who are also affected but without an obvious inheritance pattern, and the age of onset is similar to that in the general population.⁴

Sporadic forms of breast cancer account for the remaining 70% to 80% of cases. Their development can be attributed mainly to nonhereditary causes, such as the environmental and personal risk factors listed above. In general, sporadic forms of breast cancer occur at older ages, with no particular inheritance pattern and with frequency of occurrence in a family comparable to that in the general population.

IS A GENETICS CONSULTATION NEEDED?

In the case described above, the primary care physician gathered basic information about the patient’s cancer-related personal and family history. Asking a few key questions (Table  1)^5,6 can help physicians understand two important things: whether a more detailed assessment of genetic risk and counseling by a genetics professional are indicated, and whether the patient would benefit from additional cancer screening and prevention.

Table 2 summarizes the National Comprehensive Cancer Network’s recommendations for cancer genetics consultation.⁵ These red flags for a hereditary breast cancer syndrome can help primary care providers identify patients for whom a cancer genetics referral is appropriate. Of note: the maternal and paternal family histories are equally important.

Because our patient was diagnosed with breast cancer before age 50 and is of Ashkenazi Jewish ethnicity, she meets these criteria and warrants a cancer genetics consultation.

The tenets of genetic counseling, described previously in this series,⁷ are relevant to hereditary cancer syndromes. Cancer risk assessment and genetic counseling constitute the process of identifying and counseling individuals at risk of familial or hereditary cancer.⁸

As in other genetic counseling scenarios, a detailed pedigree (family tree) is taken, and this information, along with the patient’s personal medical history, allows a genetics specialist to determine if the presentation is most suggestive of sporadic, familial, or hereditary cancer.

A common misconception among patients is that there is a single genetic test for hereditary breast cancer, when in fact many highly penetrant predisposition genes have been linked to heightened risk (see below). The syndromes summarized in Table 3^5,9–18 are part of the differential diagnosis for every patient presenting with a personal or family history of breast cancer, and the detailed information from the personal and family history, ascertained during the assessment, ensures the right syndrome is explored within a family.

Cancer-focused genetic counseling may also help a patient or family process the psychological and emotional responses that can occur when cancer risk is discussed: eg, fear of cancer and death; guilt a parent may feel for passing on a genetic predisposition; and survivor guilt experienced by family members who test negative.

Genetic counselors are trained to recognize patients who may benefit from additional counseling. Not all patients pursuing cancer-focused genetic testing need a thorough evaluation by a psychologist, unlike those with adult-onset neurodegenerative conditions such as Huntington disease. Rather, the genetic counselor discusses the psychological implications of cancer-focused genetic testing and can refer the patient to a psychologist, therapist, social worker, or others if he or she feels the patient may benefit.⁸

Some patients come to a genetic counseling session with concerns about whether their insurance will pay for testing, and about whether they will face discrimination because of the testing results. In most situations, genetic testing is deemed medically necessary and is covered by the patient’s insurance. When testing is necessary, genetic counselors are skilled at preauthorizing it and writing letters of medical necessity. They are also familiar with laws and regulations that protect patients, such as the Genetic Information Nondiscrimination Act, which protects patients from insurance and employment discrimination.

Because a cancer-focused genetic counseling session typically lasts 1 hour, the counselor has enough time to address these and any other concerns that might prevent a patient who is otherwise interested in genetic testing from pursuing it.

HOW CAN GENETIC TESTING HELP?

Genetic testing for hereditary cancer syndromes can have personal benefit for the patient and at-risk family members.

Note that the syndromes in Table 3 all increase the risk of more than one type of cancer. Patients with these syndromes frequently receive care from multiple subspecialists to mitigate those risks. Guidelines exist for each of these syndromes and, if followed, may prevent the morbidity and possibly death from the genotype-specific cancers that would otherwise be in the patient’s future. For patients found to have a hereditary cancer syndrome, medical management options include more-frequent cancer screening or surveillance, prophylactic surgery, and preventive medical treatment, which will be reviewed in a future article in this series.

Identifying the specific mutation in one family member allows at-risk relatives, both female and male, to then take advantage of predictive testing, with genetic counseling. If they test positive for the risk-increasing mutation, they too can take advantage of the management options for people at high risk. If they test negative, they can continue to undergo the same screening as recommended for the general population. Also, they may be relieved to know that their cancer risk is no greater than that in the general population.

The American Society of Clinical Oncology⁹ recommends genetic counseling and testing when all of the following are true:

• There is a personal or family history suggesting genetic cancer susceptibility
• The test can be adequately interpreted
• The results will aid in the diagnosis or influence the medical or surgical management of the patient or family at hereditary risk of cancer.

Professional society guidelines also recommend that genetic testing be done only with genetic counseling before and after.^5,6,8 The National Society of Genetic Counselors provides a list of clinical genetic counselors, organized by geographical area, at www.nsgc.org.

PATIENT 1 RECEIVES GENETIC TESTING AND COUNSELING

Let’s return to the Ashkenazi Jewish patient who has a personal and family history of breast cancer, whom you referred for cancer genetics consultation and who attends this appointment. A detailed personal and family history is gathered, and a brief physical examination is done, which reveals that the patient has macrocephaly and a history of multiple uterine fibroids.

The genetic differential diagnosis for your patient includes hereditary breast and ovarian cancer syndrome (resulting from mutations in the BRCA1 and BRCA2 genes) and Cowden syndrome (from mutations in the PTEN gene) (TABLE 3). The counselor uses BRCAPRO, a statistical risk-assessment tool that estimates a patient’s risk of harboring a BRCA1 or BRCA2 mutation based on ethnicity and personal and family history of cancer, and finds her risk to be 31%. In view of this risk, genetic testing for BRCA1 and BRCA2 is offered after a detailed discussion of the genetic differential diagnosis, the implications of a positive vs a negative test result, the possibility of finding gene changes (variants) of unknown significance, and the implications of the test results for family members.

Your patient elects to pursue BRCA1 and BRCA2 genetic testing and the results are negative—no mutations in either gene are found. PTEN testing is recommended next, which your patient elects to undergo. A mutation in the PTEN gene is found, indicating that she has Cowden syndrome. This result and its implications are discussed in a posttest genetic counseling session.

Cowden syndrome is an autosomal-dominant condition that carries a heightened risk of benign and malignant neoplasms, including a lifetime risk of breast cancer of up to 85%, with the average age at diagnosis in the 40s. Mutations in the PTEN gene also predispose to other cancer types, including nonmedullary thyroid, uterine, renal, and colorectal cancers, as well as melanoma.⁹ Multiple benign skin lesions and gastrointestinal polyposis are common.²⁰

During the appointment, medical management options for patients with PTEN mutations are presented (Table 4).⁹ Given that your patient’s breast cancer was initially treated with lumpectomy, her remaining breast tissue is at risk of a second malignancy. She has never undergone thyroid imaging, colonoscopy, or kidney imaging. She reports that lately she has had occasional abnormal uterine bleeding and pain, which she believes are caused by her uterine fibroids. Given these symptoms and in light of her PTEN mutation, hysterectomy may be presented to her as an option. The genetics team sends a detailed clinical note directly to the primary care physician so they can coordinate and “quarterback” the patient’s care.

Like many patients, your patient is very concerned about how this information may affect her daughter. She first expresses some guilt at having to tell her daughter that she may have “given” her a risk of cancer. However, during the course of the genetic counseling session, she accepts that she could not have prevented her daughter from possibly inheriting this mutation, and understands that sharing this information will enable her daughter to pursue testing to help her understand her own risks.

When a known mutation exists in the family, as is the case with your patient, predictive testing only for that mutation gives a 100% accurate result. During a separate genetic counseling appointment, the patient’s daughter opts to proceed with testing and is found to be negative for her mother’s PTEN mutation.

WHAT HAPPENS WHEN GENETIC TESTING IS NOT INDICATED?

Cancer genetic risk assessment and counseling provides benefits even when genetic testing is not indicated. In some situations genetic testing is not warranted, but referral for heightened surveillance for breast cancer is deemed necessary. Patients who have a personal or family history of cancer can still gain from a detailed assessment of their personal and family history and may come away relieved after learning that they or their family members are not at high risk of developing cancer. Such patients or families may be classified as demonstrating either familial or sporadic breast cancer diagnoses.

Familial breast cancer

Familial breast cancers, believed to account for 15% to 20% of all cases of breast cancer, share features with hereditary breast cancer syndromes.⁴ In affected families, the frequency of breast cancer is higher than in the general population (multiple family members may be affected), and the age of onset tends to be close to that in the general population.

Members of a family with familial breast cancer who have not yet developed the disease may be at increased risk of it. Several risk-assessment tools (the Gail, Tyrer-Cuzick, Claus, and other models)^21–25 use personal and family history to estimate breast cancer risk.

Depending on the assessed risk, additional options for screening and surveillance are available. The American Cancer Society recommends magnetic resonance imaging (MRI) in addition to annual mammography for women whose lifetime risk of breast cancer is greater than 20%. They also recommend that women at moderately increased risk (ie, 15%–20% lifetime risk) talk to their doctor about the benefits and limitations of adding MRI screening to yearly mammography.¹

Sporadic breast cancer

Sporadic forms of breast cancer account for 70% to 80% of cases of breast cancer. Sporadic breast cancers are thought to have mainly nonhereditary causes, with environment and personal risk factors playing a large role.

Women with apparently sporadic breast cancers are diagnosed at or beyond the average age at diagnosis in the general population and do not have a family history that suggests either a hereditary cancer syndrome or familial breast cancer. If they undergo a cancer risk assessment, they may be relieved to learn that other women in their family do not have a high probability of being affected, and that they themselves do not appear to be at increased risk of other malignancies.

PATIENT 2: NEGATIVE TEST RESULTS ARE SOMETIMES ‘UNINFORMATIVE’

A healthy 35-year-old woman is referred for a genetics consultation by her gynecologist because her mother developed breast cancer at age 40 and died of the disease. A detailed personal and family history and risk assessment are done. After pretest genetic counseling, testing for BRCA1 and BRCA2 mutations (hereditary breast and ovarian cancer syndrome) is ordered, and the patient’s test results are negative. Risk assessment determines that no other hereditary cancer syndrome is likely. Therefore, no other genetic testing is offered at this time.

Genetic testing is most informative when performed first on the family member at highest risk of having a mutation. For families with breast cancer, this is typically the person with cancer diagnosed at the earliest age.

Unfortunately, sometimes these family members cannot be tested because they are deceased or otherwise unavailable. In such situations, it is acceptable to offer testing to a close, unaffected relative, such as your patient. Pretest genetic counseling in these circumstances is key, highlighting the fact that negative (normal) results would be uninformative. In your case, we cannot know whether the patient’s mother would have tested positive for a BRCA1 or BRCA2 mutation and your patient is a “true negative,” or whether her mother would have tested negative as well.

In unaffected patients with uninformative genetic testing results, medical management is based on the patient’s personal risk factors and family history of cancer. For your patient, statistical risk modeling tools (the Gail, Claus, Couch, and Tyrer-Cuzick models) determine that her risk of developing breast cancer is 22% to 28.5%, qualifying her for MRI along with yearly mammography per the American Cancer Society guidelines previously discussed.

KNOWLEDGE CONTINUES TO EXPAND

Major advances in the understanding of breast cancer susceptibility were made in the last decade through genetic linkage mapping in families that have an overabundance of members with breast cancer.^26–28 Additionally, as more information is acquired, other genes predisposing to cancer or modifying cancer risk may be identified and additional knowledge gained.

With the advent of gene-panel-based testing and exome sequencing, we will incidentally discover mutations that predispose to cancer in patients in whom we were not looking for these mutations. With improving technology and value-based health care delivery, providers must continue to embrace multidisciplinary care, and genetics will become central in guiding medical management. In the event of an incidental finding suggesting susceptibility to heritable cancer, a consult to genetic counseling is recommended.

Many studies of the genetics of breast cancer are now focusing on known hereditary breast cancer syndromes and on possibilities for risk reduction, lifestyle modification, and identification of genetic variations that may increase or decrease cancer risk for an individual patient. The Center for Personalized Genetic Healthcare at Cleveland Clinic is collaborating in one such study. Titled “Risk Factor Analysis of Hereditary Breast and Ovarian Cancer Syndrome,” it is an international study led by a leading breast cancer researcher, Dr. Steven Narod from the Women’s College Research Institute in Toronto, ON. This study is focusing on women with a BRCA1 or BRCA2 mutation and their personal cancer risk factors, lifestyle choices, and overall development of cancer. This research group and others are also focusing on identifying genetic “modifiers” of cancer risk in these high-risk women.²⁹

For patients who do not have a hereditary cancer syndrome, research is further exploring novel genes and their relation to breast cancer risk. One such study in our laboratory has found that several genes once thought only to cause an increased risk of hereditary paraganglioma may also predispose to breast and thyroid cancer.^29,31 Additional research in this area is under way to clarify these risks.

GOOD SCIENCE, BAD MEDICINE?

Other research studies have identified a number of genes currently thought to be “moderately penetrant” for breast cancer risk, meaning that they may confer a risk of breast cancer slightly greater than that in the general population, but in some instances the risk has not been proven to be high enough to alter a patient’s management.^32,33

Although a few clinical laboratories currently offer testing for these kinds of genes, the clinical utility of this testing is questionable. Before offering testing on a clinical basis, we need clear, consistent data on the types of cancers associated with these genes and on the lifetime percentage risk of acquiring these cancers. Currently, it is difficult to understand whether a variant in a moderately penetrant gene is the true explanation behind a patient’s breast cancer diagnosis. If such a variant is identified and family members pursue testing for it, should those family members who test negative be considered to have the same risk of cancer as the general population? And should family members testing positive be offered prophylactic surgical options?

Without more data these questions cannot be answered, and until such data are gathered, we believe that testing for moderately penetrant genes should not be performed outside of a research study. The Center for Personalized Genetic Healthcare in Cleveland Clinic’s Genomic Medicine Institute can assist in educating and coordinating patients’ enrollment in such research studies.

PUTTING IT ALL TOGETHER

Primary care physicians are the first-line providers to individuals and families, many of whom have a personal or family history of breast cancer. Identifying patients at risk of breast cancer and hereditary cancer syndromes can be challenging in this era of shortened appointment times and patients with complex medical histories.

Reviewing an individual’s personal and cancer family history is a necessary first step in considering appropriate medical management recommendations for cancer screening and prevention, the cornerstone of personalized health care. Patients with hereditary breast cancer syndromes and those with familial breast cancer can benefit from high-risk breast cancer surveillance.

Cancer genetics risk assessment ensures that the correct genetic testing is offered to the most appropriate patients, with personalized interpretation of results and provision of future management recommendations based on the individual patient’s personal and family history. Genetic counselors empower patients to make educated and informed decisions about genetic testing, cancer screening, and prevention.

As health care continues to focus more on prevention in this new era of genomic medicine and value-based delivery of health care, genetic counselors will serve as powerful allies to physicians.³⁴

Acknowledgments: We would like to thank Dr. Colleen Clayton and Dr. Lynn Pattimakiel of the Medicine Institute, Cleveland Clinic, for their critical review of and thoughtful feedback on this manuscript.

No. Based on current evidence and guidelines, routine acid-suppressive therapy to prevent stress ulcers has no benefit in hospitalized patients outside the critical-care setting. Only critically ill patients who meet specific criteria, as described in the guidelines of the American Society of Health System Pharmacists, should receive acid-suppressive therapy.

Unfortunately, routine stress ulcer prophylaxis is common in US hospitals, unnecessarily putting patients at risk of complications and adding costs.

STRESS ULCER AND CRITICAL ILLNESS

Stress ulcers—ulcerations of the upper part of the gastrointestinal (GI) mucosa in the setting of acute disease—usually involve the fundus and body of the stomach. The stomach is lined with a glycoprotein mucous layer rich in bicarbonates, forming a physiologic barrier to protect the gastric wall from acid insult by neutralizing hydrogen ions. Disruption of this protective layer can occur in critically ill patients (eg, those with shock or sepsis) through overproduction of uremic toxins, increased reflux of bile salts, compromised blood flow, and increased stomach acidity through gastrin stimulation of parietal cells.

More than 75% of patients with major burns or cranial trauma develop endoscopic mucosal abnormalities within 72 hours of injury.¹ In critically ill patients, the risk of ulcer-related overt bleeding is estimated to be 5% to 25%. Furthermore, 1% to 5% of stress ulcers can be deep enough to erode into the submucosa, causing clinically significant GI bleeding, defined as bleeding complicated by hemodynamic compromise or a drop in hemoglobin that requires a blood transfusion.² In contrast, in inpatients who are not critically ill, the risk of overt bleeding from stress ulcers is less than 1%.³

ADDRESSING RISK

A multicenter prospective cohort study of 2,252 intensive care patients² reported two main risk factors for significant bleeding caused by stress ulcers: mechanical ventilation for more than 48 hours and coagulopathy, defined as a platelet count below 50 × 10⁹/L, an international normalized ratio greater than 1.5, or a partial thromboplastin time more than twice the control value.⁴ In hemodynamically stable patients receiving anticoagulation in a general medical or surgical ward, the risk of GI bleeding was low, and acid suppression failed to lower the rate of stress ulcer occurrence.³

Other risk factors include severe sepsis, shock, liver failure, kidney failure, burns over 35% of the total body surface, organ transplantation, cranial trauma, spinal cord trauma, history of peptic ulcer disease, and history of upper GI bleeding.^3,5,6 Steroid therapy is not considered a risk factor for stress ulcers unless it is used in the presence of another risk factor such as use of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs).²

INDICATIONS FOR PROPHYLAXIS

Prophylaxis with a proton pump inhibitor (PPI) is indicated in specific conditions—ie, peptic ulcer disease, gastroesophageal reflux disease, chronic NSAID therapy, and Zollinger-Ellison syndrome—and to eradicate Helicobacter pylori infection.⁷ But in the United States, stress ulcer prophylaxis is overused in general-care floors despite the lack of supporting evidence.

The American Society of Health System Pharmacists guidelines recommend it in the intensive care unit for patients with any of the following: coagulopathy, prolonged mechanical ventilation (more than 48 hours), GI ulcer or bleeding within the past year, sepsis, a stay longer than 1 week in the intensive care unit, occult GI bleeding for 6 or more days, and steroid therapy with more than 250 mg of hydrocortisone daily.⁸ Hemodynamically stable patients admitted to general-care floors should not receive stress ulcer prophylaxis, as it only negligibly decreases the rate of GI bleeding, from 0.33% to 0.22%.⁹

WHY ROUTINE ULCER PROPHYLAXIS IS NOT FOR ALL HOSPITALIZED PATIENTS

Although stress ulcer prophylaxis is often considered benign, its lack of proven benefit, additional cost, and risk of adverse effects, including interactions with foods and other drugs, preclude using it routinely for all hospitalized patients.^10,11 Chronic use of PPIs has been associated with complications, as discussed below.

Infection

Acid suppression may impair the destruction of ingested microorganisms, resulting in overgrowth of bacteria.¹² Overuse of PPIs may increase the risk of several infections:

• Diarrhea due to Clostridium difficile¹²
• Community-acquired pneumonia, from increased microaspiration of overgrown microorganisms into the lung.¹²
• Spontaneous bacterial peritonitis in patients with cirrhosis,¹³ although the mechanism is not clear. (Small-bowel bacterial overgrowth is the hypothesized cause.)

Bone fracture

PPIs lower gastric acidity, and this can inhibit intestinal calcium absorption. Furthermore, PPIs may directly inhibit bone resorption by osteoclasts.¹⁴

Reduction in clopidogrel efficacy

PPIs may reduce the efficacy of clopidogrel as a result of competitive inhibition of cytochrome CYP2C19, which is necessary to metabolize clopidogrel to its active forms. Therefore, concomitant use of clopidogrel with omeprazole, esomeprazole, or other CYP2C19 inhibitors is not recommended.¹⁵

Nutritional deficiencies

The overgrown microorganisms consume cobalamin in the stomach, resulting in vitamin B₁₂ deficiency. Acid-suppressive therapy can also reduce the absorption of magnesium and iron.¹²

Unnecessary cost

Heidelbaugh and Inadomi¹⁶ reviewed the non-evidence-based use of stress ulcer prophylaxis in patients admitted to a large university hospital and estimated that it entailed a cost to the hospital of $111,791 over the course of a year.

WHICH ULCER PROPHYLAXIS SHOULD BE USED IN CRITICALLY ILL PATIENTS?

Studies have shown histamine-2 blockers to be superior to antacids and sucralfate in preventing stress ulcer and GI bleeding,^8,15 but no study has compared PPIs with sucralfate and antacids.

