While most cases of breast cancer are sporadic (ie, not inherited), up to 10% are attributable to single-gene hereditary cancer syndromes.^1–4 People with these syndromes have a lifetime risk of breast cancer much higher than in the general population, and the cancers often occur at a much earlier age.

With genetic testing becoming more common, primary care physicians need to be familiar with the known syndromes, associated risks, and evidence-based recommendations for management. Here, we review the management of cancer risk in the most common hereditary breast cancer syndromes, ie:

• Hereditary breast and ovarian cancer syndrome⁵
• Hereditary diffuse gastric cancer
• Cowden syndrome (PTEN hamartoma tumor syndrome)
• Peutz-Jeghers syndrome
• Li-Fraumeni syndrome.

IT TAKES A TEAM, BUT PRIMARY CARE PHYSICIANS ARE CENTRAL

Women who have a hereditary predisposition to breast cancer face complex and emotional decisions about the best ways to manage and reduce their risks. Their management includes close clinical surveillance, chemoprevention, and surgical risk reduction.^1,4

Referral to multiple subspecialists is an important component of these patients’ preventive care. They may need referrals to a cancer genetic counselor, a high-risk breast clinic, a gynecologic oncologist, and counseling services. They may also require referrals to gastroenterologists, colorectal surgeons, endocrinologists, and endocrine surgeons, depending on the syndrome identified.

Find a genetic counselor at www.nsgc.orgConsultation with a certified genetic counselor is critical for patients harboring mutations associated with cancer risk. The National Society of Genetic Counselors maintains a directory of genetic counselors by location and practice specialty at www.nsgc.org. The counselor’s evaluation will provide patients with a detailed explanation of the cancer risks and management guidelines for their particular condition, along with offering diagnostic genetic testing if appropriate. Women with germline mutations who plan to have children should be informed about preimplantation genetic diagnosis and about fertility specialists who can perform this service if they are interested in pursuing it.⁶

Screening and management guidelines for hereditary breast cancer syndromes are evolving. While subspecialists may be involved in enhanced surveillance and preventive care, the primary care physician is the central player, with both a broader perspective and knowledge of the patient’s competing medical issues, risks, and preferences.

In addition to breast cancer, the risk of other malignancies is also higher, with the pattern varying by syndrome (Table 1).^7–20 The management of these additional risks is beyond the scope of this review; however, primary care physicians need to be familiar with these risks to provide adequate referrals.

WHO IS AT INCREASED RISK OF BREAST CANCER?

In considering recommendations to reduce the risk of breast cancer, it is useful to think of a patient as being at either high risk or average risk.

The risk of breast cancer in women in the general population is about 12%, and most cases of breast cancer occur in patients who have no known risk factors for it. “High risk” of breast cancer generally means having more than a 20% lifetime risk (ie, before age 70) of developing the condition.

Even without a hereditary cancer syndrome, a combination of reproductive, environmental, personal, and family history factors can confer a 20% lifetime risk. But for women with hereditary syndromes, the risk far exceeds 20% regardless of such risk factors. It is likely that interactions with reproductive, environmental, and personal risk factors likely affect the individual risk of a woman with a known genetic mutation, and evidence is emerging with regard to further risk stratification.

In an earlier article in this journal, Smith and colleagues²¹ reviewed how to recognize heritable breast cancer syndromes. In general, referral for genetic counseling should be considered for patients and their families who have:

• Early-onset breast cancers (before age 50)
• Bilateral breast cancers at any age
• Ovarian cancers at any age
• “Triple-negative” breast cancers (ie, estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-nonamplified (HER2-negative)
• Male breast cancer at any age
• Cancers affecting multiple individuals and in multiple generations.
• Breast, ovarian, pancreatic or prostate cancer in families with Ashkenazi Jewish ancestry

HEREDITARY BREAST CANCER SYNDROMES

Hereditary breast and ovarian cancer syndrome

The most common of these syndromes is hereditary breast and ovarian cancer syndrome, caused by germline mutations in the tumor-suppressor genes BRCA1 or BRCA2.⁷ The estimated prevalence of BRCA1 mutations is 1 in 250 to 300, and the prevalence of BRCA2 mutations is 1 in 800.^1,4 However, in families of Ashkenazi Jewish ancestry, the population frequency of either a BRCA1 or BRCA2 mutation is approximately 1 in 40.^1,4,6

Women with BRCA1 or BRCA2 mutations have a lifetime risk of breast cancer of up to 87%

Women with BRCA1 or BRCA2 mutations have a lifetime risk of breast cancer of up to 87%, or 5 to 7 times higher than in the general population, with the risk rising steeply beginning at age 30.^1,5,8 In addition, the lifetime risk of ovarian cancer is nearly 59% in BRCA1 mutation carriers and 17% in BRCA2 mutation carriers.²²

A meta-analysis found that BRCA1 mutation carriers diagnosed with cancer in one breast have a 5-year risk of developing cancer in the other breast of 15%, and BRCA2 mutation carriers have a risk of 9%.²³ Overall, the risk of contralateral breast cancer is about 3% per year.^3,4,24

BRCA1 mutations are strongly associated with triple-negative breast cancers.^1,3,4

Hereditary diffuse gastric cancer

Hereditary diffuse gastric cancer is an autosomal-dominant syndrome associated with mutations in the CDH1 gene, although up to 75% of patients with this syndrome do not have an identifiable CDH1 mutation.^9,25,26 In cases in which there is no identifiable CDH1 mutation, the diagnosis is made on the basis of the patient’s medical and family history.

Hereditary diffuse gastric cancer is associated with an increased risk of the lobular subtype of breast cancer as well as diffuse gastric cancer. The cumulative lifetime risk of breast cancer in women with CDH1 mutations is 39% to 52%,^6,9–11,25 and their lifetime risk of diffuse gastric cancer is 83%.⁹ The combined risk of breast cancer and gastric cancer in women with this syndrome is 90% by age 80.⁹

Cowden syndrome (PTEN hamartoma tumor syndrome)

Cowden syndrome (PTEN hamartoma tumor syndrome) is caused by mutations in PTEN, another tumor-suppressor gene.¹¹ The primary clinical concerns are melanoma and breast, endometrial, thyroid (follicular or papillary), colon, and renal cell cancers. Women with a PTEN mutation have a twofold greater risk of developing any type of cancer than men with a PTEN mutation.¹² The cumulative lifetime risk of invasive breast cancer in women with this syndrome is 70% to 85%.^11–13

Peutz-Jeghers syndrome

Peutz-Jeghers syndrome is an autosomal dominant polyposis disorder caused, in most patients, by a mutation in the serine/threonine kinase tumor-suppressor gene STK11.¹⁴

Patients with Peutz-Jeghers syndrome have higher risks of gastrointestinal, breast, gynecologic (uterine, ovarian, and cervical), pancreatic, and lung cancers. In women, the lifetime risk of breast cancer is 44% to 50% by age 70, regardless of the type of mutation.^6,14,15 Breast cancers associated with Peutz-Jeghers syndrome are usually ductal, and the mean age at diagnosis is 37 years.¹⁶

Li-Fraumeni syndrome

Li-Fraumeni syndrome is an autosomal-dominant disorder caused by germline mutations in the TP53 gene, which codes for a transcription factor associated with cell proliferation and apoptosis.²⁷

Think about other highly penetrant genetic mutations in a young breast cancer patient with no mutation in BRCA1 or BRCA2These mutations confer a lifetime cancer risk of 93% in women (mainly breast cancer) and 68% in men.^1,27 Other cancers associated with TP53 mutations include sarcomas, brain cancer, leukemia, and adrenocortical tumors. Germline TP53 mutations are responsible for approximately 1% of all breast cancers.^1,4

Breast cancers can occur at a young age in patients with a TP53 mutation. Women with TP53 mutations are 18 times more likely to develop breast cancer before age 45 compared with the general population.⁴

It is important to consider a TP53 mutation in premenopausal women or women less than 30 years of age with breast cancer who have no mutations in BRCA1 and BRCA2.¹

MANAGING PATIENTS WITH GENETIC PREDISPOSITION TO BREAST CANCER

Management for patients at high risk fall into three broad categories: clinical surveillance, chemoprevention, and surgical risk reduction. The utility and benefit of each depend to a large degree on the patient’s specific mutation, family history, and comorbidities. Decisions must be shared with the patient.

CLOSE CLINICAL SURVEILLANCE

Consensus guidelines for cancer screening in the syndromes described here are available from the National Comprehensive Cancer Network at www.nccn.org and are summarized in Table 2.^26,28 While the guidelines are broadly applicable to all women with these conditions, some individualization is required based on personal and family medical history.

In general, screening begins at the ages listed in Table 2 or 10 years earlier than the age at which cancer developed in the first affected relative, whichever is earlier. However, screening decisions are shared with the patient and are sometimes affected by significant out-of-pocket costs for the patient and anxiety resulting from the test or subsequent test findings, which must all be considered.

Breast self-awareness and clinical breast examination

Although controversial in the general population, breast self-examination is recommended for patients carrying mutations that increase risk.⁶

Discuss breast self-awareness with all women patients at age 18

A discussion about breast self-awareness is recommended for all women at the age of 18. It should include the signs and symptoms of breast cancer, what feels “normal” to the patient, and what is known about modifiable risk factors for breast cancer. The patient should also be told to report any changes in her personal or family history.

Clinical breast examinations should be done every 6 months, as some cancers are found clinically, particularly in young women with dense tissue, and confirmed by diagnostic imaging and targeted ultrasonography.

Radiographic surveillance

Mammography and magnetic resonance imaging (MRI) are also important components of a breast cancer surveillance regimen in women at high risk. Adherence to a well-formulated plan of clinical and radiographic examinations increases early detection in patients who have a hereditary predisposition to breast cancer.

MRI is more sensitive than mammography and reduces the likelihood of finding advanced cancers by up to 70% compared with mammography in women at high risk of breast cancer.^29–31 The sensitivity of breast MRI alone ranges from 71% to 100%, and the sensitivity increases to 89% to 100% when combined with mammography. In contrast, the sensitivity of mammography alone is 25% to 59%.²⁹ MRI has also been shown to be cost-effective when added to mammography and physical examination in women at high risk.^5,32

Adding MRI to the breast cancer screening regimen has been under discussion and has been endorsed by the American Cancer Society in formal recommendations set forth in 2007 for patients with known hereditary cancer syndromes, in untested first-degree relatives of identified genetic mutation carriers, or in women who have an estimated lifetime risk of breast cancer of 20% or more, as determined by models largely dependent on family history.³³

But MRI has a downside—it is less specific than mammography.^29,33 Its lower specificity (77% to 90% vs 95% with mammography alone) leads to additional radiographic studies and tissue samplings for the “suspicious” lesions discovered. From 3% to 15% of screening breast MRIs result in a biopsy, and the proportion of biopsies that reveal cancer is 13% to 40%.³³ Furthermore, by itself, MRI has not been shown to reduce mortality in any high-risk group.

Mammography remains useful in conjunction with MRI due to its ability to detect breast calcifications, which may be the earliest sign of breast cancer, and ability to detect changes in breast architecture. A typical screening program (Table 2) should incorporate both modalities, commonly offset by 6 months (eg, mammography at baseline, then MRI 6 months later, then mammography again 6 months after that, and so on) to increase the detection of interval cancer development.

Chemoprevention

Chemoprevention means taking medications to reduce the risk. Certain selective estrogen receptor modulators and aromatase inhibitors decrease the risk of invasive breast cancer in healthy women at high risk. These drugs include tamoxifen, which can be used before menopause, and raloxifene, anastrozole, and exemestane, which must be used only after menopause.

Because data are limited, we cannot make any generalized recommendations about chemoprevention in patients with hereditary breast cancer syndromes. Decisions about chemoprevention should take into account the patient’s personal and family histories. Often, a medical oncologist or medical breast specialist can help by discussing the risks and benefits for the individual patient.

Tamoxifen has been the most studied, mainly in BRCA mutation carriers.^6,34–37 As in the general population, tamoxifen reduces the incidence of estrogen receptor-positive breast cancers by 50%.^36–38 It has not been shown to significantly reduce breast cancer risk in premenopausal women with BRCA1 mutations,³⁷ most likely because most cancers that occur in this group are estrogen receptor-negative. In patients with a history of breast cancer, however, tamoxifen has been shown to reduce the risk of developing contralateral breast cancer by 45% to 60% in both BRCA1 and BRCA2 mutation carriers.^6,35

There is also little evidence that giving a chemopreventive agent after bilateral salpingo-oophorectomy reduces the risk further in premenopausal BRCA mutation carriers.³⁵ These patients often receive hormonal therapy with estrogen, which currently would preclude the use of tamoxifen. Tamoxifen in postmenopausal women is associated with a small increased risk of venous thromboembolic disease and endometrial cancer.³⁸

Oral contraceptives reduce the risk of ovarian cancer by up to 50% in BRCA1 mutation carriers and up to 60% in BRCA2 mutation carriers.⁶ However, data conflict on their effect on the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.³⁹

Decisions about chemoprevention with agents other than tamoxifen and in syndromes other than hereditary breast and ovarian cancer syndrome must take into consideration the existing lack of data in this area.

SURGICAL PROPHYLAXIS

Surgical prophylactic options for patients at genetic risk of breast cancer are bilateral mastectomy and bilateral salpingo-oophorectomy.

Prophylactic mastectomy

Bilateral risk-reducing mastectomy reduces the risk of breast cancer by at least 90%^24,39,40 and greatly reduces the need for complex surveillance. Patients are often followed annually clinically, with single-view mammography if they have tissue flap reconstruction.

Nipple-sparing and skin-sparing mastectomies, which facilitate reconstruction and cosmetic outcomes, are an option in the risk-reduction setting and have been shown thus far to be safe.^41–43 In patients with breast cancer, the overall breast cancer recurrence rates with nipple-sparing mastectomy are similar to those of traditional mastectomy and breast conservation treatment.⁴¹

In patients at very high risk of breast cancer, risk-reducing operations also reduce the risk of ultimately needing chemotherapy and radiation to treat breast cancer, as the risk of developing breast cancer is significantly lowered.

The timing of risk-reducing mastectomy depends largely on personal and family medical history and personal choice. Bilateral mastectomy at age 25 results in the greatest survival gain for patients with hereditary breast and ovarian cancer syndrome.⁵ Such precise data are not available for other hereditary cancer syndromes, but it is reasonable to consider bilateral mastectomy as an option for any woman with a highly penetrant genetic mutation that predisposes her to breast cancer. Special consideration in the timing of risk-reducing mastectomy must be given to women with Li-Fraumeni syndrome, as this condition is often associated with an earlier age at breast cancer diagnosis (before age 30).¹

Family planning, sexuality, self-image, and the anxiety associated with both cancer risk and surveillance are all factors women consider when deciding whether and when to undergo mastectomy. A survey of 12 high-risk women who elected prophylactic mastectomy elicited feelings of some regret in 3 of them, while all expressed a sense of relief and reduced anxiety related to both cancer risk and screenings.²⁴ Another group of 14 women surveyed after the surgery reported initial distress related to physical appearance, self-image, and intimacy but also reported a significant decrease in anxiety related to breast cancer risk and were largely satisfied with their decision.⁴⁴

Prophylactic salpingo-oophorectomy

In patients who have pathogenic mutations in BRCA1 or 2, prophylactic salpingo-oophorectomy before age 40 decreases the risk of ovarian cancer by up to 96% and breast cancer by 50%.^1,37,45 This operation, in fact, is the only intervention that has been shown to reduce the mortality rate in patients with a hereditary predisposition to cancer.⁴⁶

We recommend that women with hereditary breast and ovarian cancer syndrome strongly consider prophylactic salpingo-oophorectomy by age 40 or when childbearing is complete for the greatest reduction in risk.^1,5 In 2006, Domchek et al⁴⁶ reported an overall decrease in the mortality rate in BRCA1/2-positive patients who underwent this surgery, but not in breast cancer-specific or ovarian cancer-specific mortality.

On the other hand, removing the ovaries before menopause places women at risk of serious complications associated with premature loss of gonadal hormones, including cardiovascular disease, decreased bone density, reduced sexual satisfaction, dyspareunia, hot flashes, and night sweats.⁴⁷ Therefore, it is generally reserved for women who are also at risk of ovarian cancer.

Hormonal therapy, ie, estrogen therapy for patients who choose complete hysterectomy, and estrogen-progesterone therapy for patients who choose to keep their uterus, reduces menopausal symptoms and symptoms of sexual dissatisfaction and has not thus far been shown to increase breast cancer risk.^1,34 However, this information is from nonrandomized studies, which are inherently limited.

It is important to address and modify risk factors for heart disease and osteoporosis in women with premature surgical menopause, as they may be particularly vulnerable to these conditions.

HEREDITARY BREAST CANCER IN MEN

Fewer than 1% of cases of breast cancer arise in men, and fewer than 1% of cases of cancer in men are breast cancer.

Male breast cancer is more likely than female breast cancer to be estrogen receptor- and progesterone receptor-positive. In an analysis of the Surveillance, Epidemiology, and End Results registry between 1973 and 2005, triple-negative breast cancer was found in 23% of female patients but only 7.6% of male patients.²

Male breast cancer is most common in families with BRCA2, and to a lesser degree, BRCA1 mutations. Other genetic disorders including Li-Fraumeni syndrome, hereditary nonpolyposis colorectal cancer, and Klinefelter syndrome also increase the risk of male breast cancer. A genetic predisposition for breast cancer is present in approximately 10% of male breast cancer patients.² Any man with breast cancer, therefore, should be referred for genetic counseling.

In men, a BRCA2 mutation confers a lifetime risk of breast cancer of 5% to 10%.² This is similar to the lifetime risk of breast cancer for the average woman but it is still significant, as the lifetime risk of breast cancer for the average man is 0.1%.^1,2

Five-year survival rates in male breast cancer range from only 36% to 66%, most likely because it is usually diagnosed in later stages, as men are not routinely screened for breast cancer. In men with known hereditary susceptibility, National Comprehensive Cancer Network guidelines recommend that they be educated about and begin breast self-examination at the age of 35 and be clinically examined every 12 months starting at age 35.⁴⁸ There are limited data to support breast imaging in men. High-risk surveillance with MRI screening in this group is not recommended. Prostate cancer screening is recommended for men with BRCA2 mutations starting at age 40, and should be considered for men with BRCA1 mutations starting at age 40.

No specific guidelines exist for pancreatic cancer and melanoma, but screening may be individualized based on cancers observed in the family.

While most cases of breast cancer are sporadic (ie, not inherited), up to 10% are attributable to single-gene hereditary cancer syndromes.^1–4 People with these syndromes have a lifetime risk of breast cancer much higher than in the general population, and the cancers often occur at a much earlier age.

With genetic testing becoming more common, primary care physicians need to be familiar with the known syndromes, associated risks, and evidence-based recommendations for management. Here, we review the management of cancer risk in the most common hereditary breast cancer syndromes, ie:

• Hereditary breast and ovarian cancer syndrome⁵
• Hereditary diffuse gastric cancer
• Cowden syndrome (PTEN hamartoma tumor syndrome)
• Peutz-Jeghers syndrome
• Li-Fraumeni syndrome.

IT TAKES A TEAM, BUT PRIMARY CARE PHYSICIANS ARE CENTRAL

Women who have a hereditary predisposition to breast cancer face complex and emotional decisions about the best ways to manage and reduce their risks. Their management includes close clinical surveillance, chemoprevention, and surgical risk reduction.^1,4

Referral to multiple subspecialists is an important component of these patients’ preventive care. They may need referrals to a cancer genetic counselor, a high-risk breast clinic, a gynecologic oncologist, and counseling services. They may also require referrals to gastroenterologists, colorectal surgeons, endocrinologists, and endocrine surgeons, depending on the syndrome identified.

Find a genetic counselor at www.nsgc.orgConsultation with a certified genetic counselor is critical for patients harboring mutations associated with cancer risk. The National Society of Genetic Counselors maintains a directory of genetic counselors by location and practice specialty at www.nsgc.org. The counselor’s evaluation will provide patients with a detailed explanation of the cancer risks and management guidelines for their particular condition, along with offering diagnostic genetic testing if appropriate. Women with germline mutations who plan to have children should be informed about preimplantation genetic diagnosis and about fertility specialists who can perform this service if they are interested in pursuing it.⁶

Screening and management guidelines for hereditary breast cancer syndromes are evolving. While subspecialists may be involved in enhanced surveillance and preventive care, the primary care physician is the central player, with both a broader perspective and knowledge of the patient’s competing medical issues, risks, and preferences.

In addition to breast cancer, the risk of other malignancies is also higher, with the pattern varying by syndrome (Table 1).^7–20 The management of these additional risks is beyond the scope of this review; however, primary care physicians need to be familiar with these risks to provide adequate referrals.

WHO IS AT INCREASED RISK OF BREAST CANCER?

In considering recommendations to reduce the risk of breast cancer, it is useful to think of a patient as being at either high risk or average risk.

The risk of breast cancer in women in the general population is about 12%, and most cases of breast cancer occur in patients who have no known risk factors for it. “High risk” of breast cancer generally means having more than a 20% lifetime risk (ie, before age 70) of developing the condition.

Even without a hereditary cancer syndrome, a combination of reproductive, environmental, personal, and family history factors can confer a 20% lifetime risk. But for women with hereditary syndromes, the risk far exceeds 20% regardless of such risk factors. It is likely that interactions with reproductive, environmental, and personal risk factors likely affect the individual risk of a woman with a known genetic mutation, and evidence is emerging with regard to further risk stratification.

In an earlier article in this journal, Smith and colleagues²¹ reviewed how to recognize heritable breast cancer syndromes. In general, referral for genetic counseling should be considered for patients and their families who have:

• Early-onset breast cancers (before age 50)
• Bilateral breast cancers at any age
• Ovarian cancers at any age
• “Triple-negative” breast cancers (ie, estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-nonamplified (HER2-negative)
• Male breast cancer at any age
• Cancers affecting multiple individuals and in multiple generations.
• Breast, ovarian, pancreatic or prostate cancer in families with Ashkenazi Jewish ancestry

HEREDITARY BREAST CANCER SYNDROMES

Hereditary breast and ovarian cancer syndrome

The most common of these syndromes is hereditary breast and ovarian cancer syndrome, caused by germline mutations in the tumor-suppressor genes BRCA1 or BRCA2.⁷ The estimated prevalence of BRCA1 mutations is 1 in 250 to 300, and the prevalence of BRCA2 mutations is 1 in 800.^1,4 However, in families of Ashkenazi Jewish ancestry, the population frequency of either a BRCA1 or BRCA2 mutation is approximately 1 in 40.^1,4,6

Women with BRCA1 or BRCA2 mutations have a lifetime risk of breast cancer of up to 87%

Women with BRCA1 or BRCA2 mutations have a lifetime risk of breast cancer of up to 87%, or 5 to 7 times higher than in the general population, with the risk rising steeply beginning at age 30.^1,5,8 In addition, the lifetime risk of ovarian cancer is nearly 59% in BRCA1 mutation carriers and 17% in BRCA2 mutation carriers.²²

A meta-analysis found that BRCA1 mutation carriers diagnosed with cancer in one breast have a 5-year risk of developing cancer in the other breast of 15%, and BRCA2 mutation carriers have a risk of 9%.²³ Overall, the risk of contralateral breast cancer is about 3% per year.^3,4,24

BRCA1 mutations are strongly associated with triple-negative breast cancers.^1,3,4

Hereditary diffuse gastric cancer

Hereditary diffuse gastric cancer is an autosomal-dominant syndrome associated with mutations in the CDH1 gene, although up to 75% of patients with this syndrome do not have an identifiable CDH1 mutation.^9,25,26 In cases in which there is no identifiable CDH1 mutation, the diagnosis is made on the basis of the patient’s medical and family history.

Hereditary diffuse gastric cancer is associated with an increased risk of the lobular subtype of breast cancer as well as diffuse gastric cancer. The cumulative lifetime risk of breast cancer in women with CDH1 mutations is 39% to 52%,^6,9–11,25 and their lifetime risk of diffuse gastric cancer is 83%.⁹ The combined risk of breast cancer and gastric cancer in women with this syndrome is 90% by age 80.⁹

Cowden syndrome (PTEN hamartoma tumor syndrome)

Cowden syndrome (PTEN hamartoma tumor syndrome) is caused by mutations in PTEN, another tumor-suppressor gene.¹¹ The primary clinical concerns are melanoma and breast, endometrial, thyroid (follicular or papillary), colon, and renal cell cancers. Women with a PTEN mutation have a twofold greater risk of developing any type of cancer than men with a PTEN mutation.¹² The cumulative lifetime risk of invasive breast cancer in women with this syndrome is 70% to 85%.^11–13

Peutz-Jeghers syndrome

Peutz-Jeghers syndrome is an autosomal dominant polyposis disorder caused, in most patients, by a mutation in the serine/threonine kinase tumor-suppressor gene STK11.¹⁴

Patients with Peutz-Jeghers syndrome have higher risks of gastrointestinal, breast, gynecologic (uterine, ovarian, and cervical), pancreatic, and lung cancers. In women, the lifetime risk of breast cancer is 44% to 50% by age 70, regardless of the type of mutation.^6,14,15 Breast cancers associated with Peutz-Jeghers syndrome are usually ductal, and the mean age at diagnosis is 37 years.¹⁶

Li-Fraumeni syndrome

Li-Fraumeni syndrome is an autosomal-dominant disorder caused by germline mutations in the TP53 gene, which codes for a transcription factor associated with cell proliferation and apoptosis.²⁷

Think about other highly penetrant genetic mutations in a young breast cancer patient with no mutation in BRCA1 or BRCA2These mutations confer a lifetime cancer risk of 93% in women (mainly breast cancer) and 68% in men.^1,27 Other cancers associated with TP53 mutations include sarcomas, brain cancer, leukemia, and adrenocortical tumors. Germline TP53 mutations are responsible for approximately 1% of all breast cancers.^1,4

Breast cancers can occur at a young age in patients with a TP53 mutation. Women with TP53 mutations are 18 times more likely to develop breast cancer before age 45 compared with the general population.⁴

It is important to consider a TP53 mutation in premenopausal women or women less than 30 years of age with breast cancer who have no mutations in BRCA1 and BRCA2.¹

MANAGING PATIENTS WITH GENETIC PREDISPOSITION TO BREAST CANCER

Management for patients at high risk fall into three broad categories: clinical surveillance, chemoprevention, and surgical risk reduction. The utility and benefit of each depend to a large degree on the patient’s specific mutation, family history, and comorbidities. Decisions must be shared with the patient.

CLOSE CLINICAL SURVEILLANCE

Consensus guidelines for cancer screening in the syndromes described here are available from the National Comprehensive Cancer Network at www.nccn.org and are summarized in Table 2.^26,28 While the guidelines are broadly applicable to all women with these conditions, some individualization is required based on personal and family medical history.

In general, screening begins at the ages listed in Table 2 or 10 years earlier than the age at which cancer developed in the first affected relative, whichever is earlier. However, screening decisions are shared with the patient and are sometimes affected by significant out-of-pocket costs for the patient and anxiety resulting from the test or subsequent test findings, which must all be considered.

Breast self-awareness and clinical breast examination

Although controversial in the general population, breast self-examination is recommended for patients carrying mutations that increase risk.⁶

Discuss breast self-awareness with all women patients at age 18

A discussion about breast self-awareness is recommended for all women at the age of 18. It should include the signs and symptoms of breast cancer, what feels “normal” to the patient, and what is known about modifiable risk factors for breast cancer. The patient should also be told to report any changes in her personal or family history.

Clinical breast examinations should be done every 6 months, as some cancers are found clinically, particularly in young women with dense tissue, and confirmed by diagnostic imaging and targeted ultrasonography.

Radiographic surveillance

Mammography and magnetic resonance imaging (MRI) are also important components of a breast cancer surveillance regimen in women at high risk. Adherence to a well-formulated plan of clinical and radiographic examinations increases early detection in patients who have a hereditary predisposition to breast cancer.

