Editorial

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.

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.

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.

Three decades ago, the only drugs we had for treating chronic heart failure were digitalis and loop diuretics. The mortality rate was very high, and heart transplantation was a newly developing treatment that could help only a very few patients.

See related article

The early 80s heralded new hope for patients with heart failure, with the introduction of angiotensin-converting enzyme (ACE) inhibitors^1–5 and, later, beta-blockers. Beta-blockers were considered contraindicated in heart failure until new trials provided evidence of dramatic benefit such as better quality of life and longer survival.^6–8 ACE inhibitors, along with beta-blockers, quickly became the standard of care for all patients with systolic heart failure.

The implantable cardioverter-defibrillator (ICD) required numerous clinical trials in ischemic and nonischemic cardiomyopathy to define its role.^9,10 Cardiac resynchronization therapy did not arrive until 15 years ago and is now indicated in a specific niche of patients with left bundle branch block.^11,12 Mineralocorticoid antagonists required three pivotal clinical trials before their important role in the treatment of systolic heart failure was defined.^13–16

And in the current decade, the roles of ACE inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid antagonists, ICDs, and cardiac resynchronization therapy have been further defined, as reflected in the latest guidelines for the treatment of systolic heart failure.¹⁷

It was hard to believe that any new additional therapy would make a significant difference

Guideline-directed medical therapy for systolic heart failure with the agents and devices mentioned above improves quality of life and extends survival. It was therefore hard to imagine that any new additive therapy could offer significant incremental improvement. However, more than 5 years ago, in an ambitious effort, the largest global clinical trial ever performed in chronic heart failure was launched with a novel agent.¹⁸

THE PARADIGM-HF TRIAL

In this issue of the Journal, Sabe et al¹⁹ describe the results of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial of the novel combination drug sacubitril-valsartan, designated LCZ696 during its development and now available as Entresto.²⁰

The mean age of the 8,442 patients in PARADIGM-HF was 64, and 78% were men. Despite guideline-directed medical therapy (93% of the patients were receiving a beta-blocker, and 60% were receiving a mineralocorticoid receptor antagonist), patients had persistent symptoms and signs of heart failure, diminished health-related quality of life, reduced ejection fraction (mean 29%), and elevated n-terminal pro-B-type natriuretic peptide levels (median 1,608 pg/mL, interquartile range 886–3,221).

The investigators reported a remarkable 20% reduction in the primary outcome of death from cardiovascular causes or hospitalization for heart failure in the patients who received sacubitril-valsartan compared with enalapril.²⁰

Sacubitril-valsartan was reviewed under a US Food and Drug Administration (FDA) program that provides expedited review of drugs that are intended to treat a serious disease or condition and that may provide a significant improvement over available therapy. It was also granted a fast-track designation, which supports FDA efforts to facilitate the development and expedite the review of drugs to treat serious and life-threatening conditions and fill an unmet medical need. The FDA approved sacubitril-valsartan on July 7, 2015, for use in place of an ACE inhibitor or ARB in patients with New York Heart Association class II, III, or IV heart failure with reduced ejection fraction.²¹

WHAT WE STILL NEED TO KNOW

The results of PARADIGM-HF are generalizable, and sacubitril-valsartan was well tolerated in patients whose blood pressure was acceptable and who were able to tolerate ACE inhibitors in target doses. More than 90% of patients were receiving a beta-blocker. The dosing of enalapril (target 10 mg twice a day) is the guideline-directed target dose, and ACE inhibition is considered the gold standard for heart failure with reduced ejection fraction. Sacubitril-valsartan vs enalapril was a very appropriate comparison.

Far fewer PARADIGM-HF patients outside the United States had an ICD than those in the United States, which is a common finding in global clinical trials. However, Desai et al reported that sacubitril-valsartan reduced rates of cardiovascular mortality both from worsening heart failure and from sudden cardiac death, independent of whether the patient had an ICD.²²

Sacubitril-valsartan is taken twice a day, but most heart failure patients already take medications at several times during the day, so this should not pose a problem.