When indicated, an oral PPI is preferred over an oral histamine-2 blocker for GI prophylaxis.¹⁷ This practice is considered cost-effective and is associated with lower rates of stress ulcer and GI bleeding. In intubated patients, however, an intravenous histamine-2 blocker is preferable to an intravenous PPI.^3,8,11 Interestingly, no difference was reported between PPIs and histamine-2 blockers in terms of mortality rate or reduction in the incidence of nosocomial pneumonia.¹⁷

OUR RECOMMENDATION

Only critically ill patients who meet the specific criteria described here should receive stress ulcer prophylaxis. More effort is needed to educate residents, medical staff, and pharmacists about current guidelines. Computerized ordering templates and reminders to discontinue prophylaxis at discharge or step-down may decrease overall use, reduce costs, and limit potential side effects.¹⁸

No. Based on current evidence and guidelines, routine acid-suppressive therapy to prevent stress ulcers has no benefit in hospitalized patients outside the critical-care setting. Only critically ill patients who meet specific criteria, as described in the guidelines of the American Society of Health System Pharmacists, should receive acid-suppressive therapy.

Unfortunately, routine stress ulcer prophylaxis is common in US hospitals, unnecessarily putting patients at risk of complications and adding costs.

STRESS ULCER AND CRITICAL ILLNESS

Stress ulcers—ulcerations of the upper part of the gastrointestinal (GI) mucosa in the setting of acute disease—usually involve the fundus and body of the stomach. The stomach is lined with a glycoprotein mucous layer rich in bicarbonates, forming a physiologic barrier to protect the gastric wall from acid insult by neutralizing hydrogen ions. Disruption of this protective layer can occur in critically ill patients (eg, those with shock or sepsis) through overproduction of uremic toxins, increased reflux of bile salts, compromised blood flow, and increased stomach acidity through gastrin stimulation of parietal cells.

More than 75% of patients with major burns or cranial trauma develop endoscopic mucosal abnormalities within 72 hours of injury.¹ In critically ill patients, the risk of ulcer-related overt bleeding is estimated to be 5% to 25%. Furthermore, 1% to 5% of stress ulcers can be deep enough to erode into the submucosa, causing clinically significant GI bleeding, defined as bleeding complicated by hemodynamic compromise or a drop in hemoglobin that requires a blood transfusion.² In contrast, in inpatients who are not critically ill, the risk of overt bleeding from stress ulcers is less than 1%.³

ADDRESSING RISK

A multicenter prospective cohort study of 2,252 intensive care patients² reported two main risk factors for significant bleeding caused by stress ulcers: mechanical ventilation for more than 48 hours and coagulopathy, defined as a platelet count below 50 × 10⁹/L, an international normalized ratio greater than 1.5, or a partial thromboplastin time more than twice the control value.⁴ In hemodynamically stable patients receiving anticoagulation in a general medical or surgical ward, the risk of GI bleeding was low, and acid suppression failed to lower the rate of stress ulcer occurrence.³

Other risk factors include severe sepsis, shock, liver failure, kidney failure, burns over 35% of the total body surface, organ transplantation, cranial trauma, spinal cord trauma, history of peptic ulcer disease, and history of upper GI bleeding.^3,5,6 Steroid therapy is not considered a risk factor for stress ulcers unless it is used in the presence of another risk factor such as use of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs).²

INDICATIONS FOR PROPHYLAXIS

Prophylaxis with a proton pump inhibitor (PPI) is indicated in specific conditions—ie, peptic ulcer disease, gastroesophageal reflux disease, chronic NSAID therapy, and Zollinger-Ellison syndrome—and to eradicate Helicobacter pylori infection.⁷ But in the United States, stress ulcer prophylaxis is overused in general-care floors despite the lack of supporting evidence.

The American Society of Health System Pharmacists guidelines recommend it in the intensive care unit for patients with any of the following: coagulopathy, prolonged mechanical ventilation (more than 48 hours), GI ulcer or bleeding within the past year, sepsis, a stay longer than 1 week in the intensive care unit, occult GI bleeding for 6 or more days, and steroid therapy with more than 250 mg of hydrocortisone daily.⁸ Hemodynamically stable patients admitted to general-care floors should not receive stress ulcer prophylaxis, as it only negligibly decreases the rate of GI bleeding, from 0.33% to 0.22%.⁹

WHY ROUTINE ULCER PROPHYLAXIS IS NOT FOR ALL HOSPITALIZED PATIENTS

Although stress ulcer prophylaxis is often considered benign, its lack of proven benefit, additional cost, and risk of adverse effects, including interactions with foods and other drugs, preclude using it routinely for all hospitalized patients.^10,11 Chronic use of PPIs has been associated with complications, as discussed below.

Infection

Acid suppression may impair the destruction of ingested microorganisms, resulting in overgrowth of bacteria.¹² Overuse of PPIs may increase the risk of several infections:

• Diarrhea due to Clostridium difficile¹²
• Community-acquired pneumonia, from increased microaspiration of overgrown microorganisms into the lung.¹²
• Spontaneous bacterial peritonitis in patients with cirrhosis,¹³ although the mechanism is not clear. (Small-bowel bacterial overgrowth is the hypothesized cause.)

Bone fracture

PPIs lower gastric acidity, and this can inhibit intestinal calcium absorption. Furthermore, PPIs may directly inhibit bone resorption by osteoclasts.¹⁴

Reduction in clopidogrel efficacy

PPIs may reduce the efficacy of clopidogrel as a result of competitive inhibition of cytochrome CYP2C19, which is necessary to metabolize clopidogrel to its active forms. Therefore, concomitant use of clopidogrel with omeprazole, esomeprazole, or other CYP2C19 inhibitors is not recommended.¹⁵

Nutritional deficiencies

The overgrown microorganisms consume cobalamin in the stomach, resulting in vitamin B₁₂ deficiency. Acid-suppressive therapy can also reduce the absorption of magnesium and iron.¹²

Unnecessary cost

Heidelbaugh and Inadomi¹⁶ reviewed the non-evidence-based use of stress ulcer prophylaxis in patients admitted to a large university hospital and estimated that it entailed a cost to the hospital of $111,791 over the course of a year.

WHICH ULCER PROPHYLAXIS SHOULD BE USED IN CRITICALLY ILL PATIENTS?

Studies have shown histamine-2 blockers to be superior to antacids and sucralfate in preventing stress ulcer and GI bleeding,^8,15 but no study has compared PPIs with sucralfate and antacids.

When indicated, an oral PPI is preferred over an oral histamine-2 blocker for GI prophylaxis.¹⁷ This practice is considered cost-effective and is associated with lower rates of stress ulcer and GI bleeding. In intubated patients, however, an intravenous histamine-2 blocker is preferable to an intravenous PPI.^3,8,11 Interestingly, no difference was reported between PPIs and histamine-2 blockers in terms of mortality rate or reduction in the incidence of nosocomial pneumonia.¹⁷

OUR RECOMMENDATION

Only critically ill patients who meet the specific criteria described here should receive stress ulcer prophylaxis. More effort is needed to educate residents, medical staff, and pharmacists about current guidelines. Computerized ordering templates and reminders to discontinue prophylaxis at discharge or step-down may decrease overall use, reduce costs, and limit potential side effects.¹⁸

No. Based on current evidence and guidelines, routine acid-suppressive therapy to prevent stress ulcers has no benefit in hospitalized patients outside the critical-care setting. Only critically ill patients who meet specific criteria, as described in the guidelines of the American Society of Health System Pharmacists, should receive acid-suppressive therapy.

Unfortunately, routine stress ulcer prophylaxis is common in US hospitals, unnecessarily putting patients at risk of complications and adding costs.

STRESS ULCER AND CRITICAL ILLNESS

Stress ulcers—ulcerations of the upper part of the gastrointestinal (GI) mucosa in the setting of acute disease—usually involve the fundus and body of the stomach. The stomach is lined with a glycoprotein mucous layer rich in bicarbonates, forming a physiologic barrier to protect the gastric wall from acid insult by neutralizing hydrogen ions. Disruption of this protective layer can occur in critically ill patients (eg, those with shock or sepsis) through overproduction of uremic toxins, increased reflux of bile salts, compromised blood flow, and increased stomach acidity through gastrin stimulation of parietal cells.

More than 75% of patients with major burns or cranial trauma develop endoscopic mucosal abnormalities within 72 hours of injury.¹ In critically ill patients, the risk of ulcer-related overt bleeding is estimated to be 5% to 25%. Furthermore, 1% to 5% of stress ulcers can be deep enough to erode into the submucosa, causing clinically significant GI bleeding, defined as bleeding complicated by hemodynamic compromise or a drop in hemoglobin that requires a blood transfusion.² In contrast, in inpatients who are not critically ill, the risk of overt bleeding from stress ulcers is less than 1%.³

ADDRESSING RISK

A multicenter prospective cohort study of 2,252 intensive care patients² reported two main risk factors for significant bleeding caused by stress ulcers: mechanical ventilation for more than 48 hours and coagulopathy, defined as a platelet count below 50 × 10⁹/L, an international normalized ratio greater than 1.5, or a partial thromboplastin time more than twice the control value.⁴ In hemodynamically stable patients receiving anticoagulation in a general medical or surgical ward, the risk of GI bleeding was low, and acid suppression failed to lower the rate of stress ulcer occurrence.³

Other risk factors include severe sepsis, shock, liver failure, kidney failure, burns over 35% of the total body surface, organ transplantation, cranial trauma, spinal cord trauma, history of peptic ulcer disease, and history of upper GI bleeding.^3,5,6 Steroid therapy is not considered a risk factor for stress ulcers unless it is used in the presence of another risk factor such as use of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs).²

INDICATIONS FOR PROPHYLAXIS

Prophylaxis with a proton pump inhibitor (PPI) is indicated in specific conditions—ie, peptic ulcer disease, gastroesophageal reflux disease, chronic NSAID therapy, and Zollinger-Ellison syndrome—and to eradicate Helicobacter pylori infection.⁷ But in the United States, stress ulcer prophylaxis is overused in general-care floors despite the lack of supporting evidence.

The American Society of Health System Pharmacists guidelines recommend it in the intensive care unit for patients with any of the following: coagulopathy, prolonged mechanical ventilation (more than 48 hours), GI ulcer or bleeding within the past year, sepsis, a stay longer than 1 week in the intensive care unit, occult GI bleeding for 6 or more days, and steroid therapy with more than 250 mg of hydrocortisone daily.⁸ Hemodynamically stable patients admitted to general-care floors should not receive stress ulcer prophylaxis, as it only negligibly decreases the rate of GI bleeding, from 0.33% to 0.22%.⁹

WHY ROUTINE ULCER PROPHYLAXIS IS NOT FOR ALL HOSPITALIZED PATIENTS

Although stress ulcer prophylaxis is often considered benign, its lack of proven benefit, additional cost, and risk of adverse effects, including interactions with foods and other drugs, preclude using it routinely for all hospitalized patients.^10,11 Chronic use of PPIs has been associated with complications, as discussed below.

Infection

Acid suppression may impair the destruction of ingested microorganisms, resulting in overgrowth of bacteria.¹² Overuse of PPIs may increase the risk of several infections:

• Diarrhea due to Clostridium difficile¹²
• Community-acquired pneumonia, from increased microaspiration of overgrown microorganisms into the lung.¹²
• Spontaneous bacterial peritonitis in patients with cirrhosis,¹³ although the mechanism is not clear. (Small-bowel bacterial overgrowth is the hypothesized cause.)

Bone fracture

PPIs lower gastric acidity, and this can inhibit intestinal calcium absorption. Furthermore, PPIs may directly inhibit bone resorption by osteoclasts.¹⁴

Reduction in clopidogrel efficacy

PPIs may reduce the efficacy of clopidogrel as a result of competitive inhibition of cytochrome CYP2C19, which is necessary to metabolize clopidogrel to its active forms. Therefore, concomitant use of clopidogrel with omeprazole, esomeprazole, or other CYP2C19 inhibitors is not recommended.¹⁵

Nutritional deficiencies

The overgrown microorganisms consume cobalamin in the stomach, resulting in vitamin B₁₂ deficiency. Acid-suppressive therapy can also reduce the absorption of magnesium and iron.¹²

Unnecessary cost

Heidelbaugh and Inadomi¹⁶ reviewed the non-evidence-based use of stress ulcer prophylaxis in patients admitted to a large university hospital and estimated that it entailed a cost to the hospital of $111,791 over the course of a year.

WHICH ULCER PROPHYLAXIS SHOULD BE USED IN CRITICALLY ILL PATIENTS?

Studies have shown histamine-2 blockers to be superior to antacids and sucralfate in preventing stress ulcer and GI bleeding,^8,15 but no study has compared PPIs with sucralfate and antacids.

When indicated, an oral PPI is preferred over an oral histamine-2 blocker for GI prophylaxis.¹⁷ This practice is considered cost-effective and is associated with lower rates of stress ulcer and GI bleeding. In intubated patients, however, an intravenous histamine-2 blocker is preferable to an intravenous PPI.^3,8,11 Interestingly, no difference was reported between PPIs and histamine-2 blockers in terms of mortality rate or reduction in the incidence of nosocomial pneumonia.¹⁷

OUR RECOMMENDATION

Only critically ill patients who meet the specific criteria described here should receive stress ulcer prophylaxis. More effort is needed to educate residents, medical staff, and pharmacists about current guidelines. Computerized ordering templates and reminders to discontinue prophylaxis at discharge or step-down may decrease overall use, reduce costs, and limit potential side effects.¹⁸

A 67-year-old man with a history of hypertension and hyperlipidemia presented to the emergency department after 3 hours of what he described as a burning sensation in his chest that woke him from sleep. He attributed it at first to a late-night meal and treated himself with some milk and yogurt, which seemed to relieve the symptoms. However, the pain recurred and was associated with difficulty breathing. At that point, he drove himself to the emergency department.

On arrival, his temperature was 36.5°C (97.7°F), blood pressure 134/67 mm Hg, heart rate 89 bpm, respirations 18/min, and oxygen saturation 98% on room air. His cardiovascular, lung, and neurologic examinations were normal. His cardiac enzyme levels (creatine kinase, creatine kinase MB fraction, and troponin T) were within normal limits.

Figure 1 depicts his initial electrocardiogram. It showed deep, symmetric T-wave inversions in the precordial leads especially in V₂ and V₃, changes known as Wellens syndrome. The ST-T changes in lead V₁ suggested a very proximal lesion in the left anterior descending artery (LAD), before the first septal perforator. Also, lateral and high lateral (V₅ and V₆) findings indicated stenoses of the branching diagonals and left circumflex myocardial territory. Furthermore, the inferior ST-T changes indicated that his LAD may have wrapped around the cardiac apex. All of these findings were prognostically significant.

The patient was given aspirin and was started on intravenous unfractionated heparin and nitroglycerin. He was sent for urgent left-heart catheterization, which showed a 50% to 60% stenosis in the left main coronary artery, with involvement of the left circumflex artery proximally, in addition to a “tight” first-diagonal stenosis, a 90% stenosis in a large (> 3.0-mm) proximal segment of the LAD, an 80% stenosis in a large (> 3.0-mm) mid-LAD segment, and a 40% stenosis in a large (> 3.0-mm) second diagonal artery (Figure 2).

He was referred for cardiac surgery and underwent triple coronary artery bypass grafting: the left internal thoracic artery was grafted to the LAD, a reverse saphenous vein graft was performed to the diagonal artery, and a reverse saphenous vein graft was performed to the obtuse marginal artery.

A PRECURSOR TO INFARCTION

Wellens et al described specific precordial T-wave changes in patients with unstable angina who subsequently developed anterior wall myocardial infarction.¹

The importance of Wellens syndrome is that it occurs in the pain-free interval when no other evidence of ischemia or angina may be present.¹ Cardiac enzyme levels are typically normal or only minimally elevated; only 12% of patients with this syndrome have elevated cardiac biomarker levels.²

Given the extent of myocardial injury, urgent echocardiography can show a wall-motion abnormality even if cardiac enzyme levels are normal. This gives important insight into electrocardiographic changes and should prompt consideration of revascularization.

Even with extensive medical management, Wellens syndrome progresses to acute anterior wall ischemia. About 75% of patients with Wellens syndrome who receive medical management but do not undergo revascularization (eg, coronary artery bypass grafting, percutaneous coronary intervention) develop extensive anterior wall infarction within days.^1,3 Despite negative cardiac biomarkers, Wellens syndrome is considered an acute coronary syndrome requiring urgent cardiac intervention.

A 67-year-old man with a history of hypertension and hyperlipidemia presented to the emergency department after 3 hours of what he described as a burning sensation in his chest that woke him from sleep. He attributed it at first to a late-night meal and treated himself with some milk and yogurt, which seemed to relieve the symptoms. However, the pain recurred and was associated with difficulty breathing. At that point, he drove himself to the emergency department.

On arrival, his temperature was 36.5°C (97.7°F), blood pressure 134/67 mm Hg, heart rate 89 bpm, respirations 18/min, and oxygen saturation 98% on room air. His cardiovascular, lung, and neurologic examinations were normal. His cardiac enzyme levels (creatine kinase, creatine kinase MB fraction, and troponin T) were within normal limits.

Figure 1 depicts his initial electrocardiogram. It showed deep, symmetric T-wave inversions in the precordial leads especially in V₂ and V₃, changes known as Wellens syndrome. The ST-T changes in lead V₁ suggested a very proximal lesion in the left anterior descending artery (LAD), before the first septal perforator. Also, lateral and high lateral (V₅ and V₆) findings indicated stenoses of the branching diagonals and left circumflex myocardial territory. Furthermore, the inferior ST-T changes indicated that his LAD may have wrapped around the cardiac apex. All of these findings were prognostically significant.

The patient was given aspirin and was started on intravenous unfractionated heparin and nitroglycerin. He was sent for urgent left-heart catheterization, which showed a 50% to 60% stenosis in the left main coronary artery, with involvement of the left circumflex artery proximally, in addition to a “tight” first-diagonal stenosis, a 90% stenosis in a large (> 3.0-mm) proximal segment of the LAD, an 80% stenosis in a large (> 3.0-mm) mid-LAD segment, and a 40% stenosis in a large (> 3.0-mm) second diagonal artery (Figure 2).

He was referred for cardiac surgery and underwent triple coronary artery bypass grafting: the left internal thoracic artery was grafted to the LAD, a reverse saphenous vein graft was performed to the diagonal artery, and a reverse saphenous vein graft was performed to the obtuse marginal artery.

A PRECURSOR TO INFARCTION

Wellens et al described specific precordial T-wave changes in patients with unstable angina who subsequently developed anterior wall myocardial infarction.¹

The importance of Wellens syndrome is that it occurs in the pain-free interval when no other evidence of ischemia or angina may be present.¹ Cardiac enzyme levels are typically normal or only minimally elevated; only 12% of patients with this syndrome have elevated cardiac biomarker levels.²

Given the extent of myocardial injury, urgent echocardiography can show a wall-motion abnormality even if cardiac enzyme levels are normal. This gives important insight into electrocardiographic changes and should prompt consideration of revascularization.

Even with extensive medical management, Wellens syndrome progresses to acute anterior wall ischemia. About 75% of patients with Wellens syndrome who receive medical management but do not undergo revascularization (eg, coronary artery bypass grafting, percutaneous coronary intervention) develop extensive anterior wall infarction within days.^1,3 Despite negative cardiac biomarkers, Wellens syndrome is considered an acute coronary syndrome requiring urgent cardiac intervention.

A 67-year-old man with a history of hypertension and hyperlipidemia presented to the emergency department after 3 hours of what he described as a burning sensation in his chest that woke him from sleep. He attributed it at first to a late-night meal and treated himself with some milk and yogurt, which seemed to relieve the symptoms. However, the pain recurred and was associated with difficulty breathing. At that point, he drove himself to the emergency department.

On arrival, his temperature was 36.5°C (97.7°F), blood pressure 134/67 mm Hg, heart rate 89 bpm, respirations 18/min, and oxygen saturation 98% on room air. His cardiovascular, lung, and neurologic examinations were normal. His cardiac enzyme levels (creatine kinase, creatine kinase MB fraction, and troponin T) were within normal limits.

Figure 1 depicts his initial electrocardiogram. It showed deep, symmetric T-wave inversions in the precordial leads especially in V₂ and V₃, changes known as Wellens syndrome. The ST-T changes in lead V₁ suggested a very proximal lesion in the left anterior descending artery (LAD), before the first septal perforator. Also, lateral and high lateral (V₅ and V₆) findings indicated stenoses of the branching diagonals and left circumflex myocardial territory. Furthermore, the inferior ST-T changes indicated that his LAD may have wrapped around the cardiac apex. All of these findings were prognostically significant.

The patient was given aspirin and was started on intravenous unfractionated heparin and nitroglycerin. He was sent for urgent left-heart catheterization, which showed a 50% to 60% stenosis in the left main coronary artery, with involvement of the left circumflex artery proximally, in addition to a “tight” first-diagonal stenosis, a 90% stenosis in a large (> 3.0-mm) proximal segment of the LAD, an 80% stenosis in a large (> 3.0-mm) mid-LAD segment, and a 40% stenosis in a large (> 3.0-mm) second diagonal artery (Figure 2).