MRI is more sensitive than mammography and reduces the likelihood of finding advanced cancers by up to 70% compared with mammography in women at high risk of breast cancer.^29–31 The sensitivity of breast MRI alone ranges from 71% to 100%, and the sensitivity increases to 89% to 100% when combined with mammography. In contrast, the sensitivity of mammography alone is 25% to 59%.²⁹ MRI has also been shown to be cost-effective when added to mammography and physical examination in women at high risk.^5,32

Adding MRI to the breast cancer screening regimen has been under discussion and has been endorsed by the American Cancer Society in formal recommendations set forth in 2007 for patients with known hereditary cancer syndromes, in untested first-degree relatives of identified genetic mutation carriers, or in women who have an estimated lifetime risk of breast cancer of 20% or more, as determined by models largely dependent on family history.³³

But MRI has a downside—it is less specific than mammography.^29,33 Its lower specificity (77% to 90% vs 95% with mammography alone) leads to additional radiographic studies and tissue samplings for the “suspicious” lesions discovered. From 3% to 15% of screening breast MRIs result in a biopsy, and the proportion of biopsies that reveal cancer is 13% to 40%.³³ Furthermore, by itself, MRI has not been shown to reduce mortality in any high-risk group.

Mammography remains useful in conjunction with MRI due to its ability to detect breast calcifications, which may be the earliest sign of breast cancer, and ability to detect changes in breast architecture. A typical screening program (Table 2) should incorporate both modalities, commonly offset by 6 months (eg, mammography at baseline, then MRI 6 months later, then mammography again 6 months after that, and so on) to increase the detection of interval cancer development.

Chemoprevention

Chemoprevention means taking medications to reduce the risk. Certain selective estrogen receptor modulators and aromatase inhibitors decrease the risk of invasive breast cancer in healthy women at high risk. These drugs include tamoxifen, which can be used before menopause, and raloxifene, anastrozole, and exemestane, which must be used only after menopause.

Because data are limited, we cannot make any generalized recommendations about chemoprevention in patients with hereditary breast cancer syndromes. Decisions about chemoprevention should take into account the patient’s personal and family histories. Often, a medical oncologist or medical breast specialist can help by discussing the risks and benefits for the individual patient.

Tamoxifen has been the most studied, mainly in BRCA mutation carriers.^6,34–37 As in the general population, tamoxifen reduces the incidence of estrogen receptor-positive breast cancers by 50%.^36–38 It has not been shown to significantly reduce breast cancer risk in premenopausal women with BRCA1 mutations,³⁷ most likely because most cancers that occur in this group are estrogen receptor-negative. In patients with a history of breast cancer, however, tamoxifen has been shown to reduce the risk of developing contralateral breast cancer by 45% to 60% in both BRCA1 and BRCA2 mutation carriers.^6,35

There is also little evidence that giving a chemopreventive agent after bilateral salpingo-oophorectomy reduces the risk further in premenopausal BRCA mutation carriers.³⁵ These patients often receive hormonal therapy with estrogen, which currently would preclude the use of tamoxifen. Tamoxifen in postmenopausal women is associated with a small increased risk of venous thromboembolic disease and endometrial cancer.³⁸

Oral contraceptives reduce the risk of ovarian cancer by up to 50% in BRCA1 mutation carriers and up to 60% in BRCA2 mutation carriers.⁶ However, data conflict on their effect on the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.³⁹

Decisions about chemoprevention with agents other than tamoxifen and in syndromes other than hereditary breast and ovarian cancer syndrome must take into consideration the existing lack of data in this area.

SURGICAL PROPHYLAXIS

Surgical prophylactic options for patients at genetic risk of breast cancer are bilateral mastectomy and bilateral salpingo-oophorectomy.

Prophylactic mastectomy

Bilateral risk-reducing mastectomy reduces the risk of breast cancer by at least 90%^24,39,40 and greatly reduces the need for complex surveillance. Patients are often followed annually clinically, with single-view mammography if they have tissue flap reconstruction.

Nipple-sparing and skin-sparing mastectomies, which facilitate reconstruction and cosmetic outcomes, are an option in the risk-reduction setting and have been shown thus far to be safe.^41–43 In patients with breast cancer, the overall breast cancer recurrence rates with nipple-sparing mastectomy are similar to those of traditional mastectomy and breast conservation treatment.⁴¹

In patients at very high risk of breast cancer, risk-reducing operations also reduce the risk of ultimately needing chemotherapy and radiation to treat breast cancer, as the risk of developing breast cancer is significantly lowered.

The timing of risk-reducing mastectomy depends largely on personal and family medical history and personal choice. Bilateral mastectomy at age 25 results in the greatest survival gain for patients with hereditary breast and ovarian cancer syndrome.⁵ Such precise data are not available for other hereditary cancer syndromes, but it is reasonable to consider bilateral mastectomy as an option for any woman with a highly penetrant genetic mutation that predisposes her to breast cancer. Special consideration in the timing of risk-reducing mastectomy must be given to women with Li-Fraumeni syndrome, as this condition is often associated with an earlier age at breast cancer diagnosis (before age 30).¹

Family planning, sexuality, self-image, and the anxiety associated with both cancer risk and surveillance are all factors women consider when deciding whether and when to undergo mastectomy. A survey of 12 high-risk women who elected prophylactic mastectomy elicited feelings of some regret in 3 of them, while all expressed a sense of relief and reduced anxiety related to both cancer risk and screenings.²⁴ Another group of 14 women surveyed after the surgery reported initial distress related to physical appearance, self-image, and intimacy but also reported a significant decrease in anxiety related to breast cancer risk and were largely satisfied with their decision.⁴⁴

Prophylactic salpingo-oophorectomy

In patients who have pathogenic mutations in BRCA1 or 2, prophylactic salpingo-oophorectomy before age 40 decreases the risk of ovarian cancer by up to 96% and breast cancer by 50%.^1,37,45 This operation, in fact, is the only intervention that has been shown to reduce the mortality rate in patients with a hereditary predisposition to cancer.⁴⁶

We recommend that women with hereditary breast and ovarian cancer syndrome strongly consider prophylactic salpingo-oophorectomy by age 40 or when childbearing is complete for the greatest reduction in risk.^1,5 In 2006, Domchek et al⁴⁶ reported an overall decrease in the mortality rate in BRCA1/2-positive patients who underwent this surgery, but not in breast cancer-specific or ovarian cancer-specific mortality.

On the other hand, removing the ovaries before menopause places women at risk of serious complications associated with premature loss of gonadal hormones, including cardiovascular disease, decreased bone density, reduced sexual satisfaction, dyspareunia, hot flashes, and night sweats.⁴⁷ Therefore, it is generally reserved for women who are also at risk of ovarian cancer.

Hormonal therapy, ie, estrogen therapy for patients who choose complete hysterectomy, and estrogen-progesterone therapy for patients who choose to keep their uterus, reduces menopausal symptoms and symptoms of sexual dissatisfaction and has not thus far been shown to increase breast cancer risk.^1,34 However, this information is from nonrandomized studies, which are inherently limited.

It is important to address and modify risk factors for heart disease and osteoporosis in women with premature surgical menopause, as they may be particularly vulnerable to these conditions.

HEREDITARY BREAST CANCER IN MEN

Fewer than 1% of cases of breast cancer arise in men, and fewer than 1% of cases of cancer in men are breast cancer.

Male breast cancer is more likely than female breast cancer to be estrogen receptor- and progesterone receptor-positive. In an analysis of the Surveillance, Epidemiology, and End Results registry between 1973 and 2005, triple-negative breast cancer was found in 23% of female patients but only 7.6% of male patients.²

Male breast cancer is most common in families with BRCA2, and to a lesser degree, BRCA1 mutations. Other genetic disorders including Li-Fraumeni syndrome, hereditary nonpolyposis colorectal cancer, and Klinefelter syndrome also increase the risk of male breast cancer. A genetic predisposition for breast cancer is present in approximately 10% of male breast cancer patients.² Any man with breast cancer, therefore, should be referred for genetic counseling.

In men, a BRCA2 mutation confers a lifetime risk of breast cancer of 5% to 10%.² This is similar to the lifetime risk of breast cancer for the average woman but it is still significant, as the lifetime risk of breast cancer for the average man is 0.1%.^1,2

Five-year survival rates in male breast cancer range from only 36% to 66%, most likely because it is usually diagnosed in later stages, as men are not routinely screened for breast cancer. In men with known hereditary susceptibility, National Comprehensive Cancer Network guidelines recommend that they be educated about and begin breast self-examination at the age of 35 and be clinically examined every 12 months starting at age 35.⁴⁸ There are limited data to support breast imaging in men. High-risk surveillance with MRI screening in this group is not recommended. Prostate cancer screening is recommended for men with BRCA2 mutations starting at age 40, and should be considered for men with BRCA1 mutations starting at age 40.

No specific guidelines exist for pancreatic cancer and melanoma, but screening may be individualized based on cancers observed in the family.

While most cases of breast cancer are sporadic (ie, not inherited), up to 10% are attributable to single-gene hereditary cancer syndromes.^1–4 People with these syndromes have a lifetime risk of breast cancer much higher than in the general population, and the cancers often occur at a much earlier age.

With genetic testing becoming more common, primary care physicians need to be familiar with the known syndromes, associated risks, and evidence-based recommendations for management. Here, we review the management of cancer risk in the most common hereditary breast cancer syndromes, ie:

• Hereditary breast and ovarian cancer syndrome⁵
• Hereditary diffuse gastric cancer
• Cowden syndrome (PTEN hamartoma tumor syndrome)
• Peutz-Jeghers syndrome
• Li-Fraumeni syndrome.

IT TAKES A TEAM, BUT PRIMARY CARE PHYSICIANS ARE CENTRAL

Women who have a hereditary predisposition to breast cancer face complex and emotional decisions about the best ways to manage and reduce their risks. Their management includes close clinical surveillance, chemoprevention, and surgical risk reduction.^1,4

Referral to multiple subspecialists is an important component of these patients’ preventive care. They may need referrals to a cancer genetic counselor, a high-risk breast clinic, a gynecologic oncologist, and counseling services. They may also require referrals to gastroenterologists, colorectal surgeons, endocrinologists, and endocrine surgeons, depending on the syndrome identified.

Find a genetic counselor at www.nsgc.orgConsultation with a certified genetic counselor is critical for patients harboring mutations associated with cancer risk. The National Society of Genetic Counselors maintains a directory of genetic counselors by location and practice specialty at www.nsgc.org. The counselor’s evaluation will provide patients with a detailed explanation of the cancer risks and management guidelines for their particular condition, along with offering diagnostic genetic testing if appropriate. Women with germline mutations who plan to have children should be informed about preimplantation genetic diagnosis and about fertility specialists who can perform this service if they are interested in pursuing it.⁶

Screening and management guidelines for hereditary breast cancer syndromes are evolving. While subspecialists may be involved in enhanced surveillance and preventive care, the primary care physician is the central player, with both a broader perspective and knowledge of the patient’s competing medical issues, risks, and preferences.

In addition to breast cancer, the risk of other malignancies is also higher, with the pattern varying by syndrome (Table 1).^7–20 The management of these additional risks is beyond the scope of this review; however, primary care physicians need to be familiar with these risks to provide adequate referrals.

WHO IS AT INCREASED RISK OF BREAST CANCER?

In considering recommendations to reduce the risk of breast cancer, it is useful to think of a patient as being at either high risk or average risk.

The risk of breast cancer in women in the general population is about 12%, and most cases of breast cancer occur in patients who have no known risk factors for it. “High risk” of breast cancer generally means having more than a 20% lifetime risk (ie, before age 70) of developing the condition.

Even without a hereditary cancer syndrome, a combination of reproductive, environmental, personal, and family history factors can confer a 20% lifetime risk. But for women with hereditary syndromes, the risk far exceeds 20% regardless of such risk factors. It is likely that interactions with reproductive, environmental, and personal risk factors likely affect the individual risk of a woman with a known genetic mutation, and evidence is emerging with regard to further risk stratification.

In an earlier article in this journal, Smith and colleagues²¹ reviewed how to recognize heritable breast cancer syndromes. In general, referral for genetic counseling should be considered for patients and their families who have:

• Early-onset breast cancers (before age 50)
• Bilateral breast cancers at any age
• Ovarian cancers at any age
• “Triple-negative” breast cancers (ie, estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-nonamplified (HER2-negative)
• Male breast cancer at any age
• Cancers affecting multiple individuals and in multiple generations.
• Breast, ovarian, pancreatic or prostate cancer in families with Ashkenazi Jewish ancestry

HEREDITARY BREAST CANCER SYNDROMES

Hereditary breast and ovarian cancer syndrome

The most common of these syndromes is hereditary breast and ovarian cancer syndrome, caused by germline mutations in the tumor-suppressor genes BRCA1 or BRCA2.⁷ The estimated prevalence of BRCA1 mutations is 1 in 250 to 300, and the prevalence of BRCA2 mutations is 1 in 800.^1,4 However, in families of Ashkenazi Jewish ancestry, the population frequency of either a BRCA1 or BRCA2 mutation is approximately 1 in 40.^1,4,6

Women with BRCA1 or BRCA2 mutations have a lifetime risk of breast cancer of up to 87%

Women with BRCA1 or BRCA2 mutations have a lifetime risk of breast cancer of up to 87%, or 5 to 7 times higher than in the general population, with the risk rising steeply beginning at age 30.^1,5,8 In addition, the lifetime risk of ovarian cancer is nearly 59% in BRCA1 mutation carriers and 17% in BRCA2 mutation carriers.²²

A meta-analysis found that BRCA1 mutation carriers diagnosed with cancer in one breast have a 5-year risk of developing cancer in the other breast of 15%, and BRCA2 mutation carriers have a risk of 9%.²³ Overall, the risk of contralateral breast cancer is about 3% per year.^3,4,24

BRCA1 mutations are strongly associated with triple-negative breast cancers.^1,3,4

Hereditary diffuse gastric cancer

Hereditary diffuse gastric cancer is an autosomal-dominant syndrome associated with mutations in the CDH1 gene, although up to 75% of patients with this syndrome do not have an identifiable CDH1 mutation.^9,25,26 In cases in which there is no identifiable CDH1 mutation, the diagnosis is made on the basis of the patient’s medical and family history.

Hereditary diffuse gastric cancer is associated with an increased risk of the lobular subtype of breast cancer as well as diffuse gastric cancer. The cumulative lifetime risk of breast cancer in women with CDH1 mutations is 39% to 52%,^6,9–11,25 and their lifetime risk of diffuse gastric cancer is 83%.⁹ The combined risk of breast cancer and gastric cancer in women with this syndrome is 90% by age 80.⁹

Cowden syndrome (PTEN hamartoma tumor syndrome)

Cowden syndrome (PTEN hamartoma tumor syndrome) is caused by mutations in PTEN, another tumor-suppressor gene.¹¹ The primary clinical concerns are melanoma and breast, endometrial, thyroid (follicular or papillary), colon, and renal cell cancers. Women with a PTEN mutation have a twofold greater risk of developing any type of cancer than men with a PTEN mutation.¹² The cumulative lifetime risk of invasive breast cancer in women with this syndrome is 70% to 85%.^11–13

Peutz-Jeghers syndrome

Peutz-Jeghers syndrome is an autosomal dominant polyposis disorder caused, in most patients, by a mutation in the serine/threonine kinase tumor-suppressor gene STK11.¹⁴

Patients with Peutz-Jeghers syndrome have higher risks of gastrointestinal, breast, gynecologic (uterine, ovarian, and cervical), pancreatic, and lung cancers. In women, the lifetime risk of breast cancer is 44% to 50% by age 70, regardless of the type of mutation.^6,14,15 Breast cancers associated with Peutz-Jeghers syndrome are usually ductal, and the mean age at diagnosis is 37 years.¹⁶

Li-Fraumeni syndrome

Li-Fraumeni syndrome is an autosomal-dominant disorder caused by germline mutations in the TP53 gene, which codes for a transcription factor associated with cell proliferation and apoptosis.²⁷

Think about other highly penetrant genetic mutations in a young breast cancer patient with no mutation in BRCA1 or BRCA2These mutations confer a lifetime cancer risk of 93% in women (mainly breast cancer) and 68% in men.^1,27 Other cancers associated with TP53 mutations include sarcomas, brain cancer, leukemia, and adrenocortical tumors. Germline TP53 mutations are responsible for approximately 1% of all breast cancers.^1,4

Breast cancers can occur at a young age in patients with a TP53 mutation. Women with TP53 mutations are 18 times more likely to develop breast cancer before age 45 compared with the general population.⁴

It is important to consider a TP53 mutation in premenopausal women or women less than 30 years of age with breast cancer who have no mutations in BRCA1 and BRCA2.¹

MANAGING PATIENTS WITH GENETIC PREDISPOSITION TO BREAST CANCER

Management for patients at high risk fall into three broad categories: clinical surveillance, chemoprevention, and surgical risk reduction. The utility and benefit of each depend to a large degree on the patient’s specific mutation, family history, and comorbidities. Decisions must be shared with the patient.

CLOSE CLINICAL SURVEILLANCE

Consensus guidelines for cancer screening in the syndromes described here are available from the National Comprehensive Cancer Network at www.nccn.org and are summarized in Table 2.^26,28 While the guidelines are broadly applicable to all women with these conditions, some individualization is required based on personal and family medical history.

In general, screening begins at the ages listed in Table 2 or 10 years earlier than the age at which cancer developed in the first affected relative, whichever is earlier. However, screening decisions are shared with the patient and are sometimes affected by significant out-of-pocket costs for the patient and anxiety resulting from the test or subsequent test findings, which must all be considered.

Breast self-awareness and clinical breast examination

Although controversial in the general population, breast self-examination is recommended for patients carrying mutations that increase risk.⁶

Discuss breast self-awareness with all women patients at age 18

A discussion about breast self-awareness is recommended for all women at the age of 18. It should include the signs and symptoms of breast cancer, what feels “normal” to the patient, and what is known about modifiable risk factors for breast cancer. The patient should also be told to report any changes in her personal or family history.

Clinical breast examinations should be done every 6 months, as some cancers are found clinically, particularly in young women with dense tissue, and confirmed by diagnostic imaging and targeted ultrasonography.

Radiographic surveillance

Mammography and magnetic resonance imaging (MRI) are also important components of a breast cancer surveillance regimen in women at high risk. Adherence to a well-formulated plan of clinical and radiographic examinations increases early detection in patients who have a hereditary predisposition to breast cancer.

MRI is more sensitive than mammography and reduces the likelihood of finding advanced cancers by up to 70% compared with mammography in women at high risk of breast cancer.^29–31 The sensitivity of breast MRI alone ranges from 71% to 100%, and the sensitivity increases to 89% to 100% when combined with mammography. In contrast, the sensitivity of mammography alone is 25% to 59%.²⁹ MRI has also been shown to be cost-effective when added to mammography and physical examination in women at high risk.^5,32

Adding MRI to the breast cancer screening regimen has been under discussion and has been endorsed by the American Cancer Society in formal recommendations set forth in 2007 for patients with known hereditary cancer syndromes, in untested first-degree relatives of identified genetic mutation carriers, or in women who have an estimated lifetime risk of breast cancer of 20% or more, as determined by models largely dependent on family history.³³

But MRI has a downside—it is less specific than mammography.^29,33 Its lower specificity (77% to 90% vs 95% with mammography alone) leads to additional radiographic studies and tissue samplings for the “suspicious” lesions discovered. From 3% to 15% of screening breast MRIs result in a biopsy, and the proportion of biopsies that reveal cancer is 13% to 40%.³³ Furthermore, by itself, MRI has not been shown to reduce mortality in any high-risk group.

Mammography remains useful in conjunction with MRI due to its ability to detect breast calcifications, which may be the earliest sign of breast cancer, and ability to detect changes in breast architecture. A typical screening program (Table 2) should incorporate both modalities, commonly offset by 6 months (eg, mammography at baseline, then MRI 6 months later, then mammography again 6 months after that, and so on) to increase the detection of interval cancer development.

Chemoprevention

Chemoprevention means taking medications to reduce the risk. Certain selective estrogen receptor modulators and aromatase inhibitors decrease the risk of invasive breast cancer in healthy women at high risk. These drugs include tamoxifen, which can be used before menopause, and raloxifene, anastrozole, and exemestane, which must be used only after menopause.

Because data are limited, we cannot make any generalized recommendations about chemoprevention in patients with hereditary breast cancer syndromes. Decisions about chemoprevention should take into account the patient’s personal and family histories. Often, a medical oncologist or medical breast specialist can help by discussing the risks and benefits for the individual patient.

Tamoxifen has been the most studied, mainly in BRCA mutation carriers.^6,34–37 As in the general population, tamoxifen reduces the incidence of estrogen receptor-positive breast cancers by 50%.^36–38 It has not been shown to significantly reduce breast cancer risk in premenopausal women with BRCA1 mutations,³⁷ most likely because most cancers that occur in this group are estrogen receptor-negative. In patients with a history of breast cancer, however, tamoxifen has been shown to reduce the risk of developing contralateral breast cancer by 45% to 60% in both BRCA1 and BRCA2 mutation carriers.^6,35

There is also little evidence that giving a chemopreventive agent after bilateral salpingo-oophorectomy reduces the risk further in premenopausal BRCA mutation carriers.³⁵ These patients often receive hormonal therapy with estrogen, which currently would preclude the use of tamoxifen. Tamoxifen in postmenopausal women is associated with a small increased risk of venous thromboembolic disease and endometrial cancer.³⁸

Oral contraceptives reduce the risk of ovarian cancer by up to 50% in BRCA1 mutation carriers and up to 60% in BRCA2 mutation carriers.⁶ However, data conflict on their effect on the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.³⁹

Decisions about chemoprevention with agents other than tamoxifen and in syndromes other than hereditary breast and ovarian cancer syndrome must take into consideration the existing lack of data in this area.

SURGICAL PROPHYLAXIS

Surgical prophylactic options for patients at genetic risk of breast cancer are bilateral mastectomy and bilateral salpingo-oophorectomy.

Prophylactic mastectomy

Bilateral risk-reducing mastectomy reduces the risk of breast cancer by at least 90%^24,39,40 and greatly reduces the need for complex surveillance. Patients are often followed annually clinically, with single-view mammography if they have tissue flap reconstruction.

Nipple-sparing and skin-sparing mastectomies, which facilitate reconstruction and cosmetic outcomes, are an option in the risk-reduction setting and have been shown thus far to be safe.^41–43 In patients with breast cancer, the overall breast cancer recurrence rates with nipple-sparing mastectomy are similar to those of traditional mastectomy and breast conservation treatment.⁴¹

In patients at very high risk of breast cancer, risk-reducing operations also reduce the risk of ultimately needing chemotherapy and radiation to treat breast cancer, as the risk of developing breast cancer is significantly lowered.

The timing of risk-reducing mastectomy depends largely on personal and family medical history and personal choice. Bilateral mastectomy at age 25 results in the greatest survival gain for patients with hereditary breast and ovarian cancer syndrome.⁵ Such precise data are not available for other hereditary cancer syndromes, but it is reasonable to consider bilateral mastectomy as an option for any woman with a highly penetrant genetic mutation that predisposes her to breast cancer. Special consideration in the timing of risk-reducing mastectomy must be given to women with Li-Fraumeni syndrome, as this condition is often associated with an earlier age at breast cancer diagnosis (before age 30).¹

Family planning, sexuality, self-image, and the anxiety associated with both cancer risk and surveillance are all factors women consider when deciding whether and when to undergo mastectomy. A survey of 12 high-risk women who elected prophylactic mastectomy elicited feelings of some regret in 3 of them, while all expressed a sense of relief and reduced anxiety related to both cancer risk and screenings.²⁴ Another group of 14 women surveyed after the surgery reported initial distress related to physical appearance, self-image, and intimacy but also reported a significant decrease in anxiety related to breast cancer risk and were largely satisfied with their decision.⁴⁴

Prophylactic salpingo-oophorectomy

In patients who have pathogenic mutations in BRCA1 or 2, prophylactic salpingo-oophorectomy before age 40 decreases the risk of ovarian cancer by up to 96% and breast cancer by 50%.^1,37,45 This operation, in fact, is the only intervention that has been shown to reduce the mortality rate in patients with a hereditary predisposition to cancer.⁴⁶

We recommend that women with hereditary breast and ovarian cancer syndrome strongly consider prophylactic salpingo-oophorectomy by age 40 or when childbearing is complete for the greatest reduction in risk.^1,5 In 2006, Domchek et al⁴⁶ reported an overall decrease in the mortality rate in BRCA1/2-positive patients who underwent this surgery, but not in breast cancer-specific or ovarian cancer-specific mortality.

On the other hand, removing the ovaries before menopause places women at risk of serious complications associated with premature loss of gonadal hormones, including cardiovascular disease, decreased bone density, reduced sexual satisfaction, dyspareunia, hot flashes, and night sweats.⁴⁷ Therefore, it is generally reserved for women who are also at risk of ovarian cancer.

Hormonal therapy, ie, estrogen therapy for patients who choose complete hysterectomy, and estrogen-progesterone therapy for patients who choose to keep their uterus, reduces menopausal symptoms and symptoms of sexual dissatisfaction and has not thus far been shown to increase breast cancer risk.^1,34 However, this information is from nonrandomized studies, which are inherently limited.

It is important to address and modify risk factors for heart disease and osteoporosis in women with premature surgical menopause, as they may be particularly vulnerable to these conditions.

HEREDITARY BREAST CANCER IN MEN

Fewer than 1% of cases of breast cancer arise in men, and fewer than 1% of cases of cancer in men are breast cancer.

Male breast cancer is more likely than female breast cancer to be estrogen receptor- and progesterone receptor-positive. In an analysis of the Surveillance, Epidemiology, and End Results registry between 1973 and 2005, triple-negative breast cancer was found in 23% of female patients but only 7.6% of male patients.²

Male breast cancer is most common in families with BRCA2, and to a lesser degree, BRCA1 mutations. Other genetic disorders including Li-Fraumeni syndrome, hereditary nonpolyposis colorectal cancer, and Klinefelter syndrome also increase the risk of male breast cancer. A genetic predisposition for breast cancer is present in approximately 10% of male breast cancer patients.² Any man with breast cancer, therefore, should be referred for genetic counseling.

In men, a BRCA2 mutation confers a lifetime risk of breast cancer of 5% to 10%.² This is similar to the lifetime risk of breast cancer for the average woman but it is still significant, as the lifetime risk of breast cancer for the average man is 0.1%.^1,2

Five-year survival rates in male breast cancer range from only 36% to 66%, most likely because it is usually diagnosed in later stages, as men are not routinely screened for breast cancer. In men with known hereditary susceptibility, National Comprehensive Cancer Network guidelines recommend that they be educated about and begin breast self-examination at the age of 35 and be clinically examined every 12 months starting at age 35.⁴⁸ There are limited data to support breast imaging in men. High-risk surveillance with MRI screening in this group is not recommended. Prostate cancer screening is recommended for men with BRCA2 mutations starting at age 40, and should be considered for men with BRCA1 mutations starting at age 40.

No specific guidelines exist for pancreatic cancer and melanoma, but screening may be individualized based on cancers observed in the family.

High blood pressure is a major cause of morbidity and death worldwide.¹ Observational data from the general population show a log-linear relationship between both systolic and diastolic blood pressure and the rate of cardiovascular death.² Placebo-controlled trials have shown a clear-cut benefit in treating moderate to severe hypertension based on diastolic pressure in initial trials, and systolic pressure subsequently.³ What remains uncertain is the optimal target for a particular patient, and whether other factors such as number of medications, starting blood pressure, and other comorbidities should influence this target.

See related article

Publication of the Systolic Blood Pressure Intervention Trial (SPRINT) furthered the debate regarding the optimal blood pressure target in hypertension treatment.⁴ SPRINT randomized 9,361 nondiabetic persons with systolic pressure higher than 130 mm Hg and increased cardiovascular risk but without prior stroke to intensive therapy (goal systolic pressure < 120 mm Hg) or standard therapy as control (goal systolic pressure < 140 mm Hg) and showed a significant reduction in the composite end point and all-cause mortality—at the expense of an increase in serious adverse events.

EARLIER TRIALS WERE GENERALLY NEGATIVE

Before SPRINT, approximately 20 randomized controlled trials attempted to define whether a more intensive target was better than standard control. These included the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial restricted to patients with diabetes⁵ and the Secondary Prevention of Small Subcortical Strokes (SPS3) trial restricted to patients with lacunar infarcts.⁶ These two groups of patients were specifically excluded from SPRINT.⁶ Many of the other trials had primary renal end points, although several had primary cardiovascular end points.

As we reviewed previously in this Journal, individually these trials were generally inconclusive.⁷ When analyzed by meta-analysis, a significant benefit was found for cardiovascular events, stroke, and end-stage renal disease, with a marginal benefit for myocardial infarction.⁸ The validity of such analysis may be questioned due to heterogeneous populations, lack of individual patient data, different blood pressure targets and medication regimens, and different primary end points.

