In Reply: We thank Dr. Blankfield for raising these two important points. Although the findings of the PARADIGM-HF study are compelling, the design and results of this trial have incited many questions.

To address his first point, about the differential dosages of the two drugs, we agree, and we did mention in our review that one concern about the results of PARADIGM-HF is the unequal dosages of valsartan and enalapril in the two different arms. We mentioned that this dosage of enalapril was chosen based on its survival benefit in previous trials. However, this still raises the question of whether the benefit seen in the sacubitril-valsartan group was due to greater inhibition of the renin-angiotensin-aldosterone system rather than to the new drug.

To address his second point, the decrease in blood pressure in the sacubitril-valsartan arm was significant, and the patients taking this drug were more likely to have symptomatic hypotension, which may contribute to patient intolerance and difficulty initiating treatment with this drug. Dr. Blankfield brings up an interesting point regarding reduction of blood pressure driving the decrease of events in the sacubitril-valsartan group. In the original trial results section, the authors mentioned that when the difference in blood pressure between the two groups was examined as a time-dependent covariate, it was not a significant predictor of the benefit of sacubitril-valsartan.¹

Furthermore, although higher blood pressure is associated with worse cardiovascular outcomes in the general population, higher blood pressure has been shown to be protective in heart failure patients.² Several studies have shown that the relationship between blood pressure and the mortality rate in patients with heart failure is paradoxical and complex.^2–4 Lee et al³ found that this relationship was U-shaped, with increased mortality risk in those with high and low blood pressures (< 120 mm Hg). Ather et al⁴ also showed that the relationship was U-shaped in patients with a mild to moderate reduction in left ventricular ejection fraction, but linear in those with severely reduced ejection fraction. This study also found that a decrease in systolic blood pressure below 110 mm Hg was associated with increased mortality risk.

The findings of PARADIGM-HF have sparked much conversation and implementation of practice change in the treatment of heart failure patients, and we await additional data on the use and limitations of sacubitril-valsartan in this group of patients.

In Reply: We thank Dr. Blankfield for raising these two important points. Although the findings of the PARADIGM-HF study are compelling, the design and results of this trial have incited many questions.

To address his first point, about the differential dosages of the two drugs, we agree, and we did mention in our review that one concern about the results of PARADIGM-HF is the unequal dosages of valsartan and enalapril in the two different arms. We mentioned that this dosage of enalapril was chosen based on its survival benefit in previous trials. However, this still raises the question of whether the benefit seen in the sacubitril-valsartan group was due to greater inhibition of the renin-angiotensin-aldosterone system rather than to the new drug.

To address his second point, the decrease in blood pressure in the sacubitril-valsartan arm was significant, and the patients taking this drug were more likely to have symptomatic hypotension, which may contribute to patient intolerance and difficulty initiating treatment with this drug. Dr. Blankfield brings up an interesting point regarding reduction of blood pressure driving the decrease of events in the sacubitril-valsartan group. In the original trial results section, the authors mentioned that when the difference in blood pressure between the two groups was examined as a time-dependent covariate, it was not a significant predictor of the benefit of sacubitril-valsartan.¹

Furthermore, although higher blood pressure is associated with worse cardiovascular outcomes in the general population, higher blood pressure has been shown to be protective in heart failure patients.² Several studies have shown that the relationship between blood pressure and the mortality rate in patients with heart failure is paradoxical and complex.^2–4 Lee et al³ found that this relationship was U-shaped, with increased mortality risk in those with high and low blood pressures (< 120 mm Hg). Ather et al⁴ also showed that the relationship was U-shaped in patients with a mild to moderate reduction in left ventricular ejection fraction, but linear in those with severely reduced ejection fraction. This study also found that a decrease in systolic blood pressure below 110 mm Hg was associated with increased mortality risk.

The findings of PARADIGM-HF have sparked much conversation and implementation of practice change in the treatment of heart failure patients, and we await additional data on the use and limitations of sacubitril-valsartan in this group of patients.

In Reply: We thank Dr. Blankfield for raising these two important points. Although the findings of the PARADIGM-HF study are compelling, the design and results of this trial have incited many questions.

To address his first point, about the differential dosages of the two drugs, we agree, and we did mention in our review that one concern about the results of PARADIGM-HF is the unequal dosages of valsartan and enalapril in the two different arms. We mentioned that this dosage of enalapril was chosen based on its survival benefit in previous trials. However, this still raises the question of whether the benefit seen in the sacubitril-valsartan group was due to greater inhibition of the renin-angiotensin-aldosterone system rather than to the new drug.

To address his second point, the decrease in blood pressure in the sacubitril-valsartan arm was significant, and the patients taking this drug were more likely to have symptomatic hypotension, which may contribute to patient intolerance and difficulty initiating treatment with this drug. Dr. Blankfield brings up an interesting point regarding reduction of blood pressure driving the decrease of events in the sacubitril-valsartan group. In the original trial results section, the authors mentioned that when the difference in blood pressure between the two groups was examined as a time-dependent covariate, it was not a significant predictor of the benefit of sacubitril-valsartan.¹

Furthermore, although higher blood pressure is associated with worse cardiovascular outcomes in the general population, higher blood pressure has been shown to be protective in heart failure patients.² Several studies have shown that the relationship between blood pressure and the mortality rate in patients with heart failure is paradoxical and complex.^2–4 Lee et al³ found that this relationship was U-shaped, with increased mortality risk in those with high and low blood pressures (< 120 mm Hg). Ather et al⁴ also showed that the relationship was U-shaped in patients with a mild to moderate reduction in left ventricular ejection fraction, but linear in those with severely reduced ejection fraction. This study also found that a decrease in systolic blood pressure below 110 mm Hg was associated with increased mortality risk.

The findings of PARADIGM-HF have sparked much conversation and implementation of practice change in the treatment of heart failure patients, and we await additional data on the use and limitations of sacubitril-valsartan in this group of patients.

Inheriting the wrong genes and eating the wrong food (ie, gluten) are necessary for celiac disease to develop, but are not enough by themselves. Something else must be contributing, and evidence is pointing to the mix of bacteria that make our guts their home, collectively called the microbiome.

See related article

Celiac disease is a highly prevalent, chronic, immune-mediated form of enteropathy.¹ It affects 0.5% to 1% of the population, and although it is mostly seen in people of northern European descent, those in other populations can develop the disease as well. Historically, celiac disease was classified as an infant condition. However, it now commonly presents later in life (between ages 10 and 40) and often with extraintestinal manifestations.²

In this issue of Cleveland Clinic Journal of Medicine, Kochhar et al provide a comprehensive updated review of celiac disease.³

GENES AND GLUTEN ARE NECESSARY BUT NOT SUFFICIENT

Although genetic factors and exposure to gluten in the diet are proven to be necessary for celiac disease to develop, they are not sufficient. Evidence of this is in the numbers; although one-third of the general population carries the HLA susceptibility genes (specifically HLA-DQ2 and DQ8),⁴ only 2% to 5% of people with these genes develop clinically evident celiac disease.

Additional environmental factors must be contributing to disease development, but these other factors are poorly understood. Some of the possible culprits that might influence the risk of disease occurrence and the timing of its onset include⁵:

• The amount and quality of gluten ingested—the higher the concentration of gluten, the higher the risk, and different grains have gluten varieties with more or less immunogenic capabilities, ie, T-cell activation properties
• The pattern of infant feeding—the risk may be lower with breastfeeding than with formula
• The age at which gluten is introduced into the diet—the risk may be higher if gluten is introduced earlier.⁶

More recently, studies of the pathogenesis of celiac disease and gene-environmental interactions have expanded beyond host predisposition and dietary factors.

OUR BODIES, OUR MICROBIOMES: A SYMBIOTIC RELATIONSHIP

The role of the human microbiome in autoimmune disease is now being elucidated.⁷ Remarkably, the microorganisms living in our bodies outnumber our body cells by a factor of 10, and their genomes vastly exceed our own protein-coding genome capabilities by a factor of 100.

The gut microbiome is now considered a true bioreactor with enzymatic and immunologic capabilities beyond (and complementary to) those of its host. The commensal microbiome of the host intestine provides benefits that can be broken down into three broad categories:

• Nutritional—producing essential amino acids and vitamins
• Metabolic—degrading complex polysaccharides from dietary fibers
• Immunologic—shaping the host immune system while cooperating with it against pathogenic microorganisms.

The immunologic function is highly relevant. We have coevolved with our bacteria in a mutually beneficial, symbiotic relationship in which we maintain an active state of low inflammation so that a constant bacterial and dietary antigenic load can be tolerated.

Evidence points to dysbiosis as a factor leading to celiac disease and other autoimmune disorders

Is there a core human microbiome shared by all individuals? And what is the impact of altering the relative microbial composition (dysbiosis) in physiologic and disease states? To find out, the National Institutes of Health launched the Human Microbiome Project⁸ in 2008. Important tools in this work include novel culture-independent approaches (high-throughput DNA sequencing and whole-microbiome “shotgun” sequencing with metagenomic analysis) and computational analytical tools.⁹

An accumulating body of evidence is now available from animal models and human studies correlating states of intestinal dysbiosis (disruption in homeostatic community composition) with various disease processes. These have ranged from inflammatory bowel disease to systemic autoimmune disorders such as psoriasis, inflammatory arthropathies, and demyelinating central nervous system diseases.^10–14

RESEARCH INTO THE MICROBIOME IN CELIAC DISEASE

Celiac disease has also served as a unique model for studying this biologic relationship, and the microbiome has been postulated to have a role in its pathogenesis.¹⁵ Multiple clinical studies demonstrate that a state of intestinal dysbiosis is indeed associated with celiac disease.

Specifically, decreases in the abundance of Firmicutes spp and increases in Proteobacteria spp have been detected in both children and adults with active celiac disease.^16,17 Intriguingly, overrepresentation of Proteobacteria was also correlated with disease activity. Other studies have reported decreases in the proportion of reportedly protective, anti-inflammatory bacteria such as Bifidobacterium and increases in the proportion of Bacteroides and Escherichia coli in patients with active disease.^18,19 Altered diversity and altered metabolic function, ie, decreased concentration of protective short-chain fatty acids of the microbiota, have also been reported in patients with celiac disease.^19,20

To move beyond correlative studies and mechanistically address the possibility of causation, multiple groups have used a gnotobiotic approach, ie, maintaining animals under germ-free conditions and incorporating microbes of interest. This approach is highly relevant in studying whether the bacterial community composition is capable of modulating loss of tolerance to gluten in genetically susceptible hosts. A few notable examples have been published.

In germ-free rats, long-term feeding of gliadin, but not albumin, from birth until 2 months of age induced moderate small-intestinal damage.²¹ Similarly, germ-free nonobese diabetic-DQ8 mice developed more severe gluten-induced disease than mice with normal intestinal bacteria.²²

In small studies, people with celiac disease had fewer Firmicutes and Bifidobacteria and more Proteobacteria, Bacteroides, and E coli

These findings suggest that the normal gut microbiome may have intrinsic beneficial properties capable of reducing the inflammatory effects associated with gluten ingestion. Notably, the specific composition of the intestinal microbiome can define the fate of gluten-induced pathology. Mice colonized with commensal microbiota are indeed protected from gluten-induced pathology, while mice colonized with Proteobacteria spp develop a moderate degree of gluten-induced disease. When Escherichia coli derived from patients with celiac disease is added to commensal colonization, the celiac disease-like phenotype develops.²³

Taken together, these studies support the hypothesis that the intestinal microbiome may be another environmental factor involved in the development of celiac disease.

QUESTIONS AND CHALLENGES REMAIN

The results of clinical studies are not necessarily consistent at the taxonomy level. The fields of metagenomics, which investigates all genes and their enzymatic function in a given community, and metabolomics, which identifies bacterial end-products, characterizing their functional capabilities, are still in their infancy and will be required to further investigate functionality of the altered microbiome in celiac disease.

Second, the directionality—the causality or consequences of this dysbiosis—and timing—the moment at which changes occur, ie, after introducing gluten or at the time when symptoms appear—remain elusive, and prospective studies in humans will be essential.

Finally, more mechanistic studies in animal models are needed to dissect the host immune response to dietary gluten and perturbation of intestinal community composition. This may lead to the possibility of future interventions in the form of prebiotics, probiotics, or specific metabolites, complementary to gluten avoidance.

In the meantime, increasing disease awareness and rapid diagnosis and treatment continue to be of utmost importance to address the clinical consequences of celiac disease in both children and adults.

Inheriting the wrong genes and eating the wrong food (ie, gluten) are necessary for celiac disease to develop, but are not enough by themselves. Something else must be contributing, and evidence is pointing to the mix of bacteria that make our guts their home, collectively called the microbiome.

See related article

Celiac disease is a highly prevalent, chronic, immune-mediated form of enteropathy.¹ It affects 0.5% to 1% of the population, and although it is mostly seen in people of northern European descent, those in other populations can develop the disease as well. Historically, celiac disease was classified as an infant condition. However, it now commonly presents later in life (between ages 10 and 40) and often with extraintestinal manifestations.²

In this issue of Cleveland Clinic Journal of Medicine, Kochhar et al provide a comprehensive updated review of celiac disease.³

GENES AND GLUTEN ARE NECESSARY BUT NOT SUFFICIENT

Although genetic factors and exposure to gluten in the diet are proven to be necessary for celiac disease to develop, they are not sufficient. Evidence of this is in the numbers; although one-third of the general population carries the HLA susceptibility genes (specifically HLA-DQ2 and DQ8),⁴ only 2% to 5% of people with these genes develop clinically evident celiac disease.

Additional environmental factors must be contributing to disease development, but these other factors are poorly understood. Some of the possible culprits that might influence the risk of disease occurrence and the timing of its onset include⁵:

• The amount and quality of gluten ingested—the higher the concentration of gluten, the higher the risk, and different grains have gluten varieties with more or less immunogenic capabilities, ie, T-cell activation properties
• The pattern of infant feeding—the risk may be lower with breastfeeding than with formula
• The age at which gluten is introduced into the diet—the risk may be higher if gluten is introduced earlier.⁶

More recently, studies of the pathogenesis of celiac disease and gene-environmental interactions have expanded beyond host predisposition and dietary factors.

OUR BODIES, OUR MICROBIOMES: A SYMBIOTIC RELATIONSHIP

The role of the human microbiome in autoimmune disease is now being elucidated.⁷ Remarkably, the microorganisms living in our bodies outnumber our body cells by a factor of 10, and their genomes vastly exceed our own protein-coding genome capabilities by a factor of 100.

The gut microbiome is now considered a true bioreactor with enzymatic and immunologic capabilities beyond (and complementary to) those of its host. The commensal microbiome of the host intestine provides benefits that can be broken down into three broad categories:

• Nutritional—producing essential amino acids and vitamins
• Metabolic—degrading complex polysaccharides from dietary fibers
• Immunologic—shaping the host immune system while cooperating with it against pathogenic microorganisms.

The immunologic function is highly relevant. We have coevolved with our bacteria in a mutually beneficial, symbiotic relationship in which we maintain an active state of low inflammation so that a constant bacterial and dietary antigenic load can be tolerated.

Evidence points to dysbiosis as a factor leading to celiac disease and other autoimmune disorders

Is there a core human microbiome shared by all individuals? And what is the impact of altering the relative microbial composition (dysbiosis) in physiologic and disease states? To find out, the National Institutes of Health launched the Human Microbiome Project⁸ in 2008. Important tools in this work include novel culture-independent approaches (high-throughput DNA sequencing and whole-microbiome “shotgun” sequencing with metagenomic analysis) and computational analytical tools.⁹

An accumulating body of evidence is now available from animal models and human studies correlating states of intestinal dysbiosis (disruption in homeostatic community composition) with various disease processes. These have ranged from inflammatory bowel disease to systemic autoimmune disorders such as psoriasis, inflammatory arthropathies, and demyelinating central nervous system diseases.^10–14

RESEARCH INTO THE MICROBIOME IN CELIAC DISEASE

Celiac disease has also served as a unique model for studying this biologic relationship, and the microbiome has been postulated to have a role in its pathogenesis.¹⁵ Multiple clinical studies demonstrate that a state of intestinal dysbiosis is indeed associated with celiac disease.

Specifically, decreases in the abundance of Firmicutes spp and increases in Proteobacteria spp have been detected in both children and adults with active celiac disease.^16,17 Intriguingly, overrepresentation of Proteobacteria was also correlated with disease activity. Other studies have reported decreases in the proportion of reportedly protective, anti-inflammatory bacteria such as Bifidobacterium and increases in the proportion of Bacteroides and Escherichia coli in patients with active disease.^18,19 Altered diversity and altered metabolic function, ie, decreased concentration of protective short-chain fatty acids of the microbiota, have also been reported in patients with celiac disease.^19,20

To move beyond correlative studies and mechanistically address the possibility of causation, multiple groups have used a gnotobiotic approach, ie, maintaining animals under germ-free conditions and incorporating microbes of interest. This approach is highly relevant in studying whether the bacterial community composition is capable of modulating loss of tolerance to gluten in genetically susceptible hosts. A few notable examples have been published.

In germ-free rats, long-term feeding of gliadin, but not albumin, from birth until 2 months of age induced moderate small-intestinal damage.²¹ Similarly, germ-free nonobese diabetic-DQ8 mice developed more severe gluten-induced disease than mice with normal intestinal bacteria.²²

In small studies, people with celiac disease had fewer Firmicutes and Bifidobacteria and more Proteobacteria, Bacteroides, and E coli

These findings suggest that the normal gut microbiome may have intrinsic beneficial properties capable of reducing the inflammatory effects associated with gluten ingestion. Notably, the specific composition of the intestinal microbiome can define the fate of gluten-induced pathology. Mice colonized with commensal microbiota are indeed protected from gluten-induced pathology, while mice colonized with Proteobacteria spp develop a moderate degree of gluten-induced disease. When Escherichia coli derived from patients with celiac disease is added to commensal colonization, the celiac disease-like phenotype develops.²³

Taken together, these studies support the hypothesis that the intestinal microbiome may be another environmental factor involved in the development of celiac disease.