He was referred for cardiac surgery and underwent triple coronary artery bypass grafting: the left internal thoracic artery was grafted to the LAD, a reverse saphenous vein graft was performed to the diagonal artery, and a reverse saphenous vein graft was performed to the obtuse marginal artery.

A PRECURSOR TO INFARCTION

Wellens et al described specific precordial T-wave changes in patients with unstable angina who subsequently developed anterior wall myocardial infarction.¹

The importance of Wellens syndrome is that it occurs in the pain-free interval when no other evidence of ischemia or angina may be present.¹ Cardiac enzyme levels are typically normal or only minimally elevated; only 12% of patients with this syndrome have elevated cardiac biomarker levels.²

Given the extent of myocardial injury, urgent echocardiography can show a wall-motion abnormality even if cardiac enzyme levels are normal. This gives important insight into electrocardiographic changes and should prompt consideration of revascularization.

Even with extensive medical management, Wellens syndrome progresses to acute anterior wall ischemia. About 75% of patients with Wellens syndrome who receive medical management but do not undergo revascularization (eg, coronary artery bypass grafting, percutaneous coronary intervention) develop extensive anterior wall infarction within days.^1,3 Despite negative cardiac biomarkers, Wellens syndrome is considered an acute coronary syndrome requiring urgent cardiac intervention.

Great effort has been spent on identifying easily measured biomarkers to predict the progression of coronary disease and chronic kidney disease (CKD). Interestingly, these two disease processes seem to share some biomarkers and perhaps some pathogenic mechanisms. An ultimate hope is that some of these markers will be found to also contribute directly to organ dysfunction and be amenable to therapy. Blood pressure and (in many people’s minds) low-density lipoprotein cholesterol fulfill this hope. The jury remains out on C-reactive protein and serum urate. There are others.

In this issue of the Journal, Stephen et al review the data indicating that albuminuria helps predict the progression of CKD, coronary disease, ventricular remodeling, and, in some studies, all-cause mortality. Proteinuria has generally been assumed to be a marker of renal injury, but, the authors point out, albumin can under some circumstances initiate inflammatory mechanisms and stimulate mediators of fibrosis.

Although not mentioned by Stephen et al, albumin (like hemoglobin) is susceptible to nonenzymatic glycosylation in patients with diabetes. There is a hint in the literature that glycosylated albumin may be preferentially excreted. Its effects on various tissues are incompletely studied, but it strikes me that perhaps this molecule plays a unique pathogenic role in diabetic renal and vascular disease, even more than native albumin. Further evaluation of this specific marker may lead to even stronger associations (although in a select population of patients with poorly controlled diabetes).

The focus on urine as a fluid with diagnostic and predictive characteristics is certainly not new. Both Hippocrates and Galen recognized the value of inspecting urine. Uroscopy (now urinalysis) may be the oldest surviving laboratory test. Recently, my friend Joe Nally, a coauthor with Stephen et al, shared with me a paper detailing the romantic yet checkered history of urinalysis.¹

Gilles de Corbeil in the 12th century wrote a poem on judging urine, intending it as an aid for remembering the supposed 20 different diagnostic colors of urine and describing in detail the use of the urine flask, a bladder-shaped container for studying the partitioning of the urine colors and substance as representative of the diseased parts of the body. A urine flask was even illustrated in a version of Chaucer’s Canterbury Tales as a recognized accoutrement of the stylish physician (Figure 1). The “art” of uroscopy grew so successful over the centuries as a component of rampant medical charlatanry (casting no aspersions, of course, on current nephrologists) that the Royal College of Physicians in 1601 felt pressed to attack the “pisse-mongers” by stating, “It is ridiculous and foolish to divine the…course of disease…from the inspection of urine.”¹ This dictate was apparently ignored then, but seemingly is too frequently followed by clinicians today, contributing to the oft-delayed diagnosis of glomerulonephritis and other renal diseases.

In 1637, Thomas Brian published The Pisse-Prophet or Certaine Pisse Pot Lectures, in which he railed against the witchcraft of uroscopy, which he said should only be performed by university-trained physicians. Jump forward to 1827, when Richard Bright elegantly described acute glomerulonephritis, although not the microscopic findings that would be illustrated in accurate detail by Golding Bird in his 1844 treatise, Urinary Deposits. Sitting on the bookshelf behind my desk is a copy of Richard W. Lippman’s Urine and Urinary Sediment: A Practical Manual and Atlas (1957). I have no urine flask—rheumatologists know their limitations.

As we enter 2014, all of us at the Journal offer you our sincere wishes for a personally healthy and universally peaceful new year.

Great effort has been spent on identifying easily measured biomarkers to predict the progression of coronary disease and chronic kidney disease (CKD). Interestingly, these two disease processes seem to share some biomarkers and perhaps some pathogenic mechanisms. An ultimate hope is that some of these markers will be found to also contribute directly to organ dysfunction and be amenable to therapy. Blood pressure and (in many people’s minds) low-density lipoprotein cholesterol fulfill this hope. The jury remains out on C-reactive protein and serum urate. There are others.

In this issue of the Journal, Stephen et al review the data indicating that albuminuria helps predict the progression of CKD, coronary disease, ventricular remodeling, and, in some studies, all-cause mortality. Proteinuria has generally been assumed to be a marker of renal injury, but, the authors point out, albumin can under some circumstances initiate inflammatory mechanisms and stimulate mediators of fibrosis.

Although not mentioned by Stephen et al, albumin (like hemoglobin) is susceptible to nonenzymatic glycosylation in patients with diabetes. There is a hint in the literature that glycosylated albumin may be preferentially excreted. Its effects on various tissues are incompletely studied, but it strikes me that perhaps this molecule plays a unique pathogenic role in diabetic renal and vascular disease, even more than native albumin. Further evaluation of this specific marker may lead to even stronger associations (although in a select population of patients with poorly controlled diabetes).

The focus on urine as a fluid with diagnostic and predictive characteristics is certainly not new. Both Hippocrates and Galen recognized the value of inspecting urine. Uroscopy (now urinalysis) may be the oldest surviving laboratory test. Recently, my friend Joe Nally, a coauthor with Stephen et al, shared with me a paper detailing the romantic yet checkered history of urinalysis.¹

Gilles de Corbeil in the 12th century wrote a poem on judging urine, intending it as an aid for remembering the supposed 20 different diagnostic colors of urine and describing in detail the use of the urine flask, a bladder-shaped container for studying the partitioning of the urine colors and substance as representative of the diseased parts of the body. A urine flask was even illustrated in a version of Chaucer’s Canterbury Tales as a recognized accoutrement of the stylish physician (Figure 1). The “art” of uroscopy grew so successful over the centuries as a component of rampant medical charlatanry (casting no aspersions, of course, on current nephrologists) that the Royal College of Physicians in 1601 felt pressed to attack the “pisse-mongers” by stating, “It is ridiculous and foolish to divine the…course of disease…from the inspection of urine.”¹ This dictate was apparently ignored then, but seemingly is too frequently followed by clinicians today, contributing to the oft-delayed diagnosis of glomerulonephritis and other renal diseases.

In 1637, Thomas Brian published The Pisse-Prophet or Certaine Pisse Pot Lectures, in which he railed against the witchcraft of uroscopy, which he said should only be performed by university-trained physicians. Jump forward to 1827, when Richard Bright elegantly described acute glomerulonephritis, although not the microscopic findings that would be illustrated in accurate detail by Golding Bird in his 1844 treatise, Urinary Deposits. Sitting on the bookshelf behind my desk is a copy of Richard W. Lippman’s Urine and Urinary Sediment: A Practical Manual and Atlas (1957). I have no urine flask—rheumatologists know their limitations.

As we enter 2014, all of us at the Journal offer you our sincere wishes for a personally healthy and universally peaceful new year.

Great effort has been spent on identifying easily measured biomarkers to predict the progression of coronary disease and chronic kidney disease (CKD). Interestingly, these two disease processes seem to share some biomarkers and perhaps some pathogenic mechanisms. An ultimate hope is that some of these markers will be found to also contribute directly to organ dysfunction and be amenable to therapy. Blood pressure and (in many people’s minds) low-density lipoprotein cholesterol fulfill this hope. The jury remains out on C-reactive protein and serum urate. There are others.

In this issue of the Journal, Stephen et al review the data indicating that albuminuria helps predict the progression of CKD, coronary disease, ventricular remodeling, and, in some studies, all-cause mortality. Proteinuria has generally been assumed to be a marker of renal injury, but, the authors point out, albumin can under some circumstances initiate inflammatory mechanisms and stimulate mediators of fibrosis.

Although not mentioned by Stephen et al, albumin (like hemoglobin) is susceptible to nonenzymatic glycosylation in patients with diabetes. There is a hint in the literature that glycosylated albumin may be preferentially excreted. Its effects on various tissues are incompletely studied, but it strikes me that perhaps this molecule plays a unique pathogenic role in diabetic renal and vascular disease, even more than native albumin. Further evaluation of this specific marker may lead to even stronger associations (although in a select population of patients with poorly controlled diabetes).

The focus on urine as a fluid with diagnostic and predictive characteristics is certainly not new. Both Hippocrates and Galen recognized the value of inspecting urine. Uroscopy (now urinalysis) may be the oldest surviving laboratory test. Recently, my friend Joe Nally, a coauthor with Stephen et al, shared with me a paper detailing the romantic yet checkered history of urinalysis.¹

Gilles de Corbeil in the 12th century wrote a poem on judging urine, intending it as an aid for remembering the supposed 20 different diagnostic colors of urine and describing in detail the use of the urine flask, a bladder-shaped container for studying the partitioning of the urine colors and substance as representative of the diseased parts of the body. A urine flask was even illustrated in a version of Chaucer’s Canterbury Tales as a recognized accoutrement of the stylish physician (Figure 1). The “art” of uroscopy grew so successful over the centuries as a component of rampant medical charlatanry (casting no aspersions, of course, on current nephrologists) that the Royal College of Physicians in 1601 felt pressed to attack the “pisse-mongers” by stating, “It is ridiculous and foolish to divine the…course of disease…from the inspection of urine.”¹ This dictate was apparently ignored then, but seemingly is too frequently followed by clinicians today, contributing to the oft-delayed diagnosis of glomerulonephritis and other renal diseases.

In 1637, Thomas Brian published The Pisse-Prophet or Certaine Pisse Pot Lectures, in which he railed against the witchcraft of uroscopy, which he said should only be performed by university-trained physicians. Jump forward to 1827, when Richard Bright elegantly described acute glomerulonephritis, although not the microscopic findings that would be illustrated in accurate detail by Golding Bird in his 1844 treatise, Urinary Deposits. Sitting on the bookshelf behind my desk is a copy of Richard W. Lippman’s Urine and Urinary Sediment: A Practical Manual and Atlas (1957). I have no urine flask—rheumatologists know their limitations.

As we enter 2014, all of us at the Journal offer you our sincere wishes for a personally healthy and universally peaceful new year.

“One can obtain considerable information concerning the general health by examining the urine.” 
—Hippocrates (460?–355? BCE)

Chronic kidney disease is a notable public health concern because it is an important risk factor for end-stage renal disease, cardiovascular disease, and death. Its prevalence¹ exceeds 10% and is considerably higher in high-risk groups, such as those with diabetes or hypertension, which are growing in the United States.

While high levels of total protein in the urine have always been recognized as pathologic, a growing body of evidence links excretion of the protein albumin to adverse cardiovascular outcomes, and most international guidelines now recommend measuring albumin specifically. Albuminuria is a predictor of declining renal function and is independently associated with adverse cardiovascular outcomes. Thus, clinicians need to detect it early, manage it effectively, and reduce concurrent risk factors for cardiovascular disease.

Therefore, this review will focus on albuminuria. However, because the traditional standard for urinary protein measurement was total protein, and because a few guidelines still recommend measuring total protein rather than albumin, we will also briefly discuss total urinary protein.

MOST URINARY PROTEIN IS ALBUMIN

Most of the protein in the urine is albumin filtered from the plasma. Less than half of the rest is derived from the distal renal tubules (uromodulin or Tamm-Horsfall mucoprotein), ² and urine also contains a small and varying proportion of immunoglobulins, low-molecular-weight proteins, and light chains.

Normal healthy people lose less than 30 mg of albumin in the urine per day. In greater amounts, albumin is the major urinary protein in most kidney diseases. Other proteins in urine can be specific markers of less-common illnesses such as plasma cell dyscrasia, glomerulopathy, and renal tubular disease.

MEASURING PROTEINURIA AND ALBUMINURIA

Albumin is not a homogeneous molecule in urine. It undergoes changes to its molecular configuration in the presence of certain ions, peptides, hormones, and drugs, and as a result of proteolytic fragmentation both in the plasma and in renal tubules.³ Consequently, measuring urinary albumin involves a trade-off between convenience and accuracy.

A 24-hour timed urine sample has long been the gold standard for measuring albuminuria, but the collection is cumbersome and time-consuming, and the test is prone to laboratory error.

Dipstick measurements are more convenient and are better at detecting albumin than other proteins in urine, but they have low sensitivity and high interobserver variation.^3–5

The albumin-to-creatinine ratio (ACR). As the quantity of protein in the urine changes with time of day, exertion, stress level, and posture, spot-checking of urine samples is not as good as timed collection. However, a simultaneous measurement of creatinine in a spot urine sample adjusts for protein concentration, which can vary with a person’s hydration status. The ACR so obtained is consistent with the 24-hour timed collection (the gold standard) and is the recommended method of assessing albuminuria.³ An early morning urine sample is favored, as it avoids orthostatic variations and varies less in the same individual.

In a study in the general population comparing the ACR in a random sample and in an early morning sample, only 44% of those who had an ACR of 30 mg/g or higher in the random sample had one this high in the early morning sample.⁶ However, getting an early morning sample is not always feasible in clinical practice. If you are going to measure albuminuria, the Kidney Disease Outcomes and Quality Initiative⁷ suggests checking the ACR in a random sample and then, if the test is positive, following up and confirming it within 3 months with an early morning sample.

Also, since creatinine excretion differs with race, diet, and muscle mass, if the 24-hour creatinine excretion is not close to 1 g, the ACR will give an erroneous estimate of the 24-hour excretion rate.³

Table 1 compares the various methods of measuring protein in the urine.^3,5,8,9 Of note, methods of measuring albumin and total protein vary considerably in their precision and accuracy, making it impossible to reliably translate values from one to the other.⁵

National and international guidelines (Table 2)^7,10–13 agree that albuminuria should be tested in diabetic patients, as it is a surrogate marker for early diabetic nephropathy.^3,13 Most guidelines also recommend measuring albuminuria by a urine ACR test as the preferred measure, even in people without diabetes.

Also, no single cutoff is universally accepted for distinguishing pathologic albuminuria from physiologic albuminuria, nor is there a universally accepted unit of measure.¹⁴ Because approximately 1 g of creatinine is lost in the urine per day, the ACR has the convenient property of numerically matching the albumin excretory rate expressed in milligrams per 24 hours. The other commonly used unit is milligrams of albumin per millimole of creatinine; 30 mg/g is roughly equal to 3 mg/mmol.

The term microalbuminuria was traditionally used to refer to albumin excretion of 30 to 299 mg per 24 hours, and macroalbuminuria to 300 mg or more per 24 hours. However, as there is no pathophysiologic basis to these thresholds (see outcomes data below), the current Kidney Disease Improving Global Outcomes (KDIGO) guidelines do not recommend using these terms.^13,15

RENAL COMPLICATIONS OF ALBUMINURIA

A failure of the glomerular filtration barrier or of proximal tubular reabsorption accounts for most cases of pathologic albuminuria.¹⁶ Processes affecting the glomerular filtration of albumin include endothelial cell dysfunction and abnormalities with the glomerular basement membrane, podocytes, or the slit diaphragms among the podocytic processes.¹⁷

Ultrafiltrated albumin has been directly implicated in tubulointerstitial damage and glomerulosclerosis through diverse pathways. In the proximal tubule, albumin up-regulates interleukin 8 (a chemoattractant for lymphocytes and neutrophils), induces synthesis of endothelin 1 (which stimulates renal cell proliferation, extracellular matrix production, and monocyte attraction), and causes apoptosis of tubular cells.¹⁸ In response to albumin, proximal tubular cells also stimulate interstitial fibroblasts via paracrine release of transforming growth factor beta, either directly or by activating complement or macrophages.^18,19

Studies linking albuminuria to kidney disease

Albuminuria has traditionally been associated with diabetes mellitus as a predictor of overt diabetic nephropathy,^20,21 although in type 1 diabetes, established albuminuria can spontaneously regress.²²

Albuminuria is also a strong predictor of progression in chronic kidney disease.²³ In fact, in the last decade, albuminuria has become an independent criterion in the definition of chronic kidney disease; excretion of more than 30 mg of albumin per day, sustained for at least 3 months, qualifies as chronic kidney disease, with independent prognostic implications (Table  3).¹³

Astor et al,²⁴ in a meta-analysis of 13 studies with more than 21,000 patients with chronic kidney disease, found that the risk of end-stage renal disease was three times higher in those with albuminuria.

Gansevoort et al,²³ in a meta-analysis of nine studies with nearly 850,000 participants from the general population, found that the risk of end-stage renal disease increased continuously as albumin excretion increased. They also found that as albuminuria increased, so did the risk of progression of chronic kidney disease and the incidence of acute kidney injury.

Hemmelgarn et al,²⁵ in a large pooled cohort study with more than 1.5 million participants from the general population, showed that increasing albuminuria was associated with a decline in the estimated glomerular filtration rate (GFR) and with progression to end-stage renal disease across all strata of baseline renal function. For example, in persons with an estimated GFR of 60 mL/min/1.73 m2

• 1 per 1,000 person-years for those with no proteinuria
• 2.8 per 1,000 person-years for those with mild proteinuria (trace or 1+ by dipstick or ACR 30–300 mg/g)
• 13.4 per 1,000 person-years for those with heavy proteinuria (2+ or ACR > 300 mg/g).

Rates of progression to end-stage renal disease were:

• 0.03 per 1,000 person-years with no proteinuria
• 0.05 per 1,000 person-years with mild proteinuria
• 1 per 1,000 person-years with heavy proteinuria.²⁵

CARDIOVASCULAR CONSEQUENCES OF ALBUMINURIA

The exact pathophysiologic link between albuminuria and cardiovascular disease is unknown, but several mechanisms have been proposed.

One is that generalized endothelial dysfunction causes both albuminuria and cardiovascular disease.²⁶ Endothelium-derived nitric oxide has vasodilator, antiplatelet, antiproliferative, antiadhesive, permeability-decreasing, and anti-inflammatory properties. Impaired endothelial synthesis of nitric oxide has been independently associated with both microalbuminuria and diabetes.²⁷

Low levels of heparan sulfate (which has antithrombogenic effects and decreases vessel permeability) in the glycocalyx lining vessel walls may also account for albuminuria and for the other cardiovascular effects.^28–30 These changes may be the consequence of chronic low-grade inflammation, which precedes the occurrence and progression of both albuminuria and atherothrombotic disease. The resulting abnormalities in the endothelial glycocalyx could lead to increased glomerular permeability to albumin and may also be implicated in the pathogenesis of atherosclerosis.²⁶

In an atherosclerotic aorta and coronary arteries, the endothelial dysfunction may cause increased leakage of cholesterol and glycated end-products into the myocardium, resulting in increasing wall stiffness and left ventricular mass. A similar atherosclerotic process may account for coronary artery microthrombi, resulting in subendocardial ischemia that could lead to systolic and diastolic heart dysfunction.³¹

Studies linking albuminuria to heart disease

There is convincing evidence that albuminuria is associated with cardiovascular disease. An ACR between 30 and 300 mg/g was independently associated with myocardial infarction and ischemia.³² People with albuminuria have more than twice the risk of severe coronary artery disease, and albuminuria is also associated with increased intimal thickening in the carotid arteries.^33,34 An ACR in the same range has been associated with increased incidence and progression of coronary artery calcification.³⁵ Higher brachial-ankle pulse-wave velocity has also been demonstrated with albuminuria in a dose-dependent fashion.^36,37

An ACR of 30 to 300 mg/g has been linked to left ventricular hypertrophy independently of other risk factors,³⁸ and functionally with diastolic dysfunction and abnormal midwall shortening.³⁹ In a study of a subgroup of patients with diabetes from a population-based cohort of Native American patients (the Strong Heart Study),³⁹ the prevalence of diastolic dysfunction was:

• 16% in those with no albuminuria
• 26% in those with an ACR of 30 to 300 mg/g
• 31% in those with an ACR greater than 300 mg/g.

The association persisted even after controlling for age, sex, hypertension, and other covariates.