Together, ACCORD in patients with diabetes, SPS3 in patients with stroke, and SPRINT in patients at increased cardiovascular risk but without diabetes or stroke cover most hypertensive patients with more than low cardiovascular risk. All three trials were government-funded, and ACCORD and SPRINT used the same blood pressure targets and treatment algorithm. It remains speculative why ACCORD was essentially negative and SPRINT was positive.

CAUTION IN GENERALIZING THE RESULTS

In this issue of the Journal, Thomas and colleagues⁹ review the SPRINT results in detail and attempt to reconcile the disparity with ACCORD.

SPRINT should be interpreted in the context of prior trials and its inclusion and exclusion criteria

We agree with their interpretation that risks and benefits of a more intensive blood pressure target (ie, < 120 mm Hg systolic) need to be addressed in the individual patient and do not apply across the board to all hypertensive patients. This more intensive target would be appropriate for patients fulfilling criteria for entry into SPRINT, ie, no diabetes or prior stroke. They must be able to tolerate more intensive therapy and should not be frail or at risk for falls. Furthermore, the increased hypertension medication burden required for stricter control will increase side effects and complexity of overall medication regimens, and will possibly foster noncompliance.

In our opinion, one must be careful in generalizing the results of SPRINT to more than the type of patient enrolled. At best, one can say that a lower target is acceptable in a patient over age 50 at increased cardiovascular risk but without diabetes or stroke.

SPRINT may not even be representative of all such patients, however. Patients requiring more than four medications were excluded from the trial, as were patients with systolic pressure higher than 180 mm Hg, or with pressure higher than 170 mm Hg requiring two medications, or with pressure higher than 160 mm Hg requiring three medications, or with pressure higher than 150 mm Hg requiring four medications. Hence, SPRINT has not determined the appropriate approach to the patient with a systolic pressure between 150 and 180 mm Hg already on multiple medications above these cutoffs. It is not hard to envision the potential for adverse events and drug interactions using four or more antihypertensive medications to achieve a lower target, in addition to other classes of medications that many patients need.

The average systolic pressure on entry into SPRINT was 139 mm Hg, and patients were taking an average of 1.8 medications. In fact, one-third of patients had systolic pressures between 130 and 132 mm Hg, a range where most physicians would probably not want to intensify therapy. By protocol, such patients in the standard treatment group in SPRINT would actually have had their baseline antihypertensive therapy reduced if the systolic pressure fell below 130 mm Hg on one occasion or below 135 mm Hg on two consecutive visits. Reduction of therapy would seem to bias the trial against the standard treatment. An identical algorithm was used in ACCORD.

We are unable to reconcile the difference in outcome between ACCORD and SPRINTWe are unable to reconcile the differences in outcome between ACCORD and SPRINT, although they were congruent in one important aspect: significantly higher rates of serious adverse events with more intensive therapy. ACCORD had fewer patients, but they were at higher risk since all had diabetes, and more had previous cardiovascular events (34% vs 17% in SPRINT). This is reflected in higher event rates:

• Myocardial infarction occurred in 1.13% per year in the intensive therapy group, and 1.28% per year with standard therapy in ACCORD, compared with 0.65% and 0.78% per year, respectively, in SPRINT.
• Cardiovascular death occurred in 0.52% per year with intensive therapy and 0.49% per year with standard therapy in ACCORD, compared with 0.25% and 0.43% per year, respectively, in SPRINT. Event rates for stroke were similar.

Overall, 445 primary end points occurred in ACCORD compared with 562 with SPRINT. After subtracting heart failure from the SPRINT data (not included in the primary end point of ACCORD), 400 events occurred, actually less than in ACCORD. The early termination of SPRINT may be partly to blame. In our opinion ACCORD and SPRINT were equally powered. While cardiovascular event risk reductions in ACCORD trended in the same direction as those in SPRINT, the total mortality rate trended in the opposite direction. Perhaps the play of chance is the best explanation.

ONE TARGET DOES NOT FIT ALL

SPRINT clearly added much needed data, but results should be interpreted in the context of previous trials as well as of the specific inclusion and exclusion criteria. One target does not fit all, and systolic pressure of less than 120 mm Hg should not automatically be the target for all hypertensive patients.

Should patients with diabetes be targeted to systolic pressure of less than 140 mm Hg based on the ACCORD results, and patients with stroke to systolic pressure of less than 130 mm Hg based on the SPS3 results? We are unsure. More data are clearly required, especially in patients already on multiple antihypertensive medications with unacceptable blood pressure.

As pointed out by Thomas and colleagues, lower systolic pressure may be better in select patients, but only as long as adverse events can be avoided or managed.

High blood pressure is a major cause of morbidity and death worldwide.¹ Observational data from the general population show a log-linear relationship between both systolic and diastolic blood pressure and the rate of cardiovascular death.² Placebo-controlled trials have shown a clear-cut benefit in treating moderate to severe hypertension based on diastolic pressure in initial trials, and systolic pressure subsequently.³ What remains uncertain is the optimal target for a particular patient, and whether other factors such as number of medications, starting blood pressure, and other comorbidities should influence this target.

See related article

Publication of the Systolic Blood Pressure Intervention Trial (SPRINT) furthered the debate regarding the optimal blood pressure target in hypertension treatment.⁴ SPRINT randomized 9,361 nondiabetic persons with systolic pressure higher than 130 mm Hg and increased cardiovascular risk but without prior stroke to intensive therapy (goal systolic pressure < 120 mm Hg) or standard therapy as control (goal systolic pressure < 140 mm Hg) and showed a significant reduction in the composite end point and all-cause mortality—at the expense of an increase in serious adverse events.

EARLIER TRIALS WERE GENERALLY NEGATIVE

Before SPRINT, approximately 20 randomized controlled trials attempted to define whether a more intensive target was better than standard control. These included the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial restricted to patients with diabetes⁵ and the Secondary Prevention of Small Subcortical Strokes (SPS3) trial restricted to patients with lacunar infarcts.⁶ These two groups of patients were specifically excluded from SPRINT.⁶ Many of the other trials had primary renal end points, although several had primary cardiovascular end points.

As we reviewed previously in this Journal, individually these trials were generally inconclusive.⁷ When analyzed by meta-analysis, a significant benefit was found for cardiovascular events, stroke, and end-stage renal disease, with a marginal benefit for myocardial infarction.⁸ The validity of such analysis may be questioned due to heterogeneous populations, lack of individual patient data, different blood pressure targets and medication regimens, and different primary end points.

Together, ACCORD in patients with diabetes, SPS3 in patients with stroke, and SPRINT in patients at increased cardiovascular risk but without diabetes or stroke cover most hypertensive patients with more than low cardiovascular risk. All three trials were government-funded, and ACCORD and SPRINT used the same blood pressure targets and treatment algorithm. It remains speculative why ACCORD was essentially negative and SPRINT was positive.

CAUTION IN GENERALIZING THE RESULTS

In this issue of the Journal, Thomas and colleagues⁹ review the SPRINT results in detail and attempt to reconcile the disparity with ACCORD.

SPRINT should be interpreted in the context of prior trials and its inclusion and exclusion criteria

We agree with their interpretation that risks and benefits of a more intensive blood pressure target (ie, < 120 mm Hg systolic) need to be addressed in the individual patient and do not apply across the board to all hypertensive patients. This more intensive target would be appropriate for patients fulfilling criteria for entry into SPRINT, ie, no diabetes or prior stroke. They must be able to tolerate more intensive therapy and should not be frail or at risk for falls. Furthermore, the increased hypertension medication burden required for stricter control will increase side effects and complexity of overall medication regimens, and will possibly foster noncompliance.

In our opinion, one must be careful in generalizing the results of SPRINT to more than the type of patient enrolled. At best, one can say that a lower target is acceptable in a patient over age 50 at increased cardiovascular risk but without diabetes or stroke.

SPRINT may not even be representative of all such patients, however. Patients requiring more than four medications were excluded from the trial, as were patients with systolic pressure higher than 180 mm Hg, or with pressure higher than 170 mm Hg requiring two medications, or with pressure higher than 160 mm Hg requiring three medications, or with pressure higher than 150 mm Hg requiring four medications. Hence, SPRINT has not determined the appropriate approach to the patient with a systolic pressure between 150 and 180 mm Hg already on multiple medications above these cutoffs. It is not hard to envision the potential for adverse events and drug interactions using four or more antihypertensive medications to achieve a lower target, in addition to other classes of medications that many patients need.

The average systolic pressure on entry into SPRINT was 139 mm Hg, and patients were taking an average of 1.8 medications. In fact, one-third of patients had systolic pressures between 130 and 132 mm Hg, a range where most physicians would probably not want to intensify therapy. By protocol, such patients in the standard treatment group in SPRINT would actually have had their baseline antihypertensive therapy reduced if the systolic pressure fell below 130 mm Hg on one occasion or below 135 mm Hg on two consecutive visits. Reduction of therapy would seem to bias the trial against the standard treatment. An identical algorithm was used in ACCORD.

We are unable to reconcile the difference in outcome between ACCORD and SPRINTWe are unable to reconcile the differences in outcome between ACCORD and SPRINT, although they were congruent in one important aspect: significantly higher rates of serious adverse events with more intensive therapy. ACCORD had fewer patients, but they were at higher risk since all had diabetes, and more had previous cardiovascular events (34% vs 17% in SPRINT). This is reflected in higher event rates:

• Myocardial infarction occurred in 1.13% per year in the intensive therapy group, and 1.28% per year with standard therapy in ACCORD, compared with 0.65% and 0.78% per year, respectively, in SPRINT.
• Cardiovascular death occurred in 0.52% per year with intensive therapy and 0.49% per year with standard therapy in ACCORD, compared with 0.25% and 0.43% per year, respectively, in SPRINT. Event rates for stroke were similar.

Overall, 445 primary end points occurred in ACCORD compared with 562 with SPRINT. After subtracting heart failure from the SPRINT data (not included in the primary end point of ACCORD), 400 events occurred, actually less than in ACCORD. The early termination of SPRINT may be partly to blame. In our opinion ACCORD and SPRINT were equally powered. While cardiovascular event risk reductions in ACCORD trended in the same direction as those in SPRINT, the total mortality rate trended in the opposite direction. Perhaps the play of chance is the best explanation.

ONE TARGET DOES NOT FIT ALL

SPRINT clearly added much needed data, but results should be interpreted in the context of previous trials as well as of the specific inclusion and exclusion criteria. One target does not fit all, and systolic pressure of less than 120 mm Hg should not automatically be the target for all hypertensive patients.

Should patients with diabetes be targeted to systolic pressure of less than 140 mm Hg based on the ACCORD results, and patients with stroke to systolic pressure of less than 130 mm Hg based on the SPS3 results? We are unsure. More data are clearly required, especially in patients already on multiple antihypertensive medications with unacceptable blood pressure.

As pointed out by Thomas and colleagues, lower systolic pressure may be better in select patients, but only as long as adverse events can be avoided or managed.

High blood pressure is a major cause of morbidity and death worldwide.¹ Observational data from the general population show a log-linear relationship between both systolic and diastolic blood pressure and the rate of cardiovascular death.² Placebo-controlled trials have shown a clear-cut benefit in treating moderate to severe hypertension based on diastolic pressure in initial trials, and systolic pressure subsequently.³ What remains uncertain is the optimal target for a particular patient, and whether other factors such as number of medications, starting blood pressure, and other comorbidities should influence this target.

See related article

Publication of the Systolic Blood Pressure Intervention Trial (SPRINT) furthered the debate regarding the optimal blood pressure target in hypertension treatment.⁴ SPRINT randomized 9,361 nondiabetic persons with systolic pressure higher than 130 mm Hg and increased cardiovascular risk but without prior stroke to intensive therapy (goal systolic pressure < 120 mm Hg) or standard therapy as control (goal systolic pressure < 140 mm Hg) and showed a significant reduction in the composite end point and all-cause mortality—at the expense of an increase in serious adverse events.

EARLIER TRIALS WERE GENERALLY NEGATIVE

Before SPRINT, approximately 20 randomized controlled trials attempted to define whether a more intensive target was better than standard control. These included the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial restricted to patients with diabetes⁵ and the Secondary Prevention of Small Subcortical Strokes (SPS3) trial restricted to patients with lacunar infarcts.⁶ These two groups of patients were specifically excluded from SPRINT.⁶ Many of the other trials had primary renal end points, although several had primary cardiovascular end points.

As we reviewed previously in this Journal, individually these trials were generally inconclusive.⁷ When analyzed by meta-analysis, a significant benefit was found for cardiovascular events, stroke, and end-stage renal disease, with a marginal benefit for myocardial infarction.⁸ The validity of such analysis may be questioned due to heterogeneous populations, lack of individual patient data, different blood pressure targets and medication regimens, and different primary end points.

Together, ACCORD in patients with diabetes, SPS3 in patients with stroke, and SPRINT in patients at increased cardiovascular risk but without diabetes or stroke cover most hypertensive patients with more than low cardiovascular risk. All three trials were government-funded, and ACCORD and SPRINT used the same blood pressure targets and treatment algorithm. It remains speculative why ACCORD was essentially negative and SPRINT was positive.

CAUTION IN GENERALIZING THE RESULTS

In this issue of the Journal, Thomas and colleagues⁹ review the SPRINT results in detail and attempt to reconcile the disparity with ACCORD.

SPRINT should be interpreted in the context of prior trials and its inclusion and exclusion criteria

We agree with their interpretation that risks and benefits of a more intensive blood pressure target (ie, < 120 mm Hg systolic) need to be addressed in the individual patient and do not apply across the board to all hypertensive patients. This more intensive target would be appropriate for patients fulfilling criteria for entry into SPRINT, ie, no diabetes or prior stroke. They must be able to tolerate more intensive therapy and should not be frail or at risk for falls. Furthermore, the increased hypertension medication burden required for stricter control will increase side effects and complexity of overall medication regimens, and will possibly foster noncompliance.

In our opinion, one must be careful in generalizing the results of SPRINT to more than the type of patient enrolled. At best, one can say that a lower target is acceptable in a patient over age 50 at increased cardiovascular risk but without diabetes or stroke.

SPRINT may not even be representative of all such patients, however. Patients requiring more than four medications were excluded from the trial, as were patients with systolic pressure higher than 180 mm Hg, or with pressure higher than 170 mm Hg requiring two medications, or with pressure higher than 160 mm Hg requiring three medications, or with pressure higher than 150 mm Hg requiring four medications. Hence, SPRINT has not determined the appropriate approach to the patient with a systolic pressure between 150 and 180 mm Hg already on multiple medications above these cutoffs. It is not hard to envision the potential for adverse events and drug interactions using four or more antihypertensive medications to achieve a lower target, in addition to other classes of medications that many patients need.

The average systolic pressure on entry into SPRINT was 139 mm Hg, and patients were taking an average of 1.8 medications. In fact, one-third of patients had systolic pressures between 130 and 132 mm Hg, a range where most physicians would probably not want to intensify therapy. By protocol, such patients in the standard treatment group in SPRINT would actually have had their baseline antihypertensive therapy reduced if the systolic pressure fell below 130 mm Hg on one occasion or below 135 mm Hg on two consecutive visits. Reduction of therapy would seem to bias the trial against the standard treatment. An identical algorithm was used in ACCORD.

We are unable to reconcile the difference in outcome between ACCORD and SPRINTWe are unable to reconcile the differences in outcome between ACCORD and SPRINT, although they were congruent in one important aspect: significantly higher rates of serious adverse events with more intensive therapy. ACCORD had fewer patients, but they were at higher risk since all had diabetes, and more had previous cardiovascular events (34% vs 17% in SPRINT). This is reflected in higher event rates:

• Myocardial infarction occurred in 1.13% per year in the intensive therapy group, and 1.28% per year with standard therapy in ACCORD, compared with 0.65% and 0.78% per year, respectively, in SPRINT.
• Cardiovascular death occurred in 0.52% per year with intensive therapy and 0.49% per year with standard therapy in ACCORD, compared with 0.25% and 0.43% per year, respectively, in SPRINT. Event rates for stroke were similar.

Overall, 445 primary end points occurred in ACCORD compared with 562 with SPRINT. After subtracting heart failure from the SPRINT data (not included in the primary end point of ACCORD), 400 events occurred, actually less than in ACCORD. The early termination of SPRINT may be partly to blame. In our opinion ACCORD and SPRINT were equally powered. While cardiovascular event risk reductions in ACCORD trended in the same direction as those in SPRINT, the total mortality rate trended in the opposite direction. Perhaps the play of chance is the best explanation.

ONE TARGET DOES NOT FIT ALL

SPRINT clearly added much needed data, but results should be interpreted in the context of previous trials as well as of the specific inclusion and exclusion criteria. One target does not fit all, and systolic pressure of less than 120 mm Hg should not automatically be the target for all hypertensive patients.

Should patients with diabetes be targeted to systolic pressure of less than 140 mm Hg based on the ACCORD results, and patients with stroke to systolic pressure of less than 130 mm Hg based on the SPS3 results? We are unsure. More data are clearly required, especially in patients already on multiple antihypertensive medications with unacceptable blood pressure.

As pointed out by Thomas and colleagues, lower systolic pressure may be better in select patients, but only as long as adverse events can be avoided or managed.

In treating hypertension, lower systolic pressure is better than higher—with caveats. This is the message of the Systolic Blood Pressure Intervention Trial (SPRINT),¹ a large, federally funded study that was halted early when patients at high cardiovascular risk who were randomized to a goal systolic pressure of less than 120 mm Hg were found to have better outcomes, including lower rates of heart failure, death from cardiovascular causes, and death from any cause, than patients randomized to a goal of less than 140 mm Hg.

See related editorial

The caveats: the benefit came at a price of more adverse events. Also, the trial excluded patients who had diabetes mellitus or previous strokes, so it is uncertain if these subgroups would also benefit from intensive lowering of systolic pressure—and in earlier trials they did not.

This article reviews the trial design and protocol, summarizes the results, and briefly discusses the implications of these results.

BEFORE SPRINT

Hypertension is very common in adults in the United States, and is a risk factor for heart disease, stroke, heart failure, and kidney disease. The estimated prevalence of hypertension in the 2011–2014 National Health and Nutrition Examination Survey (NHANES) was 29%, and the prevalence increases with age (7.3% in those ages 18 to 39, 32.2% in those ages 40 to 59, and 64.9% in those ages 60 and older).² Isolated systolic hypertension (ie, systolic blood pressure > 140 mm Hg with diastolic pressure < 90 mm Hg) is the most common form of hypertension after age 50.³

Clinical trials have provided substantial evidence that treating hypertension reduces the incidence of stroke, myocardial infarction, and heart failure.^4,5 Although observational studies show a progressive and linear rise in cardiovascular risk as systolic blood pressure rises above 115 mm Hg,⁶ clinical trials in the general population have not documented benefits of lowering systolic pressure to this level.^7–11 However, clinical trials that directly evaluated two different blood pressure goals in the general population showed benefit with achieving systolic blood pressure less than 150 mm Hg,^7,9 with limited data on lower blood pressure targets.^10–12

No benefit found in intensive systolic lowering in diabetes or after stroke

The Action to Control Cardiovascular Risk in Diabetes-Blood Pressure (ACCORD BP) trial¹³ in patients with type 2 diabetes found no benefit in lowering systolic pressure to less than 120 mm Hg compared with less than 140 mm Hg in terms of the trial’s primary composite cardiovascular outcome (ie, nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes). However, the intensively treated group in this trial did enjoy a benefit in terms of fewer stroke events.

The Secondary Prevention of Small Subcortical Strokes (SPS3) trial¹⁴ in patients with stroke found no significant benefit in lowering systolic pressure to less than 130 mm Hg compared with less than 150 mm Hg for overall risk of another stroke, but a significant benefit was noted in reduced risk of intracerebral hemorrhage.

Current guidelines, based on available evidence, advocate treatment to a systolic goal of less than 140 mm Hg in most patients, and recommend relaxing this goal to less than 150 mm Hg in the elderly.^15,16

SPRINT was stopped early due to better outcomes in the intensive treatment group

Given the uncertainty surrounding optimal systolic targets, SPRINT was designed to test the hypothesis that a goal of less than 120 mm Hg would reduce the risk of cardiovascular events more than the generally accepted systolic goal of less than 140 mm Hg.17 Patients with diabetes and stroke were excluded because a similar hypothesis was tested in the ACCORD BP and SPS3 trials, which included patients with these conditions.

SPRINT DESIGN

SPRINT was a randomized, controlled, open-label trial sponsored by the National Institutes of Health and conducted at 102 US sites.

Inclusion criteria. Participants had to be at least 50 years old, with systolic pressure of 130 to 180 mm Hg, and had to have at least one cardiovascular risk factor, eg:

• Clinical or subclinical cardiovascular disease (other than stroke)
• Chronic kidney disease, defined as estimated glomerular filtration rate (eGFR), calculated by the Modification of Diet in Renal Disease (MDRD) study equation, of 20 to less than 60 mL/min/1.73 m²
• Framingham risk score of 15% of more
• Age 75 or older.

Major exclusion criteria included:

• Diabetes
• Stroke
• Polycystic kidney disease
• Chronic kidney disease with an eGFR less than 20 mL/min/1.73 m²
• Proteinuria (excretion > 1 g/day).

Intensive vs standard treatment

Participants were randomized to receive intensive treatment (systolic goal < 120 mm Hg) or standard treatment (systolic goal < 140 mm Hg). Baseline antihypertensive medications were adjusted to achieve blood pressure goals based on randomization assignment.

Doses of medications were adjusted on the basis of an average of three seated office blood pressure measurements after a 5-minute period of rest, taken with an automated monitor (Omron Healthcare Model 907); the same monitor was used and the same protocol was followed at all participating sites. Blood pressure was also measured after standing for 1 minute to assess orthostatic change.

Intensive treatment required, on average, one more medication than standard treatment

Lifestyle modifications were encouraged in both groups. There was no restriction on using any antihypertensive medication, and this was at the discretion of individual investigators. Thiazide-type diuretics were encouraged as first-line agents (with chlorthalidone encouraged as the primary thiazide-type diuretic).

Outcomes measured

The primary outcome was a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, and cardiovascular mortality.

Secondary outcomes included individual components of the primary composite outcome, all-cause mortality, and the composite of primary outcome and all-cause mortality.

Renal outcomes were assessed as:

• Incident albuminuria (doubling of the urinary albumin-to-creatinine ratio from less than 10 mg/g to more than 10 mg/g)
• Composite of a 50% decrease in eGFR or development of end-stage renal disease requiring long-term dialysis or kidney transplantation (in those with baseline chronic kidney disease)
• A 30% decrease in eGFR (in those without chronic kidney disease).^1,17

SPRINT also recruited participants to two nested substudies: SPRINT MIND and SPRINT MIND MRI, to study differences in cognitive outcomes and small-vessel ischemic disease between intensive treatment and standard treatment.

STUDY RESULTS

Older patients at risk, but without diabetes

Of 14,692 participants screened, 9,361 were enrolled in the study between 2010 and 2013. Baseline characteristics were comparable in both groups.

Demographics. The mean age of the participants was 67.9, and about 28% were 75 or older. About 36% were women, 58% white, 30% black, and 11% Hispanic.

Cardiovascular risk. The mean Framingham risk score was 20% (ie, they had a 20% risk of having a cardiovascular event within 10 years), and 61% of the participants had a risk score of at least 15%. Twenty percent already had cardiovascular disease.

Blood pressure. The average baseline blood pressure was 139.7/78.2 mm Hg. One-third of the participants had baseline systolic pressures of 132 mm Hg or less, another third had pressures in the range of 132 to 145, and the rest had 145 mm Hg or higher.

Renal function. The mean serum creatinine level was about 1.1 mg/dL. The mean eGFR was about 71 mL/min/1.73 m² as calculated by the MDRD equation, and about 28% had eGFRs less than 60. The mean ratio of urinary albumin to creatinine was 44.1 mg/g in the intensive treatment group and 41.1 in the standard treatment group.

Other. The mean total cholesterol level was 190 mg/dL, fasting plasma glucose 99 mg/dL, and body mass index nearly 30 kg/m².

Blood pressure during treatment

People in the intensive treatment group were taking a mean of 2.8 antihypertensive medications, and those in the standard treatment group were taking 1.8. Patients in the intensive group required greater use of all classes of medications to achieve goal systolic pressure (Table 1).

Study halted early due to efficacy

Throughout the 3.26 years of follow-up, the average difference in systolic pressure between the two groups was 13.1 mm Hg, with a mean systolic pressure of 121.5 mm Hg in the intensive treatment group and 134.6 mm Hg in the standard treatment group. The mean diastolic blood pressure was 68.7 mm Hg in the intensive treatment group and 76.3 mm Hg in the standard treatment group.

Although the study was planned to run for an average follow-up of 5 years, the National Heart, Lung, and Blood Institute terminated it early at a median of 3.26 years in view of lower rates of the primary outcome and of heart failure and death in the intensive treatment group (Table 2).

The effects on the primary outcome and mortality were consistent across the prespecified subgroups of age (< 75 vs ≥ 75), sex (female vs male), race (black vs nonblack), cardiovascular disease (presence or absence at baseline), prior chronic kidney disease (presence or absence at baseline), and across blood pressure tertiles (≤ 132 mm Hg, > 132 to < 145 mm Hg, ≥ 145 mm Hg).

Follow-up for assessment of cognitive outcomes (SPRINT MIND) and small-vessel ischemic disease (SPRINT MIND MRI) is ongoing.

WHAT DOES THIS MEAN?

SPRINT is the first large, adequately powered, randomized trial to demonstrate cardiovascular and mortality benefit from lowering the systolic blood pressure (goal < 120 mm Hg) in older patients at cardiovascular risk but without a history of diabetes mellitus or stroke.¹

Most SPRINT patients had reasonably controlled blood pressure at baseline (the mean systolic pressure was 139.7 mm Hg, and two-thirds of participants had systolic pressure < 145 mm Hg). Of note, however, this trial excluded patients with systolic pressure higher than 180 mm Hg. There was excellent separation of systolic pressure between the two groups beginning at 1 year, which was consistent through the course of the trial.

The cardiovascular benefit in the intensive treatment group was predominantly driven by lower rates of heart failure (a 38% reduction in the intensive treatment group, P = .0002) and cardiovascular mortality (a 43% reduction in the intensive treatment group, P = .005), while there was no significant difference between the two groups in myocardial infarction or stroke. The beneficial effect on heart failure events is consistent with results from other trials including the Systolic Hypertension in the Elderly Program,⁷ Systolic Hypertension in Europe,⁸ and Hypertension in the Very Elderly Trial,⁹ all of which showed greatest risk reduction for heart failure events with systolic pressure-lowering (although to higher systolic levels than SPRINT).^7–9 It is unclear why there was no beneficial effect on stroke events. The reduction in all-cause mortality in the intensive treatment group in SPRINT was greater than the reduction in cardiovascular deaths, which is also unexplained.

Although the study was terminated early due to efficacy (which introduces the possible bias that the estimated effect size will be too high), the number of primary end points  reached was large (562 in the two groups combined), providing reassurance that the findings are valid. There was no blinding in the study (both participants and study investigators were aware of treatment assignment and study medications), but there was a structured assessment of outcomes and adverse events, with adjudication done by blinded reviewers.

SPRINT used an automated device for blood pressure measurement, which is known to reduce the “white coat” effect and correlates tightly with average daytime blood pressure done by ambulatory blood pressure monitoring.¹⁸ However, in clinical practice automated devices may not be available and a strict protocol for correct measurement may not be followed, with the possible result that blood pressure may be overestimated and overtreated.

What about diastolic pressure?

The trial, by design, focused on lowering systolic pressure (given the greater prevalence of isolated systolic hypertension with age), and the implications of lowering diastolic pressure are unclear. The issue of a J-shaped relationship between diastolic pressure and cardiovascular risk is debated in the literature: patients with a diastolic pressure of 60 to 65 mm Hg, especially those with existing coronary artery disease, may not tolerate aggressive blood pressure-lowering.^19,20 Further analysis of this association (if any) from SPRINT will be helpful.

What about patients with diabetes?

Patients were excluded from SPRINT if they were under age 50, were at low cardiovascular risk, or had diabetes, raising the question of whether the results apply to these groups as well.

The question is particularly relevant in diabetes, as the ACCORD BP study, which used the same blood pressure targets as SPRINT, did not show a significant difference in the primary cardiovascular outcome between the intensive and standard treatments in patients with diabetes (Table 3).¹³ In ACCORD BP, the rate of the primary outcome was 12% lower in the intensive treatment group than in the standard treatment group, but the 95% confidence interval was –27% to +6%, so the finding was not statistically significant. However, the wide confidence interval does not exclude the possibility of a benefit that was comparable to that observed in SPRINT.