QUESTIONS AND CHALLENGES REMAIN

The results of clinical studies are not necessarily consistent at the taxonomy level. The fields of metagenomics, which investigates all genes and their enzymatic function in a given community, and metabolomics, which identifies bacterial end-products, characterizing their functional capabilities, are still in their infancy and will be required to further investigate functionality of the altered microbiome in celiac disease.

Second, the directionality—the causality or consequences of this dysbiosis—and timing—the moment at which changes occur, ie, after introducing gluten or at the time when symptoms appear—remain elusive, and prospective studies in humans will be essential.

Finally, more mechanistic studies in animal models are needed to dissect the host immune response to dietary gluten and perturbation of intestinal community composition. This may lead to the possibility of future interventions in the form of prebiotics, probiotics, or specific metabolites, complementary to gluten avoidance.

In the meantime, increasing disease awareness and rapid diagnosis and treatment continue to be of utmost importance to address the clinical consequences of celiac disease in both children and adults.

Inheriting the wrong genes and eating the wrong food (ie, gluten) are necessary for celiac disease to develop, but are not enough by themselves. Something else must be contributing, and evidence is pointing to the mix of bacteria that make our guts their home, collectively called the microbiome.

See related article

Celiac disease is a highly prevalent, chronic, immune-mediated form of enteropathy.¹ It affects 0.5% to 1% of the population, and although it is mostly seen in people of northern European descent, those in other populations can develop the disease as well. Historically, celiac disease was classified as an infant condition. However, it now commonly presents later in life (between ages 10 and 40) and often with extraintestinal manifestations.²

In this issue of Cleveland Clinic Journal of Medicine, Kochhar et al provide a comprehensive updated review of celiac disease.³

GENES AND GLUTEN ARE NECESSARY BUT NOT SUFFICIENT

Although genetic factors and exposure to gluten in the diet are proven to be necessary for celiac disease to develop, they are not sufficient. Evidence of this is in the numbers; although one-third of the general population carries the HLA susceptibility genes (specifically HLA-DQ2 and DQ8),⁴ only 2% to 5% of people with these genes develop clinically evident celiac disease.

Additional environmental factors must be contributing to disease development, but these other factors are poorly understood. Some of the possible culprits that might influence the risk of disease occurrence and the timing of its onset include⁵:

• The amount and quality of gluten ingested—the higher the concentration of gluten, the higher the risk, and different grains have gluten varieties with more or less immunogenic capabilities, ie, T-cell activation properties
• The pattern of infant feeding—the risk may be lower with breastfeeding than with formula
• The age at which gluten is introduced into the diet—the risk may be higher if gluten is introduced earlier.⁶

More recently, studies of the pathogenesis of celiac disease and gene-environmental interactions have expanded beyond host predisposition and dietary factors.

OUR BODIES, OUR MICROBIOMES: A SYMBIOTIC RELATIONSHIP

The role of the human microbiome in autoimmune disease is now being elucidated.⁷ Remarkably, the microorganisms living in our bodies outnumber our body cells by a factor of 10, and their genomes vastly exceed our own protein-coding genome capabilities by a factor of 100.

The gut microbiome is now considered a true bioreactor with enzymatic and immunologic capabilities beyond (and complementary to) those of its host. The commensal microbiome of the host intestine provides benefits that can be broken down into three broad categories:

• Nutritional—producing essential amino acids and vitamins
• Metabolic—degrading complex polysaccharides from dietary fibers
• Immunologic—shaping the host immune system while cooperating with it against pathogenic microorganisms.

The immunologic function is highly relevant. We have coevolved with our bacteria in a mutually beneficial, symbiotic relationship in which we maintain an active state of low inflammation so that a constant bacterial and dietary antigenic load can be tolerated.

Evidence points to dysbiosis as a factor leading to celiac disease and other autoimmune disorders

Is there a core human microbiome shared by all individuals? And what is the impact of altering the relative microbial composition (dysbiosis) in physiologic and disease states? To find out, the National Institutes of Health launched the Human Microbiome Project⁸ in 2008. Important tools in this work include novel culture-independent approaches (high-throughput DNA sequencing and whole-microbiome “shotgun” sequencing with metagenomic analysis) and computational analytical tools.⁹

An accumulating body of evidence is now available from animal models and human studies correlating states of intestinal dysbiosis (disruption in homeostatic community composition) with various disease processes. These have ranged from inflammatory bowel disease to systemic autoimmune disorders such as psoriasis, inflammatory arthropathies, and demyelinating central nervous system diseases.^10–14

RESEARCH INTO THE MICROBIOME IN CELIAC DISEASE

Celiac disease has also served as a unique model for studying this biologic relationship, and the microbiome has been postulated to have a role in its pathogenesis.¹⁵ Multiple clinical studies demonstrate that a state of intestinal dysbiosis is indeed associated with celiac disease.

Specifically, decreases in the abundance of Firmicutes spp and increases in Proteobacteria spp have been detected in both children and adults with active celiac disease.^16,17 Intriguingly, overrepresentation of Proteobacteria was also correlated with disease activity. Other studies have reported decreases in the proportion of reportedly protective, anti-inflammatory bacteria such as Bifidobacterium and increases in the proportion of Bacteroides and Escherichia coli in patients with active disease.^18,19 Altered diversity and altered metabolic function, ie, decreased concentration of protective short-chain fatty acids of the microbiota, have also been reported in patients with celiac disease.^19,20

To move beyond correlative studies and mechanistically address the possibility of causation, multiple groups have used a gnotobiotic approach, ie, maintaining animals under germ-free conditions and incorporating microbes of interest. This approach is highly relevant in studying whether the bacterial community composition is capable of modulating loss of tolerance to gluten in genetically susceptible hosts. A few notable examples have been published.

In germ-free rats, long-term feeding of gliadin, but not albumin, from birth until 2 months of age induced moderate small-intestinal damage.²¹ Similarly, germ-free nonobese diabetic-DQ8 mice developed more severe gluten-induced disease than mice with normal intestinal bacteria.²²

In small studies, people with celiac disease had fewer Firmicutes and Bifidobacteria and more Proteobacteria, Bacteroides, and E coli

These findings suggest that the normal gut microbiome may have intrinsic beneficial properties capable of reducing the inflammatory effects associated with gluten ingestion. Notably, the specific composition of the intestinal microbiome can define the fate of gluten-induced pathology. Mice colonized with commensal microbiota are indeed protected from gluten-induced pathology, while mice colonized with Proteobacteria spp develop a moderate degree of gluten-induced disease. When Escherichia coli derived from patients with celiac disease is added to commensal colonization, the celiac disease-like phenotype develops.²³

Taken together, these studies support the hypothesis that the intestinal microbiome may be another environmental factor involved in the development of celiac disease.

QUESTIONS AND CHALLENGES REMAIN

The results of clinical studies are not necessarily consistent at the taxonomy level. The fields of metagenomics, which investigates all genes and their enzymatic function in a given community, and metabolomics, which identifies bacterial end-products, characterizing their functional capabilities, are still in their infancy and will be required to further investigate functionality of the altered microbiome in celiac disease.

Second, the directionality—the causality or consequences of this dysbiosis—and timing—the moment at which changes occur, ie, after introducing gluten or at the time when symptoms appear—remain elusive, and prospective studies in humans will be essential.

Finally, more mechanistic studies in animal models are needed to dissect the host immune response to dietary gluten and perturbation of intestinal community composition. This may lead to the possibility of future interventions in the form of prebiotics, probiotics, or specific metabolites, complementary to gluten avoidance.

In the meantime, increasing disease awareness and rapid diagnosis and treatment continue to be of utmost importance to address the clinical consequences of celiac disease in both children and adults.

Celiac disease is an autoimmune disorder that occurs in genetically predisposed individuals in response to ingestion of gluten. Its prevalence is about 0.7% of the US population.¹

See related editorial

The gold standard for diagnosis is duodenal biopsy, in which the histologic features may include varying gradations of flattening of intestinal villi, crypt hyperplasia, and infiltration of the lamina propria by lymphocytes. Many patients have no symptoms at the time of diagnosis, but presenting symptoms can include diarrhea along with features of malabsorption,² and, in about 25% of patients (mainly adults), a bullous cutaneous disorder called dermatitis herpetiformis.^3,4 The pathogenesis of celiac disease and that of dermatitis herpetiformis are similar in that in both, ingestion of gluten induces an inflammatory reaction leading to the clinical manifestations.

The mainstay of treatment of celiac disease remains avoidance of gluten in the diet.

GENETIC PREDISPOSITION AND DIETARY TRIGGER

The pathogenesis of celiac disease has been well studied in both humans and animals. The disease is thought to develop by an interplay of genetic and autoimmune factors and the ingestion of gluten (ie, an environmental factor).

Celiac disease occurs in genetically predisposed individuals, ie, those who carry the HLA alleles DQ2 (DQA1*05, DQB1*02), DQ8 (DQA1*03, DQB1*0302), or both.⁵

Ingestion of gluten is necessary for the disease to develop. Gluten, the protein component of wheat, barley, and rye, contains proteins called prolamins, which vary among the different types of grain. In wheat, the prolamin is gliadin, which is alcohol-soluble. In barley the prolamin is hordein, and in rye it is secalin.⁴ The prolamin content in gluten makes it resistant to degradation by gastric, pancreatic, and intestinal brush border proteases.⁶ Gluten crosses the epithelial barrier and promotes an inflammatory reaction by both the innate and adaptive immune systems that can ultimately result in flattening of villi and crypt hyperplasia (Figure 1).⁷

Tissue transglutaminase also plays a central role in the pathogenesis, as it further deaminates gliadin and increases its immunogenicity by causing it to bind to receptors on antigen-presenting cells with stronger affinity. Furthermore, gliadin-tissue transglutaminase complexes formed by protein cross-linkages generate an autoantibody response (predominantly immunoglobulin A [IgA] type) that can exacerbate the inflammatory process.^8,9

Certain viral infections during childhood, such as rotavirus and adenovirus infection, can increase the risk of celiac disease.^10–13 Although earlier studies reported that breast-feeding seemed to have a protective effect,¹⁴ as did introducing grains in the diet in the 4th to 6th months of life as opposed to earlier or later,¹⁵ more recent studies have not confirmed these benefits.^16,17

CLINICAL FEATURES

Most adults diagnosed with celiac disease are in their 30s, 40s, or 50s, and most are women.

Diarrhea remains a common presenting symptom, although the percentage of patients with celiac disease who present with diarrhea has decreased over time.^18,19

Abdominal pain and weight loss are also common.²⁰

Pallor or decreased exercise tolerance can develop due to anemia from iron malabsorption, and some patients have easy bruising due to vitamin K malabsorption.

Gynecologic and obstetric complications associated with celiac disease include delayed menarche, amenorrhea, spontaneous abortion, intrauterine growth retardation, preterm delivery, and low-birth-weight babies.^21,22 Patients who follow a gluten-free diet tend to have a lower incidence of intrauterine growth retardation, preterm delivery, and low-birth-weight babies compared with untreated patients.^21,22

Osteoporosis and osteopenia due to malabsorption of vitamin D are common and are seen in two-thirds of patients presenting with celiac disease.²³ A meta-analysis and position statement from Canada concluded that dual-energy x-ray absorptiometry should be done at the time of diagnosis of celiac disease if the patient is at risk of osteoporosis.²⁴ If the scan is abnormal, it should be repeated 1 to 2 years after initiation of a gluten-free diet and vitamin D supplementation to ensure that the osteopenia has improved.²⁴

OTHER DISEASE ASSOCIATIONS

Celiac disease is associated with various other autoimmune diseases (Table 1), including Hashimoto thyroiditis,²⁵ type 1 diabetes mellitus,²⁶ primary biliary cirrhosis,²⁷ primary sclerosing cholangitis,²⁸ and Addison disease.²⁹

Dermatitis herpetiformis

Dermatitis herpetiformis is one of the most common cutaneous manifestations of celiac disease. It presents between ages 10 and 50, and unlike celiac disease, it is more common in males.³⁰

Photo courtesy of Alok Vij, Department of Dermatology, Cleveland Clinic.

The characteristic lesions are pruritic, grouped erythematous papules surmounted by vesicles distributed symmetrically over the extensor surfaces of the upper and lower extremities, elbows, knees, scalp, nuchal area, and buttocks³¹ (Figures 2 and 3). In addition, some patients also present with vesicles, erythematous macules, and erosions in the oral mucosa³² or purpura on the palms and soles.^33–35

Photo courtesy of Alok Vij, MD, Department of Dermatology, Cleveland Clinic.

The pathogenesis of dermatitis herpetiformis in the skin is related to the pathogenesis of celiac disease in the gut. Like celiac disease, dermatitis herpetiformis is more common in genetically predisposed individuals carrying either the HLA-DQ2 or the HLA-DQ8 haplotype. In the skin, there is an analogue of tissue transglutaminase called epidermal transglutaminase, which helps in maintaining the integrity of cornified epithelium.³⁶ In patients with celiac disease, along with formation of IgA antibodies to tissue transglutaminase, there is also formation of IgA antibodies to epidermal transglutaminase. IgA antibodies are deposit- ed in the tips of dermal papillae and along the basement membrane.^37–39 These deposits then initiate an inflammatory response that is predominantly neutrophilic and results in formation of vesicles and bullae in the skin.⁴⁰ Also supporting the linkage between celiac disease and dermatitis herpetiformis, if patients adhere to a gluten-free diet, the deposits of immune complexes in the skin disappear.⁴¹

CELIAC DISEASE-ASSOCIATED MALIGNANCY

Patients with celiac disease have a higher risk of developing enteric malignancies, particularly intestinal T-cell lymphoma, and they have smaller increased risk of colon, oropharyngeal, esophageal, pancreatic, and hepatobiliary cancer.^42–45 For all of these cancers, the risk is higher than in the general public in the first year after celiac disease is diagnosed, but after the first year, the risk is increased only for small-bowel and hepatobiliary malignancies.⁴⁶

T-cell lymphoma

T-cell lymphoma is a rare but serious complication that has a poor prognosis.⁴⁷ Its prevalence has been increasing with time and is currently estimated to be around 0.01 to 0.02 per 100,000 people in the population as a whole.^48,49 The risk of developing lymphoma is 2.5 times higher in people with celiac disease than in the general population.⁵⁰ T-cell lymphoma is seen more commonly in patients with refractory celiac disease and DQ2 homozygosity.⁵¹

This disease is difficult to detect clinically, but sometimes it presents as an acute exacer­bation of celiac disease symptoms despite strict adherence to a gluten-free diet. Associated alarm symptoms include fever, night sweats, and laboratory abnormalities such as low albumin and high lactate dehydrogenase levels.

Strict adherence to a gluten-free diet remains the only way to prevent intestinal T-cell lymphoma.⁵²

Other malignancies

Some earlier studies reported an increased risk of thyroid cancer and malignant melanoma, but two newer studies have refuted this finding.^53,54 Conversely, celiac disease appears to have a protective effect against breast, ovarian, and endometrial cancers.⁵⁵

DIAGNOSIS: SEROLOGY, BIOPSY, GENETIC TESTING

Serologic tests

Patients strongly suspected of having celiac disease should be screened for IgA antibodies to tissue transglutaminase while on a gluten-containing diet, according to recommendations of the American College of Gastroenterology (Figure 4).⁵⁶ The sensitivity and specificity of this test are around 95%. If the patient has an IgA deficiency, screening should be done by checking the level of IgG antibodies to tissue transglutaminase.

Biopsy for confirmation

If testing for IgA to tissue transglutaminase is positive, upper endoscopy with biopsy is needed. Ideally, one to two samples should be taken from the duodenal bulb and at least four samples from the rest of the duodenum, preferably from two different locations.⁵⁶

Celiac disease has a broad spectrum of pathologic expressions, from mild distortion of crypt architecture to total villous atrophy and infiltration of lamina propria by lymphocytes⁵⁷ (Figures 5 and 6). Because these changes can be seen in a variety of diarrheal diseases, their reversal after adherence to a gluten-free diet is part of the current diagnostic criteria for the diagnosis of celiac disease.⁵⁶

Genetic testing

Photomicrograph courtesy of Homer Wiland MD, Department of Pathology, Cleveland Clinic.

Although the combination of positive serologic tests and pathologic changes confirms the diagnosis of celiac disease, in some cases one type of test is positive and the other is negative. In this situation, genetic testing for HLA-DQ2 and HLA-DQ8 can help rule out the diagnosis, as a negative genetic test rules out celiac disease in more than 99% of cases.⁵⁸

Genetic testing is also useful in patients who are already adhering to a gluten-free diet at the time of presentation to the clinic and who have had no testing done for celiac disease in the past. Here again, a negative test for both HLA-DQ2 and HLA-DQ8 makes a diagnosis of celiac disease highly unlikely.

If the test is positive, further testing needs to be done, as a positive genetic test cannot differentiate celiac disease from nonceliac gluten sensitivity. In this case, a gluten challenge needs to be done, ideally for 8 weeks, but for at least 2 weeks if the patient cannot tolerate gluten-containing food for a longer period of time. The gluten challenge is to be followed by testing for antibodies to tissue transglutaminase or obtaining duodenal biopsies to confirm the presence or absence of celiac disease.

Standard laboratory tests

Standard laboratory tests do not help much in diagnosing celiac disease, but they should include a complete blood chemistry along with a complete metabolic panel. Usually, serum albumin levels are normal.

Due to malabsorption of iron, patients may have iron deficiency anemia,⁵⁹ but anemia can also be due to a deficiency of folate or vitamin B₁₂. In patients undergoing endoscopic evaluation of iron deficiency anemia of unknown cause, celiac disease was discovered in approximately 15%.⁶⁰ Therefore, some experts believe that any patient presenting with unexplained iron deficiency anemia should be screened for celiac disease.