Those pathologic associations have been directly linked to clinical outcomes. For patients with heart failure (New York Heart Association class II–IV), a study found that albuminuria (an ACR > 30 mg/g) conferred a 41% higher risk of admission for heart failure, and an ACR greater than 300 mg/g was associated with an 88% higher risk.⁴⁰

In an analysis of a prospective cohort from the general population with albuminuria and a low prevalence of renal dysfunction (the Prevention of Renal and Vascular Endstage Disease study),⁴¹ albuminuria was associated with a modest increase in the incidence of the composite end point of myocardial infarction, stroke, ischemic heart disease, revascularization procedures, and all-cause mortality per doubling of the urine albumin excretion (hazard ratio 1.08, range 1.04 –1.12).

The relationship to cardiovascular outcomes extends below traditional lower-limit thresholds of albuminuria (corresponding to an ACR > 30 mg/g). A subgroup of patients from the Framingham Offspring Study without prevalent cardiovascular disease, hypertension, diabetes, or kidney disease, and thus with a low to intermediate probability of cardiovascular events, were found to have thresholds for albuminuria as low as 5.3 mg/g in men and 10.8 mg/g in women to discriminate between incident coronary artery disease, heart failure, cerebrovascular disease, other peripheral vascular disease, or death.⁴²

In a meta-analysis including more than 1 million patients in the general population, increasing albuminuria was associated with an increase in deaths from all causes in a continuous manner, with no threshold effect.⁴³ In patients with an ACR of 30 mg/g, the hazard ratio for death was 1.63, increasing to 2.22 for those with more than 300 mg/g compared with those with no albuminuria. A similar increase in the risk of myocardial infarction, heart failure, stroke, or sudden cardiac death was noted with higher ACR.⁴³

Important prospective cohort studies and meta-analyses related to albuminuria and kidney and cardiovascular disease and death are summarized in the eTable.^23,39–50

THE CASE FOR TREATING ALBUMINURIA

Reduced progression of renal disease

Treating patients who have proteinuric chronic kidney disease with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) can reduce the risk of progression of renal failure. However, it is unclear whether this benefit is the result of treating concomitant risk factors independent of the reduction in albuminuria, and there is no consistent treatment effect in improving renal outcomes across studies.

Fink et al,⁵¹ in a meta-analysis, found that chronic kidney disease patients with diabetes, hypertension, and macroalbuminuria had a 40% lower risk of progression to end-stage renal disease if they received an ACE inhibitor (relative risk [RR] 0.60, 95% confidence interval [CI] 0.43–0.83). In the same meta-analysis, ARBs also reduced the risk of progression to end-stage renal disease (RR 0.77, 95% CI 0.66–0.90).

Jafar et al,⁵² in an analysis of pooled patient-level data including only nondiabetic patients on ACE inhibitor therapy (n = 1,860), found that the risk of progression of renal failure, defined as a doubling of serum creatinine or end-stage renal disease, was reduced (RR 0.70, 95% CI 0.55–0.88). Patients with higher levels of albuminuria showed the most benefit, but the effect was not conclusive for albuminuria below 500 mg/day at baseline.

Maione et al,⁵³ in a meta-analysis that included patients with albuminuria who were treated with ACE inhibitors vs placebo (n = 8,231), found a similar reduction in risk of:

• Progression to end-stage renal disease (RR 0.67, 95% CI 0.54–0.84)
• Doubling of serum creatinine (RR 0.62, 95% CI 0.46–0.84)
• Progression of albuminuria (RR 0.49, 95% CI 0.36–0.65)
• Normalization of pathologic albuminuria (as defined by the trialists in the individual studies) (RR 2.99, 95% CI 1.82–4.91).

Similar results were obtained for patients with albuminuria who were treated with ARBs.⁵³

ONTARGET.⁵⁴ In contrast, in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial, the combination of an ACE inhibitor and an ARB showed no benefit in reducing the progression of renal failure, and in those patients with chronic kidney disease there was a higher risk of a doubling of serum creatinine or of the development of end-stage renal disease and hyperkalemia.

Also, in a pooled analysis of the ONTARGET and Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) trials, a 50% reduction in baseline albuminuria was associated with reduced progression of renal failure in those with a baseline ACR less than 10 mg/g.⁵⁵

Improved cardiovascular outcomes

There is also evidence of better cardiovascular outcomes with treatment of albuminuria. Again, it is uncertain whether this is a result of treating risk factors other than albuminuria with ACE inhibitors or ARBs, and there is no parallel benefit demonstrated across all studies.

LIFE.^47,48 In the Losartan Intervention for Endpoint Reduction in Hypertension trial, survival analyses suggested a decrease in risk of cardiovascular adverse events as the degree of proteinuria improved with ARB therapy.

Maione et al,⁵³ in a meta-analysis including 8,231 patients with albuminuria and at least one other risk factor, found a significant reduction in the rate of nonfatal cardiovascular outcomes (angina, myocardial infarction, revascularization, stroke, transient ischemic attack, or heart failure) with ACE inhibitors vs placebo (RR 0.88, CI 0.82–0.94) and also in 3,888 patients treated with ARBs vs placebo (RR 0.77, CI 0.61–0.98). However, the meta-analysis did not show that ACE inhibitor or ARB therapy reduced rate of cardiovascular or all-cause mortality.

Fink et al,⁵¹ in their meta-analysis of 18 trials of ACE inhibitors and four trials of ARBs, also found no evidence that ACE inhibitor or ARB therapy reduced cardiovascular mortality rates.³⁸

The ONTARGET trial evaluated the combination of an ACE inhibitor and ARB therapy in patients with diabetes or preexisting peripheral vascular disease. Reductions in the rate of cardiovascular disease or death were not observed, and in those with chronic kidney disease, there was a higher risk of doubling of serum creatinine or development of end-stage renal disease and adverse events of hyperkalemia.⁵⁶ And although an increase in baseline albuminuria was associated with worse cardiovascular outcomes, its reduction in the ONTARGET and TRANSCEND trials did not demonstrate better outcomes when the baseline ACR was greater than 10 mg/g.⁵⁵

WHO SHOULD BE TESTED?

The benefit of adding albuminuria to conventional cardiovascular risk stratification such as Framingham risk scoring is not conclusive. However, today’s clinician may view albuminuria as a biomarker for renal and cardiovascular disease, as albuminuria might be a surrogate marker for endothelial dysfunction in the glomerular capillaries or other vital vascular beds.

High-risk populations and chronic kidney disease patients

Nearly all the current guidelines recommend annual screening for albuminuria in patients with diabetes and hypertension (Table 2).^7,10–13 Other high-risk populations include people with cardiovascular disease, a family history of end-stage renal disease, and metabolic syndrome. Additionally, chronic kidney disease patients whose estimated GFR defines them as being in stage 3 or higher (ie, GFR < 60 mL/min/1.73m²), regardless of other comorbidities, should be tested for albuminuria, as it is an important risk predictor.

Most experts prefer that albuminuria be measured by urine ACR in a first morning voided sample, though this is not the only option.

Screening the general population

Given that albuminuria has been shown to be such an important prognosticator for patients at high risk and those with chronic kidney disease, the question arises whether screening for albuminuria in the asymptomatic low-risk general population would foster earlier detection and therefore enable earlier intervention and result in improved outcomes. However, a systematic review done for the United States Preventive Services Task Force and for an American College of Physicians clinical practice guideline did not find robust evidence to support this.⁵¹

OUR RECOMMENDATIONS

Who should be tested?

• Patients with chronic kidney disease stage 3, 4, or 5 (GFR < 60 mL/min/1.73m²) who are not on dialysis
• Patients who are considered at higher risk of adverse outcomes, such as those with diabetes, hypertension, a family history of end-stage renal disease, or cardiovascular disease. Testing is useful for recognizing increased renal and cardiovascular risk and may lead clinicians to prescribe or titrate a renin-angiotensin system antagonist, a statin, or both, or to modify other cardiovascular risk factors.
• Not recommended: routine screening in the general population who are asymptomatic or are considered at low risk.

Which test should be used?

Based on current evidence and most guidelines, we recommend the urine ACR test as the screening test for people with diabetes and others deemed to be at high risk.

What should be done about albuminuria?

• Controlling blood pressure is important, and though there is debate about the target blood pressure, an individualized plan should be developed with the patient based on age, comorbidities, and goals of care.
• An ACE inhibitor or ARB, if not contraindicated, is recommended for patients with diabetes whose ACR is greater than 30 mg/g and for patients with chronic kidney disease and an ACR greater than 300 mg/g.
• Current evidence does not support the combined use of an ACE inhibitor and an ARB, as proof of benefit is lacking and the risk of adverse events is higher.
• Refer patients with high or unexplained albuminuria to a nephrologist or clinic specializing in chronic kidney disease.

“One can obtain considerable information concerning the general health by examining the urine.” 
—Hippocrates (460?–355? BCE)

Chronic kidney disease is a notable public health concern because it is an important risk factor for end-stage renal disease, cardiovascular disease, and death. Its prevalence¹ exceeds 10% and is considerably higher in high-risk groups, such as those with diabetes or hypertension, which are growing in the United States.

While high levels of total protein in the urine have always been recognized as pathologic, a growing body of evidence links excretion of the protein albumin to adverse cardiovascular outcomes, and most international guidelines now recommend measuring albumin specifically. Albuminuria is a predictor of declining renal function and is independently associated with adverse cardiovascular outcomes. Thus, clinicians need to detect it early, manage it effectively, and reduce concurrent risk factors for cardiovascular disease.

Therefore, this review will focus on albuminuria. However, because the traditional standard for urinary protein measurement was total protein, and because a few guidelines still recommend measuring total protein rather than albumin, we will also briefly discuss total urinary protein.

MOST URINARY PROTEIN IS ALBUMIN

Most of the protein in the urine is albumin filtered from the plasma. Less than half of the rest is derived from the distal renal tubules (uromodulin or Tamm-Horsfall mucoprotein), ² and urine also contains a small and varying proportion of immunoglobulins, low-molecular-weight proteins, and light chains.

Normal healthy people lose less than 30 mg of albumin in the urine per day. In greater amounts, albumin is the major urinary protein in most kidney diseases. Other proteins in urine can be specific markers of less-common illnesses such as plasma cell dyscrasia, glomerulopathy, and renal tubular disease.

MEASURING PROTEINURIA AND ALBUMINURIA

Albumin is not a homogeneous molecule in urine. It undergoes changes to its molecular configuration in the presence of certain ions, peptides, hormones, and drugs, and as a result of proteolytic fragmentation both in the plasma and in renal tubules.³ Consequently, measuring urinary albumin involves a trade-off between convenience and accuracy.

A 24-hour timed urine sample has long been the gold standard for measuring albuminuria, but the collection is cumbersome and time-consuming, and the test is prone to laboratory error.

Dipstick measurements are more convenient and are better at detecting albumin than other proteins in urine, but they have low sensitivity and high interobserver variation.^3–5

The albumin-to-creatinine ratio (ACR). As the quantity of protein in the urine changes with time of day, exertion, stress level, and posture, spot-checking of urine samples is not as good as timed collection. However, a simultaneous measurement of creatinine in a spot urine sample adjusts for protein concentration, which can vary with a person’s hydration status. The ACR so obtained is consistent with the 24-hour timed collection (the gold standard) and is the recommended method of assessing albuminuria.³ An early morning urine sample is favored, as it avoids orthostatic variations and varies less in the same individual.

In a study in the general population comparing the ACR in a random sample and in an early morning sample, only 44% of those who had an ACR of 30 mg/g or higher in the random sample had one this high in the early morning sample.⁶ However, getting an early morning sample is not always feasible in clinical practice. If you are going to measure albuminuria, the Kidney Disease Outcomes and Quality Initiative⁷ suggests checking the ACR in a random sample and then, if the test is positive, following up and confirming it within 3 months with an early morning sample.

Also, since creatinine excretion differs with race, diet, and muscle mass, if the 24-hour creatinine excretion is not close to 1 g, the ACR will give an erroneous estimate of the 24-hour excretion rate.³

Table 1 compares the various methods of measuring protein in the urine.^3,5,8,9 Of note, methods of measuring albumin and total protein vary considerably in their precision and accuracy, making it impossible to reliably translate values from one to the other.⁵

National and international guidelines (Table 2)^7,10–13 agree that albuminuria should be tested in diabetic patients, as it is a surrogate marker for early diabetic nephropathy.^3,13 Most guidelines also recommend measuring albuminuria by a urine ACR test as the preferred measure, even in people without diabetes.

Also, no single cutoff is universally accepted for distinguishing pathologic albuminuria from physiologic albuminuria, nor is there a universally accepted unit of measure.¹⁴ Because approximately 1 g of creatinine is lost in the urine per day, the ACR has the convenient property of numerically matching the albumin excretory rate expressed in milligrams per 24 hours. The other commonly used unit is milligrams of albumin per millimole of creatinine; 30 mg/g is roughly equal to 3 mg/mmol.

The term microalbuminuria was traditionally used to refer to albumin excretion of 30 to 299 mg per 24 hours, and macroalbuminuria to 300 mg or more per 24 hours. However, as there is no pathophysiologic basis to these thresholds (see outcomes data below), the current Kidney Disease Improving Global Outcomes (KDIGO) guidelines do not recommend using these terms.^13,15

RENAL COMPLICATIONS OF ALBUMINURIA

A failure of the glomerular filtration barrier or of proximal tubular reabsorption accounts for most cases of pathologic albuminuria.¹⁶ Processes affecting the glomerular filtration of albumin include endothelial cell dysfunction and abnormalities with the glomerular basement membrane, podocytes, or the slit diaphragms among the podocytic processes.¹⁷

Ultrafiltrated albumin has been directly implicated in tubulointerstitial damage and glomerulosclerosis through diverse pathways. In the proximal tubule, albumin up-regulates interleukin 8 (a chemoattractant for lymphocytes and neutrophils), induces synthesis of endothelin 1 (which stimulates renal cell proliferation, extracellular matrix production, and monocyte attraction), and causes apoptosis of tubular cells.¹⁸ In response to albumin, proximal tubular cells also stimulate interstitial fibroblasts via paracrine release of transforming growth factor beta, either directly or by activating complement or macrophages.^18,19

Studies linking albuminuria to kidney disease

Albuminuria has traditionally been associated with diabetes mellitus as a predictor of overt diabetic nephropathy,^20,21 although in type 1 diabetes, established albuminuria can spontaneously regress.²²

Albuminuria is also a strong predictor of progression in chronic kidney disease.²³ In fact, in the last decade, albuminuria has become an independent criterion in the definition of chronic kidney disease; excretion of more than 30 mg of albumin per day, sustained for at least 3 months, qualifies as chronic kidney disease, with independent prognostic implications (Table  3).¹³

Astor et al,²⁴ in a meta-analysis of 13 studies with more than 21,000 patients with chronic kidney disease, found that the risk of end-stage renal disease was three times higher in those with albuminuria.

Gansevoort et al,²³ in a meta-analysis of nine studies with nearly 850,000 participants from the general population, found that the risk of end-stage renal disease increased continuously as albumin excretion increased. They also found that as albuminuria increased, so did the risk of progression of chronic kidney disease and the incidence of acute kidney injury.

Hemmelgarn et al,²⁵ in a large pooled cohort study with more than 1.5 million participants from the general population, showed that increasing albuminuria was associated with a decline in the estimated glomerular filtration rate (GFR) and with progression to end-stage renal disease across all strata of baseline renal function. For example, in persons with an estimated GFR of 60 mL/min/1.73 m2

• 1 per 1,000 person-years for those with no proteinuria
• 2.8 per 1,000 person-years for those with mild proteinuria (trace or 1+ by dipstick or ACR 30–300 mg/g)
• 13.4 per 1,000 person-years for those with heavy proteinuria (2+ or ACR > 300 mg/g).

Rates of progression to end-stage renal disease were:

• 0.03 per 1,000 person-years with no proteinuria
• 0.05 per 1,000 person-years with mild proteinuria
• 1 per 1,000 person-years with heavy proteinuria.²⁵

CARDIOVASCULAR CONSEQUENCES OF ALBUMINURIA

The exact pathophysiologic link between albuminuria and cardiovascular disease is unknown, but several mechanisms have been proposed.

One is that generalized endothelial dysfunction causes both albuminuria and cardiovascular disease.²⁶ Endothelium-derived nitric oxide has vasodilator, antiplatelet, antiproliferative, antiadhesive, permeability-decreasing, and anti-inflammatory properties. Impaired endothelial synthesis of nitric oxide has been independently associated with both microalbuminuria and diabetes.²⁷

Low levels of heparan sulfate (which has antithrombogenic effects and decreases vessel permeability) in the glycocalyx lining vessel walls may also account for albuminuria and for the other cardiovascular effects.^28–30 These changes may be the consequence of chronic low-grade inflammation, which precedes the occurrence and progression of both albuminuria and atherothrombotic disease. The resulting abnormalities in the endothelial glycocalyx could lead to increased glomerular permeability to albumin and may also be implicated in the pathogenesis of atherosclerosis.²⁶

In an atherosclerotic aorta and coronary arteries, the endothelial dysfunction may cause increased leakage of cholesterol and glycated end-products into the myocardium, resulting in increasing wall stiffness and left ventricular mass. A similar atherosclerotic process may account for coronary artery microthrombi, resulting in subendocardial ischemia that could lead to systolic and diastolic heart dysfunction.³¹

Studies linking albuminuria to heart disease

There is convincing evidence that albuminuria is associated with cardiovascular disease. An ACR between 30 and 300 mg/g was independently associated with myocardial infarction and ischemia.³² People with albuminuria have more than twice the risk of severe coronary artery disease, and albuminuria is also associated with increased intimal thickening in the carotid arteries.^33,34 An ACR in the same range has been associated with increased incidence and progression of coronary artery calcification.³⁵ Higher brachial-ankle pulse-wave velocity has also been demonstrated with albuminuria in a dose-dependent fashion.^36,37

An ACR of 30 to 300 mg/g has been linked to left ventricular hypertrophy independently of other risk factors,³⁸ and functionally with diastolic dysfunction and abnormal midwall shortening.³⁹ In a study of a subgroup of patients with diabetes from a population-based cohort of Native American patients (the Strong Heart Study),³⁹ the prevalence of diastolic dysfunction was:

• 16% in those with no albuminuria
• 26% in those with an ACR of 30 to 300 mg/g
• 31% in those with an ACR greater than 300 mg/g.

The association persisted even after controlling for age, sex, hypertension, and other covariates.

Those pathologic associations have been directly linked to clinical outcomes. For patients with heart failure (New York Heart Association class II–IV), a study found that albuminuria (an ACR > 30 mg/g) conferred a 41% higher risk of admission for heart failure, and an ACR greater than 300 mg/g was associated with an 88% higher risk.⁴⁰

In an analysis of a prospective cohort from the general population with albuminuria and a low prevalence of renal dysfunction (the Prevention of Renal and Vascular Endstage Disease study),⁴¹ albuminuria was associated with a modest increase in the incidence of the composite end point of myocardial infarction, stroke, ischemic heart disease, revascularization procedures, and all-cause mortality per doubling of the urine albumin excretion (hazard ratio 1.08, range 1.04 –1.12).

The relationship to cardiovascular outcomes extends below traditional lower-limit thresholds of albuminuria (corresponding to an ACR > 30 mg/g). A subgroup of patients from the Framingham Offspring Study without prevalent cardiovascular disease, hypertension, diabetes, or kidney disease, and thus with a low to intermediate probability of cardiovascular events, were found to have thresholds for albuminuria as low as 5.3 mg/g in men and 10.8 mg/g in women to discriminate between incident coronary artery disease, heart failure, cerebrovascular disease, other peripheral vascular disease, or death.⁴²

In a meta-analysis including more than 1 million patients in the general population, increasing albuminuria was associated with an increase in deaths from all causes in a continuous manner, with no threshold effect.⁴³ In patients with an ACR of 30 mg/g, the hazard ratio for death was 1.63, increasing to 2.22 for those with more than 300 mg/g compared with those with no albuminuria. A similar increase in the risk of myocardial infarction, heart failure, stroke, or sudden cardiac death was noted with higher ACR.⁴³

Important prospective cohort studies and meta-analyses related to albuminuria and kidney and cardiovascular disease and death are summarized in the eTable.^23,39–50

THE CASE FOR TREATING ALBUMINURIA

Reduced progression of renal disease

Treating patients who have proteinuric chronic kidney disease with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) can reduce the risk of progression of renal failure. However, it is unclear whether this benefit is the result of treating concomitant risk factors independent of the reduction in albuminuria, and there is no consistent treatment effect in improving renal outcomes across studies.

Fink et al,⁵¹ in a meta-analysis, found that chronic kidney disease patients with diabetes, hypertension, and macroalbuminuria had a 40% lower risk of progression to end-stage renal disease if they received an ACE inhibitor (relative risk [RR] 0.60, 95% confidence interval [CI] 0.43–0.83). In the same meta-analysis, ARBs also reduced the risk of progression to end-stage renal disease (RR 0.77, 95% CI 0.66–0.90).