Sacubitril-valsartan ushers in a new era in treating heart failure with reduced ejection fraction

More information is needed on the use of this new drug in patients with New York Heart Association class IV symptoms, as only 60 patients with class IV symptoms were included in the PARADIGM-HF trial. Also, the efficacy of the drug in patients unable to tolerate a full dose will need to be analyzed.

PARADIGM-HF was conducted in stable, nonhospitalized patients with chronic heart failure; the use of the drug in new-onset heart failure and its initiation in hospitalized patients will require further study. In addition, the PARAGON-HF trial²³ will examine the efficacy of sacubitril-valsartan in patients with heart failure and an ejection fraction of 45% or higher.

Sacubitril-valsartan ushers in a new era in heart failure treatment for patients with reduced ejection fraction and will certainly prompt quick revision of heart failure guidelines.

Three decades ago, the only drugs we had for treating chronic heart failure were digitalis and loop diuretics. The mortality rate was very high, and heart transplantation was a newly developing treatment that could help only a very few patients.

See related article

The early 80s heralded new hope for patients with heart failure, with the introduction of angiotensin-converting enzyme (ACE) inhibitors^1–5 and, later, beta-blockers. Beta-blockers were considered contraindicated in heart failure until new trials provided evidence of dramatic benefit such as better quality of life and longer survival.^6–8 ACE inhibitors, along with beta-blockers, quickly became the standard of care for all patients with systolic heart failure.

The implantable cardioverter-defibrillator (ICD) required numerous clinical trials in ischemic and nonischemic cardiomyopathy to define its role.^9,10 Cardiac resynchronization therapy did not arrive until 15 years ago and is now indicated in a specific niche of patients with left bundle branch block.^11,12 Mineralocorticoid antagonists required three pivotal clinical trials before their important role in the treatment of systolic heart failure was defined.^13–16

And in the current decade, the roles of ACE inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid antagonists, ICDs, and cardiac resynchronization therapy have been further defined, as reflected in the latest guidelines for the treatment of systolic heart failure.¹⁷

It was hard to believe that any new additional therapy would make a significant difference

Guideline-directed medical therapy for systolic heart failure with the agents and devices mentioned above improves quality of life and extends survival. It was therefore hard to imagine that any new additive therapy could offer significant incremental improvement. However, more than 5 years ago, in an ambitious effort, the largest global clinical trial ever performed in chronic heart failure was launched with a novel agent.¹⁸

THE PARADIGM-HF TRIAL

In this issue of the Journal, Sabe et al¹⁹ describe the results of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial of the novel combination drug sacubitril-valsartan, designated LCZ696 during its development and now available as Entresto.²⁰

The mean age of the 8,442 patients in PARADIGM-HF was 64, and 78% were men. Despite guideline-directed medical therapy (93% of the patients were receiving a beta-blocker, and 60% were receiving a mineralocorticoid receptor antagonist), patients had persistent symptoms and signs of heart failure, diminished health-related quality of life, reduced ejection fraction (mean 29%), and elevated n-terminal pro-B-type natriuretic peptide levels (median 1,608 pg/mL, interquartile range 886–3,221).

The investigators reported a remarkable 20% reduction in the primary outcome of death from cardiovascular causes or hospitalization for heart failure in the patients who received sacubitril-valsartan compared with enalapril.²⁰

Sacubitril-valsartan was reviewed under a US Food and Drug Administration (FDA) program that provides expedited review of drugs that are intended to treat a serious disease or condition and that may provide a significant improvement over available therapy. It was also granted a fast-track designation, which supports FDA efforts to facilitate the development and expedite the review of drugs to treat serious and life-threatening conditions and fill an unmet medical need. The FDA approved sacubitril-valsartan on July 7, 2015, for use in place of an ACE inhibitor or ARB in patients with New York Heart Association class II, III, or IV heart failure with reduced ejection fraction.²¹

WHAT WE STILL NEED TO KNOW

The results of PARADIGM-HF are generalizable, and sacubitril-valsartan was well tolerated in patients whose blood pressure was acceptable and who were able to tolerate ACE inhibitors in target doses. More than 90% of patients were receiving a beta-blocker. The dosing of enalapril (target 10 mg twice a day) is the guideline-directed target dose, and ACE inhibition is considered the gold standard for heart failure with reduced ejection fraction. Sacubitril-valsartan vs enalapril was a very appropriate comparison.