Because of malabsorption of vitamin D, levels of vitamin D can be low.

Elevations in levels of aminotransferases are also fairly common and usually resolve after the start of a gluten-free diet. If they persist despite adherence to a gluten-free diet, then an alternate cause of liver disease should be sought.⁶¹

Diagnosis of dermatitis herpetiformis

When trying to diagnose dermatitis herpetiformis, antibodies against epidermal transglutaminase can also be checked if testing for antibody against tissue transglutaminase is negative. A significant number of patients with biopsy-confirmed dermatitis herpetiformis are positive for epidermal transglutaminase antibodies but not for tissue transglutaminase antibodies.⁶²

The confirmatory test for dermatitis herpetiformis remains skin biopsy. Ideally, the sample should be taken while the patient is on a gluten-containing diet and from an area of normal-appearing skin around the lesions.⁶³ On histopathologic study, neutrophilic infiltrates are seen in dermal papillae and a perivascular lymphocytic infiltrate can also be seen in the superficial zones.⁶⁴ This presentation can also be seen in other bullous disorders, however. To differentiate dermatitis herpetiformis from other disorders, direct immunofluorescence is needed, which will detect granular IgA deposits in the dermal papillae or along the basement membrane, a finding pathognomic of dermatitis herpetiformis.⁶³

A GLUTEN-FREE DIET IS THE MAINSTAY OF TREATMENT

The mainstay of treatment is lifelong adherence to a gluten-free diet. Most patients report improvement in abdominal pain within days of starting this diet and improvement of diarrhea within 4 weeks.⁶⁵

The maximum amount of gluten that can be tolerated is debatable. A study established that intake of less than 10 mg a day is associated with fewer histologic abnormalities,⁶⁶ and an earlier study noted that intake of less than 50 mg a day was clinically well tolerated.⁶⁷ But patients differ in their tolerance for gluten, and it is hard to predict what the threshold of tolerance for gluten will be for a particular individual. Thus, it is better to avoid gluten completely.

Gluten-free if it is inherently gluten-free. If the food has a gluten-containing grain, then it should be processed to remove the gluten, and the resultant food product should not contain more than 20 parts per million of gluten. Gluten-free products that have gluten-containing grain that has been processed usually have a label indicating the gluten content in the food in parts per million.

Patients who understand the need to adhere to a gluten-free diet and the implications of not adhering to it are generally more compliant. Thus, patients need to be strongly educated that they need to adhere to a gluten-free diet and that nonadherence can cause further damage to the gut and can pose a higher risk of malignancy. Even though patients are usually concerned about the cost of gluten-free food and worry about adherence to the diet, these factors do not generally limit diet adherence.⁶⁸ All patients diagnosed with celiac disease should meet with a registered dietitian to discuss diet options based on their food preferences and to better address all their concerns.

With increasing awareness of celiac disease and with increasing numbers of patients being diagnosed with it, the food industry has recognized the need to produce gluten-free items. There are now plenty of food products available for these patients, who no longer have to forgo cakes, cookies, and other such items. Table 2 lists some common foods that patients with celiac disease can consume.

Nutritional supplements for some

If anemia is due purely to iron deficiency, it may resolve after starting a gluten-free diet, and no additional supplementation may be needed. However, if it is due to a combination of iron plus folate or vitamin B₁₂ deficiency, then folate, vitamin B₁₂, or both should be given.

In addition, if the patient is found to have a deficiency of vitamin D, then a vitamin D supplement should be given.⁶⁹ At the time of diagnosis, all patients with celiac disease should be screened for deficiencies of vitamins A, B₁₂, D, E, and K, as well as copper, zinc, folic acid, and iron.

Follow-up at 3 to 6 months

A follow-up visit should be scheduled for 3 to 6 months after the diagnosis and after that on an annual basis, and many of the abnormal laboratory tests will need to be repeated.

If intestinal or extraintestinal symptoms or nutrient deficiencies persist, then the patient’s adherence to the gluten-free diet needs to be checked. Adherence to a gluten-free diet can be assessed by checking for serologic markers of celiac disease. A decrease in baseline values can be seen within a few months of starting the diet.⁷⁰ Failure of serologic markers to decrease by the end of 1 year of a gluten-free diet usually indicates gluten contamination.⁷¹ If adherence is confirmed (ie, if baseline values fall) but symptoms persist, then further workup needs to be done to find the cause of refractory disease.

Skin lesions should also respond to a gluten-free diet

The first and foremost therapy for the skin lesions in dermatitis herpetiformis is the same as that for the intestinal manifestations in celiac disease, ie, adherence to a gluten-free diet. Soon after patients begin a gluten-free diet, the itching around the skin lesions goes away, and over time, most patients have complete resolution of the skin manifestations.

Dapsone is also frequently used to treat dermatitis herpetiformis if there is an incomplete response to a gluten-free diet or as an adjunct to diet to treat the pruritus. Patients often have a good response to dapsone.⁷²

The recommended starting dosage is 100 to 200 mg a day, and a response is usually seen within a few days. If the symptoms do not improve, the dose can be increased. Once the lesions resolve, the dose can be tapered and patients may not require any further medication. In some cases, patients may need to be chronically maintained on the lowest dose possible, due to the side effects of the drug.³

Dapsone is associated with significant adverse effects. Methemoglobinemia is the most common and is seen particularly in dosages exceeding 200 mg a day. Hemolytic anemia, another common adverse effect, is seen with dosages of more than 100 mg a day. Patients with a deficiency of glucose-6-phosphate dehydrogenase (G6PD) are at increased risk of hemolysis, and screening for G6PD deficiency is usually done before starting dapsone. Other rare adverse effects of dapsone include agranulocytosis, peripheral neuropathy, psychosis,⁷³ pancreatitis, cholestatic jaundice, bullous and exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, nephrotic syndrome, and renal papillary necrosis.

Besides testing for G6PD deficiency, a complete blood cell count, a reticulocyte count, a hepatic function panel, renal function tests, and urinalysis should be done before starting dapsone therapy and repeated while on therapy. The complete blood cell count and reticulocyte count should be checked weekly for the first month, twice a month for the next 2 months, and then once every 3 months. Liver and renal function tests are to be done once every 3 months.⁷⁴

NOVEL THERAPIES BEING TESTED

Research is under way for other treatments for celiac disease besides a gluten-free diet.

Larazotide (Alba Therapeutics, Baltimore, MD) is being tested in a randomized, placebo-controlled trial. Early results indicate that it is effective in controlling both gastrointestinal and nongastrointestinal symptoms of celiac disease, but it still has to undergo phase 3 clinical trials.

Sorghum is a grain commonly used in Asia and Africa. The gluten in sorghum is different from that in wheat and is not immunogenic. In a small case series in patients with known celiac disease, sorghum did not induce diarrhea or change in levels of antibodies to tissue transglutaminase.⁷⁵

Nonimmunogenic wheat that does not contain the immunogenic gluten is being developed.

Oral enzyme supplements called glutenases are being developed. Glutenases can cleave gluten, particularly the proline and glutamine residues that make gluten resistant to degradation by gastric, pancreatic, and intestinal brush border proteases. A phase 2 trial of one of these oral enzyme supplements showed that it appeared to attenuate mucosal injury in patients with biopsy-proven celiac disease.⁷⁶

These novel therapies look promising, but for now the best treatment is lifelong adherence to the gluten-free diet.

NONRESPONSIVE AND REFRACTORY CELIAC DISEASE

Celiac disease is considered nonresponsive if its symptoms or laboratory abnormalities persist after the patient is on a gluten-free diet for 6 to 12 months. It is considered refractory if symptoms persist or recur along with villous atrophy despite adherence to the diet for more than 12 months in the absence of other causes of the symptoms. Refractory celiac disease can be further classified either as type 1 if there are typical intraepithelial lymphocytes, or as type 2 if there are atypical intraepithelial lymphocytes.

Celiac disease is nonresponsive in about 10% to 19% of cases,⁷⁶ and it is refractory in 1% to 2%.⁷⁷

Managing nonresponsive celiac disease

The first step in managing a patient with nonresponsive celiac disease is to confirm the diagnosis by reviewing the serologic tests and the biopsy samples from the time of diagnosis. If celiac disease is confirmed, then one should re-evaluate for gluten ingestion, the most common cause of nonresponsiveness.⁷⁸ If strict adherence is confirmed, then check for other causes of symptoms such as lactose or fructose intolerance. If no other cause is found, then repeat the duodenal biopsies with flow cytometry to look for CD3 and CD8 expression in T cells in the small-bowel mucosa.⁷⁹ Presence or absence of villous atrophy can point to possible other causes of malabsorption including pancreatic insufficiency, small intestinal bowel overgrowth, and microscopic colitis.

Managing refractory celiac disease

Traditionally, corticosteroids have been shown to be beneficial in alleviating symptoms in patients with refractory celiac disease but do not improve the histologic findings.⁸⁰ Because of the adverse effects associated with long-term corticosteroid use, azathioprine has been successfully used to maintain remission of the disease after induction with corticosteroids in patients with type 1 refractory celiac disease.⁸¹

Cladribine, a chemotherapeutic agent used to treat hairy cell leukemia, has shown some benefit in treating type 2 refractory celiac disease.⁸²

In type 2 refractory celiac disease, use of an immunomodulator agent carries an increased risk of transformation to lymphoma.

Because of the lack of a satisfactory response to the agents available so far to treat refractory celiac disease, more treatment options acting at the molecular level are being explored.

NONCELIAC GLUTEN SENSITIVITY DISORDER

Nonceliac gluten sensitivity disorder is an evolving concept. The clinical presentation of this disorder is similar to celiac disease in that patients may have diarrhea or other extra­intestinal symptoms when on a regular diet and have resolution of symptoms on a gluten-free diet. But unlike celiac disease, there is no serologic or histologic evidence of celiac disease even when patients are on a regular diet.

One of every 17 patients who presents with clinical features suggestive of celiac disease is found to have nonceliac gluten sensitivity disorder, not celiac disease.⁸³ In contrast to celiac disease, in which the adaptive immune system is thought to contribute to the disease process, in nonceliac gluten sensitivity disorder the innate immune system is believed to play the dominant role,⁸⁴ but the exact pathogenesis of the disease is still unclear.

The diagnosis of nonceliac gluten sensitivity disorder is one of exclusion. Celiac disease needs to be ruled out by serologic testing and by duodenal biopsy while the patient is on a regular diet, and then a trial of a gluten-free diet needs to be done to confirm resolution of symptoms before the diagnosis of nonceliac gluten sensitivity disorder can be established.

As with celiac disease, the treatment involves adhering to a gluten-free diet, but it is still not known if patients need to stay on it for the rest of their life, or if they will be able to tolerate gluten-containing products after a few years.

Celiac disease is an autoimmune disorder that occurs in genetically predisposed individuals in response to ingestion of gluten. Its prevalence is about 0.7% of the US population.¹

See related editorial

The gold standard for diagnosis is duodenal biopsy, in which the histologic features may include varying gradations of flattening of intestinal villi, crypt hyperplasia, and infiltration of the lamina propria by lymphocytes. Many patients have no symptoms at the time of diagnosis, but presenting symptoms can include diarrhea along with features of malabsorption,² and, in about 25% of patients (mainly adults), a bullous cutaneous disorder called dermatitis herpetiformis.^3,4 The pathogenesis of celiac disease and that of dermatitis herpetiformis are similar in that in both, ingestion of gluten induces an inflammatory reaction leading to the clinical manifestations.

The mainstay of treatment of celiac disease remains avoidance of gluten in the diet.

GENETIC PREDISPOSITION AND DIETARY TRIGGER

The pathogenesis of celiac disease has been well studied in both humans and animals. The disease is thought to develop by an interplay of genetic and autoimmune factors and the ingestion of gluten (ie, an environmental factor).

Celiac disease occurs in genetically predisposed individuals, ie, those who carry the HLA alleles DQ2 (DQA1*05, DQB1*02), DQ8 (DQA1*03, DQB1*0302), or both.⁵

Ingestion of gluten is necessary for the disease to develop. Gluten, the protein component of wheat, barley, and rye, contains proteins called prolamins, which vary among the different types of grain. In wheat, the prolamin is gliadin, which is alcohol-soluble. In barley the prolamin is hordein, and in rye it is secalin.⁴ The prolamin content in gluten makes it resistant to degradation by gastric, pancreatic, and intestinal brush border proteases.⁶ Gluten crosses the epithelial barrier and promotes an inflammatory reaction by both the innate and adaptive immune systems that can ultimately result in flattening of villi and crypt hyperplasia (Figure 1).⁷

Tissue transglutaminase also plays a central role in the pathogenesis, as it further deaminates gliadin and increases its immunogenicity by causing it to bind to receptors on antigen-presenting cells with stronger affinity. Furthermore, gliadin-tissue transglutaminase complexes formed by protein cross-linkages generate an autoantibody response (predominantly immunoglobulin A [IgA] type) that can exacerbate the inflammatory process.^8,9

Certain viral infections during childhood, such as rotavirus and adenovirus infection, can increase the risk of celiac disease.^10–13 Although earlier studies reported that breast-feeding seemed to have a protective effect,¹⁴ as did introducing grains in the diet in the 4th to 6th months of life as opposed to earlier or later,¹⁵ more recent studies have not confirmed these benefits.^16,17

CLINICAL FEATURES

Most adults diagnosed with celiac disease are in their 30s, 40s, or 50s, and most are women.

Diarrhea remains a common presenting symptom, although the percentage of patients with celiac disease who present with diarrhea has decreased over time.^18,19

Abdominal pain and weight loss are also common.²⁰

Pallor or decreased exercise tolerance can develop due to anemia from iron malabsorption, and some patients have easy bruising due to vitamin K malabsorption.

Gynecologic and obstetric complications associated with celiac disease include delayed menarche, amenorrhea, spontaneous abortion, intrauterine growth retardation, preterm delivery, and low-birth-weight babies.^21,22 Patients who follow a gluten-free diet tend to have a lower incidence of intrauterine growth retardation, preterm delivery, and low-birth-weight babies compared with untreated patients.^21,22

Osteoporosis and osteopenia due to malabsorption of vitamin D are common and are seen in two-thirds of patients presenting with celiac disease.²³ A meta-analysis and position statement from Canada concluded that dual-energy x-ray absorptiometry should be done at the time of diagnosis of celiac disease if the patient is at risk of osteoporosis.²⁴ If the scan is abnormal, it should be repeated 1 to 2 years after initiation of a gluten-free diet and vitamin D supplementation to ensure that the osteopenia has improved.²⁴

OTHER DISEASE ASSOCIATIONS

Celiac disease is associated with various other autoimmune diseases (Table 1), including Hashimoto thyroiditis,²⁵ type 1 diabetes mellitus,²⁶ primary biliary cirrhosis,²⁷ primary sclerosing cholangitis,²⁸ and Addison disease.²⁹

Dermatitis herpetiformis

Dermatitis herpetiformis is one of the most common cutaneous manifestations of celiac disease. It presents between ages 10 and 50, and unlike celiac disease, it is more common in males.³⁰

Photo courtesy of Alok Vij, Department of Dermatology, Cleveland Clinic.

The characteristic lesions are pruritic, grouped erythematous papules surmounted by vesicles distributed symmetrically over the extensor surfaces of the upper and lower extremities, elbows, knees, scalp, nuchal area, and buttocks³¹ (Figures 2 and 3). In addition, some patients also present with vesicles, erythematous macules, and erosions in the oral mucosa³² or purpura on the palms and soles.^33–35

Photo courtesy of Alok Vij, MD, Department of Dermatology, Cleveland Clinic.

The pathogenesis of dermatitis herpetiformis in the skin is related to the pathogenesis of celiac disease in the gut. Like celiac disease, dermatitis herpetiformis is more common in genetically predisposed individuals carrying either the HLA-DQ2 or the HLA-DQ8 haplotype. In the skin, there is an analogue of tissue transglutaminase called epidermal transglutaminase, which helps in maintaining the integrity of cornified epithelium.³⁶ In patients with celiac disease, along with formation of IgA antibodies to tissue transglutaminase, there is also formation of IgA antibodies to epidermal transglutaminase. IgA antibodies are deposit- ed in the tips of dermal papillae and along the basement membrane.^37–39 These deposits then initiate an inflammatory response that is predominantly neutrophilic and results in formation of vesicles and bullae in the skin.⁴⁰ Also supporting the linkage between celiac disease and dermatitis herpetiformis, if patients adhere to a gluten-free diet, the deposits of immune complexes in the skin disappear.⁴¹

CELIAC DISEASE-ASSOCIATED MALIGNANCY

Patients with celiac disease have a higher risk of developing enteric malignancies, particularly intestinal T-cell lymphoma, and they have smaller increased risk of colon, oropharyngeal, esophageal, pancreatic, and hepatobiliary cancer.^42–45 For all of these cancers, the risk is higher than in the general public in the first year after celiac disease is diagnosed, but after the first year, the risk is increased only for small-bowel and hepatobiliary malignancies.⁴⁶

T-cell lymphoma

T-cell lymphoma is a rare but serious complication that has a poor prognosis.⁴⁷ Its prevalence has been increasing with time and is currently estimated to be around 0.01 to 0.02 per 100,000 people in the population as a whole.^48,49 The risk of developing lymphoma is 2.5 times higher in people with celiac disease than in the general population.⁵⁰ T-cell lymphoma is seen more commonly in patients with refractory celiac disease and DQ2 homozygosity.⁵¹

This disease is difficult to detect clinically, but sometimes it presents as an acute exacer­bation of celiac disease symptoms despite strict adherence to a gluten-free diet. Associated alarm symptoms include fever, night sweats, and laboratory abnormalities such as low albumin and high lactate dehydrogenase levels.