Jafar et al,⁵² in an analysis of pooled patient-level data including only nondiabetic patients on ACE inhibitor therapy (n = 1,860), found that the risk of progression of renal failure, defined as a doubling of serum creatinine or end-stage renal disease, was reduced (RR 0.70, 95% CI 0.55–0.88). Patients with higher levels of albuminuria showed the most benefit, but the effect was not conclusive for albuminuria below 500 mg/day at baseline.

Maione et al,⁵³ in a meta-analysis that included patients with albuminuria who were treated with ACE inhibitors vs placebo (n = 8,231), found a similar reduction in risk of:

• Progression to end-stage renal disease (RR 0.67, 95% CI 0.54–0.84)
• Doubling of serum creatinine (RR 0.62, 95% CI 0.46–0.84)
• Progression of albuminuria (RR 0.49, 95% CI 0.36–0.65)
• Normalization of pathologic albuminuria (as defined by the trialists in the individual studies) (RR 2.99, 95% CI 1.82–4.91).

Similar results were obtained for patients with albuminuria who were treated with ARBs.⁵³

ONTARGET.⁵⁴ In contrast, in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial, the combination of an ACE inhibitor and an ARB showed no benefit in reducing the progression of renal failure, and in those patients with chronic kidney disease there was a higher risk of a doubling of serum creatinine or of the development of end-stage renal disease and hyperkalemia.

Also, in a pooled analysis of the ONTARGET and Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) trials, a 50% reduction in baseline albuminuria was associated with reduced progression of renal failure in those with a baseline ACR less than 10 mg/g.⁵⁵

Improved cardiovascular outcomes

There is also evidence of better cardiovascular outcomes with treatment of albuminuria. Again, it is uncertain whether this is a result of treating risk factors other than albuminuria with ACE inhibitors or ARBs, and there is no parallel benefit demonstrated across all studies.

LIFE.^47,48 In the Losartan Intervention for Endpoint Reduction in Hypertension trial, survival analyses suggested a decrease in risk of cardiovascular adverse events as the degree of proteinuria improved with ARB therapy.

Maione et al,⁵³ in a meta-analysis including 8,231 patients with albuminuria and at least one other risk factor, found a significant reduction in the rate of nonfatal cardiovascular outcomes (angina, myocardial infarction, revascularization, stroke, transient ischemic attack, or heart failure) with ACE inhibitors vs placebo (RR 0.88, CI 0.82–0.94) and also in 3,888 patients treated with ARBs vs placebo (RR 0.77, CI 0.61–0.98). However, the meta-analysis did not show that ACE inhibitor or ARB therapy reduced rate of cardiovascular or all-cause mortality.

Fink et al,⁵¹ in their meta-analysis of 18 trials of ACE inhibitors and four trials of ARBs, also found no evidence that ACE inhibitor or ARB therapy reduced cardiovascular mortality rates.³⁸

The ONTARGET trial evaluated the combination of an ACE inhibitor and ARB therapy in patients with diabetes or preexisting peripheral vascular disease. Reductions in the rate of cardiovascular disease or death were not observed, and in those with chronic kidney disease, there was a higher risk of doubling of serum creatinine or development of end-stage renal disease and adverse events of hyperkalemia.⁵⁶ And although an increase in baseline albuminuria was associated with worse cardiovascular outcomes, its reduction in the ONTARGET and TRANSCEND trials did not demonstrate better outcomes when the baseline ACR was greater than 10 mg/g.⁵⁵

WHO SHOULD BE TESTED?

The benefit of adding albuminuria to conventional cardiovascular risk stratification such as Framingham risk scoring is not conclusive. However, today’s clinician may view albuminuria as a biomarker for renal and cardiovascular disease, as albuminuria might be a surrogate marker for endothelial dysfunction in the glomerular capillaries or other vital vascular beds.

High-risk populations and chronic kidney disease patients

Nearly all the current guidelines recommend annual screening for albuminuria in patients with diabetes and hypertension (Table 2).^7,10–13 Other high-risk populations include people with cardiovascular disease, a family history of end-stage renal disease, and metabolic syndrome. Additionally, chronic kidney disease patients whose estimated GFR defines them as being in stage 3 or higher (ie, GFR < 60 mL/min/1.73m²), regardless of other comorbidities, should be tested for albuminuria, as it is an important risk predictor.

Most experts prefer that albuminuria be measured by urine ACR in a first morning voided sample, though this is not the only option.

Screening the general population

Given that albuminuria has been shown to be such an important prognosticator for patients at high risk and those with chronic kidney disease, the question arises whether screening for albuminuria in the asymptomatic low-risk general population would foster earlier detection and therefore enable earlier intervention and result in improved outcomes. However, a systematic review done for the United States Preventive Services Task Force and for an American College of Physicians clinical practice guideline did not find robust evidence to support this.⁵¹

OUR RECOMMENDATIONS

Who should be tested?

• Patients with chronic kidney disease stage 3, 4, or 5 (GFR < 60 mL/min/1.73m²) who are not on dialysis
• Patients who are considered at higher risk of adverse outcomes, such as those with diabetes, hypertension, a family history of end-stage renal disease, or cardiovascular disease. Testing is useful for recognizing increased renal and cardiovascular risk and may lead clinicians to prescribe or titrate a renin-angiotensin system antagonist, a statin, or both, or to modify other cardiovascular risk factors.
• Not recommended: routine screening in the general population who are asymptomatic or are considered at low risk.

Which test should be used?

Based on current evidence and most guidelines, we recommend the urine ACR test as the screening test for people with diabetes and others deemed to be at high risk.

What should be done about albuminuria?

• Controlling blood pressure is important, and though there is debate about the target blood pressure, an individualized plan should be developed with the patient based on age, comorbidities, and goals of care.
• An ACE inhibitor or ARB, if not contraindicated, is recommended for patients with diabetes whose ACR is greater than 30 mg/g and for patients with chronic kidney disease and an ACR greater than 300 mg/g.
• Current evidence does not support the combined use of an ACE inhibitor and an ARB, as proof of benefit is lacking and the risk of adverse events is higher.
• Refer patients with high or unexplained albuminuria to a nephrologist or clinic specializing in chronic kidney disease.

“One can obtain considerable information concerning the general health by examining the urine.” 
—Hippocrates (460?–355? BCE)

Chronic kidney disease is a notable public health concern because it is an important risk factor for end-stage renal disease, cardiovascular disease, and death. Its prevalence¹ exceeds 10% and is considerably higher in high-risk groups, such as those with diabetes or hypertension, which are growing in the United States.

While high levels of total protein in the urine have always been recognized as pathologic, a growing body of evidence links excretion of the protein albumin to adverse cardiovascular outcomes, and most international guidelines now recommend measuring albumin specifically. Albuminuria is a predictor of declining renal function and is independently associated with adverse cardiovascular outcomes. Thus, clinicians need to detect it early, manage it effectively, and reduce concurrent risk factors for cardiovascular disease.

Therefore, this review will focus on albuminuria. However, because the traditional standard for urinary protein measurement was total protein, and because a few guidelines still recommend measuring total protein rather than albumin, we will also briefly discuss total urinary protein.

MOST URINARY PROTEIN IS ALBUMIN

Most of the protein in the urine is albumin filtered from the plasma. Less than half of the rest is derived from the distal renal tubules (uromodulin or Tamm-Horsfall mucoprotein), ² and urine also contains a small and varying proportion of immunoglobulins, low-molecular-weight proteins, and light chains.

Normal healthy people lose less than 30 mg of albumin in the urine per day. In greater amounts, albumin is the major urinary protein in most kidney diseases. Other proteins in urine can be specific markers of less-common illnesses such as plasma cell dyscrasia, glomerulopathy, and renal tubular disease.

MEASURING PROTEINURIA AND ALBUMINURIA

Albumin is not a homogeneous molecule in urine. It undergoes changes to its molecular configuration in the presence of certain ions, peptides, hormones, and drugs, and as a result of proteolytic fragmentation both in the plasma and in renal tubules.³ Consequently, measuring urinary albumin involves a trade-off between convenience and accuracy.

A 24-hour timed urine sample has long been the gold standard for measuring albuminuria, but the collection is cumbersome and time-consuming, and the test is prone to laboratory error.

Dipstick measurements are more convenient and are better at detecting albumin than other proteins in urine, but they have low sensitivity and high interobserver variation.^3–5

The albumin-to-creatinine ratio (ACR). As the quantity of protein in the urine changes with time of day, exertion, stress level, and posture, spot-checking of urine samples is not as good as timed collection. However, a simultaneous measurement of creatinine in a spot urine sample adjusts for protein concentration, which can vary with a person’s hydration status. The ACR so obtained is consistent with the 24-hour timed collection (the gold standard) and is the recommended method of assessing albuminuria.³ An early morning urine sample is favored, as it avoids orthostatic variations and varies less in the same individual.

In a study in the general population comparing the ACR in a random sample and in an early morning sample, only 44% of those who had an ACR of 30 mg/g or higher in the random sample had one this high in the early morning sample.⁶ However, getting an early morning sample is not always feasible in clinical practice. If you are going to measure albuminuria, the Kidney Disease Outcomes and Quality Initiative⁷ suggests checking the ACR in a random sample and then, if the test is positive, following up and confirming it within 3 months with an early morning sample.

Also, since creatinine excretion differs with race, diet, and muscle mass, if the 24-hour creatinine excretion is not close to 1 g, the ACR will give an erroneous estimate of the 24-hour excretion rate.³

Table 1 compares the various methods of measuring protein in the urine.^3,5,8,9 Of note, methods of measuring albumin and total protein vary considerably in their precision and accuracy, making it impossible to reliably translate values from one to the other.⁵

National and international guidelines (Table 2)^7,10–13 agree that albuminuria should be tested in diabetic patients, as it is a surrogate marker for early diabetic nephropathy.^3,13 Most guidelines also recommend measuring albuminuria by a urine ACR test as the preferred measure, even in people without diabetes.

Also, no single cutoff is universally accepted for distinguishing pathologic albuminuria from physiologic albuminuria, nor is there a universally accepted unit of measure.¹⁴ Because approximately 1 g of creatinine is lost in the urine per day, the ACR has the convenient property of numerically matching the albumin excretory rate expressed in milligrams per 24 hours. The other commonly used unit is milligrams of albumin per millimole of creatinine; 30 mg/g is roughly equal to 3 mg/mmol.

The term microalbuminuria was traditionally used to refer to albumin excretion of 30 to 299 mg per 24 hours, and macroalbuminuria to 300 mg or more per 24 hours. However, as there is no pathophysiologic basis to these thresholds (see outcomes data below), the current Kidney Disease Improving Global Outcomes (KDIGO) guidelines do not recommend using these terms.^13,15

RENAL COMPLICATIONS OF ALBUMINURIA

A failure of the glomerular filtration barrier or of proximal tubular reabsorption accounts for most cases of pathologic albuminuria.¹⁶ Processes affecting the glomerular filtration of albumin include endothelial cell dysfunction and abnormalities with the glomerular basement membrane, podocytes, or the slit diaphragms among the podocytic processes.¹⁷

Ultrafiltrated albumin has been directly implicated in tubulointerstitial damage and glomerulosclerosis through diverse pathways. In the proximal tubule, albumin up-regulates interleukin 8 (a chemoattractant for lymphocytes and neutrophils), induces synthesis of endothelin 1 (which stimulates renal cell proliferation, extracellular matrix production, and monocyte attraction), and causes apoptosis of tubular cells.¹⁸ In response to albumin, proximal tubular cells also stimulate interstitial fibroblasts via paracrine release of transforming growth factor beta, either directly or by activating complement or macrophages.^18,19

Studies linking albuminuria to kidney disease

Albuminuria has traditionally been associated with diabetes mellitus as a predictor of overt diabetic nephropathy,^20,21 although in type 1 diabetes, established albuminuria can spontaneously regress.²²

Albuminuria is also a strong predictor of progression in chronic kidney disease.²³ In fact, in the last decade, albuminuria has become an independent criterion in the definition of chronic kidney disease; excretion of more than 30 mg of albumin per day, sustained for at least 3 months, qualifies as chronic kidney disease, with independent prognostic implications (Table  3).¹³

Astor et al,²⁴ in a meta-analysis of 13 studies with more than 21,000 patients with chronic kidney disease, found that the risk of end-stage renal disease was three times higher in those with albuminuria.

Gansevoort et al,²³ in a meta-analysis of nine studies with nearly 850,000 participants from the general population, found that the risk of end-stage renal disease increased continuously as albumin excretion increased. They also found that as albuminuria increased, so did the risk of progression of chronic kidney disease and the incidence of acute kidney injury.

Hemmelgarn et al,²⁵ in a large pooled cohort study with more than 1.5 million participants from the general population, showed that increasing albuminuria was associated with a decline in the estimated glomerular filtration rate (GFR) and with progression to end-stage renal disease across all strata of baseline renal function. For example, in persons with an estimated GFR of 60 mL/min/1.73 m2

• 1 per 1,000 person-years for those with no proteinuria
• 2.8 per 1,000 person-years for those with mild proteinuria (trace or 1+ by dipstick or ACR 30–300 mg/g)
• 13.4 per 1,000 person-years for those with heavy proteinuria (2+ or ACR > 300 mg/g).

Rates of progression to end-stage renal disease were:

• 0.03 per 1,000 person-years with no proteinuria
• 0.05 per 1,000 person-years with mild proteinuria
• 1 per 1,000 person-years with heavy proteinuria.²⁵

CARDIOVASCULAR CONSEQUENCES OF ALBUMINURIA

The exact pathophysiologic link between albuminuria and cardiovascular disease is unknown, but several mechanisms have been proposed.

One is that generalized endothelial dysfunction causes both albuminuria and cardiovascular disease.²⁶ Endothelium-derived nitric oxide has vasodilator, antiplatelet, antiproliferative, antiadhesive, permeability-decreasing, and anti-inflammatory properties. Impaired endothelial synthesis of nitric oxide has been independently associated with both microalbuminuria and diabetes.²⁷

Low levels of heparan sulfate (which has antithrombogenic effects and decreases vessel permeability) in the glycocalyx lining vessel walls may also account for albuminuria and for the other cardiovascular effects.^28–30 These changes may be the consequence of chronic low-grade inflammation, which precedes the occurrence and progression of both albuminuria and atherothrombotic disease. The resulting abnormalities in the endothelial glycocalyx could lead to increased glomerular permeability to albumin and may also be implicated in the pathogenesis of atherosclerosis.²⁶

In an atherosclerotic aorta and coronary arteries, the endothelial dysfunction may cause increased leakage of cholesterol and glycated end-products into the myocardium, resulting in increasing wall stiffness and left ventricular mass. A similar atherosclerotic process may account for coronary artery microthrombi, resulting in subendocardial ischemia that could lead to systolic and diastolic heart dysfunction.³¹

Studies linking albuminuria to heart disease

There is convincing evidence that albuminuria is associated with cardiovascular disease. An ACR between 30 and 300 mg/g was independently associated with myocardial infarction and ischemia.³² People with albuminuria have more than twice the risk of severe coronary artery disease, and albuminuria is also associated with increased intimal thickening in the carotid arteries.^33,34 An ACR in the same range has been associated with increased incidence and progression of coronary artery calcification.³⁵ Higher brachial-ankle pulse-wave velocity has also been demonstrated with albuminuria in a dose-dependent fashion.^36,37

An ACR of 30 to 300 mg/g has been linked to left ventricular hypertrophy independently of other risk factors,³⁸ and functionally with diastolic dysfunction and abnormal midwall shortening.³⁹ In a study of a subgroup of patients with diabetes from a population-based cohort of Native American patients (the Strong Heart Study),³⁹ the prevalence of diastolic dysfunction was:

• 16% in those with no albuminuria
• 26% in those with an ACR of 30 to 300 mg/g
• 31% in those with an ACR greater than 300 mg/g.

The association persisted even after controlling for age, sex, hypertension, and other covariates.

Those pathologic associations have been directly linked to clinical outcomes. For patients with heart failure (New York Heart Association class II–IV), a study found that albuminuria (an ACR > 30 mg/g) conferred a 41% higher risk of admission for heart failure, and an ACR greater than 300 mg/g was associated with an 88% higher risk.⁴⁰

In an analysis of a prospective cohort from the general population with albuminuria and a low prevalence of renal dysfunction (the Prevention of Renal and Vascular Endstage Disease study),⁴¹ albuminuria was associated with a modest increase in the incidence of the composite end point of myocardial infarction, stroke, ischemic heart disease, revascularization procedures, and all-cause mortality per doubling of the urine albumin excretion (hazard ratio 1.08, range 1.04 –1.12).

The relationship to cardiovascular outcomes extends below traditional lower-limit thresholds of albuminuria (corresponding to an ACR > 30 mg/g). A subgroup of patients from the Framingham Offspring Study without prevalent cardiovascular disease, hypertension, diabetes, or kidney disease, and thus with a low to intermediate probability of cardiovascular events, were found to have thresholds for albuminuria as low as 5.3 mg/g in men and 10.8 mg/g in women to discriminate between incident coronary artery disease, heart failure, cerebrovascular disease, other peripheral vascular disease, or death.⁴²

In a meta-analysis including more than 1 million patients in the general population, increasing albuminuria was associated with an increase in deaths from all causes in a continuous manner, with no threshold effect.⁴³ In patients with an ACR of 30 mg/g, the hazard ratio for death was 1.63, increasing to 2.22 for those with more than 300 mg/g compared with those with no albuminuria. A similar increase in the risk of myocardial infarction, heart failure, stroke, or sudden cardiac death was noted with higher ACR.⁴³

Important prospective cohort studies and meta-analyses related to albuminuria and kidney and cardiovascular disease and death are summarized in the eTable.^23,39–50

THE CASE FOR TREATING ALBUMINURIA

Reduced progression of renal disease

Treating patients who have proteinuric chronic kidney disease with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) can reduce the risk of progression of renal failure. However, it is unclear whether this benefit is the result of treating concomitant risk factors independent of the reduction in albuminuria, and there is no consistent treatment effect in improving renal outcomes across studies.

Fink et al,⁵¹ in a meta-analysis, found that chronic kidney disease patients with diabetes, hypertension, and macroalbuminuria had a 40% lower risk of progression to end-stage renal disease if they received an ACE inhibitor (relative risk [RR] 0.60, 95% confidence interval [CI] 0.43–0.83). In the same meta-analysis, ARBs also reduced the risk of progression to end-stage renal disease (RR 0.77, 95% CI 0.66–0.90).

Jafar et al,⁵² in an analysis of pooled patient-level data including only nondiabetic patients on ACE inhibitor therapy (n = 1,860), found that the risk of progression of renal failure, defined as a doubling of serum creatinine or end-stage renal disease, was reduced (RR 0.70, 95% CI 0.55–0.88). Patients with higher levels of albuminuria showed the most benefit, but the effect was not conclusive for albuminuria below 500 mg/day at baseline.

Maione et al,⁵³ in a meta-analysis that included patients with albuminuria who were treated with ACE inhibitors vs placebo (n = 8,231), found a similar reduction in risk of:

• Progression to end-stage renal disease (RR 0.67, 95% CI 0.54–0.84)
• Doubling of serum creatinine (RR 0.62, 95% CI 0.46–0.84)
• Progression of albuminuria (RR 0.49, 95% CI 0.36–0.65)
• Normalization of pathologic albuminuria (as defined by the trialists in the individual studies) (RR 2.99, 95% CI 1.82–4.91).

Similar results were obtained for patients with albuminuria who were treated with ARBs.⁵³

ONTARGET.⁵⁴ In contrast, in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial, the combination of an ACE inhibitor and an ARB showed no benefit in reducing the progression of renal failure, and in those patients with chronic kidney disease there was a higher risk of a doubling of serum creatinine or of the development of end-stage renal disease and hyperkalemia.

Also, in a pooled analysis of the ONTARGET and Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) trials, a 50% reduction in baseline albuminuria was associated with reduced progression of renal failure in those with a baseline ACR less than 10 mg/g.⁵⁵

Improved cardiovascular outcomes

There is also evidence of better cardiovascular outcomes with treatment of albuminuria. Again, it is uncertain whether this is a result of treating risk factors other than albuminuria with ACE inhibitors or ARBs, and there is no parallel benefit demonstrated across all studies.

LIFE.^47,48 In the Losartan Intervention for Endpoint Reduction in Hypertension trial, survival analyses suggested a decrease in risk of cardiovascular adverse events as the degree of proteinuria improved with ARB therapy.

Maione et al,⁵³ in a meta-analysis including 8,231 patients with albuminuria and at least one other risk factor, found a significant reduction in the rate of nonfatal cardiovascular outcomes (angina, myocardial infarction, revascularization, stroke, transient ischemic attack, or heart failure) with ACE inhibitors vs placebo (RR 0.88, CI 0.82–0.94) and also in 3,888 patients treated with ARBs vs placebo (RR 0.77, CI 0.61–0.98). However, the meta-analysis did not show that ACE inhibitor or ARB therapy reduced rate of cardiovascular or all-cause mortality.