Far fewer PARADIGM-HF patients outside the United States had an ICD than those in the United States, which is a common finding in global clinical trials. However, Desai et al reported that sacubitril-valsartan reduced rates of cardiovascular mortality both from worsening heart failure and from sudden cardiac death, independent of whether the patient had an ICD.²²

Sacubitril-valsartan is taken twice a day, but most heart failure patients already take medications at several times during the day, so this should not pose a problem.

Sacubitril-valsartan ushers in a new era in treating heart failure with reduced ejection fraction

More information is needed on the use of this new drug in patients with New York Heart Association class IV symptoms, as only 60 patients with class IV symptoms were included in the PARADIGM-HF trial. Also, the efficacy of the drug in patients unable to tolerate a full dose will need to be analyzed.

PARADIGM-HF was conducted in stable, nonhospitalized patients with chronic heart failure; the use of the drug in new-onset heart failure and its initiation in hospitalized patients will require further study. In addition, the PARAGON-HF trial²³ will examine the efficacy of sacubitril-valsartan in patients with heart failure and an ejection fraction of 45% or higher.

Sacubitril-valsartan ushers in a new era in heart failure treatment for patients with reduced ejection fraction and will certainly prompt quick revision of heart failure guidelines.

Three decades ago, the only drugs we had for treating chronic heart failure were digitalis and loop diuretics. The mortality rate was very high, and heart transplantation was a newly developing treatment that could help only a very few patients.

See related article

The early 80s heralded new hope for patients with heart failure, with the introduction of angiotensin-converting enzyme (ACE) inhibitors^1–5 and, later, beta-blockers. Beta-blockers were considered contraindicated in heart failure until new trials provided evidence of dramatic benefit such as better quality of life and longer survival.^6–8 ACE inhibitors, along with beta-blockers, quickly became the standard of care for all patients with systolic heart failure.

The implantable cardioverter-defibrillator (ICD) required numerous clinical trials in ischemic and nonischemic cardiomyopathy to define its role.^9,10 Cardiac resynchronization therapy did not arrive until 15 years ago and is now indicated in a specific niche of patients with left bundle branch block.^11,12 Mineralocorticoid antagonists required three pivotal clinical trials before their important role in the treatment of systolic heart failure was defined.^13–16

And in the current decade, the roles of ACE inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid antagonists, ICDs, and cardiac resynchronization therapy have been further defined, as reflected in the latest guidelines for the treatment of systolic heart failure.¹⁷

It was hard to believe that any new additional therapy would make a significant difference

Guideline-directed medical therapy for systolic heart failure with the agents and devices mentioned above improves quality of life and extends survival. It was therefore hard to imagine that any new additive therapy could offer significant incremental improvement. However, more than 5 years ago, in an ambitious effort, the largest global clinical trial ever performed in chronic heart failure was launched with a novel agent.¹⁸

THE PARADIGM-HF TRIAL

In this issue of the Journal, Sabe et al¹⁹ describe the results of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial of the novel combination drug sacubitril-valsartan, designated LCZ696 during its development and now available as Entresto.²⁰

The mean age of the 8,442 patients in PARADIGM-HF was 64, and 78% were men. Despite guideline-directed medical therapy (93% of the patients were receiving a beta-blocker, and 60% were receiving a mineralocorticoid receptor antagonist), patients had persistent symptoms and signs of heart failure, diminished health-related quality of life, reduced ejection fraction (mean 29%), and elevated n-terminal pro-B-type natriuretic peptide levels (median 1,608 pg/mL, interquartile range 886–3,221).