It has been speculated that ACCORD BP was underpowered to detect significant differences in the primary outcome.²¹ An analysis combining data from both trials indicated that effects on individual outcomes were generally consistent in both trials (with no significant heterogeneity noted).²² Also, the primary composite outcome in ACCORD did not include heart failure, which is particularly sensitive to blood pressure reduction.

Additionally, ACCORD BP had a 2 × 2 factorial design involving a simultaneous comparison of intensive vs standard glycemic control, which may have influenced the effects due to blood pressure. Indeed, a post hoc analysis showed that there was a significant 26% lower risk of the primary outcome in ACCORD BP patients who received intensive systolic pressure  control plus standard glycemic control than in those receiving standard systolic control plus standard glycemic control.²³

Are more adverse events an acceptable trade-off?

Adverse events, including acute kidney injury, were more frequent in the intensive therapy group in SPRINT.

Acute kidney injury was coded as an adverse event on the basis of this diagnosis being included in the hospital discharge summary (as a primary or main secondary diagnosis) and if considered by the safety officer to be one of the top three reasons for admission or continued hospitalization. Further analysis of renal events should be forthcoming.

People in the intensive treatment group, on average, needed one more medication than those in the standard treatment group. Some of the adverse events may be related to the antihypertensive medications taken (eg, electrolyte abnormalities such as hyponatremia and hypokalemia due to diuretic use), and others may be related to blood pressure-lowering (eg, acute kidney injury due to renal hypoperfusion).

At this point, the long-term effects of these adverse events, especially on kidney function, are not known. Patients enrolled in clinical trials tend to be healthier than patients seen in clinical practice; thus, the rate of adverse events reported in the trial may be lower than one would see in the real world.

Does lower systolic pressure protect or harm the kidneys?

SPRINT included patients with stage 3 and 4 chronic kidney disease (ie, with eGFR 20–50 mL/min/1.73 m²), but it was designed to assess cardiovascular outcomes, not the progression of chronic kidney disease. The trial excluded patients with diabetic nephropathy or high degrees of proteinuria.

Only about half of hypertensive adults have their blood pressure under control, ie, < 140/90

Earlier randomized trials that focused on chronic kidney disease progression, including the MDRD²⁴ and the African American Study of Kidney Disease and Hypertension,²⁵ did not show benefit with more aggressive blood pressure-lowering (except in patients with higher degrees of proteinuria), and these trials were not powered to assess effects on cardiovascular outcomes.^24,25

The Irbesartan Diabetic Nephropathy Trial,^26,27 which was done in patients with overt diabetic nephropathy, showed that a progressively lower achieved systolic pressure down to 120 mm Hg predicted lower rates of heart failure, cardiovascular mortality, and renal events (although the trial target was ≤ 130/85 mm Hg and few participants achieved systolic pressure lower than 120 mm Hg).

IMPLICATIONS FOR MANAGEMENT

The recent estimates of hypertension prevalence and control from NHANES show that only about 53% of hypertensive adults have their blood pressure under control (defined as systolic pressure < 140 mm Hg and diastolic pressure < 90 mm Hg).² Analysis of the NHANES 2007–2012 data showed that 16.7% or 8.2 million US adults with treated hypertension meet the eligibility criteria for SPRINT.²⁸

Although the SPRINT results support the notion that “lower is better,” the risks and benefits of intensive control will need to be balanced in individual patients. Table 4 shows the number needed to treat and number needed to harm in the trial.

More aggressive management of hypertension is challenging. The median systolic pressure achieved in the intensive group in SPRINT was just over 120 mm Hg, which implies that at least half of the participants in the intensive group did not achieve the goal of less than 120 mm Hg. While it may be reasonable to aim for systolic pressure of less than 120 or 125 mm Hg in patients who fit the SPRINT criteria and can tolerate intensive blood pressure lowering, it would be prudent to aim for a more conservative goal in elderly patients who are frail and at risk for falls, considering the higher incidence of specified adverse events in the intensive group.

Results of cognitive outcomes, as well as data related to quality of life, are still awaited. Long-term renal outcomes are also unclear.

As noted above, the question of generalizability of SPRINT results to patients with diabetes is open to debate. In our opinion, with currently available evidence, it is difficult to conclusively answer the question of whether a lower systolic target provides cardiovascular benefit in diabetes. It is also unclear whether similar beneficial results would be seen with intensive treatment in a population at low cardiovascular risk. The American Heart Association and the American College of Cardiology are in the process of formulating new hypertension guidelines, and evidence from  SPRINT will inform any new recommendations.

As more medications will likely be needed for intensive systolic blood pressure control, side effects and tolerability of medications with polypharmacy and potential nonadherence with increasing complexity of medication regimens should be kept in mind. Lifestyle modifications will need to be emphasized and reinforced, with greater use of combination antihypertensive therapy.

The data from SPRINT indicate that lower systolic pressure is better, as long as untoward clinical events can be monitored and avoided or easily managed. Careful monitoring will likely entail more frequent clinic visits and more frequent assessment of renal function and electrolyte levels (participants in the intensive group in the trial were seen every month until goal was achieved). A team approach that includes pharmacists and nurse practitioners, along with optimal use of best practice algorithms and remote monitoring technology, will need to be implemented for efficient and effective care.

In treating hypertension, lower systolic pressure is better than higher—with caveats. This is the message of the Systolic Blood Pressure Intervention Trial (SPRINT),¹ a large, federally funded study that was halted early when patients at high cardiovascular risk who were randomized to a goal systolic pressure of less than 120 mm Hg were found to have better outcomes, including lower rates of heart failure, death from cardiovascular causes, and death from any cause, than patients randomized to a goal of less than 140 mm Hg.

See related editorial

The caveats: the benefit came at a price of more adverse events. Also, the trial excluded patients who had diabetes mellitus or previous strokes, so it is uncertain if these subgroups would also benefit from intensive lowering of systolic pressure—and in earlier trials they did not.

This article reviews the trial design and protocol, summarizes the results, and briefly discusses the implications of these results.

BEFORE SPRINT

Hypertension is very common in adults in the United States, and is a risk factor for heart disease, stroke, heart failure, and kidney disease. The estimated prevalence of hypertension in the 2011–2014 National Health and Nutrition Examination Survey (NHANES) was 29%, and the prevalence increases with age (7.3% in those ages 18 to 39, 32.2% in those ages 40 to 59, and 64.9% in those ages 60 and older).² Isolated systolic hypertension (ie, systolic blood pressure > 140 mm Hg with diastolic pressure < 90 mm Hg) is the most common form of hypertension after age 50.³

Clinical trials have provided substantial evidence that treating hypertension reduces the incidence of stroke, myocardial infarction, and heart failure.^4,5 Although observational studies show a progressive and linear rise in cardiovascular risk as systolic blood pressure rises above 115 mm Hg,⁶ clinical trials in the general population have not documented benefits of lowering systolic pressure to this level.^7–11 However, clinical trials that directly evaluated two different blood pressure goals in the general population showed benefit with achieving systolic blood pressure less than 150 mm Hg,^7,9 with limited data on lower blood pressure targets.^10–12

No benefit found in intensive systolic lowering in diabetes or after stroke

The Action to Control Cardiovascular Risk in Diabetes-Blood Pressure (ACCORD BP) trial¹³ in patients with type 2 diabetes found no benefit in lowering systolic pressure to less than 120 mm Hg compared with less than 140 mm Hg in terms of the trial’s primary composite cardiovascular outcome (ie, nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes). However, the intensively treated group in this trial did enjoy a benefit in terms of fewer stroke events.

The Secondary Prevention of Small Subcortical Strokes (SPS3) trial¹⁴ in patients with stroke found no significant benefit in lowering systolic pressure to less than 130 mm Hg compared with less than 150 mm Hg for overall risk of another stroke, but a significant benefit was noted in reduced risk of intracerebral hemorrhage.

Current guidelines, based on available evidence, advocate treatment to a systolic goal of less than 140 mm Hg in most patients, and recommend relaxing this goal to less than 150 mm Hg in the elderly.^15,16

SPRINT was stopped early due to better outcomes in the intensive treatment group

Given the uncertainty surrounding optimal systolic targets, SPRINT was designed to test the hypothesis that a goal of less than 120 mm Hg would reduce the risk of cardiovascular events more than the generally accepted systolic goal of less than 140 mm Hg.17 Patients with diabetes and stroke were excluded because a similar hypothesis was tested in the ACCORD BP and SPS3 trials, which included patients with these conditions.

SPRINT DESIGN

SPRINT was a randomized, controlled, open-label trial sponsored by the National Institutes of Health and conducted at 102 US sites.

Inclusion criteria. Participants had to be at least 50 years old, with systolic pressure of 130 to 180 mm Hg, and had to have at least one cardiovascular risk factor, eg:

• Clinical or subclinical cardiovascular disease (other than stroke)
• Chronic kidney disease, defined as estimated glomerular filtration rate (eGFR), calculated by the Modification of Diet in Renal Disease (MDRD) study equation, of 20 to less than 60 mL/min/1.73 m²
• Framingham risk score of 15% of more
• Age 75 or older.

Major exclusion criteria included:

• Diabetes
• Stroke
• Polycystic kidney disease
• Chronic kidney disease with an eGFR less than 20 mL/min/1.73 m²
• Proteinuria (excretion > 1 g/day).

Intensive vs standard treatment

Participants were randomized to receive intensive treatment (systolic goal < 120 mm Hg) or standard treatment (systolic goal < 140 mm Hg). Baseline antihypertensive medications were adjusted to achieve blood pressure goals based on randomization assignment.

Doses of medications were adjusted on the basis of an average of three seated office blood pressure measurements after a 5-minute period of rest, taken with an automated monitor (Omron Healthcare Model 907); the same monitor was used and the same protocol was followed at all participating sites. Blood pressure was also measured after standing for 1 minute to assess orthostatic change.

Intensive treatment required, on average, one more medication than standard treatment

Lifestyle modifications were encouraged in both groups. There was no restriction on using any antihypertensive medication, and this was at the discretion of individual investigators. Thiazide-type diuretics were encouraged as first-line agents (with chlorthalidone encouraged as the primary thiazide-type diuretic).

Outcomes measured

The primary outcome was a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, and cardiovascular mortality.

Secondary outcomes included individual components of the primary composite outcome, all-cause mortality, and the composite of primary outcome and all-cause mortality.

Renal outcomes were assessed as:

• Incident albuminuria (doubling of the urinary albumin-to-creatinine ratio from less than 10 mg/g to more than 10 mg/g)
• Composite of a 50% decrease in eGFR or development of end-stage renal disease requiring long-term dialysis or kidney transplantation (in those with baseline chronic kidney disease)
• A 30% decrease in eGFR (in those without chronic kidney disease).^1,17

SPRINT also recruited participants to two nested substudies: SPRINT MIND and SPRINT MIND MRI, to study differences in cognitive outcomes and small-vessel ischemic disease between intensive treatment and standard treatment.

STUDY RESULTS

Older patients at risk, but without diabetes

Of 14,692 participants screened, 9,361 were enrolled in the study between 2010 and 2013. Baseline characteristics were comparable in both groups.

Demographics. The mean age of the participants was 67.9, and about 28% were 75 or older. About 36% were women, 58% white, 30% black, and 11% Hispanic.

Cardiovascular risk. The mean Framingham risk score was 20% (ie, they had a 20% risk of having a cardiovascular event within 10 years), and 61% of the participants had a risk score of at least 15%. Twenty percent already had cardiovascular disease.

Blood pressure. The average baseline blood pressure was 139.7/78.2 mm Hg. One-third of the participants had baseline systolic pressures of 132 mm Hg or less, another third had pressures in the range of 132 to 145, and the rest had 145 mm Hg or higher.

Renal function. The mean serum creatinine level was about 1.1 mg/dL. The mean eGFR was about 71 mL/min/1.73 m² as calculated by the MDRD equation, and about 28% had eGFRs less than 60. The mean ratio of urinary albumin to creatinine was 44.1 mg/g in the intensive treatment group and 41.1 in the standard treatment group.

Other. The mean total cholesterol level was 190 mg/dL, fasting plasma glucose 99 mg/dL, and body mass index nearly 30 kg/m².

Blood pressure during treatment

People in the intensive treatment group were taking a mean of 2.8 antihypertensive medications, and those in the standard treatment group were taking 1.8. Patients in the intensive group required greater use of all classes of medications to achieve goal systolic pressure (Table 1).

Study halted early due to efficacy

Throughout the 3.26 years of follow-up, the average difference in systolic pressure between the two groups was 13.1 mm Hg, with a mean systolic pressure of 121.5 mm Hg in the intensive treatment group and 134.6 mm Hg in the standard treatment group. The mean diastolic blood pressure was 68.7 mm Hg in the intensive treatment group and 76.3 mm Hg in the standard treatment group.

Although the study was planned to run for an average follow-up of 5 years, the National Heart, Lung, and Blood Institute terminated it early at a median of 3.26 years in view of lower rates of the primary outcome and of heart failure and death in the intensive treatment group (Table 2).

The effects on the primary outcome and mortality were consistent across the prespecified subgroups of age (< 75 vs ≥ 75), sex (female vs male), race (black vs nonblack), cardiovascular disease (presence or absence at baseline), prior chronic kidney disease (presence or absence at baseline), and across blood pressure tertiles (≤ 132 mm Hg, > 132 to < 145 mm Hg, ≥ 145 mm Hg).

Follow-up for assessment of cognitive outcomes (SPRINT MIND) and small-vessel ischemic disease (SPRINT MIND MRI) is ongoing.

WHAT DOES THIS MEAN?

SPRINT is the first large, adequately powered, randomized trial to demonstrate cardiovascular and mortality benefit from lowering the systolic blood pressure (goal < 120 mm Hg) in older patients at cardiovascular risk but without a history of diabetes mellitus or stroke.¹

Most SPRINT patients had reasonably controlled blood pressure at baseline (the mean systolic pressure was 139.7 mm Hg, and two-thirds of participants had systolic pressure < 145 mm Hg). Of note, however, this trial excluded patients with systolic pressure higher than 180 mm Hg. There was excellent separation of systolic pressure between the two groups beginning at 1 year, which was consistent through the course of the trial.

The cardiovascular benefit in the intensive treatment group was predominantly driven by lower rates of heart failure (a 38% reduction in the intensive treatment group, P = .0002) and cardiovascular mortality (a 43% reduction in the intensive treatment group, P = .005), while there was no significant difference between the two groups in myocardial infarction or stroke. The beneficial effect on heart failure events is consistent with results from other trials including the Systolic Hypertension in the Elderly Program,⁷ Systolic Hypertension in Europe,⁸ and Hypertension in the Very Elderly Trial,⁹ all of which showed greatest risk reduction for heart failure events with systolic pressure-lowering (although to higher systolic levels than SPRINT).^7–9 It is unclear why there was no beneficial effect on stroke events. The reduction in all-cause mortality in the intensive treatment group in SPRINT was greater than the reduction in cardiovascular deaths, which is also unexplained.

Although the study was terminated early due to efficacy (which introduces the possible bias that the estimated effect size will be too high), the number of primary end points  reached was large (562 in the two groups combined), providing reassurance that the findings are valid. There was no blinding in the study (both participants and study investigators were aware of treatment assignment and study medications), but there was a structured assessment of outcomes and adverse events, with adjudication done by blinded reviewers.

SPRINT used an automated device for blood pressure measurement, which is known to reduce the “white coat” effect and correlates tightly with average daytime blood pressure done by ambulatory blood pressure monitoring.¹⁸ However, in clinical practice automated devices may not be available and a strict protocol for correct measurement may not be followed, with the possible result that blood pressure may be overestimated and overtreated.

What about diastolic pressure?

The trial, by design, focused on lowering systolic pressure (given the greater prevalence of isolated systolic hypertension with age), and the implications of lowering diastolic pressure are unclear. The issue of a J-shaped relationship between diastolic pressure and cardiovascular risk is debated in the literature: patients with a diastolic pressure of 60 to 65 mm Hg, especially those with existing coronary artery disease, may not tolerate aggressive blood pressure-lowering.^19,20 Further analysis of this association (if any) from SPRINT will be helpful.

What about patients with diabetes?

Patients were excluded from SPRINT if they were under age 50, were at low cardiovascular risk, or had diabetes, raising the question of whether the results apply to these groups as well.

The question is particularly relevant in diabetes, as the ACCORD BP study, which used the same blood pressure targets as SPRINT, did not show a significant difference in the primary cardiovascular outcome between the intensive and standard treatments in patients with diabetes (Table 3).¹³ In ACCORD BP, the rate of the primary outcome was 12% lower in the intensive treatment group than in the standard treatment group, but the 95% confidence interval was –27% to +6%, so the finding was not statistically significant. However, the wide confidence interval does not exclude the possibility of a benefit that was comparable to that observed in SPRINT.

It has been speculated that ACCORD BP was underpowered to detect significant differences in the primary outcome.²¹ An analysis combining data from both trials indicated that effects on individual outcomes were generally consistent in both trials (with no significant heterogeneity noted).²² Also, the primary composite outcome in ACCORD did not include heart failure, which is particularly sensitive to blood pressure reduction.

Additionally, ACCORD BP had a 2 × 2 factorial design involving a simultaneous comparison of intensive vs standard glycemic control, which may have influenced the effects due to blood pressure. Indeed, a post hoc analysis showed that there was a significant 26% lower risk of the primary outcome in ACCORD BP patients who received intensive systolic pressure  control plus standard glycemic control than in those receiving standard systolic control plus standard glycemic control.²³

Are more adverse events an acceptable trade-off?

Adverse events, including acute kidney injury, were more frequent in the intensive therapy group in SPRINT.

Acute kidney injury was coded as an adverse event on the basis of this diagnosis being included in the hospital discharge summary (as a primary or main secondary diagnosis) and if considered by the safety officer to be one of the top three reasons for admission or continued hospitalization. Further analysis of renal events should be forthcoming.

People in the intensive treatment group, on average, needed one more medication than those in the standard treatment group. Some of the adverse events may be related to the antihypertensive medications taken (eg, electrolyte abnormalities such as hyponatremia and hypokalemia due to diuretic use), and others may be related to blood pressure-lowering (eg, acute kidney injury due to renal hypoperfusion).

At this point, the long-term effects of these adverse events, especially on kidney function, are not known. Patients enrolled in clinical trials tend to be healthier than patients seen in clinical practice; thus, the rate of adverse events reported in the trial may be lower than one would see in the real world.

Does lower systolic pressure protect or harm the kidneys?

SPRINT included patients with stage 3 and 4 chronic kidney disease (ie, with eGFR 20–50 mL/min/1.73 m²), but it was designed to assess cardiovascular outcomes, not the progression of chronic kidney disease. The trial excluded patients with diabetic nephropathy or high degrees of proteinuria.

Only about half of hypertensive adults have their blood pressure under control, ie, < 140/90

Earlier randomized trials that focused on chronic kidney disease progression, including the MDRD²⁴ and the African American Study of Kidney Disease and Hypertension,²⁵ did not show benefit with more aggressive blood pressure-lowering (except in patients with higher degrees of proteinuria), and these trials were not powered to assess effects on cardiovascular outcomes.^24,25

The Irbesartan Diabetic Nephropathy Trial,^26,27 which was done in patients with overt diabetic nephropathy, showed that a progressively lower achieved systolic pressure down to 120 mm Hg predicted lower rates of heart failure, cardiovascular mortality, and renal events (although the trial target was ≤ 130/85 mm Hg and few participants achieved systolic pressure lower than 120 mm Hg).

IMPLICATIONS FOR MANAGEMENT

The recent estimates of hypertension prevalence and control from NHANES show that only about 53% of hypertensive adults have their blood pressure under control (defined as systolic pressure < 140 mm Hg and diastolic pressure < 90 mm Hg).² Analysis of the NHANES 2007–2012 data showed that 16.7% or 8.2 million US adults with treated hypertension meet the eligibility criteria for SPRINT.²⁸

Although the SPRINT results support the notion that “lower is better,” the risks and benefits of intensive control will need to be balanced in individual patients. Table 4 shows the number needed to treat and number needed to harm in the trial.

More aggressive management of hypertension is challenging. The median systolic pressure achieved in the intensive group in SPRINT was just over 120 mm Hg, which implies that at least half of the participants in the intensive group did not achieve the goal of less than 120 mm Hg. While it may be reasonable to aim for systolic pressure of less than 120 or 125 mm Hg in patients who fit the SPRINT criteria and can tolerate intensive blood pressure lowering, it would be prudent to aim for a more conservative goal in elderly patients who are frail and at risk for falls, considering the higher incidence of specified adverse events in the intensive group.

Results of cognitive outcomes, as well as data related to quality of life, are still awaited. Long-term renal outcomes are also unclear.

As noted above, the question of generalizability of SPRINT results to patients with diabetes is open to debate. In our opinion, with currently available evidence, it is difficult to conclusively answer the question of whether a lower systolic target provides cardiovascular benefit in diabetes. It is also unclear whether similar beneficial results would be seen with intensive treatment in a population at low cardiovascular risk. The American Heart Association and the American College of Cardiology are in the process of formulating new hypertension guidelines, and evidence from  SPRINT will inform any new recommendations.

As more medications will likely be needed for intensive systolic blood pressure control, side effects and tolerability of medications with polypharmacy and potential nonadherence with increasing complexity of medication regimens should be kept in mind. Lifestyle modifications will need to be emphasized and reinforced, with greater use of combination antihypertensive therapy.

The data from SPRINT indicate that lower systolic pressure is better, as long as untoward clinical events can be monitored and avoided or easily managed. Careful monitoring will likely entail more frequent clinic visits and more frequent assessment of renal function and electrolyte levels (participants in the intensive group in the trial were seen every month until goal was achieved). A team approach that includes pharmacists and nurse practitioners, along with optimal use of best practice algorithms and remote monitoring technology, will need to be implemented for efficient and effective care.

In treating hypertension, lower systolic pressure is better than higher—with caveats. This is the message of the Systolic Blood Pressure Intervention Trial (SPRINT),¹ a large, federally funded study that was halted early when patients at high cardiovascular risk who were randomized to a goal systolic pressure of less than 120 mm Hg were found to have better outcomes, including lower rates of heart failure, death from cardiovascular causes, and death from any cause, than patients randomized to a goal of less than 140 mm Hg.

See related editorial

The caveats: the benefit came at a price of more adverse events. Also, the trial excluded patients who had diabetes mellitus or previous strokes, so it is uncertain if these subgroups would also benefit from intensive lowering of systolic pressure—and in earlier trials they did not.

This article reviews the trial design and protocol, summarizes the results, and briefly discusses the implications of these results.

BEFORE SPRINT

Hypertension is very common in adults in the United States, and is a risk factor for heart disease, stroke, heart failure, and kidney disease. The estimated prevalence of hypertension in the 2011–2014 National Health and Nutrition Examination Survey (NHANES) was 29%, and the prevalence increases with age (7.3% in those ages 18 to 39, 32.2% in those ages 40 to 59, and 64.9% in those ages 60 and older).² Isolated systolic hypertension (ie, systolic blood pressure > 140 mm Hg with diastolic pressure < 90 mm Hg) is the most common form of hypertension after age 50.³

Clinical trials have provided substantial evidence that treating hypertension reduces the incidence of stroke, myocardial infarction, and heart failure.^4,5 Although observational studies show a progressive and linear rise in cardiovascular risk as systolic blood pressure rises above 115 mm Hg,⁶ clinical trials in the general population have not documented benefits of lowering systolic pressure to this level.^7–11 However, clinical trials that directly evaluated two different blood pressure goals in the general population showed benefit with achieving systolic blood pressure less than 150 mm Hg,^7,9 with limited data on lower blood pressure targets.^10–12

No benefit found in intensive systolic lowering in diabetes or after stroke

The Action to Control Cardiovascular Risk in Diabetes-Blood Pressure (ACCORD BP) trial¹³ in patients with type 2 diabetes found no benefit in lowering systolic pressure to less than 120 mm Hg compared with less than 140 mm Hg in terms of the trial’s primary composite cardiovascular outcome (ie, nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes). However, the intensively treated group in this trial did enjoy a benefit in terms of fewer stroke events.

The Secondary Prevention of Small Subcortical Strokes (SPS3) trial¹⁴ in patients with stroke found no significant benefit in lowering systolic pressure to less than 130 mm Hg compared with less than 150 mm Hg for overall risk of another stroke, but a significant benefit was noted in reduced risk of intracerebral hemorrhage.

Current guidelines, based on available evidence, advocate treatment to a systolic goal of less than 140 mm Hg in most patients, and recommend relaxing this goal to less than 150 mm Hg in the elderly.^15,16

SPRINT was stopped early due to better outcomes in the intensive treatment group

Given the uncertainty surrounding optimal systolic targets, SPRINT was designed to test the hypothesis that a goal of less than 120 mm Hg would reduce the risk of cardiovascular events more than the generally accepted systolic goal of less than 140 mm Hg.17 Patients with diabetes and stroke were excluded because a similar hypothesis was tested in the ACCORD BP and SPS3 trials, which included patients with these conditions.

SPRINT DESIGN

SPRINT was a randomized, controlled, open-label trial sponsored by the National Institutes of Health and conducted at 102 US sites.

Inclusion criteria. Participants had to be at least 50 years old, with systolic pressure of 130 to 180 mm Hg, and had to have at least one cardiovascular risk factor, eg:

• Clinical or subclinical cardiovascular disease (other than stroke)
• Chronic kidney disease, defined as estimated glomerular filtration rate (eGFR), calculated by the Modification of Diet in Renal Disease (MDRD) study equation, of 20 to less than 60 mL/min/1.73 m²
• Framingham risk score of 15% of more
• Age 75 or older.

Major exclusion criteria included:

• Diabetes
• Stroke
• Polycystic kidney disease
• Chronic kidney disease with an eGFR less than 20 mL/min/1.73 m²
• Proteinuria (excretion > 1 g/day).

Intensive vs standard treatment

Participants were randomized to receive intensive treatment (systolic goal < 120 mm Hg) or standard treatment (systolic goal < 140 mm Hg). Baseline antihypertensive medications were adjusted to achieve blood pressure goals based on randomization assignment.

Doses of medications were adjusted on the basis of an average of three seated office blood pressure measurements after a 5-minute period of rest, taken with an automated monitor (Omron Healthcare Model 907); the same monitor was used and the same protocol was followed at all participating sites. Blood pressure was also measured after standing for 1 minute to assess orthostatic change.

Intensive treatment required, on average, one more medication than standard treatment

Lifestyle modifications were encouraged in both groups. There was no restriction on using any antihypertensive medication, and this was at the discretion of individual investigators. Thiazide-type diuretics were encouraged as first-line agents (with chlorthalidone encouraged as the primary thiazide-type diuretic).

Outcomes measured

The primary outcome was a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, and cardiovascular mortality.

Secondary outcomes included individual components of the primary composite outcome, all-cause mortality, and the composite of primary outcome and all-cause mortality.

Renal outcomes were assessed as:

• Incident albuminuria (doubling of the urinary albumin-to-creatinine ratio from less than 10 mg/g to more than 10 mg/g)
• Composite of a 50% decrease in eGFR or development of end-stage renal disease requiring long-term dialysis or kidney transplantation (in those with baseline chronic kidney disease)
• A 30% decrease in eGFR (in those without chronic kidney disease).^1,17

SPRINT also recruited participants to two nested substudies: SPRINT MIND and SPRINT MIND MRI, to study differences in cognitive outcomes and small-vessel ischemic disease between intensive treatment and standard treatment.

STUDY RESULTS

Older patients at risk, but without diabetes

Of 14,692 participants screened, 9,361 were enrolled in the study between 2010 and 2013. Baseline characteristics were comparable in both groups.

Demographics. The mean age of the participants was 67.9, and about 28% were 75 or older. About 36% were women, 58% white, 30% black, and 11% Hispanic.

Cardiovascular risk. The mean Framingham risk score was 20% (ie, they had a 20% risk of having a cardiovascular event within 10 years), and 61% of the participants had a risk score of at least 15%. Twenty percent already had cardiovascular disease.

Blood pressure. The average baseline blood pressure was 139.7/78.2 mm Hg. One-third of the participants had baseline systolic pressures of 132 mm Hg or less, another third had pressures in the range of 132 to 145, and the rest had 145 mm Hg or higher.

Renal function. The mean serum creatinine level was about 1.1 mg/dL. The mean eGFR was about 71 mL/min/1.73 m² as calculated by the MDRD equation, and about 28% had eGFRs less than 60. The mean ratio of urinary albumin to creatinine was 44.1 mg/g in the intensive treatment group and 41.1 in the standard treatment group.