Fink et al,⁵¹ in their meta-analysis of 18 trials of ACE inhibitors and four trials of ARBs, also found no evidence that ACE inhibitor or ARB therapy reduced cardiovascular mortality rates.³⁸

The ONTARGET trial evaluated the combination of an ACE inhibitor and ARB therapy in patients with diabetes or preexisting peripheral vascular disease. Reductions in the rate of cardiovascular disease or death were not observed, and in those with chronic kidney disease, there was a higher risk of doubling of serum creatinine or development of end-stage renal disease and adverse events of hyperkalemia.⁵⁶ And although an increase in baseline albuminuria was associated with worse cardiovascular outcomes, its reduction in the ONTARGET and TRANSCEND trials did not demonstrate better outcomes when the baseline ACR was greater than 10 mg/g.⁵⁵

WHO SHOULD BE TESTED?

The benefit of adding albuminuria to conventional cardiovascular risk stratification such as Framingham risk scoring is not conclusive. However, today’s clinician may view albuminuria as a biomarker for renal and cardiovascular disease, as albuminuria might be a surrogate marker for endothelial dysfunction in the glomerular capillaries or other vital vascular beds.

High-risk populations and chronic kidney disease patients

Nearly all the current guidelines recommend annual screening for albuminuria in patients with diabetes and hypertension (Table 2).^7,10–13 Other high-risk populations include people with cardiovascular disease, a family history of end-stage renal disease, and metabolic syndrome. Additionally, chronic kidney disease patients whose estimated GFR defines them as being in stage 3 or higher (ie, GFR < 60 mL/min/1.73m²), regardless of other comorbidities, should be tested for albuminuria, as it is an important risk predictor.

Most experts prefer that albuminuria be measured by urine ACR in a first morning voided sample, though this is not the only option.

Screening the general population

Given that albuminuria has been shown to be such an important prognosticator for patients at high risk and those with chronic kidney disease, the question arises whether screening for albuminuria in the asymptomatic low-risk general population would foster earlier detection and therefore enable earlier intervention and result in improved outcomes. However, a systematic review done for the United States Preventive Services Task Force and for an American College of Physicians clinical practice guideline did not find robust evidence to support this.⁵¹

OUR RECOMMENDATIONS

Who should be tested?

• Patients with chronic kidney disease stage 3, 4, or 5 (GFR < 60 mL/min/1.73m²) who are not on dialysis
• Patients who are considered at higher risk of adverse outcomes, such as those with diabetes, hypertension, a family history of end-stage renal disease, or cardiovascular disease. Testing is useful for recognizing increased renal and cardiovascular risk and may lead clinicians to prescribe or titrate a renin-angiotensin system antagonist, a statin, or both, or to modify other cardiovascular risk factors.
• Not recommended: routine screening in the general population who are asymptomatic or are considered at low risk.

Which test should be used?

Based on current evidence and most guidelines, we recommend the urine ACR test as the screening test for people with diabetes and others deemed to be at high risk.

What should be done about albuminuria?

• Controlling blood pressure is important, and though there is debate about the target blood pressure, an individualized plan should be developed with the patient based on age, comorbidities, and goals of care.
• An ACE inhibitor or ARB, if not contraindicated, is recommended for patients with diabetes whose ACR is greater than 30 mg/g and for patients with chronic kidney disease and an ACR greater than 300 mg/g.
• Current evidence does not support the combined use of an ACE inhibitor and an ARB, as proof of benefit is lacking and the risk of adverse events is higher.
• Refer patients with high or unexplained albuminuria to a nephrologist or clinic specializing in chronic kidney disease.

An 85-year-old man with hypertension, hyperlipidemia, and coronary artery disease presented to our clinic with diffuse muscle pain. The pain had been present for about 3 months, but it had become noticeably worse over the past few weeks.

He was not aware of any trauma. He described the muscle pain as dull and particularly severe in his lower extremities (his thighs and calves). The pain did not limit his daily activities, nor did physical exertion or the time of day have any effect on the level of the pain.

His medications at that time included metoprolol, aspirin, hydrochlorothiazide, simvastatin, and a daily multivitamin.

He was not in acute distress. On neurologic and musculoskeletal examinations, all deep-tendon reflexes were intact, with no tenderness to palpation of the upper and lower extremities. No abnormalities were noted on the joint examination. He had full range of motion, with 5/5 muscle strength in the upper and lower extremities bilaterally and normal muscle tone. He was able to walk with ease. Results of initial laboratory testing, including creatine kinase and erythrocyte sedimentation rate, were normal.

1. What should be the next best step in the evaluation of this patient’s muscle pain?

• Order tests for cyclic citrullinated peptide (CCP) antibody and rheumatoid factor
• Advise him to refrain from physical activity until his symptoms resolve
• Take a more detailed history, including a review of medications and supplements
• Recommend a trial of a nonsteroidal anti-inflammatory drug (NSAID)
• Send him for radiographic imaging

Since his muscle pain has persisted for several months without improvement, a more detailed history should be taken, including a review of current medications and supplements.

Testing CCP antibody and rheumatoid factor would be useful if rheumatoid arthritis were suspected, but in the absence of demonstrable arthritis on examination, these tests would have low specificity even if the results were positive.

An NSAID may temporarily alleviate his pain, but it will not help establish a diagnosis. And in elderly patients, NSAIDs are not without complications and so should be prescribed only in appropriate situations.

Imaging would be appropriate at this point only if there was clinical suspicion of a specific disease. However, our patient has no focal deficits, and the suspicion of fracture or malignancy is low.

The medical history should include asking about current drug regimens, recent medication changes, and the use of herbal supplements, since polypharmacy is common in elderly patients with multiple comorbidities.

On further questioning, our patient said that his dose of simvastatin had been increased from 40 mg daily to 80 mg daily about 1 month before his symptoms appeared. He was taking a daily multivitamin but was not using herbal supplements or other over-the-counter products. He did not recall any constitutional symptoms before the onset of his current symptoms, and he had never had similar muscle pain in the past.

2. Based on the additional information from the history, what is the most likely cause of his muscle pain?

• Limited myositis secondary to recent viral infection
• Rhabdomyolysis
• Hypothyroidism
• Drug-drug interaction
• Statin-induced myalgia

Our patient’s history provided nothing to suggest viral myositis. Hypothyroidism should always be considered in patients with myalgia, but this is not likely in our patient, as he does not display other characteristics, such as diminished reflexes, hypotonia, cold intolerance, and mood instability. Even though calcium channel blockers have been known to cause myalgia in patients on statins, a drug-drug reaction is not likely, as he had not started taking a calcium channel blocker before his symptoms began. This patient did not show signs or symptoms of rhabdomyolysis, a type of myopathy in which necrosis of the muscle tissue occurs, generally causing profound weakness and pain.¹

Therefore, statin-induced myopathy is the most likely cause of his diffuse muscle pain, particularly since his simvastatin had been increased 1 month before the onset of symptoms.

3. What should be the next step in his management?

• Decrease the dose of simvastatin to the last known dose he was able to tolerate
• Continue simvastatin at the same dose and then monitor
• Switch to another statin
• Add coenzyme Q10
• Stop simvastatin

Decreasing the statin dosage to the last well-tolerated dose would not be appropriate in a patient with myopathy, as the symptoms would probably not improve.^2–4 Also, one should not switch to a different statin while a patient is experiencing symptoms. Rather, the statin should be stopped for at least 6 weeks or until the symptoms have fully resolved.¹

Adding coenzyme Q10 is another option, especially in a patient with previously diagnosed coronary artery disease,⁵ when continued statin therapy is thought necessary to reduce the likelihood of repeat coronary events.

We discontinued his simvastatin. Followup 3 weeks later in the outpatient clinic showed that his symptoms were slowly improving. The symptoms had resolved completely 4 months later.

4. How should we manage our patient’s hyperlipidemia once his symptoms have resolved?

• Restart simvastatin at the 80-mg dose
• Restart simvastatin at the 40-mg dose
• Start a hydrophilic statin at full dose
• Use a drug from another class of lipid-lowering drugs
• Wait another 3 months before prescribing any lipid-lowering drug

His treatment for hyperlipidemia should be continued, considering his comorbidities. However, restarting the same statin, even at a lower dose, will likely cause his symptoms to recur. Thus, a different statin should be tried once his muscle pain has resolved.

Other classes of lipid-lowering drugs are usually less efficacious than statins, particularly when trying to control low-density lipoprotein (LDL) cholesterol, so a drug from another class should not be used until other statin options have been attempted.^2,6,7

Simvastatin is lipophilic. Trying a statin with hydrophilic properties (eg, pravastatin, rosuvastatin, fluvastatin) has been shown to convey similar cardioprotective effects with a lower propensity for myalgia, as lipophilic statins have a higher propensity to penetrate muscle tissue than do hydrophilic statins.^3,4,8

Once his symptoms resolved, our patient was started on a hydrophilic statin, fluvastatin 20 mg daily. Unfortunately, his pain recurred 3 weeks later. The statin was stopped, and his symptoms again resolved.

5. Since our patient was unable to tolerate a second statin, what should be the next step in his management?

• Restart simvastatin 
• Use a drug from another class to control the hyperlipidemia
• Wait at least 6 months after symptoms resolve before trying any lipid-lowering drug
• Initiate therapy with coenzyme Q10 and fish oil
• Wait for symptoms to resolve, then restart a hydrophilic statin at a lower dose and lower frequency

Restarting simvastatin will likely cause a recurrence of the myalgia. Other lipid-lowering drugs such as nicotinic acid, bile acid resins, and fibrates are not as efficacious as statins. Coenzyme Q10 and fish oil can reduce lipid levels, but they are not as efficacious as statins.

In view of our patient’s lipid profile—LDL cholesterol elevated at 167 mg/dL, high-density lipoprotein cholesterol 31 mg/dL, triglycerides 47 mg/dL—it is important to treat his hyperlipidemia. Therefore, another attempt at statin therapy should be made once his symptoms have resolved.

Studies have shown that restarting a statin at a low dose and low frequency is effective in patients who have experienced intolerance to a statin.^3,4 Our patient was treated with low-dose pravastatin (20 mg), resulting in a moderate improvement in his LDL cholesterol to 123 mg/dL.

STATIN-INDUCED MYOPATHY: ADDRESSING THE DILEMMA

Treating hyperlipidemia is important to prevent vascular events in patients with or without coronary artery disease. Statins are the most effective agents available for controlling hypercholesterolemia, specifically LDL levels, as well as for preventing myocardial infarction.

Unfortunately, significant side effects have been reported, and myopathy is the most prevalent. Statin-induced myopathy includes a combination of muscle tenderness, myalgia, and weakness.^2–11 In randomized controlled trials, the risk of myopathy was estimated to be between 1.5% and 5%.⁶ In unselected clinic patients on high-dose statins, the rate of muscle complaints may be as high as 20%.¹²

The cause of statin-induced myopathy is not known, although studies have linked it to genetic defects.⁷ Risk factors have been identified and include personal and family history of myalgia, Asian ethnicity, hypothyroidism, and type 1 diabetes. The incidence of statin-induced myalgia is two to three times higher in patients on corticosteroid therapy. Other risk factors include female sex, liver disease, and renal dysfunction.^7,8

A less common etiology is anti-HMG coenzyme A reductase antibodies. Studies have shown that these antibody levels correlate well with the amount of myositis as measured by creatine kinase levels. However, there is no consensus yet on screening for these antibodies.¹³

Statin therapy poses a dilemma, as there is a thin line between the benefits and the risks of side effects, especially statin-induced myopathy.^3,4 Current recommendations include discontinuing the statin until symptoms fully resolve. Creatine kinase levels may be useful in assessing for potential muscle breakdown, especially in patients with reduced renal function, as this predisposes them to statin-induced myopathy, yet normal values do not preclude the diagnosis of statin-induced myopathy.^3,4,7,8

Once symptoms resolve and laboratory test results normalize, a trial of a different statin is recommended. If patients become symptomatic, a trial of a low-dose hydrophilic statin at a once- or twice-weekly interval has been recommended. Several studies have assessed the efficacy of a low-dose statin with decreased frequency of administration and have consistently shown significant improvement in lipid levels.^3,4 For instance, once-weekly rosuvastatin at a dose between 5 mg and 20 mg resulted in a 29% reduction in LDL cholesterol levels, and 80% of patients did not experience a recurrence of myalgia.³ Furthermore, a study of patients treated with 5 mg to 10 mg of rosuvastatin twice a week resulted in a 26% decrease in LDL cholesterol levels.⁴ This study also showed that when an additional non-statin lipid-lowering drug was prescribed (eg, ezetimibe, bile acid resin, nicotinic acid), more than half of the patients reached their goal lipid level.⁴

The addition of coenzyme Q10 and fish oil has also been suggested. Although, the evidence to support this is inconclusive, the potential benefit outweighs the risk, since the side effects are minimal.¹ However, no study yet has evaluated the risks vs the benefits in patients with elevated creatine kinase.

Statin-induced myopathy is a commonly encountered adverse effect. Currently, there are no guidelines on restarting statin therapy after statin-induced myopathy; however, data suggest that statin therapy should be restarted once symptoms resolve, and that variations in dose and frequency may be necessary.^1–8,14

An 85-year-old man with hypertension, hyperlipidemia, and coronary artery disease presented to our clinic with diffuse muscle pain. The pain had been present for about 3 months, but it had become noticeably worse over the past few weeks.

He was not aware of any trauma. He described the muscle pain as dull and particularly severe in his lower extremities (his thighs and calves). The pain did not limit his daily activities, nor did physical exertion or the time of day have any effect on the level of the pain.

His medications at that time included metoprolol, aspirin, hydrochlorothiazide, simvastatin, and a daily multivitamin.

He was not in acute distress. On neurologic and musculoskeletal examinations, all deep-tendon reflexes were intact, with no tenderness to palpation of the upper and lower extremities. No abnormalities were noted on the joint examination. He had full range of motion, with 5/5 muscle strength in the upper and lower extremities bilaterally and normal muscle tone. He was able to walk with ease. Results of initial laboratory testing, including creatine kinase and erythrocyte sedimentation rate, were normal.

1. What should be the next best step in the evaluation of this patient’s muscle pain?

• Order tests for cyclic citrullinated peptide (CCP) antibody and rheumatoid factor
• Advise him to refrain from physical activity until his symptoms resolve
• Take a more detailed history, including a review of medications and supplements
• Recommend a trial of a nonsteroidal anti-inflammatory drug (NSAID)
• Send him for radiographic imaging

Since his muscle pain has persisted for several months without improvement, a more detailed history should be taken, including a review of current medications and supplements.

Testing CCP antibody and rheumatoid factor would be useful if rheumatoid arthritis were suspected, but in the absence of demonstrable arthritis on examination, these tests would have low specificity even if the results were positive.

An NSAID may temporarily alleviate his pain, but it will not help establish a diagnosis. And in elderly patients, NSAIDs are not without complications and so should be prescribed only in appropriate situations.

Imaging would be appropriate at this point only if there was clinical suspicion of a specific disease. However, our patient has no focal deficits, and the suspicion of fracture or malignancy is low.

The medical history should include asking about current drug regimens, recent medication changes, and the use of herbal supplements, since polypharmacy is common in elderly patients with multiple comorbidities.

On further questioning, our patient said that his dose of simvastatin had been increased from 40 mg daily to 80 mg daily about 1 month before his symptoms appeared. He was taking a daily multivitamin but was not using herbal supplements or other over-the-counter products. He did not recall any constitutional symptoms before the onset of his current symptoms, and he had never had similar muscle pain in the past.

2. Based on the additional information from the history, what is the most likely cause of his muscle pain?

• Limited myositis secondary to recent viral infection
• Rhabdomyolysis
• Hypothyroidism
• Drug-drug interaction
• Statin-induced myalgia

Our patient’s history provided nothing to suggest viral myositis. Hypothyroidism should always be considered in patients with myalgia, but this is not likely in our patient, as he does not display other characteristics, such as diminished reflexes, hypotonia, cold intolerance, and mood instability. Even though calcium channel blockers have been known to cause myalgia in patients on statins, a drug-drug reaction is not likely, as he had not started taking a calcium channel blocker before his symptoms began. This patient did not show signs or symptoms of rhabdomyolysis, a type of myopathy in which necrosis of the muscle tissue occurs, generally causing profound weakness and pain.¹

Therefore, statin-induced myopathy is the most likely cause of his diffuse muscle pain, particularly since his simvastatin had been increased 1 month before the onset of symptoms.

3. What should be the next step in his management?

• Decrease the dose of simvastatin to the last known dose he was able to tolerate
• Continue simvastatin at the same dose and then monitor
• Switch to another statin
• Add coenzyme Q10
• Stop simvastatin

Decreasing the statin dosage to the last well-tolerated dose would not be appropriate in a patient with myopathy, as the symptoms would probably not improve.^2–4 Also, one should not switch to a different statin while a patient is experiencing symptoms. Rather, the statin should be stopped for at least 6 weeks or until the symptoms have fully resolved.¹

Adding coenzyme Q10 is another option, especially in a patient with previously diagnosed coronary artery disease,⁵ when continued statin therapy is thought necessary to reduce the likelihood of repeat coronary events.

We discontinued his simvastatin. Followup 3 weeks later in the outpatient clinic showed that his symptoms were slowly improving. The symptoms had resolved completely 4 months later.

4. How should we manage our patient’s hyperlipidemia once his symptoms have resolved?

• Restart simvastatin at the 80-mg dose
• Restart simvastatin at the 40-mg dose
• Start a hydrophilic statin at full dose
• Use a drug from another class of lipid-lowering drugs
• Wait another 3 months before prescribing any lipid-lowering drug

His treatment for hyperlipidemia should be continued, considering his comorbidities. However, restarting the same statin, even at a lower dose, will likely cause his symptoms to recur. Thus, a different statin should be tried once his muscle pain has resolved.

Other classes of lipid-lowering drugs are usually less efficacious than statins, particularly when trying to control low-density lipoprotein (LDL) cholesterol, so a drug from another class should not be used until other statin options have been attempted.^2,6,7

Simvastatin is lipophilic. Trying a statin with hydrophilic properties (eg, pravastatin, rosuvastatin, fluvastatin) has been shown to convey similar cardioprotective effects with a lower propensity for myalgia, as lipophilic statins have a higher propensity to penetrate muscle tissue than do hydrophilic statins.^3,4,8

Once his symptoms resolved, our patient was started on a hydrophilic statin, fluvastatin 20 mg daily. Unfortunately, his pain recurred 3 weeks later. The statin was stopped, and his symptoms again resolved.

5. Since our patient was unable to tolerate a second statin, what should be the next step in his management?

• Restart simvastatin 
• Use a drug from another class to control the hyperlipidemia
• Wait at least 6 months after symptoms resolve before trying any lipid-lowering drug
• Initiate therapy with coenzyme Q10 and fish oil
• Wait for symptoms to resolve, then restart a hydrophilic statin at a lower dose and lower frequency

Restarting simvastatin will likely cause a recurrence of the myalgia. Other lipid-lowering drugs such as nicotinic acid, bile acid resins, and fibrates are not as efficacious as statins. Coenzyme Q10 and fish oil can reduce lipid levels, but they are not as efficacious as statins.

In view of our patient’s lipid profile—LDL cholesterol elevated at 167 mg/dL, high-density lipoprotein cholesterol 31 mg/dL, triglycerides 47 mg/dL—it is important to treat his hyperlipidemia. Therefore, another attempt at statin therapy should be made once his symptoms have resolved.

Studies have shown that restarting a statin at a low dose and low frequency is effective in patients who have experienced intolerance to a statin.^3,4 Our patient was treated with low-dose pravastatin (20 mg), resulting in a moderate improvement in his LDL cholesterol to 123 mg/dL.

STATIN-INDUCED MYOPATHY: ADDRESSING THE DILEMMA

Treating hyperlipidemia is important to prevent vascular events in patients with or without coronary artery disease. Statins are the most effective agents available for controlling hypercholesterolemia, specifically LDL levels, as well as for preventing myocardial infarction.