The investigators reported a remarkable 20% reduction in the primary outcome of death from cardiovascular causes or hospitalization for heart failure in the patients who received sacubitril-valsartan compared with enalapril.²⁰

Sacubitril-valsartan was reviewed under a US Food and Drug Administration (FDA) program that provides expedited review of drugs that are intended to treat a serious disease or condition and that may provide a significant improvement over available therapy. It was also granted a fast-track designation, which supports FDA efforts to facilitate the development and expedite the review of drugs to treat serious and life-threatening conditions and fill an unmet medical need. The FDA approved sacubitril-valsartan on July 7, 2015, for use in place of an ACE inhibitor or ARB in patients with New York Heart Association class II, III, or IV heart failure with reduced ejection fraction.²¹

WHAT WE STILL NEED TO KNOW

The results of PARADIGM-HF are generalizable, and sacubitril-valsartan was well tolerated in patients whose blood pressure was acceptable and who were able to tolerate ACE inhibitors in target doses. More than 90% of patients were receiving a beta-blocker. The dosing of enalapril (target 10 mg twice a day) is the guideline-directed target dose, and ACE inhibition is considered the gold standard for heart failure with reduced ejection fraction. Sacubitril-valsartan vs enalapril was a very appropriate comparison.

Far fewer PARADIGM-HF patients outside the United States had an ICD than those in the United States, which is a common finding in global clinical trials. However, Desai et al reported that sacubitril-valsartan reduced rates of cardiovascular mortality both from worsening heart failure and from sudden cardiac death, independent of whether the patient had an ICD.²²

Sacubitril-valsartan is taken twice a day, but most heart failure patients already take medications at several times during the day, so this should not pose a problem.

Sacubitril-valsartan ushers in a new era in treating heart failure with reduced ejection fraction

More information is needed on the use of this new drug in patients with New York Heart Association class IV symptoms, as only 60 patients with class IV symptoms were included in the PARADIGM-HF trial. Also, the efficacy of the drug in patients unable to tolerate a full dose will need to be analyzed.

PARADIGM-HF was conducted in stable, nonhospitalized patients with chronic heart failure; the use of the drug in new-onset heart failure and its initiation in hospitalized patients will require further study. In addition, the PARAGON-HF trial²³ will examine the efficacy of sacubitril-valsartan in patients with heart failure and an ejection fraction of 45% or higher.

Sacubitril-valsartan ushers in a new era in heart failure treatment for patients with reduced ejection fraction and will certainly prompt quick revision of heart failure guidelines.

Guidelines and practice advisories issued by several medical societies, including the American Society of Anesthesiologists,¹ American Heart Association (AHA) and American College of Cardiology (ACC),² and Society of General Internal Medicine,³ advise against routine preoperative testing for patients undergoing low-risk surgical procedures. Such testing often includes routine blood chemistry, complete blood cell counts, measures of the clotting system, and cardiac stress testing.

See related article

In this issue of the Cleveland Clinic Journal of Medicine, Dr. Nathan Houchens reviews the evidence against these measures.⁴

Despite a substantial body of evidence going back more than 2 decades that includes prospective randomized controlled trials,^5–10 physicians continue to order unnecessary, ineffective, and costly tests in the perioperative period.¹¹ The process of abandoning current medical practice—a phenomenon known as medical reversal¹²—often takes years,¹³ because it is more difficult to convince physicians to discontinue a current behavior than to implement a new one.¹⁴ The study of what makes physicians accept new therapies and abandon old ones began more than half a century ago.¹⁵

More recently, Cabana et al¹⁶ created a framework to understand why physicians do not follow clinical practice guidelines. Among the reasons are lack of familiarity or agreement with the contents of the guideline, lack of outcome expectancy, inertia of previous practice, and external barriers to implementation.