Other. The mean total cholesterol level was 190 mg/dL, fasting plasma glucose 99 mg/dL, and body mass index nearly 30 kg/m².

Blood pressure during treatment

People in the intensive treatment group were taking a mean of 2.8 antihypertensive medications, and those in the standard treatment group were taking 1.8. Patients in the intensive group required greater use of all classes of medications to achieve goal systolic pressure (Table 1).

Study halted early due to efficacy

Throughout the 3.26 years of follow-up, the average difference in systolic pressure between the two groups was 13.1 mm Hg, with a mean systolic pressure of 121.5 mm Hg in the intensive treatment group and 134.6 mm Hg in the standard treatment group. The mean diastolic blood pressure was 68.7 mm Hg in the intensive treatment group and 76.3 mm Hg in the standard treatment group.

Although the study was planned to run for an average follow-up of 5 years, the National Heart, Lung, and Blood Institute terminated it early at a median of 3.26 years in view of lower rates of the primary outcome and of heart failure and death in the intensive treatment group (Table 2).

The effects on the primary outcome and mortality were consistent across the prespecified subgroups of age (< 75 vs ≥ 75), sex (female vs male), race (black vs nonblack), cardiovascular disease (presence or absence at baseline), prior chronic kidney disease (presence or absence at baseline), and across blood pressure tertiles (≤ 132 mm Hg, > 132 to < 145 mm Hg, ≥ 145 mm Hg).

Follow-up for assessment of cognitive outcomes (SPRINT MIND) and small-vessel ischemic disease (SPRINT MIND MRI) is ongoing.

WHAT DOES THIS MEAN?

SPRINT is the first large, adequately powered, randomized trial to demonstrate cardiovascular and mortality benefit from lowering the systolic blood pressure (goal < 120 mm Hg) in older patients at cardiovascular risk but without a history of diabetes mellitus or stroke.¹

Most SPRINT patients had reasonably controlled blood pressure at baseline (the mean systolic pressure was 139.7 mm Hg, and two-thirds of participants had systolic pressure < 145 mm Hg). Of note, however, this trial excluded patients with systolic pressure higher than 180 mm Hg. There was excellent separation of systolic pressure between the two groups beginning at 1 year, which was consistent through the course of the trial.

The cardiovascular benefit in the intensive treatment group was predominantly driven by lower rates of heart failure (a 38% reduction in the intensive treatment group, P = .0002) and cardiovascular mortality (a 43% reduction in the intensive treatment group, P = .005), while there was no significant difference between the two groups in myocardial infarction or stroke. The beneficial effect on heart failure events is consistent with results from other trials including the Systolic Hypertension in the Elderly Program,⁷ Systolic Hypertension in Europe,⁸ and Hypertension in the Very Elderly Trial,⁹ all of which showed greatest risk reduction for heart failure events with systolic pressure-lowering (although to higher systolic levels than SPRINT).^7–9 It is unclear why there was no beneficial effect on stroke events. The reduction in all-cause mortality in the intensive treatment group in SPRINT was greater than the reduction in cardiovascular deaths, which is also unexplained.

Although the study was terminated early due to efficacy (which introduces the possible bias that the estimated effect size will be too high), the number of primary end points  reached was large (562 in the two groups combined), providing reassurance that the findings are valid. There was no blinding in the study (both participants and study investigators were aware of treatment assignment and study medications), but there was a structured assessment of outcomes and adverse events, with adjudication done by blinded reviewers.

SPRINT used an automated device for blood pressure measurement, which is known to reduce the “white coat” effect and correlates tightly with average daytime blood pressure done by ambulatory blood pressure monitoring.¹⁸ However, in clinical practice automated devices may not be available and a strict protocol for correct measurement may not be followed, with the possible result that blood pressure may be overestimated and overtreated.

What about diastolic pressure?

The trial, by design, focused on lowering systolic pressure (given the greater prevalence of isolated systolic hypertension with age), and the implications of lowering diastolic pressure are unclear. The issue of a J-shaped relationship between diastolic pressure and cardiovascular risk is debated in the literature: patients with a diastolic pressure of 60 to 65 mm Hg, especially those with existing coronary artery disease, may not tolerate aggressive blood pressure-lowering.^19,20 Further analysis of this association (if any) from SPRINT will be helpful.

What about patients with diabetes?

Patients were excluded from SPRINT if they were under age 50, were at low cardiovascular risk, or had diabetes, raising the question of whether the results apply to these groups as well.

The question is particularly relevant in diabetes, as the ACCORD BP study, which used the same blood pressure targets as SPRINT, did not show a significant difference in the primary cardiovascular outcome between the intensive and standard treatments in patients with diabetes (Table 3).¹³ In ACCORD BP, the rate of the primary outcome was 12% lower in the intensive treatment group than in the standard treatment group, but the 95% confidence interval was –27% to +6%, so the finding was not statistically significant. However, the wide confidence interval does not exclude the possibility of a benefit that was comparable to that observed in SPRINT.

It has been speculated that ACCORD BP was underpowered to detect significant differences in the primary outcome.²¹ An analysis combining data from both trials indicated that effects on individual outcomes were generally consistent in both trials (with no significant heterogeneity noted).²² Also, the primary composite outcome in ACCORD did not include heart failure, which is particularly sensitive to blood pressure reduction.

Additionally, ACCORD BP had a 2 × 2 factorial design involving a simultaneous comparison of intensive vs standard glycemic control, which may have influenced the effects due to blood pressure. Indeed, a post hoc analysis showed that there was a significant 26% lower risk of the primary outcome in ACCORD BP patients who received intensive systolic pressure  control plus standard glycemic control than in those receiving standard systolic control plus standard glycemic control.²³

Are more adverse events an acceptable trade-off?

Adverse events, including acute kidney injury, were more frequent in the intensive therapy group in SPRINT.

Acute kidney injury was coded as an adverse event on the basis of this diagnosis being included in the hospital discharge summary (as a primary or main secondary diagnosis) and if considered by the safety officer to be one of the top three reasons for admission or continued hospitalization. Further analysis of renal events should be forthcoming.

People in the intensive treatment group, on average, needed one more medication than those in the standard treatment group. Some of the adverse events may be related to the antihypertensive medications taken (eg, electrolyte abnormalities such as hyponatremia and hypokalemia due to diuretic use), and others may be related to blood pressure-lowering (eg, acute kidney injury due to renal hypoperfusion).

At this point, the long-term effects of these adverse events, especially on kidney function, are not known. Patients enrolled in clinical trials tend to be healthier than patients seen in clinical practice; thus, the rate of adverse events reported in the trial may be lower than one would see in the real world.

Does lower systolic pressure protect or harm the kidneys?

SPRINT included patients with stage 3 and 4 chronic kidney disease (ie, with eGFR 20–50 mL/min/1.73 m²), but it was designed to assess cardiovascular outcomes, not the progression of chronic kidney disease. The trial excluded patients with diabetic nephropathy or high degrees of proteinuria.

Only about half of hypertensive adults have their blood pressure under control, ie, < 140/90

Earlier randomized trials that focused on chronic kidney disease progression, including the MDRD²⁴ and the African American Study of Kidney Disease and Hypertension,²⁵ did not show benefit with more aggressive blood pressure-lowering (except in patients with higher degrees of proteinuria), and these trials were not powered to assess effects on cardiovascular outcomes.^24,25

The Irbesartan Diabetic Nephropathy Trial,^26,27 which was done in patients with overt diabetic nephropathy, showed that a progressively lower achieved systolic pressure down to 120 mm Hg predicted lower rates of heart failure, cardiovascular mortality, and renal events (although the trial target was ≤ 130/85 mm Hg and few participants achieved systolic pressure lower than 120 mm Hg).

IMPLICATIONS FOR MANAGEMENT

The recent estimates of hypertension prevalence and control from NHANES show that only about 53% of hypertensive adults have their blood pressure under control (defined as systolic pressure < 140 mm Hg and diastolic pressure < 90 mm Hg).² Analysis of the NHANES 2007–2012 data showed that 16.7% or 8.2 million US adults with treated hypertension meet the eligibility criteria for SPRINT.²⁸

Although the SPRINT results support the notion that “lower is better,” the risks and benefits of intensive control will need to be balanced in individual patients. Table 4 shows the number needed to treat and number needed to harm in the trial.

More aggressive management of hypertension is challenging. The median systolic pressure achieved in the intensive group in SPRINT was just over 120 mm Hg, which implies that at least half of the participants in the intensive group did not achieve the goal of less than 120 mm Hg. While it may be reasonable to aim for systolic pressure of less than 120 or 125 mm Hg in patients who fit the SPRINT criteria and can tolerate intensive blood pressure lowering, it would be prudent to aim for a more conservative goal in elderly patients who are frail and at risk for falls, considering the higher incidence of specified adverse events in the intensive group.

Results of cognitive outcomes, as well as data related to quality of life, are still awaited. Long-term renal outcomes are also unclear.

As noted above, the question of generalizability of SPRINT results to patients with diabetes is open to debate. In our opinion, with currently available evidence, it is difficult to conclusively answer the question of whether a lower systolic target provides cardiovascular benefit in diabetes. It is also unclear whether similar beneficial results would be seen with intensive treatment in a population at low cardiovascular risk. The American Heart Association and the American College of Cardiology are in the process of formulating new hypertension guidelines, and evidence from  SPRINT will inform any new recommendations.

As more medications will likely be needed for intensive systolic blood pressure control, side effects and tolerability of medications with polypharmacy and potential nonadherence with increasing complexity of medication regimens should be kept in mind. Lifestyle modifications will need to be emphasized and reinforced, with greater use of combination antihypertensive therapy.

The data from SPRINT indicate that lower systolic pressure is better, as long as untoward clinical events can be monitored and avoided or easily managed. Careful monitoring will likely entail more frequent clinic visits and more frequent assessment of renal function and electrolyte levels (participants in the intensive group in the trial were seen every month until goal was achieved). A team approach that includes pharmacists and nurse practitioners, along with optimal use of best practice algorithms and remote monitoring technology, will need to be implemented for efficient and effective care.

The 2013 joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA)¹ on the treatment of blood cholesterol to reduce cardiovascular risk recommend high-intensity statin therapy for secondary prevention of cardiovascular events. The question of primary prevention is not so straightforward, and the recommended strategy has come under fire. In addition, the guidelines focus on statins and not on LDL-C levels, and the role of nonstatin lipid-lowering drugs and the value of reducing LDL-C levels to well below levels currently regarded as “normal” remain unclear.

This article comments on the 2013 ACC/AHA guidelines, reviews the data on optimal LDL-C levels, and discusses new nonstatin agents.

ACC/AHA GUIDELINES: A MIXED MESSAGE

The 2013 ACC/AHA cholesterol guidelines¹ can be characterized by the title from the famous Western film “The Good, the Bad, and the Ugly.”

The good: A clear message to treat

The guidelines deliver an unambiguous message to treat patients at high risk with high-intensity statin therapy. This mandate is very helpful as it should reduce the undertreatment of patients.

The seemingly bad

Two common misconceptions regarding the guidelines:

Reproduced from Raymond C, Cho L, Rocco M, Hazen Sl. New cholesterol guidelines: worth the wait? Cleve Clin J Med 2014; 81:11–19.

They abandon LDL-C targets. Actually, the guidelines do not argue for or against targets; they simply remain silent, citing that randomized trials have not been conducted with LDL-C targets as specific goals. Technically, this statement is true. However, it seems contrived to argue, for example, that the benefit of atorvastatin 80 mg over 10 mg in the Treating to New Targets trial could not be reliably ascribed to the lower LDL-C achieved with the higher dose, but rather to some undefined benefit of high-intensity statin therapy, especially as the guidelines define the intensity of statins by the degree of LDL-C lowering. In fact, by correlating the incidence of coronary heart disease events with the levels of LDL-C achieved in those trials, conclusions can reasonably be drawn from such data (Figure 1).²

The guidelines do not recommend nonstatin drugs. Actually, the guidelines note that clinicians are free to consider other therapies, especially those proven to reduce the risk of cardiovascular events, a central principle of medicine. Since the guidelines were published, data have emerged indicating that the role of nonstatin drugs also needs consideration.

The ugly: Risk calculator untested

The guidelines promote the use of a risk calculator developed by the ACC/AHA to estimate the 10-year risk of an atherosclerotic event for people whose LDL-C levels are between 70 and 189 mg/dL to help decide whether to initiate statin therapy for primary prevention of atherosclerotic cardiovascular disease. Such an approach is reasonable, although the risk score was promulgated without evidence to support its utility.

Media coverage of the risk calculator was fierce. Some physicians found imperfections in the risk score (as is true for all risk scores), resulting in public mistrust of the guidelines and of the medical community as a whole. This needless controversy may have compromised the main message—that LDL-C should be lowered in many people—a message backed by strong evidence.

Alternative strategies proposed

Ridker et al³ have proposed a hybrid strategy to guide statin use for apparently healthy people that combines the ACC/AHA guideline approach with entry criteria for randomized clinical trials that showed statin efficacy for primary prevention.

Genetic analysis may offer another approach. Mega et al⁴ stratified more than 48,000 people by a genetic risk score based on 27 genetic variants and found a significant association with risk of coronary events. Targeting therapy to people found to be at higher risk on this basis offers greater risk reduction than expected for the general population. Biomarkers and imaging tests are other potentially useful risk determinants.

LDL-C: LOWER IS BETTER

Although no clinical trial has yet targeted specific LDL-C levels, there is plenty of evidence that lower LDL-C levels offer greater benefit (Figure 1).²

In 1994, the Scandinavian Simvastatin Survival Study⁵ established the benefit of statins in patients with known vascular disease. The mean LDL-C level achieved in the active treatment group was 120 mg/dL. More trials followed supporting the benefits of statins and of reducing LDL-C from average levels in the 120s down to 100 mg/dL.

In 2004, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 trial⁶ observed an even greater risk reduction in patients with known risk by treating with statins; the mean LDL-C level achieved in the group randomized to an intensive regimen of atorvastatin 80 mg per day was 62 mg/dL. The same year, the Adult Treatment Panel III of the National Cholesterol Education Program⁷ issued updated guidelines including an optional goal of LDL-C less than 70 mg/dL for patients at very high risk.

In 2008, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)⁸ found a significantly lower incidence of major cardiovascular events at 2 years in apparently healthy men and women with baseline LDL-C levels of less than 130 mg/dL after treatment with rosuvastatin 20 mg daily, with an achieved median LDL-C of 55 mg/dL.

How low should LDL-C go?

Evidence from clinical trials indicates a 20% to 25% reduction in the risk of cardiovascular events for every 39-mg/dL decrease in LDL-C. Extrapolating the data, cardiovascular disease risk would be reduced to zero if LDL-C were brought down below 40 mg/dL.

Brown and Goldstein,⁹ who won the 1985 Nobel Prize in medicine for their work in cholesterol metabolism, estimated that a plasma level of LDL-C of only 25 mg/dL would be sufficient to nourish cells with cholesterol. Cells can synthesize all the cholesterol they need, underscoring that LDL-C is simply the final end-product that the liver removes from circulation.

Other evidence that lower LDL-C does not have adverse effects comes from non-Western populations as well as from other mammals. Total cholesterol levels range in the low 100s mg/dL in Native American and African tribal populations, with LDL-C estimated to be about 50 to 75 mg/dL. Elephants, baboons, and foxes have even lower levels.¹⁰

Clinical trial data also support that LDL-C levels below the current “normal” are better. The Cholesterol Treatment Trialists’ Collaboration¹¹ analyzed data from more than 160,000 patients in 26 trials that evaluated either more- vs less-intensive statin regimens or statin treatment vs control. No baseline level below which lowering LDL-C further was not beneficial was found. Patients who started out with an LDL-C level of less than 77 mg/dL had the same risk reduction of major vascular events when the level was dropped to 50 mg/dL as those who started at higher levels and reduced their LDL-C by the same amount. In the JUPITER trial, even those with a baseline LDL-C of less than 60 mg/dL benefited from statin therapy.¹²

BEYOND STATINS

Ezetimibe further lowers risk

Ezetimibe is a nonstatin drug that reduces LDL-C by about 15% to 20%. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial¹³ registered more than 18,000 patients with a baseline LDL-C level of less than 125 mg/dL (or 100 mg/dL if already on lipid-lowering therapy) who had been stabilized shortly after an acute cardiovascular event. They were randomized to receive either simvastatin 40 mg or combined simvastatin 40 mg and ezetimibe 10 mg. The study intended to determine two things: whether ezetimibe could further lower LDL-C when combined with a statin, and whether risk could be reduced further by driving the LDL-C below 70 mg/dL and down to the mid-50s.

After 1 year, the average LDL-C level was 70 mg/dL in the simvastatin group and 53 mg/dL in the combined simvastatin and ezetimibe group. At 7 years, for the primary end point (cardiovascular death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, or stroke), there was a 6% reduction of events in the combined drug treatment group, with the number of people needed to treat being 50 to prevent one event. For the narrower end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, there was a 10% risk reduction in the combined drug treatment arm.¹⁴

The amount of risk reduction is exactly what was predicted by the Cholesterol Treatment Trialists’ Collaboration’s plot of reduction in events vs reduction in LDL-C based on the analysis of 26 trials, adding further evidence that it is the LDL-C reduction itself, rather than the means by which LDL-C is reduced, that is critical for benefit.

PCSK9 inhibitors: A new approach

Mutations in the gene for proprotein convertase subtilisin kexin type 9 (PCSK9) have become a new focus of interest for reducing LDL-C and cardiovascular risk.¹⁵ PCSK9 binds to the LDL-C receptor on the surface of hepatocytes and escorts it to its destruction in the lysosomes, rather than allowing it to return to the cell surface to take more LDL-C out of circulation.

People with a gain-of-function mutation (conferring too much PCSK9, resulting in fewer LDL-C receptors and more LDL-C in circulation) are a more recently recognized subset of those with autosomal-dominant familial hypercholesterolemia. They have total cholesterol levels in the 90th percentile, tendon xanthomas, and a high risk of myocardial infarction and stroke at a young age.

Conversely, those with a nonsense mutation in PCSK9—leading to loss of function—have a 28% reduction in mean LDL-C and 88% reduction in risk of coronary heart disease compared with those without the mutation.¹⁶ Two women (ages 32 and 21, fertile) have been found who have inactivating mutations in both PCSK9 alleles, and both are in apparent good health, with LDL-C levels of 14 mg/dL and 15 mg/dL, respectively.^17,18

Dramatic reduction in LDL-C

Monoclonal antibodies have been developed that bind PCSK9 and block its action with the goal of developing new LDL-C–lowering treatments. Phase 2 clinical trials of varying doses of evolocumab (Repatha), a drug in this class, combined with standard therapy (a statin with or without ezetimibe), found a 66% reduction of LDL-C at high doses at 12 weeks compared with standard therapy alone, with concomitant reductions in other atherogenic lipoproteins.¹⁹ Patients who could not tolerate statins because of myalgia responded well to evolocumab.²⁰

Patients with heterozygous familial hypercholesterolemia also had a substantial reduction in LDL-C (55% at the highest dosage), even though they have fewer LDL-C receptors for the drug to act upon.²¹ People with homozygous familial hypercholesterolemia and no LDL-C receptors had a lesser relative reduction in LDL-C that depended on the type of mutations they had. Nonetheless, given how high LDL-C levels are in this population, the absolute decreases in LDL-C level were quite impressive.

Cardiovascular risk reduced

Data at nearly 1 year showed continued reduction of LDL-C by about 60% (absolute reduction: 73 mg/dL), as well as a lower incidence of cardiovascular events starting at just 3 months, much sooner than observed in some statin trials.²² Benefits were found regardless of subgroup (sex, age, statin use, baseline LDL-C level, or known vascular disease). No difference was found in the safety profile between the evolocumab and control arms. Only 2.4% of participants discontinued evolocumab because of adverse events, and the incidence of adverse effects did not correlate with LDL-C level achieved.

Neurocognitive effects occurred in 0.9% of the evolocumab arm vs 0.3% in the control arm. This difference has not been explained: although there is cholesterol in the central nervous system, it is generated locally, and lipoproteins—and evolocumab—are not thought to cross the blood-brain barrier.

Long-term trials of evolocumab are currently under way for patients with cardiovascular disease, as are trials of two other PCSK9 inhibitors, alirocumab and bococizumab, in addition to standard statin therapy.

On July 24, 2015, the US Food and Drug Administration (FDA) approved the first PCSK9 inhibitor, alirocumab (Praluent) for patients with heterozygous familial hypercholesterolemia or those with clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. The starting dosage is 75 mg subcutaneously every 2 weeks, which can be increased up to 150 mg every 2 weeks.

Evolocumab was approved by the FDA on August 27, 2015, for the same indications. The dosage is 140 mg subcutaneously every 2 weeks or 420 mg every month.

The 2013 joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA)¹ on the treatment of blood cholesterol to reduce cardiovascular risk recommend high-intensity statin therapy for secondary prevention of cardiovascular events. The question of primary prevention is not so straightforward, and the recommended strategy has come under fire. In addition, the guidelines focus on statins and not on LDL-C levels, and the role of nonstatin lipid-lowering drugs and the value of reducing LDL-C levels to well below levels currently regarded as “normal” remain unclear.

This article comments on the 2013 ACC/AHA guidelines, reviews the data on optimal LDL-C levels, and discusses new nonstatin agents.

ACC/AHA GUIDELINES: A MIXED MESSAGE

The 2013 ACC/AHA cholesterol guidelines¹ can be characterized by the title from the famous Western film “The Good, the Bad, and the Ugly.”

The good: A clear message to treat

The guidelines deliver an unambiguous message to treat patients at high risk with high-intensity statin therapy. This mandate is very helpful as it should reduce the undertreatment of patients.

The seemingly bad

Two common misconceptions regarding the guidelines:

Reproduced from Raymond C, Cho L, Rocco M, Hazen Sl. New cholesterol guidelines: worth the wait? Cleve Clin J Med 2014; 81:11–19.

They abandon LDL-C targets. Actually, the guidelines do not argue for or against targets; they simply remain silent, citing that randomized trials have not been conducted with LDL-C targets as specific goals. Technically, this statement is true. However, it seems contrived to argue, for example, that the benefit of atorvastatin 80 mg over 10 mg in the Treating to New Targets trial could not be reliably ascribed to the lower LDL-C achieved with the higher dose, but rather to some undefined benefit of high-intensity statin therapy, especially as the guidelines define the intensity of statins by the degree of LDL-C lowering. In fact, by correlating the incidence of coronary heart disease events with the levels of LDL-C achieved in those trials, conclusions can reasonably be drawn from such data (Figure 1).²

The guidelines do not recommend nonstatin drugs. Actually, the guidelines note that clinicians are free to consider other therapies, especially those proven to reduce the risk of cardiovascular events, a central principle of medicine. Since the guidelines were published, data have emerged indicating that the role of nonstatin drugs also needs consideration.

The ugly: Risk calculator untested

The guidelines promote the use of a risk calculator developed by the ACC/AHA to estimate the 10-year risk of an atherosclerotic event for people whose LDL-C levels are between 70 and 189 mg/dL to help decide whether to initiate statin therapy for primary prevention of atherosclerotic cardiovascular disease. Such an approach is reasonable, although the risk score was promulgated without evidence to support its utility.

Media coverage of the risk calculator was fierce. Some physicians found imperfections in the risk score (as is true for all risk scores), resulting in public mistrust of the guidelines and of the medical community as a whole. This needless controversy may have compromised the main message—that LDL-C should be lowered in many people—a message backed by strong evidence.

Alternative strategies proposed

Ridker et al³ have proposed a hybrid strategy to guide statin use for apparently healthy people that combines the ACC/AHA guideline approach with entry criteria for randomized clinical trials that showed statin efficacy for primary prevention.

Genetic analysis may offer another approach. Mega et al⁴ stratified more than 48,000 people by a genetic risk score based on 27 genetic variants and found a significant association with risk of coronary events. Targeting therapy to people found to be at higher risk on this basis offers greater risk reduction than expected for the general population. Biomarkers and imaging tests are other potentially useful risk determinants.

LDL-C: LOWER IS BETTER

Although no clinical trial has yet targeted specific LDL-C levels, there is plenty of evidence that lower LDL-C levels offer greater benefit (Figure 1).²

In 1994, the Scandinavian Simvastatin Survival Study⁵ established the benefit of statins in patients with known vascular disease. The mean LDL-C level achieved in the active treatment group was 120 mg/dL. More trials followed supporting the benefits of statins and of reducing LDL-C from average levels in the 120s down to 100 mg/dL.

In 2004, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 trial⁶ observed an even greater risk reduction in patients with known risk by treating with statins; the mean LDL-C level achieved in the group randomized to an intensive regimen of atorvastatin 80 mg per day was 62 mg/dL. The same year, the Adult Treatment Panel III of the National Cholesterol Education Program⁷ issued updated guidelines including an optional goal of LDL-C less than 70 mg/dL for patients at very high risk.

In 2008, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)⁸ found a significantly lower incidence of major cardiovascular events at 2 years in apparently healthy men and women with baseline LDL-C levels of less than 130 mg/dL after treatment with rosuvastatin 20 mg daily, with an achieved median LDL-C of 55 mg/dL.

How low should LDL-C go?

Evidence from clinical trials indicates a 20% to 25% reduction in the risk of cardiovascular events for every 39-mg/dL decrease in LDL-C. Extrapolating the data, cardiovascular disease risk would be reduced to zero if LDL-C were brought down below 40 mg/dL.

Brown and Goldstein,⁹ who won the 1985 Nobel Prize in medicine for their work in cholesterol metabolism, estimated that a plasma level of LDL-C of only 25 mg/dL would be sufficient to nourish cells with cholesterol. Cells can synthesize all the cholesterol they need, underscoring that LDL-C is simply the final end-product that the liver removes from circulation.

Other evidence that lower LDL-C does not have adverse effects comes from non-Western populations as well as from other mammals. Total cholesterol levels range in the low 100s mg/dL in Native American and African tribal populations, with LDL-C estimated to be about 50 to 75 mg/dL. Elephants, baboons, and foxes have even lower levels.¹⁰

Clinical trial data also support that LDL-C levels below the current “normal” are better. The Cholesterol Treatment Trialists’ Collaboration¹¹ analyzed data from more than 160,000 patients in 26 trials that evaluated either more- vs less-intensive statin regimens or statin treatment vs control. No baseline level below which lowering LDL-C further was not beneficial was found. Patients who started out with an LDL-C level of less than 77 mg/dL had the same risk reduction of major vascular events when the level was dropped to 50 mg/dL as those who started at higher levels and reduced their LDL-C by the same amount. In the JUPITER trial, even those with a baseline LDL-C of less than 60 mg/dL benefited from statin therapy.¹²

BEYOND STATINS

Ezetimibe further lowers risk

Ezetimibe is a nonstatin drug that reduces LDL-C by about 15% to 20%. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial¹³ registered more than 18,000 patients with a baseline LDL-C level of less than 125 mg/dL (or 100 mg/dL if already on lipid-lowering therapy) who had been stabilized shortly after an acute cardiovascular event. They were randomized to receive either simvastatin 40 mg or combined simvastatin 40 mg and ezetimibe 10 mg. The study intended to determine two things: whether ezetimibe could further lower LDL-C when combined with a statin, and whether risk could be reduced further by driving the LDL-C below 70 mg/dL and down to the mid-50s.

After 1 year, the average LDL-C level was 70 mg/dL in the simvastatin group and 53 mg/dL in the combined simvastatin and ezetimibe group. At 7 years, for the primary end point (cardiovascular death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, or stroke), there was a 6% reduction of events in the combined drug treatment group, with the number of people needed to treat being 50 to prevent one event. For the narrower end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, there was a 10% risk reduction in the combined drug treatment arm.¹⁴

The amount of risk reduction is exactly what was predicted by the Cholesterol Treatment Trialists’ Collaboration’s plot of reduction in events vs reduction in LDL-C based on the analysis of 26 trials, adding further evidence that it is the LDL-C reduction itself, rather than the means by which LDL-C is reduced, that is critical for benefit.

PCSK9 inhibitors: A new approach

Mutations in the gene for proprotein convertase subtilisin kexin type 9 (PCSK9) have become a new focus of interest for reducing LDL-C and cardiovascular risk.¹⁵ PCSK9 binds to the LDL-C receptor on the surface of hepatocytes and escorts it to its destruction in the lysosomes, rather than allowing it to return to the cell surface to take more LDL-C out of circulation.