Unfortunately, significant side effects have been reported, and myopathy is the most prevalent. Statin-induced myopathy includes a combination of muscle tenderness, myalgia, and weakness.^2–11 In randomized controlled trials, the risk of myopathy was estimated to be between 1.5% and 5%.⁶ In unselected clinic patients on high-dose statins, the rate of muscle complaints may be as high as 20%.¹²

The cause of statin-induced myopathy is not known, although studies have linked it to genetic defects.⁷ Risk factors have been identified and include personal and family history of myalgia, Asian ethnicity, hypothyroidism, and type 1 diabetes. The incidence of statin-induced myalgia is two to three times higher in patients on corticosteroid therapy. Other risk factors include female sex, liver disease, and renal dysfunction.^7,8

A less common etiology is anti-HMG coenzyme A reductase antibodies. Studies have shown that these antibody levels correlate well with the amount of myositis as measured by creatine kinase levels. However, there is no consensus yet on screening for these antibodies.¹³

Statin therapy poses a dilemma, as there is a thin line between the benefits and the risks of side effects, especially statin-induced myopathy.^3,4 Current recommendations include discontinuing the statin until symptoms fully resolve. Creatine kinase levels may be useful in assessing for potential muscle breakdown, especially in patients with reduced renal function, as this predisposes them to statin-induced myopathy, yet normal values do not preclude the diagnosis of statin-induced myopathy.^3,4,7,8

Once symptoms resolve and laboratory test results normalize, a trial of a different statin is recommended. If patients become symptomatic, a trial of a low-dose hydrophilic statin at a once- or twice-weekly interval has been recommended. Several studies have assessed the efficacy of a low-dose statin with decreased frequency of administration and have consistently shown significant improvement in lipid levels.^3,4 For instance, once-weekly rosuvastatin at a dose between 5 mg and 20 mg resulted in a 29% reduction in LDL cholesterol levels, and 80% of patients did not experience a recurrence of myalgia.³ Furthermore, a study of patients treated with 5 mg to 10 mg of rosuvastatin twice a week resulted in a 26% decrease in LDL cholesterol levels.⁴ This study also showed that when an additional non-statin lipid-lowering drug was prescribed (eg, ezetimibe, bile acid resin, nicotinic acid), more than half of the patients reached their goal lipid level.⁴

The addition of coenzyme Q10 and fish oil has also been suggested. Although, the evidence to support this is inconclusive, the potential benefit outweighs the risk, since the side effects are minimal.¹ However, no study yet has evaluated the risks vs the benefits in patients with elevated creatine kinase.

Statin-induced myopathy is a commonly encountered adverse effect. Currently, there are no guidelines on restarting statin therapy after statin-induced myopathy; however, data suggest that statin therapy should be restarted once symptoms resolve, and that variations in dose and frequency may be necessary.^1–8,14

An 85-year-old man with hypertension, hyperlipidemia, and coronary artery disease presented to our clinic with diffuse muscle pain. The pain had been present for about 3 months, but it had become noticeably worse over the past few weeks.

He was not aware of any trauma. He described the muscle pain as dull and particularly severe in his lower extremities (his thighs and calves). The pain did not limit his daily activities, nor did physical exertion or the time of day have any effect on the level of the pain.

His medications at that time included metoprolol, aspirin, hydrochlorothiazide, simvastatin, and a daily multivitamin.

He was not in acute distress. On neurologic and musculoskeletal examinations, all deep-tendon reflexes were intact, with no tenderness to palpation of the upper and lower extremities. No abnormalities were noted on the joint examination. He had full range of motion, with 5/5 muscle strength in the upper and lower extremities bilaterally and normal muscle tone. He was able to walk with ease. Results of initial laboratory testing, including creatine kinase and erythrocyte sedimentation rate, were normal.

1. What should be the next best step in the evaluation of this patient’s muscle pain?

• Order tests for cyclic citrullinated peptide (CCP) antibody and rheumatoid factor
• Advise him to refrain from physical activity until his symptoms resolve
• Take a more detailed history, including a review of medications and supplements
• Recommend a trial of a nonsteroidal anti-inflammatory drug (NSAID)
• Send him for radiographic imaging

Since his muscle pain has persisted for several months without improvement, a more detailed history should be taken, including a review of current medications and supplements.

Testing CCP antibody and rheumatoid factor would be useful if rheumatoid arthritis were suspected, but in the absence of demonstrable arthritis on examination, these tests would have low specificity even if the results were positive.

An NSAID may temporarily alleviate his pain, but it will not help establish a diagnosis. And in elderly patients, NSAIDs are not without complications and so should be prescribed only in appropriate situations.

Imaging would be appropriate at this point only if there was clinical suspicion of a specific disease. However, our patient has no focal deficits, and the suspicion of fracture or malignancy is low.

The medical history should include asking about current drug regimens, recent medication changes, and the use of herbal supplements, since polypharmacy is common in elderly patients with multiple comorbidities.

On further questioning, our patient said that his dose of simvastatin had been increased from 40 mg daily to 80 mg daily about 1 month before his symptoms appeared. He was taking a daily multivitamin but was not using herbal supplements or other over-the-counter products. He did not recall any constitutional symptoms before the onset of his current symptoms, and he had never had similar muscle pain in the past.

2. Based on the additional information from the history, what is the most likely cause of his muscle pain?

• Limited myositis secondary to recent viral infection
• Rhabdomyolysis
• Hypothyroidism
• Drug-drug interaction
• Statin-induced myalgia

Our patient’s history provided nothing to suggest viral myositis. Hypothyroidism should always be considered in patients with myalgia, but this is not likely in our patient, as he does not display other characteristics, such as diminished reflexes, hypotonia, cold intolerance, and mood instability. Even though calcium channel blockers have been known to cause myalgia in patients on statins, a drug-drug reaction is not likely, as he had not started taking a calcium channel blocker before his symptoms began. This patient did not show signs or symptoms of rhabdomyolysis, a type of myopathy in which necrosis of the muscle tissue occurs, generally causing profound weakness and pain.¹

Therefore, statin-induced myopathy is the most likely cause of his diffuse muscle pain, particularly since his simvastatin had been increased 1 month before the onset of symptoms.

3. What should be the next step in his management?

• Decrease the dose of simvastatin to the last known dose he was able to tolerate
• Continue simvastatin at the same dose and then monitor
• Switch to another statin
• Add coenzyme Q10
• Stop simvastatin

Decreasing the statin dosage to the last well-tolerated dose would not be appropriate in a patient with myopathy, as the symptoms would probably not improve.^2–4 Also, one should not switch to a different statin while a patient is experiencing symptoms. Rather, the statin should be stopped for at least 6 weeks or until the symptoms have fully resolved.¹

Adding coenzyme Q10 is another option, especially in a patient with previously diagnosed coronary artery disease,⁵ when continued statin therapy is thought necessary to reduce the likelihood of repeat coronary events.

We discontinued his simvastatin. Followup 3 weeks later in the outpatient clinic showed that his symptoms were slowly improving. The symptoms had resolved completely 4 months later.

4. How should we manage our patient’s hyperlipidemia once his symptoms have resolved?

• Restart simvastatin at the 80-mg dose
• Restart simvastatin at the 40-mg dose
• Start a hydrophilic statin at full dose
• Use a drug from another class of lipid-lowering drugs
• Wait another 3 months before prescribing any lipid-lowering drug

His treatment for hyperlipidemia should be continued, considering his comorbidities. However, restarting the same statin, even at a lower dose, will likely cause his symptoms to recur. Thus, a different statin should be tried once his muscle pain has resolved.

Other classes of lipid-lowering drugs are usually less efficacious than statins, particularly when trying to control low-density lipoprotein (LDL) cholesterol, so a drug from another class should not be used until other statin options have been attempted.^2,6,7

Simvastatin is lipophilic. Trying a statin with hydrophilic properties (eg, pravastatin, rosuvastatin, fluvastatin) has been shown to convey similar cardioprotective effects with a lower propensity for myalgia, as lipophilic statins have a higher propensity to penetrate muscle tissue than do hydrophilic statins.^3,4,8

Once his symptoms resolved, our patient was started on a hydrophilic statin, fluvastatin 20 mg daily. Unfortunately, his pain recurred 3 weeks later. The statin was stopped, and his symptoms again resolved.

5. Since our patient was unable to tolerate a second statin, what should be the next step in his management?

• Restart simvastatin 
• Use a drug from another class to control the hyperlipidemia
• Wait at least 6 months after symptoms resolve before trying any lipid-lowering drug
• Initiate therapy with coenzyme Q10 and fish oil
• Wait for symptoms to resolve, then restart a hydrophilic statin at a lower dose and lower frequency

Restarting simvastatin will likely cause a recurrence of the myalgia. Other lipid-lowering drugs such as nicotinic acid, bile acid resins, and fibrates are not as efficacious as statins. Coenzyme Q10 and fish oil can reduce lipid levels, but they are not as efficacious as statins.

In view of our patient’s lipid profile—LDL cholesterol elevated at 167 mg/dL, high-density lipoprotein cholesterol 31 mg/dL, triglycerides 47 mg/dL—it is important to treat his hyperlipidemia. Therefore, another attempt at statin therapy should be made once his symptoms have resolved.

Studies have shown that restarting a statin at a low dose and low frequency is effective in patients who have experienced intolerance to a statin.^3,4 Our patient was treated with low-dose pravastatin (20 mg), resulting in a moderate improvement in his LDL cholesterol to 123 mg/dL.

STATIN-INDUCED MYOPATHY: ADDRESSING THE DILEMMA

Treating hyperlipidemia is important to prevent vascular events in patients with or without coronary artery disease. Statins are the most effective agents available for controlling hypercholesterolemia, specifically LDL levels, as well as for preventing myocardial infarction.

Unfortunately, significant side effects have been reported, and myopathy is the most prevalent. Statin-induced myopathy includes a combination of muscle tenderness, myalgia, and weakness.^2–11 In randomized controlled trials, the risk of myopathy was estimated to be between 1.5% and 5%.⁶ In unselected clinic patients on high-dose statins, the rate of muscle complaints may be as high as 20%.¹²

The cause of statin-induced myopathy is not known, although studies have linked it to genetic defects.⁷ Risk factors have been identified and include personal and family history of myalgia, Asian ethnicity, hypothyroidism, and type 1 diabetes. The incidence of statin-induced myalgia is two to three times higher in patients on corticosteroid therapy. Other risk factors include female sex, liver disease, and renal dysfunction.^7,8

A less common etiology is anti-HMG coenzyme A reductase antibodies. Studies have shown that these antibody levels correlate well with the amount of myositis as measured by creatine kinase levels. However, there is no consensus yet on screening for these antibodies.¹³

Statin therapy poses a dilemma, as there is a thin line between the benefits and the risks of side effects, especially statin-induced myopathy.^3,4 Current recommendations include discontinuing the statin until symptoms fully resolve. Creatine kinase levels may be useful in assessing for potential muscle breakdown, especially in patients with reduced renal function, as this predisposes them to statin-induced myopathy, yet normal values do not preclude the diagnosis of statin-induced myopathy.^3,4,7,8

Once symptoms resolve and laboratory test results normalize, a trial of a different statin is recommended. If patients become symptomatic, a trial of a low-dose hydrophilic statin at a once- or twice-weekly interval has been recommended. Several studies have assessed the efficacy of a low-dose statin with decreased frequency of administration and have consistently shown significant improvement in lipid levels.^3,4 For instance, once-weekly rosuvastatin at a dose between 5 mg and 20 mg resulted in a 29% reduction in LDL cholesterol levels, and 80% of patients did not experience a recurrence of myalgia.³ Furthermore, a study of patients treated with 5 mg to 10 mg of rosuvastatin twice a week resulted in a 26% decrease in LDL cholesterol levels.⁴ This study also showed that when an additional non-statin lipid-lowering drug was prescribed (eg, ezetimibe, bile acid resin, nicotinic acid), more than half of the patients reached their goal lipid level.⁴

The addition of coenzyme Q10 and fish oil has also been suggested. Although, the evidence to support this is inconclusive, the potential benefit outweighs the risk, since the side effects are minimal.¹ However, no study yet has evaluated the risks vs the benefits in patients with elevated creatine kinase.

Statin-induced myopathy is a commonly encountered adverse effect. Currently, there are no guidelines on restarting statin therapy after statin-induced myopathy; however, data suggest that statin therapy should be restarted once symptoms resolve, and that variations in dose and frequency may be necessary.^1–8,14

On November 12, 2013, a joint task force for the American College of Cardiology and American Heart Association released new guidelines for treating high blood cholesterol to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in adults.¹

This document arrives after several years of intense deliberation, 12 years after the third Adult Treatment Panel (ATP III) guidelines,² and 8 years after an ATP III update recommending that low-density lipoprotein cholesterol (LDL-C) levels be lowered aggressively (to less than 70 mg/dL) as an option in patients at high risk.³ It represents a major shift in the approach to and management of high blood cholesterol and has sparked considerable controversy.

In the following commentary, we summarize the new guidelines and the philosophy employed by the task force in generating them. We will also examine some advantages and what we believe to be several shortcomings of the new guidelines. These latter points are illustrated through case examples.

IN RANDOMIZED CONTROLLED TRIALS WE TRUST

In collaboration with the National Heart, Lung, and Blood Institute of the National Institutes of Health, the American College of Cardiology and American Heart Association formed an expert panel task force in 2008.

The task force elected to use only evidence from randomized controlled trials, systematic reviews, and meta-analyses of randomized controlled trials (and only predefined outcomes of the trials, not post hoc analyses) in formulating its recommendations, with the goal of providing the strongest possible evidence.

The authors state that “By using [randomized controlled trial] data to identify those most likely to benefit [emphasis in original] from cholesterol-lowering statin therapy, the recommendations will be of value to primary care clinicians as well as specialists concerned with ASCVD prevention. Importantly, the recommendations were designed to be easy to use in the clinical setting, facilitating the implementation of a strategy of risk assessment and treatment focused on the prevention of ASCVD.”³ They also state the guidelines are meant to “inform clinical judgment, not replace it” and that clinician judgment in addition to discussion with patients remains vital.

During the deliberations, the National Heart, Lung, and Blood Institute removed itself from participating, stating its mission no longer included drafting new guidelines. Additionally, other initial members of the task force removed themselves because of disagreement and concerns about the direction of the new guidelines.

These guidelines, and their accompanying new cardiovascular risk calculator,⁴ were released without a preliminary period to allow for open discussion, comment, and critique by physicians outside the panel. No attempt was made to harmonize the guidelines with previous versions (eg, ATP III) or with current international guidelines.

WHAT’S NEW IN THE GUIDELINES?

The following are the major changes in the new guidelines for treating high blood cholesterol:

• Treatment goals for LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) are no longer recommended.
• High-intensity and moderate-intensity statin treatment is emphasized, and low-intensity statin therapy is nearly eliminated.
• “ASCVD” now includes stroke in addition to coronary heart disease and peripheral arterial disease.
• Four groups are targeted for treatment (see below).
• Nonstatin therapies have been markedly de-emphasized.
• No guidelines are provided for treating high triglyceride levels.

The new guidelines emphasize lifestyle modification as the foundation for reducing risk, regardless of cholesterol therapy. No recommendations are given for patients with New York Heart Association class II, III, or IV heart failure or for hemodialysis patients, because there were insufficient data from randomized controlled trials to support recommendations. Similarly, the guidelines apply only to people between the ages of 40 and 75 (risk calculator ages 40–79), because the authors believed there was not enough evidence from randomized controlled trials to allow development of guidelines outside of this age range.

FOUR MAJOR STATIN TREATMENT GROUPS

The new guidelines specify four groups that merit intensive or moderately intensive statin therapy (Table 1)¹:

• People with clinical ASCVD
• People with LDL-C levels of 190 mg/dL or higher
• People with diabetes, age 40 to 75
• People without diabetes, age 40 to 75, with LDL-C levels 70–189 mg/dL, and a 10-year ASCVD risk of 7.5% or higher as determined by the new risk calculator⁴ (which also calculates the lifetime risk of ASCVD).

Below, we will address each of these four groups and provide case scenarios to consider. In general, our major disagreements with the new recommendations pertain to the first and fourth categories.

GROUP 1: PEOPLE WITH CLINICAL ASCVD

Advantages of the new guidelines

• They appropriately recommend statins in the highest tolerated doses as first-line treatment for this group at high risk.
• They designate all patients with ASCVD, including those with coronary, peripheral, and cerebrovascular disease, as a high-risk group.
• Without target LDL-C levels, treatment is simpler than before, requiring less monitoring of lipid levels. (This can also be seen as a limitation, as we discuss below.)

Limitations of the new guidelines

• They make follow-up LDL-C levels irrelevant, seeming to assume that there is no gradation in residual risk and, thus, no need to tailor therapy to the individual.
• Patients no longer have a goal to strive for or a way to monitor their progress.
• The guidelines ignore the pathophysiology of coronary artery disease and evidence of residual risk in patients on both moderate-intensity and high-intensity statin therapy.
• They also ignore the potential benefits of treating to lower LDL-C or non-HDL-C goals, thus eliminating consideration of multidrug therapy. They do not address patients with recurrent cardiovascular events already on maximal tolerated statin doses.
• They undermine the potential development and use of new therapies for dysplipidemia in patients with ASCVD.

Case 1: Is LDL-C 110 mg/dL low enough?

A 52-year-old African American man presents with newly discovered moderate coronary artery disease that is not severe enough to warrant stenting. He has no history of hypertension, diabetes mellitus, or smoking. His systolic blood pressure is 130 mm Hg, and his body mass index is 26 kg/m². He exercises regularly and follows a low-cholesterol diet. He has the following fasting lipid values:

• Total cholesterol 290 mg/dL
• HDL-C 50 mg/dL
• Triglycerides 250 mg/dL
• Calculated LDL-C 190 mg/dL.

Two months later, after beginning atorvastatin 80 mg daily, meeting with a nutritionist, and redoubling his dietary efforts, his fasting lipid concentrations are:

• Total cholesterol 180 mg/dL
• HDL-C 55 mg/dL
• Triglycerides 75 mg/dL
• Calculated LDL-C 110 mg/dL.

Comment: Lack of LDL-C goals is a flaw

The new guidelines call for patients with known ASCVD, such as this patient, to receive intensive statin therapy—which he got.

However, once a patient is on therapy, the new guidelines do not encourage repeating the lipid panel other than to assess compliance. With intensive therapy, we expect a reduction in LDL-C of at least 50% (Table 1), but patient-to-patient differences in response to medications are common, and without repeat testing we would have no way of gauging this patient’s residual risk.

Further, the new guidelines emphasize the lack of hard outcome data supporting the addition of another lipid-lowering drug to a statin, although they do indicate that one can consider it. In a patient at high risk, such as this one, would you be comfortable with an LDL-C value of 110 mg/dL on maximum statin therapy? Would you consider adding a nonstatin drug?

A preponderance of data shows that LDL plays a causal role in ASCVD development and adverse events. Genetic data show that the LDL particle and the LDL receptor pathway are mechanistically linked to ASCVD pathogenesis, with lifetime exposure as a critical determinant of risk.^5,6 Moreover, randomized controlled trials of statins and other studies of cholesterol-lowering show a reproducible relationship between the LDL-C level achieved and absolute risk (Figure 1).^7–24 We believe the totality of data constitutes a strong rationale for targeting LDL-C and establishing goals for lowering its levels. For these reasons, we believe that removing LDL-C goals is a fundamental flaw of the new guidelines.

The reason for the lack of data from randomized controlled trials demonstrating benefits of adding therapies to statins (when LDL-C is still high) or benefits of treating to specific goals is that no such trials have been performed. Even trials of nonpharmacologic means of lowering LDL-C, such as ileal bypass, which was used in the Program on the Surgical Control of the Hyperlipidemias trial,²⁰ provide independent evidence that lowering LDL-C reduces the risk of ASCVD (Figure 1).

In addition, trials of nonstatin drugs, such as the Coronary Drug Project,25 which tested niacin, also showed outcome benefits. On the other hand, studies such as the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health26 and Treatment of HDL to Reduce the Incidence of Vascular Events27 trials did not show additional risk reduction when niacin was added to statin therapy. However, the study designs arguably had flaws, including requirement of aggressive LDL-lowering with statins, with LDL-C levels below 70 to 80 mg/dL before randomization.

Therefore, these trials do not tell us what to do for a patient on maximal intensive therapy who has recurrent ASCVD events or who, like our patient, has an LDL-C level higher than previous targets.

For this patient, we would recommend adding a second medication to further lower his LDL-C, but discussing with him the absence of proven benefit in clinical trials and the risks of side effects. At present, lacking LDL-C goals in the new guidelines, we are keeping with the ATP III goals to help guide therapeutic choices and individualize patient management.

GROUP 2: PEOPLE WITH LDL-C ≥ 190

Advantages of the new guidelines

• They state that these patients should receive statins in the highest tolerated doses, which is universally accepted.

Limitations of the new guidelines

• The new guidelines mention only that one “may consider” adding a second agent if LDL-C remains above 190 mg/dL after maximum-dose therapy. Patients with familial hypercholesterolemia or other severe forms of hypercholesterolemia typically end up on multidrug therapy to further reduce LDL-C. The absence of randomized controlled trial data in this setting to show an additive value of second and third lipid-lowering agents does not mean these agents do not provide benefit.

GROUP 3: DIABETES, AGE 40–75, LDL-C 70–189, NO CLINICAL ASCVD

Advantages of the new guidelines

• They call for aggressive treatment of people with diabetes, a group at high risk that derives significant benefit from statin therapy, as shown in randomized controlled trials.