Strict adherence to a gluten-free diet remains the only way to prevent intestinal T-cell lymphoma.⁵²

Other malignancies

Some earlier studies reported an increased risk of thyroid cancer and malignant melanoma, but two newer studies have refuted this finding.^53,54 Conversely, celiac disease appears to have a protective effect against breast, ovarian, and endometrial cancers.⁵⁵

DIAGNOSIS: SEROLOGY, BIOPSY, GENETIC TESTING

Serologic tests

Patients strongly suspected of having celiac disease should be screened for IgA antibodies to tissue transglutaminase while on a gluten-containing diet, according to recommendations of the American College of Gastroenterology (Figure 4).⁵⁶ The sensitivity and specificity of this test are around 95%. If the patient has an IgA deficiency, screening should be done by checking the level of IgG antibodies to tissue transglutaminase.

Biopsy for confirmation

If testing for IgA to tissue transglutaminase is positive, upper endoscopy with biopsy is needed. Ideally, one to two samples should be taken from the duodenal bulb and at least four samples from the rest of the duodenum, preferably from two different locations.⁵⁶

Celiac disease has a broad spectrum of pathologic expressions, from mild distortion of crypt architecture to total villous atrophy and infiltration of lamina propria by lymphocytes⁵⁷ (Figures 5 and 6). Because these changes can be seen in a variety of diarrheal diseases, their reversal after adherence to a gluten-free diet is part of the current diagnostic criteria for the diagnosis of celiac disease.⁵⁶

Genetic testing

Photomicrograph courtesy of Homer Wiland MD, Department of Pathology, Cleveland Clinic.

Although the combination of positive serologic tests and pathologic changes confirms the diagnosis of celiac disease, in some cases one type of test is positive and the other is negative. In this situation, genetic testing for HLA-DQ2 and HLA-DQ8 can help rule out the diagnosis, as a negative genetic test rules out celiac disease in more than 99% of cases.⁵⁸

Genetic testing is also useful in patients who are already adhering to a gluten-free diet at the time of presentation to the clinic and who have had no testing done for celiac disease in the past. Here again, a negative test for both HLA-DQ2 and HLA-DQ8 makes a diagnosis of celiac disease highly unlikely.

If the test is positive, further testing needs to be done, as a positive genetic test cannot differentiate celiac disease from nonceliac gluten sensitivity. In this case, a gluten challenge needs to be done, ideally for 8 weeks, but for at least 2 weeks if the patient cannot tolerate gluten-containing food for a longer period of time. The gluten challenge is to be followed by testing for antibodies to tissue transglutaminase or obtaining duodenal biopsies to confirm the presence or absence of celiac disease.

Standard laboratory tests

Standard laboratory tests do not help much in diagnosing celiac disease, but they should include a complete blood chemistry along with a complete metabolic panel. Usually, serum albumin levels are normal.

Due to malabsorption of iron, patients may have iron deficiency anemia,⁵⁹ but anemia can also be due to a deficiency of folate or vitamin B₁₂. In patients undergoing endoscopic evaluation of iron deficiency anemia of unknown cause, celiac disease was discovered in approximately 15%.⁶⁰ Therefore, some experts believe that any patient presenting with unexplained iron deficiency anemia should be screened for celiac disease.

Because of malabsorption of vitamin D, levels of vitamin D can be low.

Elevations in levels of aminotransferases are also fairly common and usually resolve after the start of a gluten-free diet. If they persist despite adherence to a gluten-free diet, then an alternate cause of liver disease should be sought.⁶¹

Diagnosis of dermatitis herpetiformis

When trying to diagnose dermatitis herpetiformis, antibodies against epidermal transglutaminase can also be checked if testing for antibody against tissue transglutaminase is negative. A significant number of patients with biopsy-confirmed dermatitis herpetiformis are positive for epidermal transglutaminase antibodies but not for tissue transglutaminase antibodies.⁶²

The confirmatory test for dermatitis herpetiformis remains skin biopsy. Ideally, the sample should be taken while the patient is on a gluten-containing diet and from an area of normal-appearing skin around the lesions.⁶³ On histopathologic study, neutrophilic infiltrates are seen in dermal papillae and a perivascular lymphocytic infiltrate can also be seen in the superficial zones.⁶⁴ This presentation can also be seen in other bullous disorders, however. To differentiate dermatitis herpetiformis from other disorders, direct immunofluorescence is needed, which will detect granular IgA deposits in the dermal papillae or along the basement membrane, a finding pathognomic of dermatitis herpetiformis.⁶³

A GLUTEN-FREE DIET IS THE MAINSTAY OF TREATMENT

The mainstay of treatment is lifelong adherence to a gluten-free diet. Most patients report improvement in abdominal pain within days of starting this diet and improvement of diarrhea within 4 weeks.⁶⁵

The maximum amount of gluten that can be tolerated is debatable. A study established that intake of less than 10 mg a day is associated with fewer histologic abnormalities,⁶⁶ and an earlier study noted that intake of less than 50 mg a day was clinically well tolerated.⁶⁷ But patients differ in their tolerance for gluten, and it is hard to predict what the threshold of tolerance for gluten will be for a particular individual. Thus, it is better to avoid gluten completely.

Gluten-free if it is inherently gluten-free. If the food has a gluten-containing grain, then it should be processed to remove the gluten, and the resultant food product should not contain more than 20 parts per million of gluten. Gluten-free products that have gluten-containing grain that has been processed usually have a label indicating the gluten content in the food in parts per million.

Patients who understand the need to adhere to a gluten-free diet and the implications of not adhering to it are generally more compliant. Thus, patients need to be strongly educated that they need to adhere to a gluten-free diet and that nonadherence can cause further damage to the gut and can pose a higher risk of malignancy. Even though patients are usually concerned about the cost of gluten-free food and worry about adherence to the diet, these factors do not generally limit diet adherence.⁶⁸ All patients diagnosed with celiac disease should meet with a registered dietitian to discuss diet options based on their food preferences and to better address all their concerns.

With increasing awareness of celiac disease and with increasing numbers of patients being diagnosed with it, the food industry has recognized the need to produce gluten-free items. There are now plenty of food products available for these patients, who no longer have to forgo cakes, cookies, and other such items. Table 2 lists some common foods that patients with celiac disease can consume.

Nutritional supplements for some

If anemia is due purely to iron deficiency, it may resolve after starting a gluten-free diet, and no additional supplementation may be needed. However, if it is due to a combination of iron plus folate or vitamin B₁₂ deficiency, then folate, vitamin B₁₂, or both should be given.

In addition, if the patient is found to have a deficiency of vitamin D, then a vitamin D supplement should be given.⁶⁹ At the time of diagnosis, all patients with celiac disease should be screened for deficiencies of vitamins A, B₁₂, D, E, and K, as well as copper, zinc, folic acid, and iron.

Follow-up at 3 to 6 months

A follow-up visit should be scheduled for 3 to 6 months after the diagnosis and after that on an annual basis, and many of the abnormal laboratory tests will need to be repeated.

If intestinal or extraintestinal symptoms or nutrient deficiencies persist, then the patient’s adherence to the gluten-free diet needs to be checked. Adherence to a gluten-free diet can be assessed by checking for serologic markers of celiac disease. A decrease in baseline values can be seen within a few months of starting the diet.⁷⁰ Failure of serologic markers to decrease by the end of 1 year of a gluten-free diet usually indicates gluten contamination.⁷¹ If adherence is confirmed (ie, if baseline values fall) but symptoms persist, then further workup needs to be done to find the cause of refractory disease.

Skin lesions should also respond to a gluten-free diet

The first and foremost therapy for the skin lesions in dermatitis herpetiformis is the same as that for the intestinal manifestations in celiac disease, ie, adherence to a gluten-free diet. Soon after patients begin a gluten-free diet, the itching around the skin lesions goes away, and over time, most patients have complete resolution of the skin manifestations.

Dapsone is also frequently used to treat dermatitis herpetiformis if there is an incomplete response to a gluten-free diet or as an adjunct to diet to treat the pruritus. Patients often have a good response to dapsone.⁷²

The recommended starting dosage is 100 to 200 mg a day, and a response is usually seen within a few days. If the symptoms do not improve, the dose can be increased. Once the lesions resolve, the dose can be tapered and patients may not require any further medication. In some cases, patients may need to be chronically maintained on the lowest dose possible, due to the side effects of the drug.³

Dapsone is associated with significant adverse effects. Methemoglobinemia is the most common and is seen particularly in dosages exceeding 200 mg a day. Hemolytic anemia, another common adverse effect, is seen with dosages of more than 100 mg a day. Patients with a deficiency of glucose-6-phosphate dehydrogenase (G6PD) are at increased risk of hemolysis, and screening for G6PD deficiency is usually done before starting dapsone. Other rare adverse effects of dapsone include agranulocytosis, peripheral neuropathy, psychosis,⁷³ pancreatitis, cholestatic jaundice, bullous and exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, nephrotic syndrome, and renal papillary necrosis.

Besides testing for G6PD deficiency, a complete blood cell count, a reticulocyte count, a hepatic function panel, renal function tests, and urinalysis should be done before starting dapsone therapy and repeated while on therapy. The complete blood cell count and reticulocyte count should be checked weekly for the first month, twice a month for the next 2 months, and then once every 3 months. Liver and renal function tests are to be done once every 3 months.⁷⁴

NOVEL THERAPIES BEING TESTED

Research is under way for other treatments for celiac disease besides a gluten-free diet.

Larazotide (Alba Therapeutics, Baltimore, MD) is being tested in a randomized, placebo-controlled trial. Early results indicate that it is effective in controlling both gastrointestinal and nongastrointestinal symptoms of celiac disease, but it still has to undergo phase 3 clinical trials.

Sorghum is a grain commonly used in Asia and Africa. The gluten in sorghum is different from that in wheat and is not immunogenic. In a small case series in patients with known celiac disease, sorghum did not induce diarrhea or change in levels of antibodies to tissue transglutaminase.⁷⁵

Nonimmunogenic wheat that does not contain the immunogenic gluten is being developed.

Oral enzyme supplements called glutenases are being developed. Glutenases can cleave gluten, particularly the proline and glutamine residues that make gluten resistant to degradation by gastric, pancreatic, and intestinal brush border proteases. A phase 2 trial of one of these oral enzyme supplements showed that it appeared to attenuate mucosal injury in patients with biopsy-proven celiac disease.⁷⁶

These novel therapies look promising, but for now the best treatment is lifelong adherence to the gluten-free diet.

NONRESPONSIVE AND REFRACTORY CELIAC DISEASE

Celiac disease is considered nonresponsive if its symptoms or laboratory abnormalities persist after the patient is on a gluten-free diet for 6 to 12 months. It is considered refractory if symptoms persist or recur along with villous atrophy despite adherence to the diet for more than 12 months in the absence of other causes of the symptoms. Refractory celiac disease can be further classified either as type 1 if there are typical intraepithelial lymphocytes, or as type 2 if there are atypical intraepithelial lymphocytes.

Celiac disease is nonresponsive in about 10% to 19% of cases,⁷⁶ and it is refractory in 1% to 2%.⁷⁷

Managing nonresponsive celiac disease

The first step in managing a patient with nonresponsive celiac disease is to confirm the diagnosis by reviewing the serologic tests and the biopsy samples from the time of diagnosis. If celiac disease is confirmed, then one should re-evaluate for gluten ingestion, the most common cause of nonresponsiveness.⁷⁸ If strict adherence is confirmed, then check for other causes of symptoms such as lactose or fructose intolerance. If no other cause is found, then repeat the duodenal biopsies with flow cytometry to look for CD3 and CD8 expression in T cells in the small-bowel mucosa.⁷⁹ Presence or absence of villous atrophy can point to possible other causes of malabsorption including pancreatic insufficiency, small intestinal bowel overgrowth, and microscopic colitis.

Managing refractory celiac disease

Traditionally, corticosteroids have been shown to be beneficial in alleviating symptoms in patients with refractory celiac disease but do not improve the histologic findings.⁸⁰ Because of the adverse effects associated with long-term corticosteroid use, azathioprine has been successfully used to maintain remission of the disease after induction with corticosteroids in patients with type 1 refractory celiac disease.⁸¹

Cladribine, a chemotherapeutic agent used to treat hairy cell leukemia, has shown some benefit in treating type 2 refractory celiac disease.⁸²

In type 2 refractory celiac disease, use of an immunomodulator agent carries an increased risk of transformation to lymphoma.

Because of the lack of a satisfactory response to the agents available so far to treat refractory celiac disease, more treatment options acting at the molecular level are being explored.

NONCELIAC GLUTEN SENSITIVITY DISORDER

Nonceliac gluten sensitivity disorder is an evolving concept. The clinical presentation of this disorder is similar to celiac disease in that patients may have diarrhea or other extra­intestinal symptoms when on a regular diet and have resolution of symptoms on a gluten-free diet. But unlike celiac disease, there is no serologic or histologic evidence of celiac disease even when patients are on a regular diet.

One of every 17 patients who presents with clinical features suggestive of celiac disease is found to have nonceliac gluten sensitivity disorder, not celiac disease.⁸³ In contrast to celiac disease, in which the adaptive immune system is thought to contribute to the disease process, in nonceliac gluten sensitivity disorder the innate immune system is believed to play the dominant role,⁸⁴ but the exact pathogenesis of the disease is still unclear.

The diagnosis of nonceliac gluten sensitivity disorder is one of exclusion. Celiac disease needs to be ruled out by serologic testing and by duodenal biopsy while the patient is on a regular diet, and then a trial of a gluten-free diet needs to be done to confirm resolution of symptoms before the diagnosis of nonceliac gluten sensitivity disorder can be established.

As with celiac disease, the treatment involves adhering to a gluten-free diet, but it is still not known if patients need to stay on it for the rest of their life, or if they will be able to tolerate gluten-containing products after a few years.

Celiac disease is an autoimmune disorder that occurs in genetically predisposed individuals in response to ingestion of gluten. Its prevalence is about 0.7% of the US population.¹

See related editorial

The gold standard for diagnosis is duodenal biopsy, in which the histologic features may include varying gradations of flattening of intestinal villi, crypt hyperplasia, and infiltration of the lamina propria by lymphocytes. Many patients have no symptoms at the time of diagnosis, but presenting symptoms can include diarrhea along with features of malabsorption,² and, in about 25% of patients (mainly adults), a bullous cutaneous disorder called dermatitis herpetiformis.^3,4 The pathogenesis of celiac disease and that of dermatitis herpetiformis are similar in that in both, ingestion of gluten induces an inflammatory reaction leading to the clinical manifestations.

The mainstay of treatment of celiac disease remains avoidance of gluten in the diet.

GENETIC PREDISPOSITION AND DIETARY TRIGGER

The pathogenesis of celiac disease has been well studied in both humans and animals. The disease is thought to develop by an interplay of genetic and autoimmune factors and the ingestion of gluten (ie, an environmental factor).

Celiac disease occurs in genetically predisposed individuals, ie, those who carry the HLA alleles DQ2 (DQA1*05, DQB1*02), DQ8 (DQA1*03, DQB1*0302), or both.⁵

Ingestion of gluten is necessary for the disease to develop. Gluten, the protein component of wheat, barley, and rye, contains proteins called prolamins, which vary among the different types of grain. In wheat, the prolamin is gliadin, which is alcohol-soluble. In barley the prolamin is hordein, and in rye it is secalin.⁴ The prolamin content in gluten makes it resistant to degradation by gastric, pancreatic, and intestinal brush border proteases.⁶ Gluten crosses the epithelial barrier and promotes an inflammatory reaction by both the innate and adaptive immune systems that can ultimately result in flattening of villi and crypt hyperplasia (Figure 1).⁷

Tissue transglutaminase also plays a central role in the pathogenesis, as it further deaminates gliadin and increases its immunogenicity by causing it to bind to receptors on antigen-presenting cells with stronger affinity. Furthermore, gliadin-tissue transglutaminase complexes formed by protein cross-linkages generate an autoantibody response (predominantly immunoglobulin A [IgA] type) that can exacerbate the inflammatory process.^8,9

Certain viral infections during childhood, such as rotavirus and adenovirus infection, can increase the risk of celiac disease.^10–13 Although earlier studies reported that breast-feeding seemed to have a protective effect,¹⁴ as did introducing grains in the diet in the 4th to 6th months of life as opposed to earlier or later,¹⁵ more recent studies have not confirmed these benefits.^16,17

CLINICAL FEATURES

Most adults diagnosed with celiac disease are in their 30s, 40s, or 50s, and most are women.

Diarrhea remains a common presenting symptom, although the percentage of patients with celiac disease who present with diarrhea has decreased over time.^18,19

Abdominal pain and weight loss are also common.²⁰

Pallor or decreased exercise tolerance can develop due to anemia from iron malabsorption, and some patients have easy bruising due to vitamin K malabsorption.

Gynecologic and obstetric complications associated with celiac disease include delayed menarche, amenorrhea, spontaneous abortion, intrauterine growth retardation, preterm delivery, and low-birth-weight babies.^21,22 Patients who follow a gluten-free diet tend to have a lower incidence of intrauterine growth retardation, preterm delivery, and low-birth-weight babies compared with untreated patients.^21,22

Osteoporosis and osteopenia due to malabsorption of vitamin D are common and are seen in two-thirds of patients presenting with celiac disease.²³ A meta-analysis and position statement from Canada concluded that dual-energy x-ray absorptiometry should be done at the time of diagnosis of celiac disease if the patient is at risk of osteoporosis.²⁴ If the scan is abnormal, it should be repeated 1 to 2 years after initiation of a gluten-free diet and vitamin D supplementation to ensure that the osteopenia has improved.²⁴

OTHER DISEASE ASSOCIATIONS

Celiac disease is associated with various other autoimmune diseases (Table 1), including Hashimoto thyroiditis,²⁵ type 1 diabetes mellitus,²⁶ primary biliary cirrhosis,²⁷ primary sclerosing cholangitis,²⁸ and Addison disease.²⁹

Dermatitis herpetiformis

Dermatitis herpetiformis is one of the most common cutaneous manifestations of celiac disease. It presents between ages 10 and 50, and unlike celiac disease, it is more common in males.³⁰

Photo courtesy of Alok Vij, Department of Dermatology, Cleveland Clinic.