It is harder to convince physicians to discontinue a current behavior than to implement a new one

The rapid proliferation of guidelines in the past 20 years has led to numerous conflicting recommendations, many of which are based primarily on expert opinion.¹⁷ Guidelines based solely on randomized trials have also come under fire.^18,19

In the case of preoperative testing, the recommendations are generally evidence-based and consistent. Why then do physicians appear to disregard the evidence? We propose several reasons why they might do so.

SOME PHYSICIANS ARE UNFAMILIAR WITH THE EVIDENCE

The complexity of the evidence summarized in guidelines has increased exponentially in the last decade, but physician time to assess the evidence has not increased. For example, the number of references in the executive summary of the ACC/AHA perioperative guidelines increased from 96 in 2002 to 252 in 2014. Most of the recommendations are backed by substantial amounts of high-quality evidence. For example, there are 17 prospective and 13 retrospective studies demonstrating that routine testing with the prothrombin time and the partial thromboplastin time is not helpful in asymptomatic patients.²⁰

Although compliance with medical evidence varies among specialties,²¹ most physicians do not have time to keep up with the ever-increasing amount of information. Specifically in the area of cardiac risk assessment, there has been a rapid proliferation of tests that can be used to assess cardiac risk.^22–28 In a Harris Interactive survey from 2008, physicians reported not applying medical evidence routinely. One-third believed they would do it more if they had the time.²⁹ Without information technology support to provide medical information at the point of care,³⁰ especially in small practices, using evidence may not be practical. Simply making the information available online and not promoting it actively does not improve utilization.³¹

As a consequence, physicians continue to order unnecessary tests, even though they may not feel confident interpreting the results.³²

PHYSICIANS MAY NOT BELIEVE THE EVIDENCE

A lack of transparency in evidence-based guidelines and, sometimes, a lack of flexibility and relevance to clinical practice are important barriers to physicians’ acceptance of and adherence to evidence-based clinical practice guidelines.³⁰

Most physicians do not have time to keep up with the ever-increasing amount of information

Even experts who write guidelines may not be swayed by the evidence. For example, a randomized prospective trial of almost 6,000 patients reported that coronary artery revascularization before elective major vascular surgery does not affect long-term mortality rates.³³ Based on this study, the 2014 ACC/AHA guidelines² advised against revascularization before noncardiac surgery exclusively to reduce perioperative cardiac events. Yet the same guidelines do recommend assessing for myocardial ischemia in patients with elevated risk and poor or unknown functional capacity, using a pharmacologic stress test. Based on the extent of the stress test abnormalities, coronary angiography and revascularization are then suggested for patients willing to undergo coronary artery bypass grafting (CABG) or percutaneous coronary intervention.²

The 2014 European Society of Cardiology and European Society of Anaesthesiology guidelines directly recommend revascularization before high-risk surgery, depending on the extent of a stress-induced perfusion defect.³⁴ This recommendation relies on data from the Coronary Artery Surgery Study registry, which included almost 25,000 patients who underwent coronary angiography from 1975 through 1979. At a mean follow-up of 4.1 years, 1,961 patients underwent high-risk surgery. In this observational cohort, patients who underwent CABG had a lower risk of death and myocardial infarction after surgery.³⁵ The reliance of medical societies³⁴ on data that are more than 30 years old—when operative mortality rates and the treatment of coronary artery disease have changed substantially in the interim and despite the fact that this study did not test whether preoperative revascularization can reduce postoperative mortality—reflects a certain resistance to accept the results of the more recent and relevant randomized trial.³³

Other physicians may also prefer to rely on selective data or to simply defer to guidelines that support their beliefs. Some physicians find that evidence-based guidelines are impractical and rigid and reduce their autonomy.³⁶ For many physicians, trials that use surrogate end points and short-term outcomes are not sufficiently compelling to make them abandon current practice.³⁷ Finally, when members of the guideline committees have financial associations with the pharmaceutical industry, or when corporations interested in the outcomes provide financial support for a trial’s development, the likelihood of a recommendation being trusted and used by physicians is drastically reduced.³⁸

PRACTICING DEFENSIVELY

Even if physicians are familiar with the evidence and believe it, they may choose not to act on it. One reason is fear of litigation.