People with a gain-of-function mutation (conferring too much PCSK9, resulting in fewer LDL-C receptors and more LDL-C in circulation) are a more recently recognized subset of those with autosomal-dominant familial hypercholesterolemia. They have total cholesterol levels in the 90th percentile, tendon xanthomas, and a high risk of myocardial infarction and stroke at a young age.

Conversely, those with a nonsense mutation in PCSK9—leading to loss of function—have a 28% reduction in mean LDL-C and 88% reduction in risk of coronary heart disease compared with those without the mutation.¹⁶ Two women (ages 32 and 21, fertile) have been found who have inactivating mutations in both PCSK9 alleles, and both are in apparent good health, with LDL-C levels of 14 mg/dL and 15 mg/dL, respectively.^17,18

Dramatic reduction in LDL-C

Monoclonal antibodies have been developed that bind PCSK9 and block its action with the goal of developing new LDL-C–lowering treatments. Phase 2 clinical trials of varying doses of evolocumab (Repatha), a drug in this class, combined with standard therapy (a statin with or without ezetimibe), found a 66% reduction of LDL-C at high doses at 12 weeks compared with standard therapy alone, with concomitant reductions in other atherogenic lipoproteins.¹⁹ Patients who could not tolerate statins because of myalgia responded well to evolocumab.²⁰

Patients with heterozygous familial hypercholesterolemia also had a substantial reduction in LDL-C (55% at the highest dosage), even though they have fewer LDL-C receptors for the drug to act upon.²¹ People with homozygous familial hypercholesterolemia and no LDL-C receptors had a lesser relative reduction in LDL-C that depended on the type of mutations they had. Nonetheless, given how high LDL-C levels are in this population, the absolute decreases in LDL-C level were quite impressive.

Cardiovascular risk reduced

Data at nearly 1 year showed continued reduction of LDL-C by about 60% (absolute reduction: 73 mg/dL), as well as a lower incidence of cardiovascular events starting at just 3 months, much sooner than observed in some statin trials.²² Benefits were found regardless of subgroup (sex, age, statin use, baseline LDL-C level, or known vascular disease). No difference was found in the safety profile between the evolocumab and control arms. Only 2.4% of participants discontinued evolocumab because of adverse events, and the incidence of adverse effects did not correlate with LDL-C level achieved.

Neurocognitive effects occurred in 0.9% of the evolocumab arm vs 0.3% in the control arm. This difference has not been explained: although there is cholesterol in the central nervous system, it is generated locally, and lipoproteins—and evolocumab—are not thought to cross the blood-brain barrier.

Long-term trials of evolocumab are currently under way for patients with cardiovascular disease, as are trials of two other PCSK9 inhibitors, alirocumab and bococizumab, in addition to standard statin therapy.

On July 24, 2015, the US Food and Drug Administration (FDA) approved the first PCSK9 inhibitor, alirocumab (Praluent) for patients with heterozygous familial hypercholesterolemia or those with clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. The starting dosage is 75 mg subcutaneously every 2 weeks, which can be increased up to 150 mg every 2 weeks.

Evolocumab was approved by the FDA on August 27, 2015, for the same indications. The dosage is 140 mg subcutaneously every 2 weeks or 420 mg every month.

The 2013 joint guidelines of the American College of Cardiology and American Heart Association (ACC/AHA)¹ on the treatment of blood cholesterol to reduce cardiovascular risk recommend high-intensity statin therapy for secondary prevention of cardiovascular events. The question of primary prevention is not so straightforward, and the recommended strategy has come under fire. In addition, the guidelines focus on statins and not on LDL-C levels, and the role of nonstatin lipid-lowering drugs and the value of reducing LDL-C levels to well below levels currently regarded as “normal” remain unclear.

This article comments on the 2013 ACC/AHA guidelines, reviews the data on optimal LDL-C levels, and discusses new nonstatin agents.

ACC/AHA GUIDELINES: A MIXED MESSAGE

The 2013 ACC/AHA cholesterol guidelines¹ can be characterized by the title from the famous Western film “The Good, the Bad, and the Ugly.”

The good: A clear message to treat

The guidelines deliver an unambiguous message to treat patients at high risk with high-intensity statin therapy. This mandate is very helpful as it should reduce the undertreatment of patients.

The seemingly bad

Two common misconceptions regarding the guidelines:

Reproduced from Raymond C, Cho L, Rocco M, Hazen Sl. New cholesterol guidelines: worth the wait? Cleve Clin J Med 2014; 81:11–19.

They abandon LDL-C targets. Actually, the guidelines do not argue for or against targets; they simply remain silent, citing that randomized trials have not been conducted with LDL-C targets as specific goals. Technically, this statement is true. However, it seems contrived to argue, for example, that the benefit of atorvastatin 80 mg over 10 mg in the Treating to New Targets trial could not be reliably ascribed to the lower LDL-C achieved with the higher dose, but rather to some undefined benefit of high-intensity statin therapy, especially as the guidelines define the intensity of statins by the degree of LDL-C lowering. In fact, by correlating the incidence of coronary heart disease events with the levels of LDL-C achieved in those trials, conclusions can reasonably be drawn from such data (Figure 1).²

The guidelines do not recommend nonstatin drugs. Actually, the guidelines note that clinicians are free to consider other therapies, especially those proven to reduce the risk of cardiovascular events, a central principle of medicine. Since the guidelines were published, data have emerged indicating that the role of nonstatin drugs also needs consideration.

The ugly: Risk calculator untested

The guidelines promote the use of a risk calculator developed by the ACC/AHA to estimate the 10-year risk of an atherosclerotic event for people whose LDL-C levels are between 70 and 189 mg/dL to help decide whether to initiate statin therapy for primary prevention of atherosclerotic cardiovascular disease. Such an approach is reasonable, although the risk score was promulgated without evidence to support its utility.

Media coverage of the risk calculator was fierce. Some physicians found imperfections in the risk score (as is true for all risk scores), resulting in public mistrust of the guidelines and of the medical community as a whole. This needless controversy may have compromised the main message—that LDL-C should be lowered in many people—a message backed by strong evidence.

Alternative strategies proposed

Ridker et al³ have proposed a hybrid strategy to guide statin use for apparently healthy people that combines the ACC/AHA guideline approach with entry criteria for randomized clinical trials that showed statin efficacy for primary prevention.

Genetic analysis may offer another approach. Mega et al⁴ stratified more than 48,000 people by a genetic risk score based on 27 genetic variants and found a significant association with risk of coronary events. Targeting therapy to people found to be at higher risk on this basis offers greater risk reduction than expected for the general population. Biomarkers and imaging tests are other potentially useful risk determinants.

LDL-C: LOWER IS BETTER

Although no clinical trial has yet targeted specific LDL-C levels, there is plenty of evidence that lower LDL-C levels offer greater benefit (Figure 1).²

In 1994, the Scandinavian Simvastatin Survival Study⁵ established the benefit of statins in patients with known vascular disease. The mean LDL-C level achieved in the active treatment group was 120 mg/dL. More trials followed supporting the benefits of statins and of reducing LDL-C from average levels in the 120s down to 100 mg/dL.

In 2004, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 trial⁶ observed an even greater risk reduction in patients with known risk by treating with statins; the mean LDL-C level achieved in the group randomized to an intensive regimen of atorvastatin 80 mg per day was 62 mg/dL. The same year, the Adult Treatment Panel III of the National Cholesterol Education Program⁷ issued updated guidelines including an optional goal of LDL-C less than 70 mg/dL for patients at very high risk.

In 2008, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)⁸ found a significantly lower incidence of major cardiovascular events at 2 years in apparently healthy men and women with baseline LDL-C levels of less than 130 mg/dL after treatment with rosuvastatin 20 mg daily, with an achieved median LDL-C of 55 mg/dL.

How low should LDL-C go?

Evidence from clinical trials indicates a 20% to 25% reduction in the risk of cardiovascular events for every 39-mg/dL decrease in LDL-C. Extrapolating the data, cardiovascular disease risk would be reduced to zero if LDL-C were brought down below 40 mg/dL.

Brown and Goldstein,⁹ who won the 1985 Nobel Prize in medicine for their work in cholesterol metabolism, estimated that a plasma level of LDL-C of only 25 mg/dL would be sufficient to nourish cells with cholesterol. Cells can synthesize all the cholesterol they need, underscoring that LDL-C is simply the final end-product that the liver removes from circulation.

Other evidence that lower LDL-C does not have adverse effects comes from non-Western populations as well as from other mammals. Total cholesterol levels range in the low 100s mg/dL in Native American and African tribal populations, with LDL-C estimated to be about 50 to 75 mg/dL. Elephants, baboons, and foxes have even lower levels.¹⁰

Clinical trial data also support that LDL-C levels below the current “normal” are better. The Cholesterol Treatment Trialists’ Collaboration¹¹ analyzed data from more than 160,000 patients in 26 trials that evaluated either more- vs less-intensive statin regimens or statin treatment vs control. No baseline level below which lowering LDL-C further was not beneficial was found. Patients who started out with an LDL-C level of less than 77 mg/dL had the same risk reduction of major vascular events when the level was dropped to 50 mg/dL as those who started at higher levels and reduced their LDL-C by the same amount. In the JUPITER trial, even those with a baseline LDL-C of less than 60 mg/dL benefited from statin therapy.¹²

BEYOND STATINS

Ezetimibe further lowers risk

Ezetimibe is a nonstatin drug that reduces LDL-C by about 15% to 20%. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial¹³ registered more than 18,000 patients with a baseline LDL-C level of less than 125 mg/dL (or 100 mg/dL if already on lipid-lowering therapy) who had been stabilized shortly after an acute cardiovascular event. They were randomized to receive either simvastatin 40 mg or combined simvastatin 40 mg and ezetimibe 10 mg. The study intended to determine two things: whether ezetimibe could further lower LDL-C when combined with a statin, and whether risk could be reduced further by driving the LDL-C below 70 mg/dL and down to the mid-50s.

After 1 year, the average LDL-C level was 70 mg/dL in the simvastatin group and 53 mg/dL in the combined simvastatin and ezetimibe group. At 7 years, for the primary end point (cardiovascular death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, or stroke), there was a 6% reduction of events in the combined drug treatment group, with the number of people needed to treat being 50 to prevent one event. For the narrower end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, there was a 10% risk reduction in the combined drug treatment arm.¹⁴

The amount of risk reduction is exactly what was predicted by the Cholesterol Treatment Trialists’ Collaboration’s plot of reduction in events vs reduction in LDL-C based on the analysis of 26 trials, adding further evidence that it is the LDL-C reduction itself, rather than the means by which LDL-C is reduced, that is critical for benefit.

PCSK9 inhibitors: A new approach

Mutations in the gene for proprotein convertase subtilisin kexin type 9 (PCSK9) have become a new focus of interest for reducing LDL-C and cardiovascular risk.¹⁵ PCSK9 binds to the LDL-C receptor on the surface of hepatocytes and escorts it to its destruction in the lysosomes, rather than allowing it to return to the cell surface to take more LDL-C out of circulation.

People with a gain-of-function mutation (conferring too much PCSK9, resulting in fewer LDL-C receptors and more LDL-C in circulation) are a more recently recognized subset of those with autosomal-dominant familial hypercholesterolemia. They have total cholesterol levels in the 90th percentile, tendon xanthomas, and a high risk of myocardial infarction and stroke at a young age.

Conversely, those with a nonsense mutation in PCSK9—leading to loss of function—have a 28% reduction in mean LDL-C and 88% reduction in risk of coronary heart disease compared with those without the mutation.¹⁶ Two women (ages 32 and 21, fertile) have been found who have inactivating mutations in both PCSK9 alleles, and both are in apparent good health, with LDL-C levels of 14 mg/dL and 15 mg/dL, respectively.^17,18

Dramatic reduction in LDL-C

Monoclonal antibodies have been developed that bind PCSK9 and block its action with the goal of developing new LDL-C–lowering treatments. Phase 2 clinical trials of varying doses of evolocumab (Repatha), a drug in this class, combined with standard therapy (a statin with or without ezetimibe), found a 66% reduction of LDL-C at high doses at 12 weeks compared with standard therapy alone, with concomitant reductions in other atherogenic lipoproteins.¹⁹ Patients who could not tolerate statins because of myalgia responded well to evolocumab.²⁰

Patients with heterozygous familial hypercholesterolemia also had a substantial reduction in LDL-C (55% at the highest dosage), even though they have fewer LDL-C receptors for the drug to act upon.²¹ People with homozygous familial hypercholesterolemia and no LDL-C receptors had a lesser relative reduction in LDL-C that depended on the type of mutations they had. Nonetheless, given how high LDL-C levels are in this population, the absolute decreases in LDL-C level were quite impressive.

Cardiovascular risk reduced

Data at nearly 1 year showed continued reduction of LDL-C by about 60% (absolute reduction: 73 mg/dL), as well as a lower incidence of cardiovascular events starting at just 3 months, much sooner than observed in some statin trials.²² Benefits were found regardless of subgroup (sex, age, statin use, baseline LDL-C level, or known vascular disease). No difference was found in the safety profile between the evolocumab and control arms. Only 2.4% of participants discontinued evolocumab because of adverse events, and the incidence of adverse effects did not correlate with LDL-C level achieved.

Neurocognitive effects occurred in 0.9% of the evolocumab arm vs 0.3% in the control arm. This difference has not been explained: although there is cholesterol in the central nervous system, it is generated locally, and lipoproteins—and evolocumab—are not thought to cross the blood-brain barrier.

Long-term trials of evolocumab are currently under way for patients with cardiovascular disease, as are trials of two other PCSK9 inhibitors, alirocumab and bococizumab, in addition to standard statin therapy.

On July 24, 2015, the US Food and Drug Administration (FDA) approved the first PCSK9 inhibitor, alirocumab (Praluent) for patients with heterozygous familial hypercholesterolemia or those with clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. The starting dosage is 75 mg subcutaneously every 2 weeks, which can be increased up to 150 mg every 2 weeks.

Evolocumab was approved by the FDA on August 27, 2015, for the same indications. The dosage is 140 mg subcutaneously every 2 weeks or 420 mg every month.

“I am forever humbled.” So said a heart failure specialist on rounds when I was a resident in the intensive care unit several decades ago. He was talking about the perpetual mismatch between a physician’s level of knowledge and the unpredictability inherent in the management and outcome of critically ill patients. His words ring true for me nearly every day. We should never think we are so smart that we are truly in control of our patients’ outcomes or that we don’t make mistakes—but we also cannot become so paralyzed by the awareness of our limitations that we don’t make decisions.

I have spoken those same powerful words many times on teaching rounds. I also frequently push them to the back of my mind. As a consultant at a major medical center, I am supposed to know. It is a fine line we walk.

I know I am not alone in harboring these self-doubts. Ready access to online information does little to assuage the concern that we can never know enough. Have I ordered enough diagnostic tests to be sure? Have I ordered too many tests and thus will be penalized for providing cost-ineffective care? Should we follow generic guidelines, or deviate from the guidelines based on our clinical instincts, our own interpretation of the literature, and the patient’s unique circumstances and desires?

And then what happens when we make wrong decisions, or even the right decisions that result in a poor patient outcome, which of course is at some point inevitable? We are told to be open about errors, to be honest and transparent about our limitations, to throw down our elaborate emotional and intellectual defensive shields and expose our vulnerability.

But what do we experience emotionally when we are named in a malpractice suit? We may have done all that we thought we could do: we responsibly explored the diagnostic and therapeutic options, provided empathetic care, and listened to the voice of the patient. Yet an adverse outcome still occurred. The practice of medicine is indeed humbling. We feel crushed. We revisit the patient’s care in a vivid perpetual replay loop in our head. Maybe we didn’t evaluate all the options as we should have. If we had been a bit smarter, a bit more efficient, maybe the outcome would have been different.

Then during a deposition, the plaintiff’s counsel points out the temporal and documentary inconsistencies in the electronic medical record: “Doctor, you say you saw the patient at 2:00 pm, but there was no note finalized until 10:00 pm…and why was your documented physical exam exactly the same as the one from the day before and exactly the same as that of the resident who saw the patient that afternoon?” We now feel crushed, totally vulnerable, emotionally trampled, and often isolated and disconnected from our patients and peers. The intellectualized humility becomes transformed into a sense of inadequacy. Why should I keep doing this?

In this issue of the Journal, experienced malpractice attorney Kevin Giordano explores aspects of the malpractice process as they relate to the physicians he defends. He notes how the electronic medical record, a tool ostensibly in place to improve communication and the sharing of medical information between caregivers and patients, can be our worst enemy in a courtroom. He discusses the pressures of our complicated healthcare system that promote documentation errors that he must try to explain away to the jury in our defense, demonstrating that these documentation errors do not necessarily mirror the care and caring of the named physicians. This is critically important information for us to understand and to act on for our personal protection, but it is not his most important message to us.

Mr. Giordano is a sincere, empathetic, and proficient professional. He has spoken for and to many physicians. He has listened to us and observed our behaviors. And as he has defended many of us in a court of law, he has learned to diagnose in his clients the damage that can persist following involvement in a malpractice case and the emotional scars the malpractice experience leaves on physicians. He emphasizes that we must not let the event of a malpractice suit force us to withdraw and strip us of our connection and engagement to patients. If anything, he and Drs. Susan Rehm and Bradford Borden, in an accompanying editorial, urge us to keep in mind that our personal engagement with patients and the mindful practice of medicine is our raison d’être as physicians.

I am continuously humbled by the breadth of the pathology, clinical medicine, and social challenges that I encounter on a daily basis, armed with limited knowledge and experience. It is intellectually rewarding to make an arcane diagnosis or to see an individualized therapy work as I had hoped. But I agree with Mr. Giordano that it is the genuine engagement with patients that provides us with the real joy in the practice of medicine and pushes us to deliver care at a consistently proficient level. We must not forget that, even in the face of significant and emotionally challenging events such as being named in a malpractice suit. It is the nature of our engagement with our patients and our colleagues that make what we do more than a job.

As more physicians in the United States become employed by health systems, I hope that the administrative leaders within these systems truly recognize these issues. As they struggle to balance the provision of safe high-quality care to patients with their increasingly complex financial spreadsheets, I hope that the emotional health of their physician employees is not forgotten. And not just after a malpractice suit.

“I am forever humbled.” So said a heart failure specialist on rounds when I was a resident in the intensive care unit several decades ago. He was talking about the perpetual mismatch between a physician’s level of knowledge and the unpredictability inherent in the management and outcome of critically ill patients. His words ring true for me nearly every day. We should never think we are so smart that we are truly in control of our patients’ outcomes or that we don’t make mistakes—but we also cannot become so paralyzed by the awareness of our limitations that we don’t make decisions.

I have spoken those same powerful words many times on teaching rounds. I also frequently push them to the back of my mind. As a consultant at a major medical center, I am supposed to know. It is a fine line we walk.

I know I am not alone in harboring these self-doubts. Ready access to online information does little to assuage the concern that we can never know enough. Have I ordered enough diagnostic tests to be sure? Have I ordered too many tests and thus will be penalized for providing cost-ineffective care? Should we follow generic guidelines, or deviate from the guidelines based on our clinical instincts, our own interpretation of the literature, and the patient’s unique circumstances and desires?

And then what happens when we make wrong decisions, or even the right decisions that result in a poor patient outcome, which of course is at some point inevitable? We are told to be open about errors, to be honest and transparent about our limitations, to throw down our elaborate emotional and intellectual defensive shields and expose our vulnerability.

But what do we experience emotionally when we are named in a malpractice suit? We may have done all that we thought we could do: we responsibly explored the diagnostic and therapeutic options, provided empathetic care, and listened to the voice of the patient. Yet an adverse outcome still occurred. The practice of medicine is indeed humbling. We feel crushed. We revisit the patient’s care in a vivid perpetual replay loop in our head. Maybe we didn’t evaluate all the options as we should have. If we had been a bit smarter, a bit more efficient, maybe the outcome would have been different.

Then during a deposition, the plaintiff’s counsel points out the temporal and documentary inconsistencies in the electronic medical record: “Doctor, you say you saw the patient at 2:00 pm, but there was no note finalized until 10:00 pm…and why was your documented physical exam exactly the same as the one from the day before and exactly the same as that of the resident who saw the patient that afternoon?” We now feel crushed, totally vulnerable, emotionally trampled, and often isolated and disconnected from our patients and peers. The intellectualized humility becomes transformed into a sense of inadequacy. Why should I keep doing this?

In this issue of the Journal, experienced malpractice attorney Kevin Giordano explores aspects of the malpractice process as they relate to the physicians he defends. He notes how the electronic medical record, a tool ostensibly in place to improve communication and the sharing of medical information between caregivers and patients, can be our worst enemy in a courtroom. He discusses the pressures of our complicated healthcare system that promote documentation errors that he must try to explain away to the jury in our defense, demonstrating that these documentation errors do not necessarily mirror the care and caring of the named physicians. This is critically important information for us to understand and to act on for our personal protection, but it is not his most important message to us.

Mr. Giordano is a sincere, empathetic, and proficient professional. He has spoken for and to many physicians. He has listened to us and observed our behaviors. And as he has defended many of us in a court of law, he has learned to diagnose in his clients the damage that can persist following involvement in a malpractice case and the emotional scars the malpractice experience leaves on physicians. He emphasizes that we must not let the event of a malpractice suit force us to withdraw and strip us of our connection and engagement to patients. If anything, he and Drs. Susan Rehm and Bradford Borden, in an accompanying editorial, urge us to keep in mind that our personal engagement with patients and the mindful practice of medicine is our raison d’être as physicians.

I am continuously humbled by the breadth of the pathology, clinical medicine, and social challenges that I encounter on a daily basis, armed with limited knowledge and experience. It is intellectually rewarding to make an arcane diagnosis or to see an individualized therapy work as I had hoped. But I agree with Mr. Giordano that it is the genuine engagement with patients that provides us with the real joy in the practice of medicine and pushes us to deliver care at a consistently proficient level. We must not forget that, even in the face of significant and emotionally challenging events such as being named in a malpractice suit. It is the nature of our engagement with our patients and our colleagues that make what we do more than a job.

As more physicians in the United States become employed by health systems, I hope that the administrative leaders within these systems truly recognize these issues. As they struggle to balance the provision of safe high-quality care to patients with their increasingly complex financial spreadsheets, I hope that the emotional health of their physician employees is not forgotten. And not just after a malpractice suit.

“I am forever humbled.” So said a heart failure specialist on rounds when I was a resident in the intensive care unit several decades ago. He was talking about the perpetual mismatch between a physician’s level of knowledge and the unpredictability inherent in the management and outcome of critically ill patients. His words ring true for me nearly every day. We should never think we are so smart that we are truly in control of our patients’ outcomes or that we don’t make mistakes—but we also cannot become so paralyzed by the awareness of our limitations that we don’t make decisions.

I have spoken those same powerful words many times on teaching rounds. I also frequently push them to the back of my mind. As a consultant at a major medical center, I am supposed to know. It is a fine line we walk.

I know I am not alone in harboring these self-doubts. Ready access to online information does little to assuage the concern that we can never know enough. Have I ordered enough diagnostic tests to be sure? Have I ordered too many tests and thus will be penalized for providing cost-ineffective care? Should we follow generic guidelines, or deviate from the guidelines based on our clinical instincts, our own interpretation of the literature, and the patient’s unique circumstances and desires?

And then what happens when we make wrong decisions, or even the right decisions that result in a poor patient outcome, which of course is at some point inevitable? We are told to be open about errors, to be honest and transparent about our limitations, to throw down our elaborate emotional and intellectual defensive shields and expose our vulnerability.

But what do we experience emotionally when we are named in a malpractice suit? We may have done all that we thought we could do: we responsibly explored the diagnostic and therapeutic options, provided empathetic care, and listened to the voice of the patient. Yet an adverse outcome still occurred. The practice of medicine is indeed humbling. We feel crushed. We revisit the patient’s care in a vivid perpetual replay loop in our head. Maybe we didn’t evaluate all the options as we should have. If we had been a bit smarter, a bit more efficient, maybe the outcome would have been different.

Then during a deposition, the plaintiff’s counsel points out the temporal and documentary inconsistencies in the electronic medical record: “Doctor, you say you saw the patient at 2:00 pm, but there was no note finalized until 10:00 pm…and why was your documented physical exam exactly the same as the one from the day before and exactly the same as that of the resident who saw the patient that afternoon?” We now feel crushed, totally vulnerable, emotionally trampled, and often isolated and disconnected from our patients and peers. The intellectualized humility becomes transformed into a sense of inadequacy. Why should I keep doing this?

In this issue of the Journal, experienced malpractice attorney Kevin Giordano explores aspects of the malpractice process as they relate to the physicians he defends. He notes how the electronic medical record, a tool ostensibly in place to improve communication and the sharing of medical information between caregivers and patients, can be our worst enemy in a courtroom. He discusses the pressures of our complicated healthcare system that promote documentation errors that he must try to explain away to the jury in our defense, demonstrating that these documentation errors do not necessarily mirror the care and caring of the named physicians. This is critically important information for us to understand and to act on for our personal protection, but it is not his most important message to us.

Mr. Giordano is a sincere, empathetic, and proficient professional. He has spoken for and to many physicians. He has listened to us and observed our behaviors. And as he has defended many of us in a court of law, he has learned to diagnose in his clients the damage that can persist following involvement in a malpractice case and the emotional scars the malpractice experience leaves on physicians. He emphasizes that we must not let the event of a malpractice suit force us to withdraw and strip us of our connection and engagement to patients. If anything, he and Drs. Susan Rehm and Bradford Borden, in an accompanying editorial, urge us to keep in mind that our personal engagement with patients and the mindful practice of medicine is our raison d’être as physicians.

I am continuously humbled by the breadth of the pathology, clinical medicine, and social challenges that I encounter on a daily basis, armed with limited knowledge and experience. It is intellectually rewarding to make an arcane diagnosis or to see an individualized therapy work as I had hoped. But I agree with Mr. Giordano that it is the genuine engagement with patients that provides us with the real joy in the practice of medicine and pushes us to deliver care at a consistently proficient level. We must not forget that, even in the face of significant and emotionally challenging events such as being named in a malpractice suit. It is the nature of our engagement with our patients and our colleagues that make what we do more than a job.

As more physicians in the United States become employed by health systems, I hope that the administrative leaders within these systems truly recognize these issues. As they struggle to balance the provision of safe high-quality care to patients with their increasingly complex financial spreadsheets, I hope that the emotional health of their physician employees is not forgotten. And not just after a malpractice suit.

Physicians who have been involved in malpractice actions are all too familiar with the range of emotions they experience during the process. Anxiety, fear, frustration, remorse, self-doubt, shame, betrayal, anger…no pleasant feelings here. Add malpractice stress to the high level of pressure experienced at home and at work, and crisis looms.

In his commentary in this issue, Kevin Giordano states, “it is not easy to stay connected in a healthcare system in which the system’s structure is driving physicians and other members of the healthcare team toward disconnection.”¹

See related commentary

Because of the nature of our work as physicians, we are isolated, and malpractice isolates us further. Because of embarrassment, we avoid talking with our colleagues and managers. Legal counsel reminds us to correspond with no one about the details of the case. Spouses and friends may offer support, but it is difficult— perhaps impossible—to be reassured.

Isolation fuels our self-doubt and erodes our confidence, leading us to focus on what may go wrong, rather than on healing. Every decision is fraught with anxiety, and efficiency evaporates. Paralysis may set in, leading to disengagement from patient care and increasing the chance of further problems. 

IT TAKES RESILIENCE TO THRIVE

It takes resilience to thrive in today’s pressure-cooker healthcare environment, let alone in the setting of malpractice stress. Resilient people are able to face reality and see a better future, put things into perspective, and bounce back from adversity.² Resilience, a trait that protects against stress and burnout, is relevant at the personal, managerial, and system levels. Though this definition is not specific to caregiver or malpractice stress, it is applicable. It is an essential component of wellness and requires perpetual attention to self-care for successful maintenance.

Resilient people can face reality, see a better future, put things into perspective, and bounce back from adversity

Studies of physicians who have avoided burnout reveal remarkably consistent qualities, including finding gratification related to work, maintaining useful habits and practices, and developing attitudes that keep them resilient.³ Rather than adding activities to their full schedules, these physicians stayed resilient through mindfulness of various aspects of their daily lives. Interactions with colleagues—discussing cases, treatments, and outcomes (including errors)—proved vital. Professional development, encompassing activities such as continuing education, coaching, mentoring, and counseling, was recognized as an important self-directed resilience measure. Maintenance of relationships with family and friends, cultivation of leisure-time activities, and appreciation of the need for personal reflection time were traits often found in resilient physicians.