The characteristic lesions are pruritic, grouped erythematous papules surmounted by vesicles distributed symmetrically over the extensor surfaces of the upper and lower extremities, elbows, knees, scalp, nuchal area, and buttocks³¹ (Figures 2 and 3). In addition, some patients also present with vesicles, erythematous macules, and erosions in the oral mucosa³² or purpura on the palms and soles.^33–35

Photo courtesy of Alok Vij, MD, Department of Dermatology, Cleveland Clinic.

The pathogenesis of dermatitis herpetiformis in the skin is related to the pathogenesis of celiac disease in the gut. Like celiac disease, dermatitis herpetiformis is more common in genetically predisposed individuals carrying either the HLA-DQ2 or the HLA-DQ8 haplotype. In the skin, there is an analogue of tissue transglutaminase called epidermal transglutaminase, which helps in maintaining the integrity of cornified epithelium.³⁶ In patients with celiac disease, along with formation of IgA antibodies to tissue transglutaminase, there is also formation of IgA antibodies to epidermal transglutaminase. IgA antibodies are deposit- ed in the tips of dermal papillae and along the basement membrane.^37–39 These deposits then initiate an inflammatory response that is predominantly neutrophilic and results in formation of vesicles and bullae in the skin.⁴⁰ Also supporting the linkage between celiac disease and dermatitis herpetiformis, if patients adhere to a gluten-free diet, the deposits of immune complexes in the skin disappear.⁴¹

CELIAC DISEASE-ASSOCIATED MALIGNANCY

Patients with celiac disease have a higher risk of developing enteric malignancies, particularly intestinal T-cell lymphoma, and they have smaller increased risk of colon, oropharyngeal, esophageal, pancreatic, and hepatobiliary cancer.^42–45 For all of these cancers, the risk is higher than in the general public in the first year after celiac disease is diagnosed, but after the first year, the risk is increased only for small-bowel and hepatobiliary malignancies.⁴⁶

T-cell lymphoma

T-cell lymphoma is a rare but serious complication that has a poor prognosis.⁴⁷ Its prevalence has been increasing with time and is currently estimated to be around 0.01 to 0.02 per 100,000 people in the population as a whole.^48,49 The risk of developing lymphoma is 2.5 times higher in people with celiac disease than in the general population.⁵⁰ T-cell lymphoma is seen more commonly in patients with refractory celiac disease and DQ2 homozygosity.⁵¹

This disease is difficult to detect clinically, but sometimes it presents as an acute exacer­bation of celiac disease symptoms despite strict adherence to a gluten-free diet. Associated alarm symptoms include fever, night sweats, and laboratory abnormalities such as low albumin and high lactate dehydrogenase levels.

Strict adherence to a gluten-free diet remains the only way to prevent intestinal T-cell lymphoma.⁵²

Other malignancies

Some earlier studies reported an increased risk of thyroid cancer and malignant melanoma, but two newer studies have refuted this finding.^53,54 Conversely, celiac disease appears to have a protective effect against breast, ovarian, and endometrial cancers.⁵⁵

DIAGNOSIS: SEROLOGY, BIOPSY, GENETIC TESTING

Serologic tests

Patients strongly suspected of having celiac disease should be screened for IgA antibodies to tissue transglutaminase while on a gluten-containing diet, according to recommendations of the American College of Gastroenterology (Figure 4).⁵⁶ The sensitivity and specificity of this test are around 95%. If the patient has an IgA deficiency, screening should be done by checking the level of IgG antibodies to tissue transglutaminase.

Biopsy for confirmation

If testing for IgA to tissue transglutaminase is positive, upper endoscopy with biopsy is needed. Ideally, one to two samples should be taken from the duodenal bulb and at least four samples from the rest of the duodenum, preferably from two different locations.⁵⁶

Celiac disease has a broad spectrum of pathologic expressions, from mild distortion of crypt architecture to total villous atrophy and infiltration of lamina propria by lymphocytes⁵⁷ (Figures 5 and 6). Because these changes can be seen in a variety of diarrheal diseases, their reversal after adherence to a gluten-free diet is part of the current diagnostic criteria for the diagnosis of celiac disease.⁵⁶

Genetic testing

Photomicrograph courtesy of Homer Wiland MD, Department of Pathology, Cleveland Clinic.

Although the combination of positive serologic tests and pathologic changes confirms the diagnosis of celiac disease, in some cases one type of test is positive and the other is negative. In this situation, genetic testing for HLA-DQ2 and HLA-DQ8 can help rule out the diagnosis, as a negative genetic test rules out celiac disease in more than 99% of cases.⁵⁸

Genetic testing is also useful in patients who are already adhering to a gluten-free diet at the time of presentation to the clinic and who have had no testing done for celiac disease in the past. Here again, a negative test for both HLA-DQ2 and HLA-DQ8 makes a diagnosis of celiac disease highly unlikely.

If the test is positive, further testing needs to be done, as a positive genetic test cannot differentiate celiac disease from nonceliac gluten sensitivity. In this case, a gluten challenge needs to be done, ideally for 8 weeks, but for at least 2 weeks if the patient cannot tolerate gluten-containing food for a longer period of time. The gluten challenge is to be followed by testing for antibodies to tissue transglutaminase or obtaining duodenal biopsies to confirm the presence or absence of celiac disease.

Standard laboratory tests

Standard laboratory tests do not help much in diagnosing celiac disease, but they should include a complete blood chemistry along with a complete metabolic panel. Usually, serum albumin levels are normal.

Due to malabsorption of iron, patients may have iron deficiency anemia,⁵⁹ but anemia can also be due to a deficiency of folate or vitamin B₁₂. In patients undergoing endoscopic evaluation of iron deficiency anemia of unknown cause, celiac disease was discovered in approximately 15%.⁶⁰ Therefore, some experts believe that any patient presenting with unexplained iron deficiency anemia should be screened for celiac disease.

Because of malabsorption of vitamin D, levels of vitamin D can be low.

Elevations in levels of aminotransferases are also fairly common and usually resolve after the start of a gluten-free diet. If they persist despite adherence to a gluten-free diet, then an alternate cause of liver disease should be sought.⁶¹

Diagnosis of dermatitis herpetiformis

When trying to diagnose dermatitis herpetiformis, antibodies against epidermal transglutaminase can also be checked if testing for antibody against tissue transglutaminase is negative. A significant number of patients with biopsy-confirmed dermatitis herpetiformis are positive for epidermal transglutaminase antibodies but not for tissue transglutaminase antibodies.⁶²

The confirmatory test for dermatitis herpetiformis remains skin biopsy. Ideally, the sample should be taken while the patient is on a gluten-containing diet and from an area of normal-appearing skin around the lesions.⁶³ On histopathologic study, neutrophilic infiltrates are seen in dermal papillae and a perivascular lymphocytic infiltrate can also be seen in the superficial zones.⁶⁴ This presentation can also be seen in other bullous disorders, however. To differentiate dermatitis herpetiformis from other disorders, direct immunofluorescence is needed, which will detect granular IgA deposits in the dermal papillae or along the basement membrane, a finding pathognomic of dermatitis herpetiformis.⁶³

A GLUTEN-FREE DIET IS THE MAINSTAY OF TREATMENT

The mainstay of treatment is lifelong adherence to a gluten-free diet. Most patients report improvement in abdominal pain within days of starting this diet and improvement of diarrhea within 4 weeks.⁶⁵

The maximum amount of gluten that can be tolerated is debatable. A study established that intake of less than 10 mg a day is associated with fewer histologic abnormalities,⁶⁶ and an earlier study noted that intake of less than 50 mg a day was clinically well tolerated.⁶⁷ But patients differ in their tolerance for gluten, and it is hard to predict what the threshold of tolerance for gluten will be for a particular individual. Thus, it is better to avoid gluten completely.

Gluten-free if it is inherently gluten-free. If the food has a gluten-containing grain, then it should be processed to remove the gluten, and the resultant food product should not contain more than 20 parts per million of gluten. Gluten-free products that have gluten-containing grain that has been processed usually have a label indicating the gluten content in the food in parts per million.

Patients who understand the need to adhere to a gluten-free diet and the implications of not adhering to it are generally more compliant. Thus, patients need to be strongly educated that they need to adhere to a gluten-free diet and that nonadherence can cause further damage to the gut and can pose a higher risk of malignancy. Even though patients are usually concerned about the cost of gluten-free food and worry about adherence to the diet, these factors do not generally limit diet adherence.⁶⁸ All patients diagnosed with celiac disease should meet with a registered dietitian to discuss diet options based on their food preferences and to better address all their concerns.

With increasing awareness of celiac disease and with increasing numbers of patients being diagnosed with it, the food industry has recognized the need to produce gluten-free items. There are now plenty of food products available for these patients, who no longer have to forgo cakes, cookies, and other such items. Table 2 lists some common foods that patients with celiac disease can consume.

Nutritional supplements for some

If anemia is due purely to iron deficiency, it may resolve after starting a gluten-free diet, and no additional supplementation may be needed. However, if it is due to a combination of iron plus folate or vitamin B₁₂ deficiency, then folate, vitamin B₁₂, or both should be given.

In addition, if the patient is found to have a deficiency of vitamin D, then a vitamin D supplement should be given.⁶⁹ At the time of diagnosis, all patients with celiac disease should be screened for deficiencies of vitamins A, B₁₂, D, E, and K, as well as copper, zinc, folic acid, and iron.

Follow-up at 3 to 6 months

A follow-up visit should be scheduled for 3 to 6 months after the diagnosis and after that on an annual basis, and many of the abnormal laboratory tests will need to be repeated.

If intestinal or extraintestinal symptoms or nutrient deficiencies persist, then the patient’s adherence to the gluten-free diet needs to be checked. Adherence to a gluten-free diet can be assessed by checking for serologic markers of celiac disease. A decrease in baseline values can be seen within a few months of starting the diet.⁷⁰ Failure of serologic markers to decrease by the end of 1 year of a gluten-free diet usually indicates gluten contamination.⁷¹ If adherence is confirmed (ie, if baseline values fall) but symptoms persist, then further workup needs to be done to find the cause of refractory disease.

Skin lesions should also respond to a gluten-free diet

The first and foremost therapy for the skin lesions in dermatitis herpetiformis is the same as that for the intestinal manifestations in celiac disease, ie, adherence to a gluten-free diet. Soon after patients begin a gluten-free diet, the itching around the skin lesions goes away, and over time, most patients have complete resolution of the skin manifestations.

Dapsone is also frequently used to treat dermatitis herpetiformis if there is an incomplete response to a gluten-free diet or as an adjunct to diet to treat the pruritus. Patients often have a good response to dapsone.⁷²

The recommended starting dosage is 100 to 200 mg a day, and a response is usually seen within a few days. If the symptoms do not improve, the dose can be increased. Once the lesions resolve, the dose can be tapered and patients may not require any further medication. In some cases, patients may need to be chronically maintained on the lowest dose possible, due to the side effects of the drug.³

Dapsone is associated with significant adverse effects. Methemoglobinemia is the most common and is seen particularly in dosages exceeding 200 mg a day. Hemolytic anemia, another common adverse effect, is seen with dosages of more than 100 mg a day. Patients with a deficiency of glucose-6-phosphate dehydrogenase (G6PD) are at increased risk of hemolysis, and screening for G6PD deficiency is usually done before starting dapsone. Other rare adverse effects of dapsone include agranulocytosis, peripheral neuropathy, psychosis,⁷³ pancreatitis, cholestatic jaundice, bullous and exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, nephrotic syndrome, and renal papillary necrosis.

Besides testing for G6PD deficiency, a complete blood cell count, a reticulocyte count, a hepatic function panel, renal function tests, and urinalysis should be done before starting dapsone therapy and repeated while on therapy. The complete blood cell count and reticulocyte count should be checked weekly for the first month, twice a month for the next 2 months, and then once every 3 months. Liver and renal function tests are to be done once every 3 months.⁷⁴

NOVEL THERAPIES BEING TESTED

Research is under way for other treatments for celiac disease besides a gluten-free diet.

Larazotide (Alba Therapeutics, Baltimore, MD) is being tested in a randomized, placebo-controlled trial. Early results indicate that it is effective in controlling both gastrointestinal and nongastrointestinal symptoms of celiac disease, but it still has to undergo phase 3 clinical trials.

Sorghum is a grain commonly used in Asia and Africa. The gluten in sorghum is different from that in wheat and is not immunogenic. In a small case series in patients with known celiac disease, sorghum did not induce diarrhea or change in levels of antibodies to tissue transglutaminase.⁷⁵

Nonimmunogenic wheat that does not contain the immunogenic gluten is being developed.

Oral enzyme supplements called glutenases are being developed. Glutenases can cleave gluten, particularly the proline and glutamine residues that make gluten resistant to degradation by gastric, pancreatic, and intestinal brush border proteases. A phase 2 trial of one of these oral enzyme supplements showed that it appeared to attenuate mucosal injury in patients with biopsy-proven celiac disease.⁷⁶

These novel therapies look promising, but for now the best treatment is lifelong adherence to the gluten-free diet.

NONRESPONSIVE AND REFRACTORY CELIAC DISEASE

Celiac disease is considered nonresponsive if its symptoms or laboratory abnormalities persist after the patient is on a gluten-free diet for 6 to 12 months. It is considered refractory if symptoms persist or recur along with villous atrophy despite adherence to the diet for more than 12 months in the absence of other causes of the symptoms. Refractory celiac disease can be further classified either as type 1 if there are typical intraepithelial lymphocytes, or as type 2 if there are atypical intraepithelial lymphocytes.

Celiac disease is nonresponsive in about 10% to 19% of cases,⁷⁶ and it is refractory in 1% to 2%.⁷⁷

Managing nonresponsive celiac disease

The first step in managing a patient with nonresponsive celiac disease is to confirm the diagnosis by reviewing the serologic tests and the biopsy samples from the time of diagnosis. If celiac disease is confirmed, then one should re-evaluate for gluten ingestion, the most common cause of nonresponsiveness.⁷⁸ If strict adherence is confirmed, then check for other causes of symptoms such as lactose or fructose intolerance. If no other cause is found, then repeat the duodenal biopsies with flow cytometry to look for CD3 and CD8 expression in T cells in the small-bowel mucosa.⁷⁹ Presence or absence of villous atrophy can point to possible other causes of malabsorption including pancreatic insufficiency, small intestinal bowel overgrowth, and microscopic colitis.

Managing refractory celiac disease

Traditionally, corticosteroids have been shown to be beneficial in alleviating symptoms in patients with refractory celiac disease but do not improve the histologic findings.⁸⁰ Because of the adverse effects associated with long-term corticosteroid use, azathioprine has been successfully used to maintain remission of the disease after induction with corticosteroids in patients with type 1 refractory celiac disease.⁸¹

Cladribine, a chemotherapeutic agent used to treat hairy cell leukemia, has shown some benefit in treating type 2 refractory celiac disease.⁸²

In type 2 refractory celiac disease, use of an immunomodulator agent carries an increased risk of transformation to lymphoma.

Because of the lack of a satisfactory response to the agents available so far to treat refractory celiac disease, more treatment options acting at the molecular level are being explored.

NONCELIAC GLUTEN SENSITIVITY DISORDER

Nonceliac gluten sensitivity disorder is an evolving concept. The clinical presentation of this disorder is similar to celiac disease in that patients may have diarrhea or other extra­intestinal symptoms when on a regular diet and have resolution of symptoms on a gluten-free diet. But unlike celiac disease, there is no serologic or histologic evidence of celiac disease even when patients are on a regular diet.

One of every 17 patients who presents with clinical features suggestive of celiac disease is found to have nonceliac gluten sensitivity disorder, not celiac disease.⁸³ In contrast to celiac disease, in which the adaptive immune system is thought to contribute to the disease process, in nonceliac gluten sensitivity disorder the innate immune system is believed to play the dominant role,⁸⁴ but the exact pathogenesis of the disease is still unclear.

The diagnosis of nonceliac gluten sensitivity disorder is one of exclusion. Celiac disease needs to be ruled out by serologic testing and by duodenal biopsy while the patient is on a regular diet, and then a trial of a gluten-free diet needs to be done to confirm resolution of symptoms before the diagnosis of nonceliac gluten sensitivity disorder can be established.

As with celiac disease, the treatment involves adhering to a gluten-free diet, but it is still not known if patients need to stay on it for the rest of their life, or if they will be able to tolerate gluten-containing products after a few years.

Chronic pain affects an estimated 100 million Americans, at a cost of $635 billion each year in medical expenses, lost wages, and reduced productivity.¹ It is often managed in primary care settings with opioids by clinicians who have little or no formal training in pain management.^2,3 Some primary care providers may seek assistance from board-certified pain specialists, but with only four such experts for every 100,000 patients with chronic pain, primary care providers are typically on their own.⁴

Although opioids may help in some chronic pain syndromes, they also carry the risk of serious harm, including unintentional overdose and death. In 2009, unintentional drug overdoses, most commonly with opioids, surpassed motor vehicle accidents as the leading cause of accidental death in the United States.⁵ Additionally, nonmedical use of prescription drugs is the third most common category of drug abuse, after marijuana and alcohol.⁶

Unfortunately, clinicians cannot accurately predict future medication misuse.⁷ And while the potential harms of opioids are many, the long-term benefits are questionable.^8,9

For these reasons, providers need to understand the indications for and potential benefits of opioids, as well as the potential harms and how to monitor their safe use. Also important to know is how and when to discontinue opioids while preserving the therapeutic relationship.

This paper offers practical strategies to primary care providers and their care teams on how to safely initiate, monitor, and discontinue chronic opioid therapy.