In court, attorneys can use guidelines as well as articles from medical journals as both exculpatory and inculpatory evidence. But they more frequently rely on the standard of care, or what most physicians would do under similar circumstances. If a patient has a bad outcome, such as a perioperative myocardial infarction or life-threatening bleeding, the defendant may assert that testing was unwarranted because guidelines do not recommend it or because the probability of such an outcome was low. However, because the outcome occurred, the jury may not believe that the probability was low enough not to consider, especially if expert witnesses testify that the standard of care would be to order the test.

In areas of controversy, physicians generally believe that erring on the side of more testing is more defensible in court.³⁹ Indeed, following established practice traditions, learned during residency,^11,40 may absolve physicians in negligence claims if the way medical care was delivered is supported by recognized and respected physicians.⁴¹

Even physicians who write the guidelines may be unswayed by the evidence

As a consequence, physicians prefer to practice the same way their peers do rather than follow the evidence. Unfortunately, the more procedures physicians perform for low-risk patients, the more likely these tests will become accepted as the legal standard of care.⁴² In this vicious circle, the new standard of care can increase the risk of litigation for others.⁴³ Although unnecessary testing that leads to harmful invasive tests or procedures can also result in malpractice litigation, physicians may not consider this possibility.

FINANCIAL INCENTIVES

The threat of malpractice litigation provides a negative financial incentive to keep performing unnecessary tests, but there are a number of positive incentives as well.

First, physicians often feel compelled to order tests when they believe that physicians referring the patients want the tests done, or when they fear that not completing the tests could delay or cancel the scheduled surgery.⁴⁰ Refusing to order the test could result in a loss of future referrals. In contrast, ordering tests allows them to meet expectations, preserve trust, and appear more valuable to referring physicians and their patients.

Insurance companies are complicit in these practices. Paying for unnecessary tests can create direct financial incentives for physicians or institutions that own on-site laboratories or diagnostic imaging equipment. Evidence shows that under those circumstances physicians do order more tests. Self-referral and referral to facilities where physicians have a financial interest is associated with increased healthcare costs.⁴⁴ In addition to direct revenues for the tests performed, physicians may also bill for test interpretation, follow-up visits, and additional procedures generated from test results.

This may be one explanation why the ordering of cardiac tests (stress testing, echocardiography, vascular ultrasonography) by US physicians varies widely from state to state.⁴⁵

RECOMMENDATIONS TO REDUCE INAPPROPRIATE TESTING

To counter these influences, we propose a multifaceted intervention that includes the following:

• Establish preoperative clinics staffed by experts. Despite the large volume of potentially relevant evidence, the number of articles directly supporting or refuting preoperative laboratory testing is small enough that physicians who routinely engage in preoperative assessment should easily master the evidence.
• Identify local leaders who can convince colleagues of the evidence. Distribute evidence summaries or guidelines with references to major articles that support each recommendation.
• Work with clinical practice committees to establish new standards of care within the hospital. Establish hospital care paths to dictate and support local standards of care. Measure individual physician performance and offer feedback with the goal of reducing utilization.
• National societies should recommend that insurance companies remove inappropriate financial incentives. If companies deny payment for inappropriate testing, physicians will stop ordering it. Even requirements for preauthorization of tests should reduce utilization. The Choosing Wisely campaign (www.choosingwisely.org) would be a good place to start.

Guidelines and practice advisories issued by several medical societies, including the American Society of Anesthesiologists,¹ American Heart Association (AHA) and American College of Cardiology (ACC),² and Society of General Internal Medicine,³ advise against routine preoperative testing for patients undergoing low-risk surgical procedures. Such testing often includes routine blood chemistry, complete blood cell counts, measures of the clotting system, and cardiac stress testing.