Limitations of the new guidelines

• Although high-intensity statin therapy is indicated for this group, we believe that, using the new risk calculator, some patients may receive overly aggressive treatment, thus increasing the possibility of statin side effects.
• The guidelines do not address patients younger than 40 or older than 75.
• Diabetic patients have a high residual risk of ASCVD events, even on statin therapy. Yet the guidelines ignore the potential benefits of more aggressive LDL-lowering or non-LDL secondary targets for therapy.

Case 2: How low is too low?

A 63-year-old white woman, a nonsmoker with recently diagnosed diabetes, is seen by her primary care physician. She has hypertension, for which she takes lisinopril 5 mg daily. Her fasting lipid values are:

• Total cholesterol 160 mg/dL
• HDL-C 64 mg/dL
• Triglycerides 100 mg/dL
• Calculated LDL-C 76 mg/dL.

Her systolic blood pressure is 129 mm Hg, and based on the new risk calculator, her 10-year risk of cardiovascular disease is 10.2%. According to the new guidelines, she should be started on high-intensity statin treatment (Table 1).

Although this is an acceptable initial course of action, it necessitates close vigilance, since it may actually drive her LDL-C level too low. Randomized controlled trials have typically used an LDL-C concentration of less than or equal to 25 mg/dL as the safety cutoff. With a typical LDL-C reduction of at least 50% on high-intensity statins, our patient’s expected LDL-C level will likely be in the low 30s. We believe this would be a good outcome, provided that she tolerates the medication without adverse effects. However, responses to statins vary from patient to patient.

High-intensity statin therapy may not be necessary to reduce risk adequately in all patients who have diabetes without preexisting vascular disease. The Collaborative Atorvastatin Diabetes Study¹² compared atorvastatin 10 mg vs placebo in people with type 2 diabetes, age 40 to 75, who had one or more cardiovascular risk factors but no signs or symptoms of preexisting ASCVD and who had only average or below-average cholesterol levels—precisely like this patient. The trial was terminated early because of a clear benefit (a 37% reduction in the composite end point of major adverse cardiovascular events) in the intervention group. For our patient, we believe an alternative and acceptable approach would be to begin moderate-intensity statin therapy (eg, with atorvastatin 10 mg) (Table 1).

Alternatively, in a patient with diabetes and previous atherosclerotic vascular disease or with a high 10-year risk and high LDL-C, limiting treatment to high-intensity statin therapy by itself may deny them the potential benefits of combination therapies and targeting to lower LDL-C levels or non-HDL-C secondary targets. Guidelines from the American Diabetes Association²⁸ and the American Association of Clinical Endocrinologists²⁹ continue to recommend an LDL-C goal of less than 70 mg/dL in patients at high risk, a non-HDL-C less than 100 mg/dL, an apolipoprotein B less than 80 mg/dL, and an LDL particle number less than 1,000 nmol/L.

GROUP 4: AGE 40–75, LDL-C 70–189, NO ASCVD, BUT 10-YEAR RISK ≥ 7.5%

Advantages of the new guidelines

• They may reduce ASCVD events for patients at higher risk.
• The risk calculator is easy to use and focuses on global risk, ie, all forms of ASCVD.
• The guidelines promote discussion of risks and benefits between patients and providers.

Limitations of the new guidelines

• The new risk calculator is controversial (see below).
• There is potential for overtreatment, particularly in older patients.
• There is potential for undertreatment, particularly in patients with an elevated LDL-C but whose 10-year risk is less than 7.5% because they are young.
• The guidelines do not address patients younger than 40 or older than 75.
• They do not take into account some traditional risk factors, such as family history, and nontraditional risk factors such as C-reactive protein as measured by ultrasensitive assays, lipoprotein(a), and apolipoprotein B.

Risk calculator controversy

The new risk calculator has aroused strong opinions on both sides of the aisle.

Shortly after the new guidelines were released, cardiologists Dr. Paul Ridker and Dr. Nancy Cook from Brigham and Women’s Hospital in Boston published analyses³⁰ showing that the new risk calculator, which was based on older data from several large cohorts such as the Atherosclerosis Risk in Communities study,³¹ the Cardiovascular Health Study,³² the Coronary Artery Risk Development in Young Adults study,³³ and the Framingham Heart Study,^34,35 was inaccurate in other cohorts. Specifically, in more-recent cohorts (the Women’s Health Study,³⁶ Physicians’ Health Study,³⁷ and Women’s Health Initiative³⁸), the new calculator overestimates the 10-year risk of ASCVD by 75% to 150%.³⁰ Using the new calculator would make approximately 30 million more Americans eligible for statin treatment. The concern is that patients at lower risk would be treated and exposed to potential side effects of statin therapy.

In addition, the risk calculator relies heavily on age and sex and does not include other factors such as triglyceride level, family history, C-reactive protein, or lipoprotein(a). Importantly, and somewhat ironically given the otherwise absolute adherence to randomized controlled trial data for guideline development, the risk calculator has never been verified in prospective studies to adequately show that using it reduces ASCVD events.

Based on the risk calculator, essentially any African American man in his early 60s with no other risk factors has a 10-year risk of ASCVD of 7.5% or higher and, according to the new guidelines, should receive at least moderate-intensity statin therapy.

For example, consider a 64-year-old African American man whose systolic blood pressure is 129 mm Hg, who does not smoke, does not have diabetes, and does not have hypertension, and whose total cholesterol level is 180 mg/dL, HDL-C 70 mg/dL, triglycerides 130 mg/dL, and calculated LDL-C 84 mg/dL. His calculated 10-year risk is, surprisingly, 7.5%.

Alternatively, his twin brother is a two-pack-per-day smoker with untreated hypertension and systolic blood pressure 150 mm Hg, with fasting total cholesterol 153 mg/dL, HDL-C 70 mg/dL, triglycerides 60 mg/dL, and LDL-C 71 mg/dL. His calculated 10-year risk is 10.5%, so according to the new guidelines, he too should receive high-intensity statin therapy. Yet this patient clearly needs better blood pressure control and smoking cessation as his primary risk-reduction efforts, not a statin. While assessing global risk is important, a shortcoming of the new guidelines is that they can inappropriately lead to treating the risk score, not individualizing the treatment to the patient. Because of the errors inherent in the risk calculator, some experts have called for a temporary halt on implementing the new guidelines until the risk calculator can be further validated. In November 2013, the American Heart Association and the American College of Cardiology reaffirmed their support of the new guidelines and recommended that they be implemented as planned. As of the time this manuscript goes to print, there are no plans to halt implementation of the new guidelines.

Case 4: Undertreating a primary prevention patient

A 25-year-old white man with no medical history has a total cholesterol level of 310 mg/dL, HDL-C 50 mg/dL, triglycerides 400 mg/dL, and calculated LDL-C 180 mg/dL. He does not smoke or have hypertension or diabetes but has a strong family history of premature coronary disease (his father died of myocardial infarction at age 42). His body mass index is 25 kg/m². Because he is less than 40 years old, the risk calculator does not apply to him.

If we assume he remains untreated and returns at age 40 with the same clinical factors and laboratory values, his calculated 10-year risk of an ASCVD event according to the new risk calculator will still be only 3.1%. Assuming his medical history remains unchanged as he continues to age, his 10-year risk would not reach 7.5% until he is 58. Would you feel comfortable waiting 33 years before starting statin therapy in this patient?

Waiting for dyslipidemic patients to reach middle age before starting LDL-C-lowering therapy is a failure of prevention. For practical reasons, there are no data from randomized controlled trials with hard outcomes in younger people. Nevertheless, a tenet of preventive cardiology is that cumulative exposure accelerates the “vascular age” ahead of the chronological age. This case illustrates why individualized recommendations guided by LDL-C goals as a target for therapy are needed. For this 25-year-old patient, we would recommend starting an intermediate- or high-potency statin.

Case 5: Rheumatoid arthritis

A 60-year-old postmenopausal white woman with severe rheumatoid arthritis presents for cholesterol evaluation. Her total cholesterol level is 235 mg/dL, HDL-C 50 mg/dL, and LDL-C 165 mg/dL. She does not smoke or have hypertension or diabetes. Her systolic blood pressure is 110 mm Hg. She has elevated C-reactive protein on an ultrasensitive assay and elevated lipoprotein(a).

Her calculated 10-year risk of ASCVD is 3.0%. Assuming her medical history remains the same, she would not reach a calculated 10-year risk of at least 7.5% until age 70. We suggest starting moderate- or high-dose statin therapy in this case, based on data (not from randomized controlled trials) showing an increased risk of ASCVD events in patients with rheumatologic disease, increased lipoprotein(a), and inflammatory markers like C-reactive protein. However, the current guidelines do not address this scenario, other than to suggest that clinician consideration can be given to other risk markers such as these, and that these findings should be discussed in detail with the patient. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial¹⁶ showed a dramatic ASCVD risk reduction in just such patients (Figure 1).

APPLAUSE—AND RESERVATIONS

The newest guidelines for treating high blood cholesterol represent a monumental shift away from using target levels of LDL-C and non-HDL-C and toward a focus on statin intensity for patients in the four highest-risk groups.

We applaud the expert panel for its idealistic approach of using only data from randomized controlled trials, for placing more emphasis on higher-intensity statin treatment, for including stroke in the new definition of ASCVD, and for focusing more attention on treating diabetic patients more aggressively. Simplifying the guidelines is a noble goal. Emphasizing moderate-to-high-intensity statin therapy in patients at moderate-to-high risk should have substantial long-term public health benefits.

However, as we have shown in the case examples, there are significant limitations, and some patients can end up being overtreated, while others may be undertreated.

Guidelines need to be crafted by looking at all the evidence, including the pathophysiology of the disease process, not just data from randomized controlled trials. It is difficult to implement a guideline that on one hand used randomized controlled trials exclusively for recommendations, but on the other hand used an untested risk calculator to guide therapy. Randomized controlled trials are not available for every scenario.

Further, absence of randomized controlled trial data in a given scenario should not be interpreted as evidence of lack of benefit. An example of this is a primary-prevention patient under age 40 with elevated LDL-C below the 190 mg/dL cutoff who otherwise is healthy and without risk factors (eg, Case 4). By disregarding all evidence that is not from randomized controlled trials, the expert panel fails to account for the extensive pathophysiology of ASCVD, which often begins at a young age and takes decades to develop.^5,6,39 An entire generation of patients who have not reached the age of inclusion in most randomized controlled trials with hard outcomes is excluded (unless the LDL-C level is very high), potentially setting back decades of progress in the field of prevention. Prevention only works if started. With childhood and young adult obesity sharply rising, we should not fail to address the under-40-year-old patient population in our guidelines.

Guidelines are designed to be expert opinion, not to dictate practice. Focusing on the individual patient instead of the general population at risk, the expert panel appropriately emphasizes the “importance of clinician judgment, weighing potential benefits, adverse effects, drug-drug interactions and patient preferences.” However, by excluding all data that do not come from randomized controlled trials, the panel neglects a very large base of knowledge and leaves many clinicians without as much expert opinion as we had hoped for.

LDL-C goals are important: they provide a scorecard to help the patient with lifestyle and dietary changes. They provide the health care provider guidance in making treatment decisions and focusing on treatment of a single patient, not a population. Moreover, if a patient has difficulty taking standard doses of statins because of side effects, the absence of LDL-C goals makes decision-making nearly impossible. We hope physicians will rely on LDL-C goals in such situations, falling back on the ATP III recommendations, although many patients may simply go untreated until they present with ASCVD or until they “age in” to a higher risk category.

We suggest caution in strict adherence to the new guidelines and instead urge physicians to consider a hybrid of the old guidelines (using the ATP III LDL-C goals) and the new ones (emphasizing global risk assessment and high-intensity statin treatment).

On November 12, 2013, a joint task force for the American College of Cardiology and American Heart Association released new guidelines for treating high blood cholesterol to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in adults.¹

This document arrives after several years of intense deliberation, 12 years after the third Adult Treatment Panel (ATP III) guidelines,² and 8 years after an ATP III update recommending that low-density lipoprotein cholesterol (LDL-C) levels be lowered aggressively (to less than 70 mg/dL) as an option in patients at high risk.³ It represents a major shift in the approach to and management of high blood cholesterol and has sparked considerable controversy.

In the following commentary, we summarize the new guidelines and the philosophy employed by the task force in generating them. We will also examine some advantages and what we believe to be several shortcomings of the new guidelines. These latter points are illustrated through case examples.

IN RANDOMIZED CONTROLLED TRIALS WE TRUST

In collaboration with the National Heart, Lung, and Blood Institute of the National Institutes of Health, the American College of Cardiology and American Heart Association formed an expert panel task force in 2008.

The task force elected to use only evidence from randomized controlled trials, systematic reviews, and meta-analyses of randomized controlled trials (and only predefined outcomes of the trials, not post hoc analyses) in formulating its recommendations, with the goal of providing the strongest possible evidence.

The authors state that “By using [randomized controlled trial] data to identify those most likely to benefit [emphasis in original] from cholesterol-lowering statin therapy, the recommendations will be of value to primary care clinicians as well as specialists concerned with ASCVD prevention. Importantly, the recommendations were designed to be easy to use in the clinical setting, facilitating the implementation of a strategy of risk assessment and treatment focused on the prevention of ASCVD.”³ They also state the guidelines are meant to “inform clinical judgment, not replace it” and that clinician judgment in addition to discussion with patients remains vital.

During the deliberations, the National Heart, Lung, and Blood Institute removed itself from participating, stating its mission no longer included drafting new guidelines. Additionally, other initial members of the task force removed themselves because of disagreement and concerns about the direction of the new guidelines.

These guidelines, and their accompanying new cardiovascular risk calculator,⁴ were released without a preliminary period to allow for open discussion, comment, and critique by physicians outside the panel. No attempt was made to harmonize the guidelines with previous versions (eg, ATP III) or with current international guidelines.

WHAT’S NEW IN THE GUIDELINES?

The following are the major changes in the new guidelines for treating high blood cholesterol:

• Treatment goals for LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) are no longer recommended.
• High-intensity and moderate-intensity statin treatment is emphasized, and low-intensity statin therapy is nearly eliminated.
• “ASCVD” now includes stroke in addition to coronary heart disease and peripheral arterial disease.
• Four groups are targeted for treatment (see below).
• Nonstatin therapies have been markedly de-emphasized.
• No guidelines are provided for treating high triglyceride levels.

The new guidelines emphasize lifestyle modification as the foundation for reducing risk, regardless of cholesterol therapy. No recommendations are given for patients with New York Heart Association class II, III, or IV heart failure or for hemodialysis patients, because there were insufficient data from randomized controlled trials to support recommendations. Similarly, the guidelines apply only to people between the ages of 40 and 75 (risk calculator ages 40–79), because the authors believed there was not enough evidence from randomized controlled trials to allow development of guidelines outside of this age range.

FOUR MAJOR STATIN TREATMENT GROUPS

The new guidelines specify four groups that merit intensive or moderately intensive statin therapy (Table 1)¹:

• People with clinical ASCVD
• People with LDL-C levels of 190 mg/dL or higher
• People with diabetes, age 40 to 75
• People without diabetes, age 40 to 75, with LDL-C levels 70–189 mg/dL, and a 10-year ASCVD risk of 7.5% or higher as determined by the new risk calculator⁴ (which also calculates the lifetime risk of ASCVD).

Below, we will address each of these four groups and provide case scenarios to consider. In general, our major disagreements with the new recommendations pertain to the first and fourth categories.

GROUP 1: PEOPLE WITH CLINICAL ASCVD

Advantages of the new guidelines

• They appropriately recommend statins in the highest tolerated doses as first-line treatment for this group at high risk.
• They designate all patients with ASCVD, including those with coronary, peripheral, and cerebrovascular disease, as a high-risk group.
• Without target LDL-C levels, treatment is simpler than before, requiring less monitoring of lipid levels. (This can also be seen as a limitation, as we discuss below.)

Limitations of the new guidelines

• They make follow-up LDL-C levels irrelevant, seeming to assume that there is no gradation in residual risk and, thus, no need to tailor therapy to the individual.
• Patients no longer have a goal to strive for or a way to monitor their progress.
• The guidelines ignore the pathophysiology of coronary artery disease and evidence of residual risk in patients on both moderate-intensity and high-intensity statin therapy.
• They also ignore the potential benefits of treating to lower LDL-C or non-HDL-C goals, thus eliminating consideration of multidrug therapy. They do not address patients with recurrent cardiovascular events already on maximal tolerated statin doses.
• They undermine the potential development and use of new therapies for dysplipidemia in patients with ASCVD.

Case 1: Is LDL-C 110 mg/dL low enough?

A 52-year-old African American man presents with newly discovered moderate coronary artery disease that is not severe enough to warrant stenting. He has no history of hypertension, diabetes mellitus, or smoking. His systolic blood pressure is 130 mm Hg, and his body mass index is 26 kg/m². He exercises regularly and follows a low-cholesterol diet. He has the following fasting lipid values:

• Total cholesterol 290 mg/dL
• HDL-C 50 mg/dL
• Triglycerides 250 mg/dL
• Calculated LDL-C 190 mg/dL.

Two months later, after beginning atorvastatin 80 mg daily, meeting with a nutritionist, and redoubling his dietary efforts, his fasting lipid concentrations are:

• Total cholesterol 180 mg/dL
• HDL-C 55 mg/dL
• Triglycerides 75 mg/dL
• Calculated LDL-C 110 mg/dL.

Comment: Lack of LDL-C goals is a flaw

The new guidelines call for patients with known ASCVD, such as this patient, to receive intensive statin therapy—which he got.

However, once a patient is on therapy, the new guidelines do not encourage repeating the lipid panel other than to assess compliance. With intensive therapy, we expect a reduction in LDL-C of at least 50% (Table 1), but patient-to-patient differences in response to medications are common, and without repeat testing we would have no way of gauging this patient’s residual risk.

Further, the new guidelines emphasize the lack of hard outcome data supporting the addition of another lipid-lowering drug to a statin, although they do indicate that one can consider it. In a patient at high risk, such as this one, would you be comfortable with an LDL-C value of 110 mg/dL on maximum statin therapy? Would you consider adding a nonstatin drug?

A preponderance of data shows that LDL plays a causal role in ASCVD development and adverse events. Genetic data show that the LDL particle and the LDL receptor pathway are mechanistically linked to ASCVD pathogenesis, with lifetime exposure as a critical determinant of risk.^5,6 Moreover, randomized controlled trials of statins and other studies of cholesterol-lowering show a reproducible relationship between the LDL-C level achieved and absolute risk (Figure 1).^7–24 We believe the totality of data constitutes a strong rationale for targeting LDL-C and establishing goals for lowering its levels. For these reasons, we believe that removing LDL-C goals is a fundamental flaw of the new guidelines.

The reason for the lack of data from randomized controlled trials demonstrating benefits of adding therapies to statins (when LDL-C is still high) or benefits of treating to specific goals is that no such trials have been performed. Even trials of nonpharmacologic means of lowering LDL-C, such as ileal bypass, which was used in the Program on the Surgical Control of the Hyperlipidemias trial,²⁰ provide independent evidence that lowering LDL-C reduces the risk of ASCVD (Figure 1).

In addition, trials of nonstatin drugs, such as the Coronary Drug Project,25 which tested niacin, also showed outcome benefits. On the other hand, studies such as the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health26 and Treatment of HDL to Reduce the Incidence of Vascular Events27 trials did not show additional risk reduction when niacin was added to statin therapy. However, the study designs arguably had flaws, including requirement of aggressive LDL-lowering with statins, with LDL-C levels below 70 to 80 mg/dL before randomization.

Therefore, these trials do not tell us what to do for a patient on maximal intensive therapy who has recurrent ASCVD events or who, like our patient, has an LDL-C level higher than previous targets.

For this patient, we would recommend adding a second medication to further lower his LDL-C, but discussing with him the absence of proven benefit in clinical trials and the risks of side effects. At present, lacking LDL-C goals in the new guidelines, we are keeping with the ATP III goals to help guide therapeutic choices and individualize patient management.

GROUP 2: PEOPLE WITH LDL-C ≥ 190

Advantages of the new guidelines

• They state that these patients should receive statins in the highest tolerated doses, which is universally accepted.

Limitations of the new guidelines

• The new guidelines mention only that one “may consider” adding a second agent if LDL-C remains above 190 mg/dL after maximum-dose therapy. Patients with familial hypercholesterolemia or other severe forms of hypercholesterolemia typically end up on multidrug therapy to further reduce LDL-C. The absence of randomized controlled trial data in this setting to show an additive value of second and third lipid-lowering agents does not mean these agents do not provide benefit.

GROUP 3: DIABETES, AGE 40–75, LDL-C 70–189, NO CLINICAL ASCVD

Advantages of the new guidelines

• They call for aggressive treatment of people with diabetes, a group at high risk that derives significant benefit from statin therapy, as shown in randomized controlled trials.

Limitations of the new guidelines