STARTING OPIOID THERAPY FOR CHRONIC PAIN

Guidelines recommend considering starting patients on opioid therapy when the benefits are likely to outweigh the risks, when pain is moderate to severe, and when other multimodal treatment strategies have not achieved functional goals.¹⁰ Unfortunately, few studies have examined or demonstrated long-term benefit, and those that did examine this outcome reported reduction of pain severity but did not assess functional improvement.⁹ Meanwhile, data are increasingly clear that long-term use increases the risk of harm, both acute (eg, overdose) and chronic (eg, osteoporosis), especially with high doses.

Tools have been developed to predict the risk of misuse,^11–13 but few have been validated in primary care, where most opioids are prescribed. This limitation aside, consensus guidelines state that untreated substance use disorders, poorly controlled psychiatric disease, and erratic treatment adherence are contraindications to opioid therapy, at least until these other issues are treated.¹⁰

We are increasingly avoiding chronic opioid therapy in younger patients with chronic pain

Faced with the benefit-harm conundrum, we recommend a generally conservative approach to opioid initiation. With long-term functional benefit questionable and toxicity relatively common, we are increasingly avoiding chronic opioid therapy in younger patients with chronic pain.

Empathize and partner with your patient

Chronic pain care can be fraught with frustration and mutual distrust between patient and provider.¹⁴ Empathy and a collaborative stance help signal to the patient that the provider has the patient’s best interest in mind,¹⁵ whether initiating or deciding not to initiate opioids.

Optimize nonopioid therapy

In light of the risks associated with chronic opioid therapy, the clinician is urged to review and optimize nonopioid therapy before starting a patient on opioid treatment, and to maintain this approach if opioid therapy is started. Whenever possible, nonopioid treatment should include disease-modifying therapy and nondrug modalities such as physical therapy.

Judicious use of adequately dosed analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs may be sufficient to achieve analgesic goals if not contraindicated, and in some patients the addition of a topical analgesic (eg, diclofenac gel, lidocaine patches), a tricyclic or serotonin-norepinephrine reuptake inhibitor antidepressant, an anticonvulsant (eg, gabapentin), or a combination of the above can effectively address underlying pain-generating mechanisms.¹⁶ As with opioids, the risks and benefits of nonopioid pharmacotherapy should be reviewed both at initiation and periodically thereafter.

Frame the opioid treatment plan as a ‘therapeutic trial’

Starting an opioid should be framed as a “therapeutic trial.” These drugs should be continued only if safe and effective, at the lowest effective dose, and as one component of a multimodal pain treatment plan. Concurrent use of nonpharmacologic therapies (eg, physical therapy, structured exercise, yoga, relaxation training, biofeedback, cognitive behavioral therapy) and rational pharmacotherapy while promoting patient self-care is the standard of pain management called for by the Institute of Medicine.¹

Set functional goals

We recommend clearly defining functional goals with each patient before starting therapy. These goals should be written into the treatment plan as a way for patient and provider to evaluate the effectiveness of chronic opioid therapy. A useful mnemonic to help identify such goals is SMART, an acronym for specific, measurable, action-oriented, realistic, and time-bound. Specific goals will depend on pain severity, but examples could include being able to do grocery shopping without assistance, to play on the floor with grandchildren, or to engage in healthy exercise habits such as 20 minutes of moderately brisk walking 3 days per week.

Obtain informed consent, and document it thoroughly

Providers must communicate risks, potential benefits, and safe medication-taking practices, including how to safely store and dispose of unused opioids, and document this conversation clearly in the medical record. From a medicolegal perspective, if it wasn’t documented, it did not happen.¹⁷

From a medicolegal perspective, if it wasn’t documented, it didn’t happen

Informed consent can be further advanced with the use of a controlled substance agreement that outlines the treatment plan as well as potential risks, benefits, and practice policies in a structured way. Most states now either recommend or mandate the use of such agreements.¹⁸

Controlled substance agreements give providers a greater sense of mastery and comfort when prescribing opioids,¹⁹ but they have important limitations. In particular, there is a lack of consensus on what the agreement should say and relatively weak evidence that these agreements are efficacious. Additionally, a poorly written agreement can be stigmatizing and can erode trust.²⁰ However, we believe that when the agreement is written in an appropriate framework of safety at an appropriate level of health literacy and with a focus on shared decision-making, it can be very helpful and should be used.

Employ safe, rational pharmacotherapy

Considerations when choosing an opioid include its potency, onset of action, and half-life. Comorbid conditions (eg, advanced age,²¹ sleep-disordered breathing²²) and concurrent medications (eg, benzodiazepines, anticonvulsants, muscle relaxants) also affect decisions about the formulation, starting dose, rapidity of titration, and ceiling dose. Risk of harm  increases in patients with such comorbid factors, and it is prudent to start with lower doses of shorter-acting medications until patients can demonstrate safe use. Risk of unintentional overdose is higher with higher prescribed doses.²³ Pharmacologically there is no analgesic dose ceiling, but we urge caution, particularly in opioid-naive patients.

Try a less addictive agent such as tramadol or codeine before escalating to hydrocodone, oxycodone, or morphine

A patient’s response to any particular opioid is idiosyncratic and variable. There are more than 100 known polymorphisms in the human opioid mu-receptor gene, and thus differences in receptor affinity and activation as well as in metabolism make it difficult to predict which opioid will work best for a particular patient.²⁴ However, a less potent opioid receptor agonist with less addictive potential, such as tramadol or codeine, should generally be tried first before escalating to a riskier, more potent opioid such as hydrocodone, oxycodone, or morphine. This “analgesic ladder,” a concept introduced by the World Health Organization in 1986 to provide a framework for managing cancer pain, has been adapted to a variety of chronic pain syndromes.²⁵

Methadone deserves special mention. A strongly lipophilic molecule with a long and variable half-life, it accumulates in fat,²⁶ and long after the analgesic effect has worn off, methadone will still be present. Repeated dosing or rapid dose escalation in an attempt to achieve adequate analgesia may result in inadvertent overdose. Additionally, methadone can prolong the QT interval, and periodic electrocardiographic monitoring is recommended.²⁷ For these reasons, we recommend avoiding the use of methadone in most cases unless the provider has significant experience, expertise, or support in the safe use of this medication.

Table 1 summarizes these recommendations.

MONITORING AND SAFETY

Providers must periodically reassess the safety and efficacy of chronic opioid therapy to be sure that it is still indicated.¹⁰ Since we cannot accurately predict which patients will suffer adverse reactions or demonstrate aberrant behaviors,⁷ it is important to be transparent and consistent with monitoring practices for all patients on chronic opioid therapy.¹⁷ By framing monitoring in terms of safety and employing it universally, providers can minimize miscommunication and accidental stigmatization.

Prescription monitoring programs

In 2002, Congress appropriated funding to the US Department of Justice to support prescription monitoring programs nationally.²⁸ At the time of this writing, Missouri is the only state without an approved monitoring program.²⁹

Although the design and function of the programs vary from state to state, they require pharmacies to collect and report data on controlled substances for individual patients and prescribers. These data are sometimes shared across state lines, and the programs enhance the capacity of regulatory and law enforcement agencies to analyze controlled substance use.

Prescribers can (and are sometimes required to) register for access in their state and use this resource to assess the opioid refill history of their patients. This powerful tool improves detection of “doctor-shopping” and other common scams.³⁰

Additionally, recognizing that the risk of death from overdose increases as the total daily dose of opioids increases,²³ some states provide data on their composite report expressing the morphine equivalent daily dose or daily morphine milligram equivalents of the opioids prescribed. This information is valuable to the busy clinician; at a glance the prescriber can quickly discern the total daily opioid dose and use that information to assess risk and manage change. Furthermore, some states restrict further dose escalation when the morphine equivalent daily dose exceeds a predetermined amount (typically 100 to 120 morphine milligram equivalents).

Tamper-resistant prescribing

To minimize the risk of prescription tampering, simple techniques such as writing out the number of tablets dispensed can help, and use of tamper-resistant prescription paper has been required for Medicaid recipients since 2008.³¹

When possible, we recommend products with abuse-deterrent properties. Although the science of abuse deterrence is relatively new and few products are labeled as such, a number of opioids are formulated to resist deformation, vaporization, dissolving, or other physical tampering. Additionally, some abuse-deterrent opioid formulations contain naloxone, which is released only when the drug is deformed in some way, thereby decreasing the user’s response to an abused substance or resulting in opioid withdrawal.³²

Urine drug testing

Although complex and nuanced, guidelines recommend urine drug testing to confirm the presence or absence of prescribed and illicit substances in the body.¹⁰ There is no consensus on when or how often to test, but it should be done randomly and without forewarning to foil efforts to defeat testing such as provision of synthetic, adulterated, or substituted urine.

Providers underuse urine drug testing.³³ We recommend that it be done at the start of opioid therapy, sporadically thereafter, when therapy is changed, and whenever the provider is concerned about possible aberrant drug use.

Understanding opioid metabolism, cross-reactivity, and the types of tests available will help avoid misinterpretation of results.³⁴ For example, a positive “opiate” result in most screening immunoassay tests does not reflect oxycodone use, since tests for synthetic opioids often need to be ordered separately; the commonly used Cedia opiate assay cross-reacts with oxycodone at a concentration of 10,000 ng/mL only 3.1% of the time.³⁵ Immunoassay screening tests are widely available, sensitive, inexpensive, and fast, but they are qualitative, have limited specificity, and are subject to false-positive and false-negative results.³⁶  Table 2 outlines some common characteristics of substances on screening immunoassays, including reported causes of false-positive results.^37–39

Confirmatory testing using gas chromatography or mass spectroscopy is more expensive and slower to process, but is highly sensitive and specific, quantitative, and useful when screening results are difficult to interpret.

Knowing how and when to order the right urine drug test and knowing how to interpret the results are skills prescribers should master.

DISCONTINUING OPIOIDS

When opioids are no longer safe or effective, they should be stopped. The decision can be difficult for both the patient and provider, and a certain degree of equanimity is needed to approach it rationally.

Strong indications for discontinuation

Respiratory depression, cognitive impairment, falls, and motor vehicle accidents mean harm is already apparent. At a minimum, dose reduction is warranted and discontinuation should be strongly considered. Similarly, overdose (intentional or accidental) and active suicidal ideation contraindicate ongoing opioid prescribing unless the ongoing risk can be decisively mitigated.

Certain aberrant behaviors such as prescription forgery or theft, threats of violence to obtain analgesics, and diversion (transfer of the drug to another person for nonmedical use) also warrant immediate discontinuation. Continuing to prescribe an opioid while knowing diversion is taking place may be a violation of federal or state law or both.⁴⁰

Another reason to stop is failure to achieve the expected benefit from chronic opioid therapy (ie, agreed-upon functional goals) despite appropriate dose adjustment. In these cases, ongoing risk by definition outweighs observed benefit.

Relative indications for discontinuation

Opioid therapy has many potential adverse effects. Depending on the severity and duration of the symptom and its response to either dose reduction or adjunctive management, opioids may need to be discontinued.

For example, pruritus, constipation, urinary retention, nausea, sedation, and sexual dysfunction may all be reasons to stop chronic opioid therapy. Similarly, chronic opioid therapy may paradoxically worsen pain in some susceptible patients, a complication known as opioid-induced hyperalgesia; in these cases, tapering off opioids should be considered as well.⁴¹ Aberrant behaviors should prompt reconsideration of chronic opioid therapy; these include hazardous alcohol consumption, use of illicit drugs, pill hoarding, and use of opioids in a manner different than intended by the prescriber.

Another relative indication for discontinuation is receipt of controlled substances from other providers. A well-written controlled substance agreement and adequate counseling may help mitigate this risk; poor communication between providers, lack of integration of electronic medical record systems, urgent or emergency room care, and poor health literacy may all lead to redundant prescribing in some circumstances. While unintentional use of controlled substances from different providers is no less dangerous than intentional misuse, the specifics of each case need to be considered before opioids are reflexively discontinued.

How to discontinue opioids

In most cases, opioids should be tapered to reduce the risk and severity of withdrawal symptoms. Decreasing the dose by 10% of the original dose per week is usually well tolerated with minimal adverse effects.⁴² Tapering can be done much faster, and numerous rapid detoxification protocols are available. In general, a patient needs 20% of the previous day’s dose to prevent withdrawal symptoms.⁴³

Withdrawal symptoms are rarely life-threatening but can be very uncomfortable. Some providers add clonidine to attenuate associated autonomic symptoms such as hypertension, nausea, cramps, diaphoresis, and tachycardia if they occur. Other adjunctive medications include nonsteroidal anti-inflammatory drugs for body aches, antiemetics for nausea and vomiting, bismuth subsalicylate for diarrhea, and trazodone for insomnia.

It is unlawful for primary care physicians to use another opioid to treat symptoms of withdrawal in the outpatient setting unless it is issued through a federally certified narcotic treatment program or prescribed by a qualified clinician registered with the US Drug Enforcement Administration to prescribe buprenorphine-naloxone.⁴⁴

In some circumstances, it may be appropriate to abruptly discontinue opioids without a taper, such as when diversion is evident. However, a decision to discontinue opioids due to misuse should not equate to an automatic decision to terminate a patient from the practice. Instead, providers should use this opportunity to offer empathy and referral to drug treatment counseling and rehabilitation. A decision to discontinue opioids because they are no longer safe or effective does not mean that the patient’s pain is not real—it is “real” for them, even if caused by the pain of addiction—or that shared decision-making is no longer possible or appropriate.

Handling difficult conversations when discontinuing opioids

The conversation between patient and provider when discontinuing opioids can be difficult. Misaligned expectations of both parties, patient fear of uncontrolled pain, and provider concern about causing suffering are frequent contributing factors. Patients abusing prescription drugs may also have a stronger relationship with their medication than with their provider and may use manipulative strategies including overt hostility and threats to obtain a prescription. Providers need to maintain their composure to de-escalate these potentially upsetting confrontations.

Table 3 outlines some specific suggestions that may be helpful, including the following:

• Frame the discussion in terms of safety—opioids are being discontinued because the benefit no longer outweighs the risk
  

• Don’t debate your decision with the patient, but present your reasoning in a considered manner
• Focus on the appropriateness of the treatment and not on the patient’s character
• Avoid the use of labels (eg, “drug addict”)
• Emphasize your commitment to the patient’s well-being and an alternative treatment plan (ie, nonabandonment)
• Respond to emotional distress with empathy, but do not let that change your decision to discontinue opioids.

Finally, we strongly encourage providers to insist on being treated respectfully. When safety cannot be ensured, providers should remove themselves from the room until the patient can calm down or the provider can ask for assistance from colleagues.

Maintaining empathy by understanding grief

Discontinuing opioids may trigger in a patient an emotional response similar to grief. When considered in this framework, it may empower an otherwise frustrated provider to remain empathetic even in the midst of a difficult confrontation. Paralleling Kübler-Ross’s five stages of grief,⁴⁵ we propose a similar model we call the “five stages of opioid loss”; this model has been successfully used in the residency continuity clinic at the University of Connecticut as a training aid.

Hopelessness and helplessness. During the first stage of the discussion the patient struggles with how to move forward. This conversation is frequently characterized by tearfulness and explanations to account for aberrant behavior or willingness to continue to suffer side effects. Active listening, empathy, and a focus on the factors that led to discontinuation of opioids while still validating pain are important.

Some patients go through five stages of opioid loss when stopping these drugs

Demanding and indignant. During the second stage, patients frequently push the limits of “no.” Accusations of abandonment and lack of empathy may accompany this stage and can be quite upsetting for the unprepared provider. A novice clinician can use role-play as a tool to better prepare for this type of encounter. Patients should be allowed to express their frustration but ultimatums and threats of violence should not be tolerated. Reassuring patients that their pain will be addressed using nonopioid therapy can be helpful, and a simple offer of continued care can help to preserve the therapeutic relationship.

Bargaining, the third stage of this model, is characterized by attempts to negotiate continued prescribing. While it can be frustrating, this push and pull is the beginning of real conversation and identification of a treatment plan for the future.

Resignation. The fourth stage begins when the patient has resigned himself or herself to your decision, but may not have accepted the available treatment options. At this point the patient may return for care or seek out a new provider. Empathy is again the element most crucial to success; this stage carries an opportunity to develop mutual respect.

Acceptance. The patients who choose to continue care with you have progressed to the final phase. They begin to look toward the future, having chosen the better of the two paths: partnering with a caring provider to develop a shared therapeutic plan.

A CONSISTENT AND TRANSPARENT APPROACH

Opioids can be useful for selected patients when they are carefully prescribed, but the prescriber must fully consider the risks and benefits specific to each patient and mitigate risk whenever possible.

Collaborating with patients to use opioids rationally is easier when it is part of a multimodal pain management plan and is initiated with clear functional goals and parameters for discontinuation. Presenting risks and benefits in a framework of safety and educating patients will help to reduce the stigma that may otherwise accompany safety monitoring using tools such as controlled substance agreements and urine toxicology testing.

Despite these efforts, patients may become psychologically dependent on opioids and discontinuation may prove difficult. However, a consistent and transparent approach to prescribing with special efforts to empathize with suffering patients may empower providers to navigate this process effectively.

Chronic pain affects an estimated 100 million Americans, at a cost of $635 billion each year in medical expenses, lost wages, and reduced productivity.¹ It is often managed in primary care settings with opioids by clinicians who have little or no formal training in pain management.^2,3 Some primary care providers may seek assistance from board-certified pain specialists, but with only four such experts for every 100,000 patients with chronic pain, primary care providers are typically on their own.⁴

Although opioids may help in some chronic pain syndromes, they also carry the risk of serious harm, including unintentional overdose and death. In 2009, unintentional drug overdoses, most commonly with opioids, surpassed motor vehicle accidents as the leading cause of accidental death in the United States.⁵ Additionally, nonmedical use of prescription drugs is the third most common category of drug abuse, after marijuana and alcohol.⁶

Unfortunately, clinicians cannot accurately predict future medication misuse.⁷ And while the potential harms of opioids are many, the long-term benefits are questionable.^8,9

For these reasons, providers need to understand the indications for and potential benefits of opioids, as well as the potential harms and how to monitor their safe use. Also important to know is how and when to discontinue opioids while preserving the therapeutic relationship.