See related article

In this issue of the Cleveland Clinic Journal of Medicine, Dr. Nathan Houchens reviews the evidence against these measures.⁴

Despite a substantial body of evidence going back more than 2 decades that includes prospective randomized controlled trials,^5–10 physicians continue to order unnecessary, ineffective, and costly tests in the perioperative period.¹¹ The process of abandoning current medical practice—a phenomenon known as medical reversal¹²—often takes years,¹³ because it is more difficult to convince physicians to discontinue a current behavior than to implement a new one.¹⁴ The study of what makes physicians accept new therapies and abandon old ones began more than half a century ago.¹⁵

More recently, Cabana et al¹⁶ created a framework to understand why physicians do not follow clinical practice guidelines. Among the reasons are lack of familiarity or agreement with the contents of the guideline, lack of outcome expectancy, inertia of previous practice, and external barriers to implementation.

It is harder to convince physicians to discontinue a current behavior than to implement a new one

The rapid proliferation of guidelines in the past 20 years has led to numerous conflicting recommendations, many of which are based primarily on expert opinion.¹⁷ Guidelines based solely on randomized trials have also come under fire.^18,19

In the case of preoperative testing, the recommendations are generally evidence-based and consistent. Why then do physicians appear to disregard the evidence? We propose several reasons why they might do so.

SOME PHYSICIANS ARE UNFAMILIAR WITH THE EVIDENCE

The complexity of the evidence summarized in guidelines has increased exponentially in the last decade, but physician time to assess the evidence has not increased. For example, the number of references in the executive summary of the ACC/AHA perioperative guidelines increased from 96 in 2002 to 252 in 2014. Most of the recommendations are backed by substantial amounts of high-quality evidence. For example, there are 17 prospective and 13 retrospective studies demonstrating that routine testing with the prothrombin time and the partial thromboplastin time is not helpful in asymptomatic patients.²⁰

Although compliance with medical evidence varies among specialties,²¹ most physicians do not have time to keep up with the ever-increasing amount of information. Specifically in the area of cardiac risk assessment, there has been a rapid proliferation of tests that can be used to assess cardiac risk.^22–28 In a Harris Interactive survey from 2008, physicians reported not applying medical evidence routinely. One-third believed they would do it more if they had the time.²⁹ Without information technology support to provide medical information at the point of care,³⁰ especially in small practices, using evidence may not be practical. Simply making the information available online and not promoting it actively does not improve utilization.³¹

As a consequence, physicians continue to order unnecessary tests, even though they may not feel confident interpreting the results.³²

PHYSICIANS MAY NOT BELIEVE THE EVIDENCE

A lack of transparency in evidence-based guidelines and, sometimes, a lack of flexibility and relevance to clinical practice are important barriers to physicians’ acceptance of and adherence to evidence-based clinical practice guidelines.³⁰

Most physicians do not have time to keep up with the ever-increasing amount of information

Even experts who write guidelines may not be swayed by the evidence. For example, a randomized prospective trial of almost 6,000 patients reported that coronary artery revascularization before elective major vascular surgery does not affect long-term mortality rates.³³ Based on this study, the 2014 ACC/AHA guidelines² advised against revascularization before noncardiac surgery exclusively to reduce perioperative cardiac events. Yet the same guidelines do recommend assessing for myocardial ischemia in patients with elevated risk and poor or unknown functional capacity, using a pharmacologic stress test. Based on the extent of the stress test abnormalities, coronary angiography and revascularization are then suggested for patients willing to undergo coronary artery bypass grafting (CABG) or percutaneous coronary intervention.²