FOSTERING RESILIENCE

As part of the Mayo Clinic’s biannual survey of its physicians, Shanafelt et al⁴ studied relationships between qualities of physician leaders and burnout and satisfaction among the physicians they supervised. Many of the desirable leadership traits were related to building relationships through respectful communication, along with provision of opportunities for personal and professional development. The acknowledgment that resilient, healthy physicians are satisfied, productive, and able to provide safer and higher-quality patient care should lead to the establishment of physician wellness as a “dashboard metric.” This makes priorities clear by rewarding managers who foster self-care and resilience among their staff.

Likewise, at the healthcare system level, Beckman⁵ recognized that organizations can provide opportunities to promote resilience among caregivers. Organizational initiatives that set the stage for resilience include:

• Curricula to enhance communication with patients, coworkers, and family
• “Best practices” for efficient and effective patient care
• Self-care through health insurance incentives and educational sessions
• Accessible, affordable, and confidential behavioral health support
• Time for self-care activities during the workday
• Coaching and mentoring programs
• Narrative-and-reflection groups and mindfulness training.⁵

Through an atmosphere of support for resilience, organizations provide a place for physicians to maintain a sense of meaning and purpose in their work. For individuals facing malpractice action, this infrastructure can be used to weather the storm. As Mr. Giordano writes, staying engaged “may allow you to draw meaning and reconciliation from the fact that throughout the patient’s illness, undeterred by the complexities of today’s healthcare system, you remained the attentive and compassionate healer you hoped to be when you first became a healthcare professional.”¹ We must pay attention to developing individual physicians, educating managers, and building systems so that caregivers can remain engaged and resilient. It may help those affected by malpractice stress, and perhaps as importantly, it may reduce the chance of future “disconnection” leading to recourse in the legal system.

Physicians who have been involved in malpractice actions are all too familiar with the range of emotions they experience during the process. Anxiety, fear, frustration, remorse, self-doubt, shame, betrayal, anger…no pleasant feelings here. Add malpractice stress to the high level of pressure experienced at home and at work, and crisis looms.

In his commentary in this issue, Kevin Giordano states, “it is not easy to stay connected in a healthcare system in which the system’s structure is driving physicians and other members of the healthcare team toward disconnection.”¹

See related commentary

Because of the nature of our work as physicians, we are isolated, and malpractice isolates us further. Because of embarrassment, we avoid talking with our colleagues and managers. Legal counsel reminds us to correspond with no one about the details of the case. Spouses and friends may offer support, but it is difficult— perhaps impossible—to be reassured.

Isolation fuels our self-doubt and erodes our confidence, leading us to focus on what may go wrong, rather than on healing. Every decision is fraught with anxiety, and efficiency evaporates. Paralysis may set in, leading to disengagement from patient care and increasing the chance of further problems. 

IT TAKES RESILIENCE TO THRIVE

It takes resilience to thrive in today’s pressure-cooker healthcare environment, let alone in the setting of malpractice stress. Resilient people are able to face reality and see a better future, put things into perspective, and bounce back from adversity.² Resilience, a trait that protects against stress and burnout, is relevant at the personal, managerial, and system levels. Though this definition is not specific to caregiver or malpractice stress, it is applicable. It is an essential component of wellness and requires perpetual attention to self-care for successful maintenance.

Resilient people can face reality, see a better future, put things into perspective, and bounce back from adversity

Studies of physicians who have avoided burnout reveal remarkably consistent qualities, including finding gratification related to work, maintaining useful habits and practices, and developing attitudes that keep them resilient.³ Rather than adding activities to their full schedules, these physicians stayed resilient through mindfulness of various aspects of their daily lives. Interactions with colleagues—discussing cases, treatments, and outcomes (including errors)—proved vital. Professional development, encompassing activities such as continuing education, coaching, mentoring, and counseling, was recognized as an important self-directed resilience measure. Maintenance of relationships with family and friends, cultivation of leisure-time activities, and appreciation of the need for personal reflection time were traits often found in resilient physicians.

FOSTERING RESILIENCE

As part of the Mayo Clinic’s biannual survey of its physicians, Shanafelt et al⁴ studied relationships between qualities of physician leaders and burnout and satisfaction among the physicians they supervised. Many of the desirable leadership traits were related to building relationships through respectful communication, along with provision of opportunities for personal and professional development. The acknowledgment that resilient, healthy physicians are satisfied, productive, and able to provide safer and higher-quality patient care should lead to the establishment of physician wellness as a “dashboard metric.” This makes priorities clear by rewarding managers who foster self-care and resilience among their staff.

Likewise, at the healthcare system level, Beckman⁵ recognized that organizations can provide opportunities to promote resilience among caregivers. Organizational initiatives that set the stage for resilience include:

• Curricula to enhance communication with patients, coworkers, and family
• “Best practices” for efficient and effective patient care
• Self-care through health insurance incentives and educational sessions
• Accessible, affordable, and confidential behavioral health support
• Time for self-care activities during the workday
• Coaching and mentoring programs
• Narrative-and-reflection groups and mindfulness training.⁵

Through an atmosphere of support for resilience, organizations provide a place for physicians to maintain a sense of meaning and purpose in their work. For individuals facing malpractice action, this infrastructure can be used to weather the storm. As Mr. Giordano writes, staying engaged “may allow you to draw meaning and reconciliation from the fact that throughout the patient’s illness, undeterred by the complexities of today’s healthcare system, you remained the attentive and compassionate healer you hoped to be when you first became a healthcare professional.”¹ We must pay attention to developing individual physicians, educating managers, and building systems so that caregivers can remain engaged and resilient. It may help those affected by malpractice stress, and perhaps as importantly, it may reduce the chance of future “disconnection” leading to recourse in the legal system.

Physicians who have been involved in malpractice actions are all too familiar with the range of emotions they experience during the process. Anxiety, fear, frustration, remorse, self-doubt, shame, betrayal, anger…no pleasant feelings here. Add malpractice stress to the high level of pressure experienced at home and at work, and crisis looms.

In his commentary in this issue, Kevin Giordano states, “it is not easy to stay connected in a healthcare system in which the system’s structure is driving physicians and other members of the healthcare team toward disconnection.”¹

See related commentary

Because of the nature of our work as physicians, we are isolated, and malpractice isolates us further. Because of embarrassment, we avoid talking with our colleagues and managers. Legal counsel reminds us to correspond with no one about the details of the case. Spouses and friends may offer support, but it is difficult— perhaps impossible—to be reassured.

Isolation fuels our self-doubt and erodes our confidence, leading us to focus on what may go wrong, rather than on healing. Every decision is fraught with anxiety, and efficiency evaporates. Paralysis may set in, leading to disengagement from patient care and increasing the chance of further problems. 

IT TAKES RESILIENCE TO THRIVE

It takes resilience to thrive in today’s pressure-cooker healthcare environment, let alone in the setting of malpractice stress. Resilient people are able to face reality and see a better future, put things into perspective, and bounce back from adversity.² Resilience, a trait that protects against stress and burnout, is relevant at the personal, managerial, and system levels. Though this definition is not specific to caregiver or malpractice stress, it is applicable. It is an essential component of wellness and requires perpetual attention to self-care for successful maintenance.

Resilient people can face reality, see a better future, put things into perspective, and bounce back from adversity

Studies of physicians who have avoided burnout reveal remarkably consistent qualities, including finding gratification related to work, maintaining useful habits and practices, and developing attitudes that keep them resilient.³ Rather than adding activities to their full schedules, these physicians stayed resilient through mindfulness of various aspects of their daily lives. Interactions with colleagues—discussing cases, treatments, and outcomes (including errors)—proved vital. Professional development, encompassing activities such as continuing education, coaching, mentoring, and counseling, was recognized as an important self-directed resilience measure. Maintenance of relationships with family and friends, cultivation of leisure-time activities, and appreciation of the need for personal reflection time were traits often found in resilient physicians.

FOSTERING RESILIENCE

As part of the Mayo Clinic’s biannual survey of its physicians, Shanafelt et al⁴ studied relationships between qualities of physician leaders and burnout and satisfaction among the physicians they supervised. Many of the desirable leadership traits were related to building relationships through respectful communication, along with provision of opportunities for personal and professional development. The acknowledgment that resilient, healthy physicians are satisfied, productive, and able to provide safer and higher-quality patient care should lead to the establishment of physician wellness as a “dashboard metric.” This makes priorities clear by rewarding managers who foster self-care and resilience among their staff.

Likewise, at the healthcare system level, Beckman⁵ recognized that organizations can provide opportunities to promote resilience among caregivers. Organizational initiatives that set the stage for resilience include:

• Curricula to enhance communication with patients, coworkers, and family
• “Best practices” for efficient and effective patient care
• Self-care through health insurance incentives and educational sessions
• Accessible, affordable, and confidential behavioral health support
• Time for self-care activities during the workday
• Coaching and mentoring programs
• Narrative-and-reflection groups and mindfulness training.⁵

Through an atmosphere of support for resilience, organizations provide a place for physicians to maintain a sense of meaning and purpose in their work. For individuals facing malpractice action, this infrastructure can be used to weather the storm. As Mr. Giordano writes, staying engaged “may allow you to draw meaning and reconciliation from the fact that throughout the patient’s illness, undeterred by the complexities of today’s healthcare system, you remained the attentive and compassionate healer you hoped to be when you first became a healthcare professional.”¹ We must pay attention to developing individual physicians, educating managers, and building systems so that caregivers can remain engaged and resilient. It may help those affected by malpractice stress, and perhaps as importantly, it may reduce the chance of future “disconnection” leading to recourse in the legal system.

During my 25 years as a defense attorney, I have seen the traumatic impact that the allegation of medical malpractice can have on healthcare providers. And I have seen many times that in the aftermath of a case it remains difficult, if not impossible, for the practitioner to return to the clinical setting unscarred by the process. Although vindication by the jury provides some solace, by itself it does not create healing. Instead, the critic’s voice continues to resonate long after the trial.

See related editorial

During a lawsuit, physicians and other providers are commonly confronted with incidental imperfections in the care they provided, errors in their documentation, or both. Consequently, a provider’s perception of events and ultimately the meaning derived from the experience is shaped less by the valid defenses and opinions of the supportive defense experts than by the inconsequential flaws and errors that can often be found in any medical record.

A RECENT CASE

Recently, I defended a hospital team consisting of a hospitalist, trauma surgeon, three residents, and a nurse. The case involved a 74-year-old man who was admitted to the hospital with pancreatitis of unknown cause. Six days after admission, he died of complications of acute respiratory distress syndrome. The team was accused of causing the patient’s death. Specifically, the plaintiff alleged that although the patient’s liver enzyme levels were improving, his condition was deteriorating, and he ultimately developed hemorrhagic pancreatitis. It was the plaintiff’s contention that proper ongoing evaluation, including computed tomographic imaging, would have led to treatment that would have avoided the worsening of pancreatitis, development of an ileus, and ultimately the insult to his bowel and lungs that they claim caused acute respiratory distress syndrome and death. The patient was survived by his wife and their three children. After his death, hospital representatives and the hospitalist met with her in an effort to explain the events that led to her husband’s death. Unfortunately, these discussions did not ameliorate her feelings of loss and anger. She filed a lawsuit, and 4 years later, the case went to trial.

Vindication provides some solace, but the critic’s voice can resonate long after the trial

During the trial, the plaintiff’s attorney highlighted errors in the electronic medical record. Entries had been cut and pasted, saving time, but without updating information that had changed in the interim. The inaccuracies included “assessment: worsening pancreatitis” on a day it was considered to have improved. Another entry contained “persistent fever” on a day when no fever was present. Other mistakes involved notes that contained care plans made after morning rounds that were not revised later in the day after changes in the patient’s condition necessitated a change in the plan. In fact, most references to medication dosing in the progress notes on the last 2 days did not match the medication dosing documented in the medication administration record.

In the end, the plaintiff’s counsel did not convince the jury that the healthcare team had been negligent, but unfortunately, she planted doubt in the minds of the caregivers themselves. Perhaps in part, these doubts were the result of having to defend a bad outcome in the face of criticism that was based solely in retrospect. But the providers’ doubts seemed mostly to emanate from the inadequacies in their documentation as they observed how every entry in a far-from-perfect medical record was scrutinized and then manipulated to challenge its textual integrity—and to portray the healthcare team as unengaged and substandard clinicians.

Despite the team’s high level of engagement and the quality of care they provided, any imperfection—whether a documentation error or a minor omission in some aspect of the care provided to this complex patient—became a source of self-doubt and self-criticism.

THE ELECTRONIC MEDICAL RECORD: A MIXED BLESSING

Documentation failures have long been used to “prove” that physicians are disconnected from the clinical situation. The electronic medical record has not proved to be a strong shield against malpractice allegations. In fact, because the electronic medical record absorbs more of the physician’s time and that of the care team’s members, efforts to save time through work-arounds and shortcuts have increased the risk of errors in entering information.

For instance, drop-down menus have led to wrong selections. Cutting and pasting has led to entries that contain data superseded by clinical events, thus creating contradictions within the record itself, and worse, with the physician’s own testimony pertaining to the basis of the clinical decision-making. And boilerplate language has created difficulties when the language does not completely fit the context or when inapplicable verbiage that fills itself in automatically goes unedited. An emergency department physician I represented at trial had to awkwardly explain that some of the data reported in his physical exam findings were inaccurate because of programmed language and should have been deleted; he had no explanation for his oversight.

But my experience has been that juries can forgive imperfections in documentation and even incidental aspects of care. They want to trust that the clinician was there for, and there with, the patient. This emphasis is what allowed us to defend the case involving the patient with pancreatitis. Clinical judgment means being engaged enough to choose what you pay attention to and to process the data you receive.

The electronic medical record has not proved to be a strong shield against malpractice allegations

Unfortunately, the electronic medical record seems designed more for billing and for guarding against claims of fraud than for communication among clinicians or documenting clinically significant events. Many clinicians believe that redundancy and standardized phraseology have weakened the meaningful use of the medical record, as the clinical information is now of questionable reliability or value or is simply hard to find. Consequently, the electronic medical record has become less effective as a communication tool for providing continuity of care.

More importantly, the electronic medical record too often places the physician in front of a computer, so that the computer becomes the focus, not the patient. Studies suggest that the way the electronic medical record is currently used in the examination room affects the quality of physician-patient communication as well as the physician’s cognitive processing of information. Unless the physician is alert and attuned, the electronic medical record can be a barrier to connection. This not only creates the potential for mistakes, but it can also cause patients to question the quality of care they are getting and to distrust the level of the provider’s engagement. In this context, the likelihood that the patient retains an attorney increases when a bad outcome occurs, avoidable or not.

WHAT PATIENTS WANT FROM PHYSICIANS

When I first began seeing my own primary care physician, her office was 5 minutes from my home. Then she relocated to a practice 15 minutes away. And then, because of office consolidation and acquisition, her office was relocated 40 minutes away.

So why do I still go to her? Her training is not better than that of most internists, and my medical history is not so complex that I require more care than most 55-year-old men. I am only speculating, but I would guess that she is not the most financially productive physician in her group. I know that her transition to the electronic medical record has been difficult. Recently, I asked her about it. Except in some situations, she does not type while taking a history, and she stays totally away from the computer while in the examination room with me. She sits a couple of feet from me, and it feels like the days before the electronic medical record. She is clearly more comfortable listening and taking notes first and worrying about the electronic record later. I imagine she stays later to do her notes than most of the other physicians, or she finishes them at home.

The reason I continue to see her as my primary care physician is that she remains totally engaged during my office visit. What tells me that is not just her avoidance of the computer or her body language, but the depth of questions she asks. My responses often prompt her to look back at an earlier office note, and she will then ask follow-up questions to confirm what she had previously recorded. Her examination is thorough, with testing to confirm and retesting to be sure. Doing this may mean that she has difficulty meeting financial or administrative benchmarks established by her practice. I don’t know. But I have no doubt that the likelihood of her missing something in her clinical care is small, and what I suspect is even smaller is the risk that one of her patients would bring a lawsuit against her, given the time she takes to listen and remain connected throughout the office visit.

STAYING CONNECTED, IN SPITE OF EVERYTHING

Be the attentive, compassionate healer you hoped to be when you first entered practice

My point is not to suggest that everyone must conform to the same practice philosophy, particularly with the economic pressures in the medical field. What I am suggesting is that it is not easy to stay connected in a healthcare system in which the system’s structure is driving physicians and other members of the healthcare team towards disconnection. Quality healthcare means making every effort to remain engaged at all times with your patient’s care, which will reduce the likelihood of a bad outcome and may preserve the physician-patient relationship even when a bad outcome occurs.

In the end, perhaps it is not possible to avoid being named as a defendant in a malpractice case, just as it is not possible to avoid all bad medical outcomes despite exceptional care. In law, as in medicine, there are always factors beyond your control. My aspiration is to find a pathway to get providers through the system unbroken—also not an easy task. But one thing I know is true: the more you can stay engaged in the care you provide and in your documentation, the more you will preclude a plaintiff’s attorney from exploiting the effects of the forces within the system that drive providers toward disconnection. As long as you stay engaged and supported by the knowledge that the care provided was appropriate, it is my hope that the voice of the critic will not count as much in the aftermath of a malpractice case. But more importantly, it may allow you to draw meaning and reconciliation from the fact that throughout the patient’s illness, undeterred by the complexities of today’s healthcare system, you remained the attentive and compassionate healer you hoped to be when you first became a healthcare professional.

During my 25 years as a defense attorney, I have seen the traumatic impact that the allegation of medical malpractice can have on healthcare providers. And I have seen many times that in the aftermath of a case it remains difficult, if not impossible, for the practitioner to return to the clinical setting unscarred by the process. Although vindication by the jury provides some solace, by itself it does not create healing. Instead, the critic’s voice continues to resonate long after the trial.

See related editorial

During a lawsuit, physicians and other providers are commonly confronted with incidental imperfections in the care they provided, errors in their documentation, or both. Consequently, a provider’s perception of events and ultimately the meaning derived from the experience is shaped less by the valid defenses and opinions of the supportive defense experts than by the inconsequential flaws and errors that can often be found in any medical record.

A RECENT CASE

Recently, I defended a hospital team consisting of a hospitalist, trauma surgeon, three residents, and a nurse. The case involved a 74-year-old man who was admitted to the hospital with pancreatitis of unknown cause. Six days after admission, he died of complications of acute respiratory distress syndrome. The team was accused of causing the patient’s death. Specifically, the plaintiff alleged that although the patient’s liver enzyme levels were improving, his condition was deteriorating, and he ultimately developed hemorrhagic pancreatitis. It was the plaintiff’s contention that proper ongoing evaluation, including computed tomographic imaging, would have led to treatment that would have avoided the worsening of pancreatitis, development of an ileus, and ultimately the insult to his bowel and lungs that they claim caused acute respiratory distress syndrome and death. The patient was survived by his wife and their three children. After his death, hospital representatives and the hospitalist met with her in an effort to explain the events that led to her husband’s death. Unfortunately, these discussions did not ameliorate her feelings of loss and anger. She filed a lawsuit, and 4 years later, the case went to trial.

Vindication provides some solace, but the critic’s voice can resonate long after the trial

During the trial, the plaintiff’s attorney highlighted errors in the electronic medical record. Entries had been cut and pasted, saving time, but without updating information that had changed in the interim. The inaccuracies included “assessment: worsening pancreatitis” on a day it was considered to have improved. Another entry contained “persistent fever” on a day when no fever was present. Other mistakes involved notes that contained care plans made after morning rounds that were not revised later in the day after changes in the patient’s condition necessitated a change in the plan. In fact, most references to medication dosing in the progress notes on the last 2 days did not match the medication dosing documented in the medication administration record.

In the end, the plaintiff’s counsel did not convince the jury that the healthcare team had been negligent, but unfortunately, she planted doubt in the minds of the caregivers themselves. Perhaps in part, these doubts were the result of having to defend a bad outcome in the face of criticism that was based solely in retrospect. But the providers’ doubts seemed mostly to emanate from the inadequacies in their documentation as they observed how every entry in a far-from-perfect medical record was scrutinized and then manipulated to challenge its textual integrity—and to portray the healthcare team as unengaged and substandard clinicians.

Despite the team’s high level of engagement and the quality of care they provided, any imperfection—whether a documentation error or a minor omission in some aspect of the care provided to this complex patient—became a source of self-doubt and self-criticism.

THE ELECTRONIC MEDICAL RECORD: A MIXED BLESSING

Documentation failures have long been used to “prove” that physicians are disconnected from the clinical situation. The electronic medical record has not proved to be a strong shield against malpractice allegations. In fact, because the electronic medical record absorbs more of the physician’s time and that of the care team’s members, efforts to save time through work-arounds and shortcuts have increased the risk of errors in entering information.

For instance, drop-down menus have led to wrong selections. Cutting and pasting has led to entries that contain data superseded by clinical events, thus creating contradictions within the record itself, and worse, with the physician’s own testimony pertaining to the basis of the clinical decision-making. And boilerplate language has created difficulties when the language does not completely fit the context or when inapplicable verbiage that fills itself in automatically goes unedited. An emergency department physician I represented at trial had to awkwardly explain that some of the data reported in his physical exam findings were inaccurate because of programmed language and should have been deleted; he had no explanation for his oversight.

But my experience has been that juries can forgive imperfections in documentation and even incidental aspects of care. They want to trust that the clinician was there for, and there with, the patient. This emphasis is what allowed us to defend the case involving the patient with pancreatitis. Clinical judgment means being engaged enough to choose what you pay attention to and to process the data you receive.

The electronic medical record has not proved to be a strong shield against malpractice allegations

Unfortunately, the electronic medical record seems designed more for billing and for guarding against claims of fraud than for communication among clinicians or documenting clinically significant events. Many clinicians believe that redundancy and standardized phraseology have weakened the meaningful use of the medical record, as the clinical information is now of questionable reliability or value or is simply hard to find. Consequently, the electronic medical record has become less effective as a communication tool for providing continuity of care.

More importantly, the electronic medical record too often places the physician in front of a computer, so that the computer becomes the focus, not the patient. Studies suggest that the way the electronic medical record is currently used in the examination room affects the quality of physician-patient communication as well as the physician’s cognitive processing of information. Unless the physician is alert and attuned, the electronic medical record can be a barrier to connection. This not only creates the potential for mistakes, but it can also cause patients to question the quality of care they are getting and to distrust the level of the provider’s engagement. In this context, the likelihood that the patient retains an attorney increases when a bad outcome occurs, avoidable or not.

WHAT PATIENTS WANT FROM PHYSICIANS

When I first began seeing my own primary care physician, her office was 5 minutes from my home. Then she relocated to a practice 15 minutes away. And then, because of office consolidation and acquisition, her office was relocated 40 minutes away.

So why do I still go to her? Her training is not better than that of most internists, and my medical history is not so complex that I require more care than most 55-year-old men. I am only speculating, but I would guess that she is not the most financially productive physician in her group. I know that her transition to the electronic medical record has been difficult. Recently, I asked her about it. Except in some situations, she does not type while taking a history, and she stays totally away from the computer while in the examination room with me. She sits a couple of feet from me, and it feels like the days before the electronic medical record. She is clearly more comfortable listening and taking notes first and worrying about the electronic record later. I imagine she stays later to do her notes than most of the other physicians, or she finishes them at home.

The reason I continue to see her as my primary care physician is that she remains totally engaged during my office visit. What tells me that is not just her avoidance of the computer or her body language, but the depth of questions she asks. My responses often prompt her to look back at an earlier office note, and she will then ask follow-up questions to confirm what she had previously recorded. Her examination is thorough, with testing to confirm and retesting to be sure. Doing this may mean that she has difficulty meeting financial or administrative benchmarks established by her practice. I don’t know. But I have no doubt that the likelihood of her missing something in her clinical care is small, and what I suspect is even smaller is the risk that one of her patients would bring a lawsuit against her, given the time she takes to listen and remain connected throughout the office visit.

STAYING CONNECTED, IN SPITE OF EVERYTHING

Be the attentive, compassionate healer you hoped to be when you first entered practice

My point is not to suggest that everyone must conform to the same practice philosophy, particularly with the economic pressures in the medical field. What I am suggesting is that it is not easy to stay connected in a healthcare system in which the system’s structure is driving physicians and other members of the healthcare team towards disconnection. Quality healthcare means making every effort to remain engaged at all times with your patient’s care, which will reduce the likelihood of a bad outcome and may preserve the physician-patient relationship even when a bad outcome occurs.

In the end, perhaps it is not possible to avoid being named as a defendant in a malpractice case, just as it is not possible to avoid all bad medical outcomes despite exceptional care. In law, as in medicine, there are always factors beyond your control. My aspiration is to find a pathway to get providers through the system unbroken—also not an easy task. But one thing I know is true: the more you can stay engaged in the care you provide and in your documentation, the more you will preclude a plaintiff’s attorney from exploiting the effects of the forces within the system that drive providers toward disconnection. As long as you stay engaged and supported by the knowledge that the care provided was appropriate, it is my hope that the voice of the critic will not count as much in the aftermath of a malpractice case. But more importantly, it may allow you to draw meaning and reconciliation from the fact that throughout the patient’s illness, undeterred by the complexities of today’s healthcare system, you remained the attentive and compassionate healer you hoped to be when you first became a healthcare professional.

During my 25 years as a defense attorney, I have seen the traumatic impact that the allegation of medical malpractice can have on healthcare providers. And I have seen many times that in the aftermath of a case it remains difficult, if not impossible, for the practitioner to return to the clinical setting unscarred by the process. Although vindication by the jury provides some solace, by itself it does not create healing. Instead, the critic’s voice continues to resonate long after the trial.

See related editorial

During a lawsuit, physicians and other providers are commonly confronted with incidental imperfections in the care they provided, errors in their documentation, or both. Consequently, a provider’s perception of events and ultimately the meaning derived from the experience is shaped less by the valid defenses and opinions of the supportive defense experts than by the inconsequential flaws and errors that can often be found in any medical record.

A RECENT CASE

Recently, I defended a hospital team consisting of a hospitalist, trauma surgeon, three residents, and a nurse. The case involved a 74-year-old man who was admitted to the hospital with pancreatitis of unknown cause. Six days after admission, he died of complications of acute respiratory distress syndrome. The team was accused of causing the patient’s death. Specifically, the plaintiff alleged that although the patient’s liver enzyme levels were improving, his condition was deteriorating, and he ultimately developed hemorrhagic pancreatitis. It was the plaintiff’s contention that proper ongoing evaluation, including computed tomographic imaging, would have led to treatment that would have avoided the worsening of pancreatitis, development of an ileus, and ultimately the insult to his bowel and lungs that they claim caused acute respiratory distress syndrome and death. The patient was survived by his wife and their three children. After his death, hospital representatives and the hospitalist met with her in an effort to explain the events that led to her husband’s death. Unfortunately, these discussions did not ameliorate her feelings of loss and anger. She filed a lawsuit, and 4 years later, the case went to trial.

Vindication provides some solace, but the critic’s voice can resonate long after the trial

During the trial, the plaintiff’s attorney highlighted errors in the electronic medical record. Entries had been cut and pasted, saving time, but without updating information that had changed in the interim. The inaccuracies included “assessment: worsening pancreatitis” on a day it was considered to have improved. Another entry contained “persistent fever” on a day when no fever was present. Other mistakes involved notes that contained care plans made after morning rounds that were not revised later in the day after changes in the patient’s condition necessitated a change in the plan. In fact, most references to medication dosing in the progress notes on the last 2 days did not match the medication dosing documented in the medication administration record.

In the end, the plaintiff’s counsel did not convince the jury that the healthcare team had been negligent, but unfortunately, she planted doubt in the minds of the caregivers themselves. Perhaps in part, these doubts were the result of having to defend a bad outcome in the face of criticism that was based solely in retrospect. But the providers’ doubts seemed mostly to emanate from the inadequacies in their documentation as they observed how every entry in a far-from-perfect medical record was scrutinized and then manipulated to challenge its textual integrity—and to portray the healthcare team as unengaged and substandard clinicians.

Despite the team’s high level of engagement and the quality of care they provided, any imperfection—whether a documentation error or a minor omission in some aspect of the care provided to this complex patient—became a source of self-doubt and self-criticism.