This paper offers practical strategies to primary care providers and their care teams on how to safely initiate, monitor, and discontinue chronic opioid therapy.

STARTING OPIOID THERAPY FOR CHRONIC PAIN

Guidelines recommend considering starting patients on opioid therapy when the benefits are likely to outweigh the risks, when pain is moderate to severe, and when other multimodal treatment strategies have not achieved functional goals.¹⁰ Unfortunately, few studies have examined or demonstrated long-term benefit, and those that did examine this outcome reported reduction of pain severity but did not assess functional improvement.⁹ Meanwhile, data are increasingly clear that long-term use increases the risk of harm, both acute (eg, overdose) and chronic (eg, osteoporosis), especially with high doses.

Tools have been developed to predict the risk of misuse,^11–13 but few have been validated in primary care, where most opioids are prescribed. This limitation aside, consensus guidelines state that untreated substance use disorders, poorly controlled psychiatric disease, and erratic treatment adherence are contraindications to opioid therapy, at least until these other issues are treated.¹⁰

We are increasingly avoiding chronic opioid therapy in younger patients with chronic pain

Faced with the benefit-harm conundrum, we recommend a generally conservative approach to opioid initiation. With long-term functional benefit questionable and toxicity relatively common, we are increasingly avoiding chronic opioid therapy in younger patients with chronic pain.

Empathize and partner with your patient

Chronic pain care can be fraught with frustration and mutual distrust between patient and provider.¹⁴ Empathy and a collaborative stance help signal to the patient that the provider has the patient’s best interest in mind,¹⁵ whether initiating or deciding not to initiate opioids.

Optimize nonopioid therapy

In light of the risks associated with chronic opioid therapy, the clinician is urged to review and optimize nonopioid therapy before starting a patient on opioid treatment, and to maintain this approach if opioid therapy is started. Whenever possible, nonopioid treatment should include disease-modifying therapy and nondrug modalities such as physical therapy.

Judicious use of adequately dosed analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs may be sufficient to achieve analgesic goals if not contraindicated, and in some patients the addition of a topical analgesic (eg, diclofenac gel, lidocaine patches), a tricyclic or serotonin-norepinephrine reuptake inhibitor antidepressant, an anticonvulsant (eg, gabapentin), or a combination of the above can effectively address underlying pain-generating mechanisms.¹⁶ As with opioids, the risks and benefits of nonopioid pharmacotherapy should be reviewed both at initiation and periodically thereafter.

Frame the opioid treatment plan as a ‘therapeutic trial’

Starting an opioid should be framed as a “therapeutic trial.” These drugs should be continued only if safe and effective, at the lowest effective dose, and as one component of a multimodal pain treatment plan. Concurrent use of nonpharmacologic therapies (eg, physical therapy, structured exercise, yoga, relaxation training, biofeedback, cognitive behavioral therapy) and rational pharmacotherapy while promoting patient self-care is the standard of pain management called for by the Institute of Medicine.¹

Set functional goals

We recommend clearly defining functional goals with each patient before starting therapy. These goals should be written into the treatment plan as a way for patient and provider to evaluate the effectiveness of chronic opioid therapy. A useful mnemonic to help identify such goals is SMART, an acronym for specific, measurable, action-oriented, realistic, and time-bound. Specific goals will depend on pain severity, but examples could include being able to do grocery shopping without assistance, to play on the floor with grandchildren, or to engage in healthy exercise habits such as 20 minutes of moderately brisk walking 3 days per week.

Obtain informed consent, and document it thoroughly

Providers must communicate risks, potential benefits, and safe medication-taking practices, including how to safely store and dispose of unused opioids, and document this conversation clearly in the medical record. From a medicolegal perspective, if it wasn’t documented, it did not happen.¹⁷

From a medicolegal perspective, if it wasn’t documented, it didn’t happen

Informed consent can be further advanced with the use of a controlled substance agreement that outlines the treatment plan as well as potential risks, benefits, and practice policies in a structured way. Most states now either recommend or mandate the use of such agreements.¹⁸

Controlled substance agreements give providers a greater sense of mastery and comfort when prescribing opioids,¹⁹ but they have important limitations. In particular, there is a lack of consensus on what the agreement should say and relatively weak evidence that these agreements are efficacious. Additionally, a poorly written agreement can be stigmatizing and can erode trust.²⁰ However, we believe that when the agreement is written in an appropriate framework of safety at an appropriate level of health literacy and with a focus on shared decision-making, it can be very helpful and should be used.

Employ safe, rational pharmacotherapy

Considerations when choosing an opioid include its potency, onset of action, and half-life. Comorbid conditions (eg, advanced age,²¹ sleep-disordered breathing²²) and concurrent medications (eg, benzodiazepines, anticonvulsants, muscle relaxants) also affect decisions about the formulation, starting dose, rapidity of titration, and ceiling dose. Risk of harm  increases in patients with such comorbid factors, and it is prudent to start with lower doses of shorter-acting medications until patients can demonstrate safe use. Risk of unintentional overdose is higher with higher prescribed doses.²³ Pharmacologically there is no analgesic dose ceiling, but we urge caution, particularly in opioid-naive patients.

Try a less addictive agent such as tramadol or codeine before escalating to hydrocodone, oxycodone, or morphine

A patient’s response to any particular opioid is idiosyncratic and variable. There are more than 100 known polymorphisms in the human opioid mu-receptor gene, and thus differences in receptor affinity and activation as well as in metabolism make it difficult to predict which opioid will work best for a particular patient.²⁴ However, a less potent opioid receptor agonist with less addictive potential, such as tramadol or codeine, should generally be tried first before escalating to a riskier, more potent opioid such as hydrocodone, oxycodone, or morphine. This “analgesic ladder,” a concept introduced by the World Health Organization in 1986 to provide a framework for managing cancer pain, has been adapted to a variety of chronic pain syndromes.²⁵

Methadone deserves special mention. A strongly lipophilic molecule with a long and variable half-life, it accumulates in fat,²⁶ and long after the analgesic effect has worn off, methadone will still be present. Repeated dosing or rapid dose escalation in an attempt to achieve adequate analgesia may result in inadvertent overdose. Additionally, methadone can prolong the QT interval, and periodic electrocardiographic monitoring is recommended.²⁷ For these reasons, we recommend avoiding the use of methadone in most cases unless the provider has significant experience, expertise, or support in the safe use of this medication.

Table 1 summarizes these recommendations.

MONITORING AND SAFETY

Providers must periodically reassess the safety and efficacy of chronic opioid therapy to be sure that it is still indicated.¹⁰ Since we cannot accurately predict which patients will suffer adverse reactions or demonstrate aberrant behaviors,⁷ it is important to be transparent and consistent with monitoring practices for all patients on chronic opioid therapy.¹⁷ By framing monitoring in terms of safety and employing it universally, providers can minimize miscommunication and accidental stigmatization.

Prescription monitoring programs

In 2002, Congress appropriated funding to the US Department of Justice to support prescription monitoring programs nationally.²⁸ At the time of this writing, Missouri is the only state without an approved monitoring program.²⁹

Although the design and function of the programs vary from state to state, they require pharmacies to collect and report data on controlled substances for individual patients and prescribers. These data are sometimes shared across state lines, and the programs enhance the capacity of regulatory and law enforcement agencies to analyze controlled substance use.

Prescribers can (and are sometimes required to) register for access in their state and use this resource to assess the opioid refill history of their patients. This powerful tool improves detection of “doctor-shopping” and other common scams.³⁰

Additionally, recognizing that the risk of death from overdose increases as the total daily dose of opioids increases,²³ some states provide data on their composite report expressing the morphine equivalent daily dose or daily morphine milligram equivalents of the opioids prescribed. This information is valuable to the busy clinician; at a glance the prescriber can quickly discern the total daily opioid dose and use that information to assess risk and manage change. Furthermore, some states restrict further dose escalation when the morphine equivalent daily dose exceeds a predetermined amount (typically 100 to 120 morphine milligram equivalents).

Tamper-resistant prescribing

To minimize the risk of prescription tampering, simple techniques such as writing out the number of tablets dispensed can help, and use of tamper-resistant prescription paper has been required for Medicaid recipients since 2008.³¹

When possible, we recommend products with abuse-deterrent properties. Although the science of abuse deterrence is relatively new and few products are labeled as such, a number of opioids are formulated to resist deformation, vaporization, dissolving, or other physical tampering. Additionally, some abuse-deterrent opioid formulations contain naloxone, which is released only when the drug is deformed in some way, thereby decreasing the user’s response to an abused substance or resulting in opioid withdrawal.³²

Urine drug testing

Although complex and nuanced, guidelines recommend urine drug testing to confirm the presence or absence of prescribed and illicit substances in the body.¹⁰ There is no consensus on when or how often to test, but it should be done randomly and without forewarning to foil efforts to defeat testing such as provision of synthetic, adulterated, or substituted urine.

Providers underuse urine drug testing.³³ We recommend that it be done at the start of opioid therapy, sporadically thereafter, when therapy is changed, and whenever the provider is concerned about possible aberrant drug use.

Understanding opioid metabolism, cross-reactivity, and the types of tests available will help avoid misinterpretation of results.³⁴ For example, a positive “opiate” result in most screening immunoassay tests does not reflect oxycodone use, since tests for synthetic opioids often need to be ordered separately; the commonly used Cedia opiate assay cross-reacts with oxycodone at a concentration of 10,000 ng/mL only 3.1% of the time.³⁵ Immunoassay screening tests are widely available, sensitive, inexpensive, and fast, but they are qualitative, have limited specificity, and are subject to false-positive and false-negative results.³⁶  Table 2 outlines some common characteristics of substances on screening immunoassays, including reported causes of false-positive results.^37–39

Confirmatory testing using gas chromatography or mass spectroscopy is more expensive and slower to process, but is highly sensitive and specific, quantitative, and useful when screening results are difficult to interpret.

Knowing how and when to order the right urine drug test and knowing how to interpret the results are skills prescribers should master.

DISCONTINUING OPIOIDS

When opioids are no longer safe or effective, they should be stopped. The decision can be difficult for both the patient and provider, and a certain degree of equanimity is needed to approach it rationally.

Strong indications for discontinuation

Respiratory depression, cognitive impairment, falls, and motor vehicle accidents mean harm is already apparent. At a minimum, dose reduction is warranted and discontinuation should be strongly considered. Similarly, overdose (intentional or accidental) and active suicidal ideation contraindicate ongoing opioid prescribing unless the ongoing risk can be decisively mitigated.

Certain aberrant behaviors such as prescription forgery or theft, threats of violence to obtain analgesics, and diversion (transfer of the drug to another person for nonmedical use) also warrant immediate discontinuation. Continuing to prescribe an opioid while knowing diversion is taking place may be a violation of federal or state law or both.⁴⁰

Another reason to stop is failure to achieve the expected benefit from chronic opioid therapy (ie, agreed-upon functional goals) despite appropriate dose adjustment. In these cases, ongoing risk by definition outweighs observed benefit.

Relative indications for discontinuation

Opioid therapy has many potential adverse effects. Depending on the severity and duration of the symptom and its response to either dose reduction or adjunctive management, opioids may need to be discontinued.

For example, pruritus, constipation, urinary retention, nausea, sedation, and sexual dysfunction may all be reasons to stop chronic opioid therapy. Similarly, chronic opioid therapy may paradoxically worsen pain in some susceptible patients, a complication known as opioid-induced hyperalgesia; in these cases, tapering off opioids should be considered as well.⁴¹ Aberrant behaviors should prompt reconsideration of chronic opioid therapy; these include hazardous alcohol consumption, use of illicit drugs, pill hoarding, and use of opioids in a manner different than intended by the prescriber.

Another relative indication for discontinuation is receipt of controlled substances from other providers. A well-written controlled substance agreement and adequate counseling may help mitigate this risk; poor communication between providers, lack of integration of electronic medical record systems, urgent or emergency room care, and poor health literacy may all lead to redundant prescribing in some circumstances. While unintentional use of controlled substances from different providers is no less dangerous than intentional misuse, the specifics of each case need to be considered before opioids are reflexively discontinued.

How to discontinue opioids

In most cases, opioids should be tapered to reduce the risk and severity of withdrawal symptoms. Decreasing the dose by 10% of the original dose per week is usually well tolerated with minimal adverse effects.⁴² Tapering can be done much faster, and numerous rapid detoxification protocols are available. In general, a patient needs 20% of the previous day’s dose to prevent withdrawal symptoms.⁴³

Withdrawal symptoms are rarely life-threatening but can be very uncomfortable. Some providers add clonidine to attenuate associated autonomic symptoms such as hypertension, nausea, cramps, diaphoresis, and tachycardia if they occur. Other adjunctive medications include nonsteroidal anti-inflammatory drugs for body aches, antiemetics for nausea and vomiting, bismuth subsalicylate for diarrhea, and trazodone for insomnia.

It is unlawful for primary care physicians to use another opioid to treat symptoms of withdrawal in the outpatient setting unless it is issued through a federally certified narcotic treatment program or prescribed by a qualified clinician registered with the US Drug Enforcement Administration to prescribe buprenorphine-naloxone.⁴⁴

In some circumstances, it may be appropriate to abruptly discontinue opioids without a taper, such as when diversion is evident. However, a decision to discontinue opioids due to misuse should not equate to an automatic decision to terminate a patient from the practice. Instead, providers should use this opportunity to offer empathy and referral to drug treatment counseling and rehabilitation. A decision to discontinue opioids because they are no longer safe or effective does not mean that the patient’s pain is not real—it is “real” for them, even if caused by the pain of addiction—or that shared decision-making is no longer possible or appropriate.

Handling difficult conversations when discontinuing opioids

The conversation between patient and provider when discontinuing opioids can be difficult. Misaligned expectations of both parties, patient fear of uncontrolled pain, and provider concern about causing suffering are frequent contributing factors. Patients abusing prescription drugs may also have a stronger relationship with their medication than with their provider and may use manipulative strategies including overt hostility and threats to obtain a prescription. Providers need to maintain their composure to de-escalate these potentially upsetting confrontations.

Table 3 outlines some specific suggestions that may be helpful, including the following:

• Frame the discussion in terms of safety—opioids are being discontinued because the benefit no longer outweighs the risk
  

• Don’t debate your decision with the patient, but present your reasoning in a considered manner
• Focus on the appropriateness of the treatment and not on the patient’s character
• Avoid the use of labels (eg, “drug addict”)
• Emphasize your commitment to the patient’s well-being and an alternative treatment plan (ie, nonabandonment)
• Respond to emotional distress with empathy, but do not let that change your decision to discontinue opioids.

Finally, we strongly encourage providers to insist on being treated respectfully. When safety cannot be ensured, providers should remove themselves from the room until the patient can calm down or the provider can ask for assistance from colleagues.

Maintaining empathy by understanding grief

Discontinuing opioids may trigger in a patient an emotional response similar to grief. When considered in this framework, it may empower an otherwise frustrated provider to remain empathetic even in the midst of a difficult confrontation. Paralleling Kübler-Ross’s five stages of grief,⁴⁵ we propose a similar model we call the “five stages of opioid loss”; this model has been successfully used in the residency continuity clinic at the University of Connecticut as a training aid.

Hopelessness and helplessness. During the first stage of the discussion the patient struggles with how to move forward. This conversation is frequently characterized by tearfulness and explanations to account for aberrant behavior or willingness to continue to suffer side effects. Active listening, empathy, and a focus on the factors that led to discontinuation of opioids while still validating pain are important.

Some patients go through five stages of opioid loss when stopping these drugs

Demanding and indignant. During the second stage, patients frequently push the limits of “no.” Accusations of abandonment and lack of empathy may accompany this stage and can be quite upsetting for the unprepared provider. A novice clinician can use role-play as a tool to better prepare for this type of encounter. Patients should be allowed to express their frustration but ultimatums and threats of violence should not be tolerated. Reassuring patients that their pain will be addressed using nonopioid therapy can be helpful, and a simple offer of continued care can help to preserve the therapeutic relationship.

Bargaining, the third stage of this model, is characterized by attempts to negotiate continued prescribing. While it can be frustrating, this push and pull is the beginning of real conversation and identification of a treatment plan for the future.

Resignation. The fourth stage begins when the patient has resigned himself or herself to your decision, but may not have accepted the available treatment options. At this point the patient may return for care or seek out a new provider. Empathy is again the element most crucial to success; this stage carries an opportunity to develop mutual respect.

Acceptance. The patients who choose to continue care with you have progressed to the final phase. They begin to look toward the future, having chosen the better of the two paths: partnering with a caring provider to develop a shared therapeutic plan.

A CONSISTENT AND TRANSPARENT APPROACH

Opioids can be useful for selected patients when they are carefully prescribed, but the prescriber must fully consider the risks and benefits specific to each patient and mitigate risk whenever possible.

Collaborating with patients to use opioids rationally is easier when it is part of a multimodal pain management plan and is initiated with clear functional goals and parameters for discontinuation. Presenting risks and benefits in a framework of safety and educating patients will help to reduce the stigma that may otherwise accompany safety monitoring using tools such as controlled substance agreements and urine toxicology testing.

Despite these efforts, patients may become psychologically dependent on opioids and discontinuation may prove difficult. However, a consistent and transparent approach to prescribing with special efforts to empathize with suffering patients may empower providers to navigate this process effectively.