THE ELECTRONIC MEDICAL RECORD: A MIXED BLESSING

Documentation failures have long been used to “prove” that physicians are disconnected from the clinical situation. The electronic medical record has not proved to be a strong shield against malpractice allegations. In fact, because the electronic medical record absorbs more of the physician’s time and that of the care team’s members, efforts to save time through work-arounds and shortcuts have increased the risk of errors in entering information.

For instance, drop-down menus have led to wrong selections. Cutting and pasting has led to entries that contain data superseded by clinical events, thus creating contradictions within the record itself, and worse, with the physician’s own testimony pertaining to the basis of the clinical decision-making. And boilerplate language has created difficulties when the language does not completely fit the context or when inapplicable verbiage that fills itself in automatically goes unedited. An emergency department physician I represented at trial had to awkwardly explain that some of the data reported in his physical exam findings were inaccurate because of programmed language and should have been deleted; he had no explanation for his oversight.

But my experience has been that juries can forgive imperfections in documentation and even incidental aspects of care. They want to trust that the clinician was there for, and there with, the patient. This emphasis is what allowed us to defend the case involving the patient with pancreatitis. Clinical judgment means being engaged enough to choose what you pay attention to and to process the data you receive.

The electronic medical record has not proved to be a strong shield against malpractice allegations

Unfortunately, the electronic medical record seems designed more for billing and for guarding against claims of fraud than for communication among clinicians or documenting clinically significant events. Many clinicians believe that redundancy and standardized phraseology have weakened the meaningful use of the medical record, as the clinical information is now of questionable reliability or value or is simply hard to find. Consequently, the electronic medical record has become less effective as a communication tool for providing continuity of care.

More importantly, the electronic medical record too often places the physician in front of a computer, so that the computer becomes the focus, not the patient. Studies suggest that the way the electronic medical record is currently used in the examination room affects the quality of physician-patient communication as well as the physician’s cognitive processing of information. Unless the physician is alert and attuned, the electronic medical record can be a barrier to connection. This not only creates the potential for mistakes, but it can also cause patients to question the quality of care they are getting and to distrust the level of the provider’s engagement. In this context, the likelihood that the patient retains an attorney increases when a bad outcome occurs, avoidable or not.

WHAT PATIENTS WANT FROM PHYSICIANS

When I first began seeing my own primary care physician, her office was 5 minutes from my home. Then she relocated to a practice 15 minutes away. And then, because of office consolidation and acquisition, her office was relocated 40 minutes away.

So why do I still go to her? Her training is not better than that of most internists, and my medical history is not so complex that I require more care than most 55-year-old men. I am only speculating, but I would guess that she is not the most financially productive physician in her group. I know that her transition to the electronic medical record has been difficult. Recently, I asked her about it. Except in some situations, she does not type while taking a history, and she stays totally away from the computer while in the examination room with me. She sits a couple of feet from me, and it feels like the days before the electronic medical record. She is clearly more comfortable listening and taking notes first and worrying about the electronic record later. I imagine she stays later to do her notes than most of the other physicians, or she finishes them at home.

The reason I continue to see her as my primary care physician is that she remains totally engaged during my office visit. What tells me that is not just her avoidance of the computer or her body language, but the depth of questions she asks. My responses often prompt her to look back at an earlier office note, and she will then ask follow-up questions to confirm what she had previously recorded. Her examination is thorough, with testing to confirm and retesting to be sure. Doing this may mean that she has difficulty meeting financial or administrative benchmarks established by her practice. I don’t know. But I have no doubt that the likelihood of her missing something in her clinical care is small, and what I suspect is even smaller is the risk that one of her patients would bring a lawsuit against her, given the time she takes to listen and remain connected throughout the office visit.

STAYING CONNECTED, IN SPITE OF EVERYTHING

Be the attentive, compassionate healer you hoped to be when you first entered practice

My point is not to suggest that everyone must conform to the same practice philosophy, particularly with the economic pressures in the medical field. What I am suggesting is that it is not easy to stay connected in a healthcare system in which the system’s structure is driving physicians and other members of the healthcare team towards disconnection. Quality healthcare means making every effort to remain engaged at all times with your patient’s care, which will reduce the likelihood of a bad outcome and may preserve the physician-patient relationship even when a bad outcome occurs.

In the end, perhaps it is not possible to avoid being named as a defendant in a malpractice case, just as it is not possible to avoid all bad medical outcomes despite exceptional care. In law, as in medicine, there are always factors beyond your control. My aspiration is to find a pathway to get providers through the system unbroken—also not an easy task. But one thing I know is true: the more you can stay engaged in the care you provide and in your documentation, the more you will preclude a plaintiff’s attorney from exploiting the effects of the forces within the system that drive providers toward disconnection. As long as you stay engaged and supported by the knowledge that the care provided was appropriate, it is my hope that the voice of the critic will not count as much in the aftermath of a malpractice case. But more importantly, it may allow you to draw meaning and reconciliation from the fact that throughout the patient’s illness, undeterred by the complexities of today’s healthcare system, you remained the attentive and compassionate healer you hoped to be when you first became a healthcare professional.

THE DIFFERENTIAL DIAGNOSIS

The appearance of sterile pustules after starting a new antibiotic raised suspicion for acute localized exanthematous pustulosis, a variant of acute generalized exanthematous pustulosis. It is a serious but uncommon adverse drug reaction, with a frequency of one to five cases per million per year. The eruption of erythematous plaques studded with sterile pustules classically appears 1 to 5 days after starting a drug.¹ Piperacillin-tazobactam has been infrequently reported in association with acute exanthematous pustulosis, but antibiotics in general are among the most commonly reported culprits.^2–4

Clues to the correct diagnosis

Although our concern for acute localized exanthematous pustulosis was warranted, the morphology and distribution of this patient’s exanthem also raised suspicion of fungal folliculitis, which is more common.

Malassezia folliculitis appears as a monomorphic papular and pustular eruption on the chest, back, and face,⁵ as in our patient. Differentiating fungal folliculitis from pustulosis is important, as each condition is treated differently: Malassezia folliculitis is treated with antifungals,⁵ and acute localized exanthematous pustulosis is managed with cessation of the offending drug, supportive care, and systemic or topical steroids.⁴

Take-home point

Our experience with this patient was a reminder to consider fungal folliculitis in the differential diagnosis of a pustular eruption, so as to allow appropriate management and to avert discontinuation of potentially life-saving medications.

THE DIFFERENTIAL DIAGNOSIS

The appearance of sterile pustules after starting a new antibiotic raised suspicion for acute localized exanthematous pustulosis, a variant of acute generalized exanthematous pustulosis. It is a serious but uncommon adverse drug reaction, with a frequency of one to five cases per million per year. The eruption of erythematous plaques studded with sterile pustules classically appears 1 to 5 days after starting a drug.¹ Piperacillin-tazobactam has been infrequently reported in association with acute exanthematous pustulosis, but antibiotics in general are among the most commonly reported culprits.^2–4

Clues to the correct diagnosis

Although our concern for acute localized exanthematous pustulosis was warranted, the morphology and distribution of this patient’s exanthem also raised suspicion of fungal folliculitis, which is more common.

Malassezia folliculitis appears as a monomorphic papular and pustular eruption on the chest, back, and face,⁵ as in our patient. Differentiating fungal folliculitis from pustulosis is important, as each condition is treated differently: Malassezia folliculitis is treated with antifungals,⁵ and acute localized exanthematous pustulosis is managed with cessation of the offending drug, supportive care, and systemic or topical steroids.⁴

Take-home point

Our experience with this patient was a reminder to consider fungal folliculitis in the differential diagnosis of a pustular eruption, so as to allow appropriate management and to avert discontinuation of potentially life-saving medications.

THE DIFFERENTIAL DIAGNOSIS

The appearance of sterile pustules after starting a new antibiotic raised suspicion for acute localized exanthematous pustulosis, a variant of acute generalized exanthematous pustulosis. It is a serious but uncommon adverse drug reaction, with a frequency of one to five cases per million per year. The eruption of erythematous plaques studded with sterile pustules classically appears 1 to 5 days after starting a drug.¹ Piperacillin-tazobactam has been infrequently reported in association with acute exanthematous pustulosis, but antibiotics in general are among the most commonly reported culprits.^2–4

Clues to the correct diagnosis

Although our concern for acute localized exanthematous pustulosis was warranted, the morphology and distribution of this patient’s exanthem also raised suspicion of fungal folliculitis, which is more common.

Malassezia folliculitis appears as a monomorphic papular and pustular eruption on the chest, back, and face,⁵ as in our patient. Differentiating fungal folliculitis from pustulosis is important, as each condition is treated differently: Malassezia folliculitis is treated with antifungals,⁵ and acute localized exanthematous pustulosis is managed with cessation of the offending drug, supportive care, and systemic or topical steroids.⁴

Take-home point

Our experience with this patient was a reminder to consider fungal folliculitis in the differential diagnosis of a pustular eruption, so as to allow appropriate management and to avert discontinuation of potentially life-saving medications.

The Food and Drug Administration has ordered Bayer to conduct a 2,000-patient postmarketing study of the Essure implantable birth control device, to explore the risks it may pose to some women and examine how it is being employed in clinical practice.

Bayer, which manufactures the device, will also be required to add a boxed warning to the label, describing potential adverse events, and a “Patient Decision Checklist” to help guide preimplantation discussions, under draft guidance issued by the FDA on Feb. 29.

The 3-year observational study will compare data on complications, pregnancy, and pregnancy loss in Essure patients and in women who undergo bilateral tubal ligation, according to Dr. William Maisel, chief scientist at the FDA’s Center for Devices and Radiological Health.

“This will be a large observational study,” he said during an FDA press briefing on Feb. 29. “The specific questions will relate to overall complications rates; perforation, migration, and expulsion; chronic pelvic pain; abnormal uterine bleeding; allergy and hypersensitivity,” and obstetric outcomes.

Because FDA is requiring such a large patient cohort with long-term follow-up, final study results will be years away. Therefore, Bayer will be required to release data intermittently to keep the public well informed as research progresses, Dr. Maisel said.

Courtesy Bayer

The requested study will also examine why some patients don’t have a confirmation test to ensure that Essure has been properly placed 3 months after insertion – a key area that seems related to a number of reported adverse events, including pregnancy and device migration.

Despite the push for additional data, the FDA still believes that Essure is an appropriate and safe permanent option for the majority of women who want permanent birth control, Dr. Maisel said.

“It’s the only nonincisional form of permanent birth control. It requires no general anesthetic to insert, and most women go back to work in a day,” he said. “It is highly effective at preventing pregnancy, and it contains no drugs or hormones. Essure should remain an option for women seeking permanent birth control who are informed of its risks.”

Bayer officials said they will continue to work closely with the FDA to support the safe and effective use of the device.

“Patient safety and appropriate use of Essure are our greatest priorities,” Dr. Dario Mirski, senior vice president and head of medical affairs Americas at Bayer said in a statement. “A woman’s decision to choose a birth control method is a very important and personal one, and Bayer is committed to providing physicians with resources, tools, and information to help them counsel women about Essure.”

The boxed warning announced by the FDA will outline the adverse events that may be associated with Essure, including those that might occur during insertion and removal. The “Patient Decision Checklist” will be designed to help doctors stress the importance of the 3-month confirmation test to determine that it is correctly placed and that sufficient scar tissue has formed to prevent pregnancy. Both patient and physician will have to sign off on the checklist before the device is employed.

The FDA is seeking public comments on the proposed language for the warnings. The docket will be open for 60 days.

“The actions we are taking today will encourage important conversations between women and their doctors to help patients make more informed decisions about whether or not Essure is right for them,” said Dr. Maisel. “They also reflect our recognition that more rigorous research is needed to better understand if certain women are at heightened risk of complications.”

The draft guidance solidifies discussions that occurred last fall during a meeting of the FDA Obstetrics and Gynecology Devices Panel. During that meeting, the 19-member panel heard testimony from dozens of women who developed pain and other serious problems, including autoimmune diseases, after receiving Essure.

Since the device was approved in 2002, the FDA has received more than 5,000 complaints of such adverse reactions. These include 631 pregnancies and 294 pregnancy losses.

Between the September meeting and the FDA’s draft guidance announcement, the agency has received even more information from patients. A 22,000-person support group called Essure Problems collected and submitted a large amount of personal and clinical data. The package was submitted to the FDA on Feb. 22 and includes surgical notes and photos; letters from doctors and surgeons; pregnancy records; data on fetal death, ectopic pregnancies and miscarriage; and a series of electromicrographic images purporting to show defects of the coils’ metal ribbons.

The administrators of the Essure Problems groups blasted the FDA for requiring studies, rather than removing the device from the market. “These studies could take several years, and leaving the device on the market will only put more women’s lives at risk,” they wrote.

Rep. Mike Fitzpatrick (R-Pa.), who has been critical of Essure, said that the FDA’s actions are inadequate and said he will push for congressional action, including blocking government agencies from purchasing the device and revoking the FDA’s approval of Essure.

[email protected]

The Food and Drug Administration has ordered Bayer to conduct a 2,000-patient postmarketing study of the Essure implantable birth control device, to explore the risks it may pose to some women and examine how it is being employed in clinical practice.

Bayer, which manufactures the device, will also be required to add a boxed warning to the label, describing potential adverse events, and a “Patient Decision Checklist” to help guide preimplantation discussions, under draft guidance issued by the FDA on Feb. 29.

The 3-year observational study will compare data on complications, pregnancy, and pregnancy loss in Essure patients and in women who undergo bilateral tubal ligation, according to Dr. William Maisel, chief scientist at the FDA’s Center for Devices and Radiological Health.

“This will be a large observational study,” he said during an FDA press briefing on Feb. 29. “The specific questions will relate to overall complications rates; perforation, migration, and expulsion; chronic pelvic pain; abnormal uterine bleeding; allergy and hypersensitivity,” and obstetric outcomes.

Because FDA is requiring such a large patient cohort with long-term follow-up, final study results will be years away. Therefore, Bayer will be required to release data intermittently to keep the public well informed as research progresses, Dr. Maisel said.

Courtesy Bayer

The requested study will also examine why some patients don’t have a confirmation test to ensure that Essure has been properly placed 3 months after insertion – a key area that seems related to a number of reported adverse events, including pregnancy and device migration.

Despite the push for additional data, the FDA still believes that Essure is an appropriate and safe permanent option for the majority of women who want permanent birth control, Dr. Maisel said.

“It’s the only nonincisional form of permanent birth control. It requires no general anesthetic to insert, and most women go back to work in a day,” he said. “It is highly effective at preventing pregnancy, and it contains no drugs or hormones. Essure should remain an option for women seeking permanent birth control who are informed of its risks.”

Bayer officials said they will continue to work closely with the FDA to support the safe and effective use of the device.

“Patient safety and appropriate use of Essure are our greatest priorities,” Dr. Dario Mirski, senior vice president and head of medical affairs Americas at Bayer said in a statement. “A woman’s decision to choose a birth control method is a very important and personal one, and Bayer is committed to providing physicians with resources, tools, and information to help them counsel women about Essure.”

The boxed warning announced by the FDA will outline the adverse events that may be associated with Essure, including those that might occur during insertion and removal. The “Patient Decision Checklist” will be designed to help doctors stress the importance of the 3-month confirmation test to determine that it is correctly placed and that sufficient scar tissue has formed to prevent pregnancy. Both patient and physician will have to sign off on the checklist before the device is employed.

The FDA is seeking public comments on the proposed language for the warnings. The docket will be open for 60 days.

“The actions we are taking today will encourage important conversations between women and their doctors to help patients make more informed decisions about whether or not Essure is right for them,” said Dr. Maisel. “They also reflect our recognition that more rigorous research is needed to better understand if certain women are at heightened risk of complications.”

The draft guidance solidifies discussions that occurred last fall during a meeting of the FDA Obstetrics and Gynecology Devices Panel. During that meeting, the 19-member panel heard testimony from dozens of women who developed pain and other serious problems, including autoimmune diseases, after receiving Essure.

Since the device was approved in 2002, the FDA has received more than 5,000 complaints of such adverse reactions. These include 631 pregnancies and 294 pregnancy losses.

Between the September meeting and the FDA’s draft guidance announcement, the agency has received even more information from patients. A 22,000-person support group called Essure Problems collected and submitted a large amount of personal and clinical data. The package was submitted to the FDA on Feb. 22 and includes surgical notes and photos; letters from doctors and surgeons; pregnancy records; data on fetal death, ectopic pregnancies and miscarriage; and a series of electromicrographic images purporting to show defects of the coils’ metal ribbons.

The administrators of the Essure Problems groups blasted the FDA for requiring studies, rather than removing the device from the market. “These studies could take several years, and leaving the device on the market will only put more women’s lives at risk,” they wrote.

Rep. Mike Fitzpatrick (R-Pa.), who has been critical of Essure, said that the FDA’s actions are inadequate and said he will push for congressional action, including blocking government agencies from purchasing the device and revoking the FDA’s approval of Essure.

[email protected]

The Food and Drug Administration has ordered Bayer to conduct a 2,000-patient postmarketing study of the Essure implantable birth control device, to explore the risks it may pose to some women and examine how it is being employed in clinical practice.

Bayer, which manufactures the device, will also be required to add a boxed warning to the label, describing potential adverse events, and a “Patient Decision Checklist” to help guide preimplantation discussions, under draft guidance issued by the FDA on Feb. 29.

The 3-year observational study will compare data on complications, pregnancy, and pregnancy loss in Essure patients and in women who undergo bilateral tubal ligation, according to Dr. William Maisel, chief scientist at the FDA’s Center for Devices and Radiological Health.

“This will be a large observational study,” he said during an FDA press briefing on Feb. 29. “The specific questions will relate to overall complications rates; perforation, migration, and expulsion; chronic pelvic pain; abnormal uterine bleeding; allergy and hypersensitivity,” and obstetric outcomes.

Because FDA is requiring such a large patient cohort with long-term follow-up, final study results will be years away. Therefore, Bayer will be required to release data intermittently to keep the public well informed as research progresses, Dr. Maisel said.

Courtesy Bayer

The requested study will also examine why some patients don’t have a confirmation test to ensure that Essure has been properly placed 3 months after insertion – a key area that seems related to a number of reported adverse events, including pregnancy and device migration.

Despite the push for additional data, the FDA still believes that Essure is an appropriate and safe permanent option for the majority of women who want permanent birth control, Dr. Maisel said.

“It’s the only nonincisional form of permanent birth control. It requires no general anesthetic to insert, and most women go back to work in a day,” he said. “It is highly effective at preventing pregnancy, and it contains no drugs or hormones. Essure should remain an option for women seeking permanent birth control who are informed of its risks.”

Bayer officials said they will continue to work closely with the FDA to support the safe and effective use of the device.

“Patient safety and appropriate use of Essure are our greatest priorities,” Dr. Dario Mirski, senior vice president and head of medical affairs Americas at Bayer said in a statement. “A woman’s decision to choose a birth control method is a very important and personal one, and Bayer is committed to providing physicians with resources, tools, and information to help them counsel women about Essure.”

The boxed warning announced by the FDA will outline the adverse events that may be associated with Essure, including those that might occur during insertion and removal. The “Patient Decision Checklist” will be designed to help doctors stress the importance of the 3-month confirmation test to determine that it is correctly placed and that sufficient scar tissue has formed to prevent pregnancy. Both patient and physician will have to sign off on the checklist before the device is employed.

The FDA is seeking public comments on the proposed language for the warnings. The docket will be open for 60 days.

“The actions we are taking today will encourage important conversations between women and their doctors to help patients make more informed decisions about whether or not Essure is right for them,” said Dr. Maisel. “They also reflect our recognition that more rigorous research is needed to better understand if certain women are at heightened risk of complications.”

The draft guidance solidifies discussions that occurred last fall during a meeting of the FDA Obstetrics and Gynecology Devices Panel. During that meeting, the 19-member panel heard testimony from dozens of women who developed pain and other serious problems, including autoimmune diseases, after receiving Essure.

Since the device was approved in 2002, the FDA has received more than 5,000 complaints of such adverse reactions. These include 631 pregnancies and 294 pregnancy losses.

Between the September meeting and the FDA’s draft guidance announcement, the agency has received even more information from patients. A 22,000-person support group called Essure Problems collected and submitted a large amount of personal and clinical data. The package was submitted to the FDA on Feb. 22 and includes surgical notes and photos; letters from doctors and surgeons; pregnancy records; data on fetal death, ectopic pregnancies and miscarriage; and a series of electromicrographic images purporting to show defects of the coils’ metal ribbons.

The administrators of the Essure Problems groups blasted the FDA for requiring studies, rather than removing the device from the market. “These studies could take several years, and leaving the device on the market will only put more women’s lives at risk,” they wrote.

Rep. Mike Fitzpatrick (R-Pa.), who has been critical of Essure, said that the FDA’s actions are inadequate and said he will push for congressional action, including blocking government agencies from purchasing the device and revoking the FDA’s approval of Essure.

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Serological evidence from French Polynesia links an outbreak of Zika virus to a spike in cases of Guillain-Barré syndrome seen there in 2013-2014.

The research, published online Feb. 29 in The Lancet, is the first to use a case-control design to demonstrate that Zika, a mosquito-borne flavivirus, is associated with Guillain-Barré syndrome (Lancet. 2016 Feb 29. doi: 10.1016/S0140-6736(16)00562-6).

Guillain-Barré syndrome (GBS) is an immune-mediated flaccid paralysis that can follow viral or bacterial infections. Most patients with GBS recover with intensive care in hospitals, although the syndrome can be permanently debilitating or, in rare cases, fatal.

Courtesy Wikimedia Commons/Muhammad Mahdi Karim/Creative Commons License

As a large outbreak of Zika continues in Central and South America, hospitals should be prepared for excess GBS cases, the authors of the study say, and assure adequate intensive-care capacity to treat them. Based on the 66% attack rate of Zika during the French Polynesia outbreak, investigators estimated the incidence of GBS at 0.24 per 1,000 Zika infections, but noted that it could be different in the current outbreak.

Dr. Van-Mai Cao-Lormeau of the Unit of Emerging Infectious Diseases at Institut Louis Malardé in Papeete, French Polynesia, alongside colleagues in France and French Polynesia, used a case-control design to compare serological samples from 42 patients (74% male) diagnosed at a Tahiti hospital with GBS with samples from age-and sex-matched patients who presented at the same hospital, also during the time of the outbreak, with a nonfebrile illness (n = 98) or with acute Zika disease without neurological symptoms (n = 70).

The investigators found that all but one patient with GBS had Zika virus antibodies, and all of them had neutralizing antibodies to Zika virus. By comparison, only 56% (n = 54) of the control group admitted with nonfebrile illness had neutralizing antibodies (P less than .0001).

Also, 93% of the GBS patients had Zika virus immunoglobulin M (IgM) and 88% reported symptoms consistent with Zika infection a mean of 6 days before onset of neurological symptoms. Acute Zika infection is usually characterized by rash, fever, and conjunctivitis.

Past dengue virus infection, which had been considered a possible risk factor for Zika-mediated GBS, did not differ significantly between patients in the control groups and those with GBS.

The investigators were also able to subtype the clinical characteristics of the GBS cases as consistent with acute motor axonal neuropathy, or AMAN, phenotype. However, the antibodies typically seen associated with AMAN were not seen in these patients, leading investigators to suspect that a different biological pathway was responsible.

More than a third of the GBS patients in the study required intensive care, most of these also with respiratory support, though none died.

The government of France, the European Union, and the Wellcome Trust funded the study. The researchers declared that they had no competing interests.

Serological evidence from French Polynesia links an outbreak of Zika virus to a spike in cases of Guillain-Barré syndrome seen there in 2013-2014.

The research, published online Feb. 29 in The Lancet, is the first to use a case-control design to demonstrate that Zika, a mosquito-borne flavivirus, is associated with Guillain-Barré syndrome (Lancet. 2016 Feb 29. doi: 10.1016/S0140-6736(16)00562-6).

Guillain-Barré syndrome (GBS) is an immune-mediated flaccid paralysis that can follow viral or bacterial infections. Most patients with GBS recover with intensive care in hospitals, although the syndrome can be permanently debilitating or, in rare cases, fatal.

Courtesy Wikimedia Commons/Muhammad Mahdi Karim/Creative Commons License

As a large outbreak of Zika continues in Central and South America, hospitals should be prepared for excess GBS cases, the authors of the study say, and assure adequate intensive-care capacity to treat them. Based on the 66% attack rate of Zika during the French Polynesia outbreak, investigators estimated the incidence of GBS at 0.24 per 1,000 Zika infections, but noted that it could be different in the current outbreak.

Dr. Van-Mai Cao-Lormeau of the Unit of Emerging Infectious Diseases at Institut Louis Malardé in Papeete, French Polynesia, alongside colleagues in France and French Polynesia, used a case-control design to compare serological samples from 42 patients (74% male) diagnosed at a Tahiti hospital with GBS with samples from age-and sex-matched patients who presented at the same hospital, also during the time of the outbreak, with a nonfebrile illness (n = 98) or with acute Zika disease without neurological symptoms (n = 70).

The investigators found that all but one patient with GBS had Zika virus antibodies, and all of them had neutralizing antibodies to Zika virus. By comparison, only 56% (n = 54) of the control group admitted with nonfebrile illness had neutralizing antibodies (P less than .0001).

Also, 93% of the GBS patients had Zika virus immunoglobulin M (IgM) and 88% reported symptoms consistent with Zika infection a mean of 6 days before onset of neurological symptoms. Acute Zika infection is usually characterized by rash, fever, and conjunctivitis.

Past dengue virus infection, which had been considered a possible risk factor for Zika-mediated GBS, did not differ significantly between patients in the control groups and those with GBS.

The investigators were also able to subtype the clinical characteristics of the GBS cases as consistent with acute motor axonal neuropathy, or AMAN, phenotype. However, the antibodies typically seen associated with AMAN were not seen in these patients, leading investigators to suspect that a different biological pathway was responsible.

More than a third of the GBS patients in the study required intensive care, most of these also with respiratory support, though none died.

The government of France, the European Union, and the Wellcome Trust funded the study. The researchers declared that they had no competing interests.

Serological evidence from French Polynesia links an outbreak of Zika virus to a spike in cases of Guillain-Barré syndrome seen there in 2013-2014.

The research, published online Feb. 29 in The Lancet, is the first to use a case-control design to demonstrate that Zika, a mosquito-borne flavivirus, is associated with Guillain-Barré syndrome (Lancet. 2016 Feb 29. doi: 10.1016/S0140-6736(16)00562-6).

Guillain-Barré syndrome (GBS) is an immune-mediated flaccid paralysis that can follow viral or bacterial infections. Most patients with GBS recover with intensive care in hospitals, although the syndrome can be permanently debilitating or, in rare cases, fatal.

Courtesy Wikimedia Commons/Muhammad Mahdi Karim/Creative Commons License

As a large outbreak of Zika continues in Central and South America, hospitals should be prepared for excess GBS cases, the authors of the study say, and assure adequate intensive-care capacity to treat them. Based on the 66% attack rate of Zika during the French Polynesia outbreak, investigators estimated the incidence of GBS at 0.24 per 1,000 Zika infections, but noted that it could be different in the current outbreak.

Dr. Van-Mai Cao-Lormeau of the Unit of Emerging Infectious Diseases at Institut Louis Malardé in Papeete, French Polynesia, alongside colleagues in France and French Polynesia, used a case-control design to compare serological samples from 42 patients (74% male) diagnosed at a Tahiti hospital with GBS with samples from age-and sex-matched patients who presented at the same hospital, also during the time of the outbreak, with a nonfebrile illness (n = 98) or with acute Zika disease without neurological symptoms (n = 70).

The investigators found that all but one patient with GBS had Zika virus antibodies, and all of them had neutralizing antibodies to Zika virus. By comparison, only 56% (n = 54) of the control group admitted with nonfebrile illness had neutralizing antibodies (P less than .0001).

Also, 93% of the GBS patients had Zika virus immunoglobulin M (IgM) and 88% reported symptoms consistent with Zika infection a mean of 6 days before onset of neurological symptoms. Acute Zika infection is usually characterized by rash, fever, and conjunctivitis.

Past dengue virus infection, which had been considered a possible risk factor for Zika-mediated GBS, did not differ significantly between patients in the control groups and those with GBS.

The investigators were also able to subtype the clinical characteristics of the GBS cases as consistent with acute motor axonal neuropathy, or AMAN, phenotype. However, the antibodies typically seen associated with AMAN were not seen in these patients, leading investigators to suspect that a different biological pathway was responsible.

More than a third of the GBS patients in the study required intensive care, most of these also with respiratory support, though none died.

The government of France, the European Union, and the Wellcome Trust funded the study. The researchers declared that they had no competing interests.