Chronic pain affects an estimated 100 million Americans, at a cost of $635 billion each year in medical expenses, lost wages, and reduced productivity.¹ It is often managed in primary care settings with opioids by clinicians who have little or no formal training in pain management.^2,3 Some primary care providers may seek assistance from board-certified pain specialists, but with only four such experts for every 100,000 patients with chronic pain, primary care providers are typically on their own.⁴

Although opioids may help in some chronic pain syndromes, they also carry the risk of serious harm, including unintentional overdose and death. In 2009, unintentional drug overdoses, most commonly with opioids, surpassed motor vehicle accidents as the leading cause of accidental death in the United States.⁵ Additionally, nonmedical use of prescription drugs is the third most common category of drug abuse, after marijuana and alcohol.⁶

Unfortunately, clinicians cannot accurately predict future medication misuse.⁷ And while the potential harms of opioids are many, the long-term benefits are questionable.^8,9

For these reasons, providers need to understand the indications for and potential benefits of opioids, as well as the potential harms and how to monitor their safe use. Also important to know is how and when to discontinue opioids while preserving the therapeutic relationship.

This paper offers practical strategies to primary care providers and their care teams on how to safely initiate, monitor, and discontinue chronic opioid therapy.

STARTING OPIOID THERAPY FOR CHRONIC PAIN

Guidelines recommend considering starting patients on opioid therapy when the benefits are likely to outweigh the risks, when pain is moderate to severe, and when other multimodal treatment strategies have not achieved functional goals.¹⁰ Unfortunately, few studies have examined or demonstrated long-term benefit, and those that did examine this outcome reported reduction of pain severity but did not assess functional improvement.⁹ Meanwhile, data are increasingly clear that long-term use increases the risk of harm, both acute (eg, overdose) and chronic (eg, osteoporosis), especially with high doses.

Tools have been developed to predict the risk of misuse,^11–13 but few have been validated in primary care, where most opioids are prescribed. This limitation aside, consensus guidelines state that untreated substance use disorders, poorly controlled psychiatric disease, and erratic treatment adherence are contraindications to opioid therapy, at least until these other issues are treated.¹⁰

We are increasingly avoiding chronic opioid therapy in younger patients with chronic pain

Faced with the benefit-harm conundrum, we recommend a generally conservative approach to opioid initiation. With long-term functional benefit questionable and toxicity relatively common, we are increasingly avoiding chronic opioid therapy in younger patients with chronic pain.

Empathize and partner with your patient

Chronic pain care can be fraught with frustration and mutual distrust between patient and provider.¹⁴ Empathy and a collaborative stance help signal to the patient that the provider has the patient’s best interest in mind,¹⁵ whether initiating or deciding not to initiate opioids.

Optimize nonopioid therapy

In light of the risks associated with chronic opioid therapy, the clinician is urged to review and optimize nonopioid therapy before starting a patient on opioid treatment, and to maintain this approach if opioid therapy is started. Whenever possible, nonopioid treatment should include disease-modifying therapy and nondrug modalities such as physical therapy.

Judicious use of adequately dosed analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs may be sufficient to achieve analgesic goals if not contraindicated, and in some patients the addition of a topical analgesic (eg, diclofenac gel, lidocaine patches), a tricyclic or serotonin-norepinephrine reuptake inhibitor antidepressant, an anticonvulsant (eg, gabapentin), or a combination of the above can effectively address underlying pain-generating mechanisms.¹⁶ As with opioids, the risks and benefits of nonopioid pharmacotherapy should be reviewed both at initiation and periodically thereafter.

Frame the opioid treatment plan as a ‘therapeutic trial’

Starting an opioid should be framed as a “therapeutic trial.” These drugs should be continued only if safe and effective, at the lowest effective dose, and as one component of a multimodal pain treatment plan. Concurrent use of nonpharmacologic therapies (eg, physical therapy, structured exercise, yoga, relaxation training, biofeedback, cognitive behavioral therapy) and rational pharmacotherapy while promoting patient self-care is the standard of pain management called for by the Institute of Medicine.¹

Set functional goals

We recommend clearly defining functional goals with each patient before starting therapy. These goals should be written into the treatment plan as a way for patient and provider to evaluate the effectiveness of chronic opioid therapy. A useful mnemonic to help identify such goals is SMART, an acronym for specific, measurable, action-oriented, realistic, and time-bound. Specific goals will depend on pain severity, but examples could include being able to do grocery shopping without assistance, to play on the floor with grandchildren, or to engage in healthy exercise habits such as 20 minutes of moderately brisk walking 3 days per week.

Obtain informed consent, and document it thoroughly

Providers must communicate risks, potential benefits, and safe medication-taking practices, including how to safely store and dispose of unused opioids, and document this conversation clearly in the medical record. From a medicolegal perspective, if it wasn’t documented, it did not happen.¹⁷

From a medicolegal perspective, if it wasn’t documented, it didn’t happen

Informed consent can be further advanced with the use of a controlled substance agreement that outlines the treatment plan as well as potential risks, benefits, and practice policies in a structured way. Most states now either recommend or mandate the use of such agreements.¹⁸

Controlled substance agreements give providers a greater sense of mastery and comfort when prescribing opioids,¹⁹ but they have important limitations. In particular, there is a lack of consensus on what the agreement should say and relatively weak evidence that these agreements are efficacious. Additionally, a poorly written agreement can be stigmatizing and can erode trust.²⁰ However, we believe that when the agreement is written in an appropriate framework of safety at an appropriate level of health literacy and with a focus on shared decision-making, it can be very helpful and should be used.

Employ safe, rational pharmacotherapy

Considerations when choosing an opioid include its potency, onset of action, and half-life. Comorbid conditions (eg, advanced age,²¹ sleep-disordered breathing²²) and concurrent medications (eg, benzodiazepines, anticonvulsants, muscle relaxants) also affect decisions about the formulation, starting dose, rapidity of titration, and ceiling dose. Risk of harm  increases in patients with such comorbid factors, and it is prudent to start with lower doses of shorter-acting medications until patients can demonstrate safe use. Risk of unintentional overdose is higher with higher prescribed doses.²³ Pharmacologically there is no analgesic dose ceiling, but we urge caution, particularly in opioid-naive patients.

Try a less addictive agent such as tramadol or codeine before escalating to hydrocodone, oxycodone, or morphine

A patient’s response to any particular opioid is idiosyncratic and variable. There are more than 100 known polymorphisms in the human opioid mu-receptor gene, and thus differences in receptor affinity and activation as well as in metabolism make it difficult to predict which opioid will work best for a particular patient.²⁴ However, a less potent opioid receptor agonist with less addictive potential, such as tramadol or codeine, should generally be tried first before escalating to a riskier, more potent opioid such as hydrocodone, oxycodone, or morphine. This “analgesic ladder,” a concept introduced by the World Health Organization in 1986 to provide a framework for managing cancer pain, has been adapted to a variety of chronic pain syndromes.²⁵

Methadone deserves special mention. A strongly lipophilic molecule with a long and variable half-life, it accumulates in fat,²⁶ and long after the analgesic effect has worn off, methadone will still be present. Repeated dosing or rapid dose escalation in an attempt to achieve adequate analgesia may result in inadvertent overdose. Additionally, methadone can prolong the QT interval, and periodic electrocardiographic monitoring is recommended.²⁷ For these reasons, we recommend avoiding the use of methadone in most cases unless the provider has significant experience, expertise, or support in the safe use of this medication.

Table 1 summarizes these recommendations.

MONITORING AND SAFETY

Providers must periodically reassess the safety and efficacy of chronic opioid therapy to be sure that it is still indicated.¹⁰ Since we cannot accurately predict which patients will suffer adverse reactions or demonstrate aberrant behaviors,⁷ it is important to be transparent and consistent with monitoring practices for all patients on chronic opioid therapy.¹⁷ By framing monitoring in terms of safety and employing it universally, providers can minimize miscommunication and accidental stigmatization.

Prescription monitoring programs

In 2002, Congress appropriated funding to the US Department of Justice to support prescription monitoring programs nationally.²⁸ At the time of this writing, Missouri is the only state without an approved monitoring program.²⁹

Although the design and function of the programs vary from state to state, they require pharmacies to collect and report data on controlled substances for individual patients and prescribers. These data are sometimes shared across state lines, and the programs enhance the capacity of regulatory and law enforcement agencies to analyze controlled substance use.

Prescribers can (and are sometimes required to) register for access in their state and use this resource to assess the opioid refill history of their patients. This powerful tool improves detection of “doctor-shopping” and other common scams.³⁰

Additionally, recognizing that the risk of death from overdose increases as the total daily dose of opioids increases,²³ some states provide data on their composite report expressing the morphine equivalent daily dose or daily morphine milligram equivalents of the opioids prescribed. This information is valuable to the busy clinician; at a glance the prescriber can quickly discern the total daily opioid dose and use that information to assess risk and manage change. Furthermore, some states restrict further dose escalation when the morphine equivalent daily dose exceeds a predetermined amount (typically 100 to 120 morphine milligram equivalents).

Tamper-resistant prescribing

To minimize the risk of prescription tampering, simple techniques such as writing out the number of tablets dispensed can help, and use of tamper-resistant prescription paper has been required for Medicaid recipients since 2008.³¹

When possible, we recommend products with abuse-deterrent properties. Although the science of abuse deterrence is relatively new and few products are labeled as such, a number of opioids are formulated to resist deformation, vaporization, dissolving, or other physical tampering. Additionally, some abuse-deterrent opioid formulations contain naloxone, which is released only when the drug is deformed in some way, thereby decreasing the user’s response to an abused substance or resulting in opioid withdrawal.³²

Urine drug testing

Although complex and nuanced, guidelines recommend urine drug testing to confirm the presence or absence of prescribed and illicit substances in the body.¹⁰ There is no consensus on when or how often to test, but it should be done randomly and without forewarning to foil efforts to defeat testing such as provision of synthetic, adulterated, or substituted urine.

Providers underuse urine drug testing.³³ We recommend that it be done at the start of opioid therapy, sporadically thereafter, when therapy is changed, and whenever the provider is concerned about possible aberrant drug use.

Understanding opioid metabolism, cross-reactivity, and the types of tests available will help avoid misinterpretation of results.³⁴ For example, a positive “opiate” result in most screening immunoassay tests does not reflect oxycodone use, since tests for synthetic opioids often need to be ordered separately; the commonly used Cedia opiate assay cross-reacts with oxycodone at a concentration of 10,000 ng/mL only 3.1% of the time.³⁵ Immunoassay screening tests are widely available, sensitive, inexpensive, and fast, but they are qualitative, have limited specificity, and are subject to false-positive and false-negative results.³⁶  Table 2 outlines some common characteristics of substances on screening immunoassays, including reported causes of false-positive results.^37–39

Confirmatory testing using gas chromatography or mass spectroscopy is more expensive and slower to process, but is highly sensitive and specific, quantitative, and useful when screening results are difficult to interpret.

Knowing how and when to order the right urine drug test and knowing how to interpret the results are skills prescribers should master.

DISCONTINUING OPIOIDS

When opioids are no longer safe or effective, they should be stopped. The decision can be difficult for both the patient and provider, and a certain degree of equanimity is needed to approach it rationally.

Strong indications for discontinuation

Respiratory depression, cognitive impairment, falls, and motor vehicle accidents mean harm is already apparent. At a minimum, dose reduction is warranted and discontinuation should be strongly considered. Similarly, overdose (intentional or accidental) and active suicidal ideation contraindicate ongoing opioid prescribing unless the ongoing risk can be decisively mitigated.

Certain aberrant behaviors such as prescription forgery or theft, threats of violence to obtain analgesics, and diversion (transfer of the drug to another person for nonmedical use) also warrant immediate discontinuation. Continuing to prescribe an opioid while knowing diversion is taking place may be a violation of federal or state law or both.⁴⁰

Another reason to stop is failure to achieve the expected benefit from chronic opioid therapy (ie, agreed-upon functional goals) despite appropriate dose adjustment. In these cases, ongoing risk by definition outweighs observed benefit.

Relative indications for discontinuation

Opioid therapy has many potential adverse effects. Depending on the severity and duration of the symptom and its response to either dose reduction or adjunctive management, opioids may need to be discontinued.

For example, pruritus, constipation, urinary retention, nausea, sedation, and sexual dysfunction may all be reasons to stop chronic opioid therapy. Similarly, chronic opioid therapy may paradoxically worsen pain in some susceptible patients, a complication known as opioid-induced hyperalgesia; in these cases, tapering off opioids should be considered as well.⁴¹ Aberrant behaviors should prompt reconsideration of chronic opioid therapy; these include hazardous alcohol consumption, use of illicit drugs, pill hoarding, and use of opioids in a manner different than intended by the prescriber.

Another relative indication for discontinuation is receipt of controlled substances from other providers. A well-written controlled substance agreement and adequate counseling may help mitigate this risk; poor communication between providers, lack of integration of electronic medical record systems, urgent or emergency room care, and poor health literacy may all lead to redundant prescribing in some circumstances. While unintentional use of controlled substances from different providers is no less dangerous than intentional misuse, the specifics of each case need to be considered before opioids are reflexively discontinued.

How to discontinue opioids

In most cases, opioids should be tapered to reduce the risk and severity of withdrawal symptoms. Decreasing the dose by 10% of the original dose per week is usually well tolerated with minimal adverse effects.⁴² Tapering can be done much faster, and numerous rapid detoxification protocols are available. In general, a patient needs 20% of the previous day’s dose to prevent withdrawal symptoms.⁴³

Withdrawal symptoms are rarely life-threatening but can be very uncomfortable. Some providers add clonidine to attenuate associated autonomic symptoms such as hypertension, nausea, cramps, diaphoresis, and tachycardia if they occur. Other adjunctive medications include nonsteroidal anti-inflammatory drugs for body aches, antiemetics for nausea and vomiting, bismuth subsalicylate for diarrhea, and trazodone for insomnia.

It is unlawful for primary care physicians to use another opioid to treat symptoms of withdrawal in the outpatient setting unless it is issued through a federally certified narcotic treatment program or prescribed by a qualified clinician registered with the US Drug Enforcement Administration to prescribe buprenorphine-naloxone.⁴⁴

In some circumstances, it may be appropriate to abruptly discontinue opioids without a taper, such as when diversion is evident. However, a decision to discontinue opioids due to misuse should not equate to an automatic decision to terminate a patient from the practice. Instead, providers should use this opportunity to offer empathy and referral to drug treatment counseling and rehabilitation. A decision to discontinue opioids because they are no longer safe or effective does not mean that the patient’s pain is not real—it is “real” for them, even if caused by the pain of addiction—or that shared decision-making is no longer possible or appropriate.

Handling difficult conversations when discontinuing opioids

The conversation between patient and provider when discontinuing opioids can be difficult. Misaligned expectations of both parties, patient fear of uncontrolled pain, and provider concern about causing suffering are frequent contributing factors. Patients abusing prescription drugs may also have a stronger relationship with their medication than with their provider and may use manipulative strategies including overt hostility and threats to obtain a prescription. Providers need to maintain their composure to de-escalate these potentially upsetting confrontations.

Table 3 outlines some specific suggestions that may be helpful, including the following:

• Frame the discussion in terms of safety—opioids are being discontinued because the benefit no longer outweighs the risk
  

• Don’t debate your decision with the patient, but present your reasoning in a considered manner
• Focus on the appropriateness of the treatment and not on the patient’s character
• Avoid the use of labels (eg, “drug addict”)
• Emphasize your commitment to the patient’s well-being and an alternative treatment plan (ie, nonabandonment)
• Respond to emotional distress with empathy, but do not let that change your decision to discontinue opioids.

Finally, we strongly encourage providers to insist on being treated respectfully. When safety cannot be ensured, providers should remove themselves from the room until the patient can calm down or the provider can ask for assistance from colleagues.

Maintaining empathy by understanding grief

Discontinuing opioids may trigger in a patient an emotional response similar to grief. When considered in this framework, it may empower an otherwise frustrated provider to remain empathetic even in the midst of a difficult confrontation. Paralleling Kübler-Ross’s five stages of grief,⁴⁵ we propose a similar model we call the “five stages of opioid loss”; this model has been successfully used in the residency continuity clinic at the University of Connecticut as a training aid.

Hopelessness and helplessness. During the first stage of the discussion the patient struggles with how to move forward. This conversation is frequently characterized by tearfulness and explanations to account for aberrant behavior or willingness to continue to suffer side effects. Active listening, empathy, and a focus on the factors that led to discontinuation of opioids while still validating pain are important.

Some patients go through five stages of opioid loss when stopping these drugs

Demanding and indignant. During the second stage, patients frequently push the limits of “no.” Accusations of abandonment and lack of empathy may accompany this stage and can be quite upsetting for the unprepared provider. A novice clinician can use role-play as a tool to better prepare for this type of encounter. Patients should be allowed to express their frustration but ultimatums and threats of violence should not be tolerated. Reassuring patients that their pain will be addressed using nonopioid therapy can be helpful, and a simple offer of continued care can help to preserve the therapeutic relationship.

Bargaining, the third stage of this model, is characterized by attempts to negotiate continued prescribing. While it can be frustrating, this push and pull is the beginning of real conversation and identification of a treatment plan for the future.

Resignation. The fourth stage begins when the patient has resigned himself or herself to your decision, but may not have accepted the available treatment options. At this point the patient may return for care or seek out a new provider. Empathy is again the element most crucial to success; this stage carries an opportunity to develop mutual respect.

Acceptance. The patients who choose to continue care with you have progressed to the final phase. They begin to look toward the future, having chosen the better of the two paths: partnering with a caring provider to develop a shared therapeutic plan.

A CONSISTENT AND TRANSPARENT APPROACH

Opioids can be useful for selected patients when they are carefully prescribed, but the prescriber must fully consider the risks and benefits specific to each patient and mitigate risk whenever possible.

Collaborating with patients to use opioids rationally is easier when it is part of a multimodal pain management plan and is initiated with clear functional goals and parameters for discontinuation. Presenting risks and benefits in a framework of safety and educating patients will help to reduce the stigma that may otherwise accompany safety monitoring using tools such as controlled substance agreements and urine toxicology testing.

Despite these efforts, patients may become psychologically dependent on opioids and discontinuation may prove difficult. However, a consistent and transparent approach to prescribing with special efforts to empathize with suffering patients may empower providers to navigate this process effectively.

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.