The 2014 European Society of Cardiology and European Society of Anaesthesiology guidelines directly recommend revascularization before high-risk surgery, depending on the extent of a stress-induced perfusion defect.³⁴ This recommendation relies on data from the Coronary Artery Surgery Study registry, which included almost 25,000 patients who underwent coronary angiography from 1975 through 1979. At a mean follow-up of 4.1 years, 1,961 patients underwent high-risk surgery. In this observational cohort, patients who underwent CABG had a lower risk of death and myocardial infarction after surgery.³⁵ The reliance of medical societies³⁴ on data that are more than 30 years old—when operative mortality rates and the treatment of coronary artery disease have changed substantially in the interim and despite the fact that this study did not test whether preoperative revascularization can reduce postoperative mortality—reflects a certain resistance to accept the results of the more recent and relevant randomized trial.³³

Other physicians may also prefer to rely on selective data or to simply defer to guidelines that support their beliefs. Some physicians find that evidence-based guidelines are impractical and rigid and reduce their autonomy.³⁶ For many physicians, trials that use surrogate end points and short-term outcomes are not sufficiently compelling to make them abandon current practice.³⁷ Finally, when members of the guideline committees have financial associations with the pharmaceutical industry, or when corporations interested in the outcomes provide financial support for a trial’s development, the likelihood of a recommendation being trusted and used by physicians is drastically reduced.³⁸

PRACTICING DEFENSIVELY

Even if physicians are familiar with the evidence and believe it, they may choose not to act on it. One reason is fear of litigation.

In court, attorneys can use guidelines as well as articles from medical journals as both exculpatory and inculpatory evidence. But they more frequently rely on the standard of care, or what most physicians would do under similar circumstances. If a patient has a bad outcome, such as a perioperative myocardial infarction or life-threatening bleeding, the defendant may assert that testing was unwarranted because guidelines do not recommend it or because the probability of such an outcome was low. However, because the outcome occurred, the jury may not believe that the probability was low enough not to consider, especially if expert witnesses testify that the standard of care would be to order the test.

In areas of controversy, physicians generally believe that erring on the side of more testing is more defensible in court.³⁹ Indeed, following established practice traditions, learned during residency,^11,40 may absolve physicians in negligence claims if the way medical care was delivered is supported by recognized and respected physicians.⁴¹

Even physicians who write the guidelines may be unswayed by the evidence

As a consequence, physicians prefer to practice the same way their peers do rather than follow the evidence. Unfortunately, the more procedures physicians perform for low-risk patients, the more likely these tests will become accepted as the legal standard of care.⁴² In this vicious circle, the new standard of care can increase the risk of litigation for others.⁴³ Although unnecessary testing that leads to harmful invasive tests or procedures can also result in malpractice litigation, physicians may not consider this possibility.

FINANCIAL INCENTIVES

The threat of malpractice litigation provides a negative financial incentive to keep performing unnecessary tests, but there are a number of positive incentives as well.

First, physicians often feel compelled to order tests when they believe that physicians referring the patients want the tests done, or when they fear that not completing the tests could delay or cancel the scheduled surgery.⁴⁰ Refusing to order the test could result in a loss of future referrals. In contrast, ordering tests allows them to meet expectations, preserve trust, and appear more valuable to referring physicians and their patients.

Insurance companies are complicit in these practices. Paying for unnecessary tests can create direct financial incentives for physicians or institutions that own on-site laboratories or diagnostic imaging equipment. Evidence shows that under those circumstances physicians do order more tests. Self-referral and referral to facilities where physicians have a financial interest is associated with increased healthcare costs.⁴⁴ In addition to direct revenues for the tests performed, physicians may also bill for test interpretation, follow-up visits, and additional procedures generated from test results.

This may be one explanation why the ordering of cardiac tests (stress testing, echocardiography, vascular ultrasonography) by US physicians varies widely from state to state.⁴⁵

RECOMMENDATIONS TO REDUCE INAPPROPRIATE TESTING

To counter these influences, we propose a multifaceted intervention that includes the following:

• Establish preoperative clinics staffed by experts. Despite the large volume of potentially relevant evidence, the number of articles directly supporting or refuting preoperative laboratory testing is small enough that physicians who routinely engage in preoperative assessment should easily master the evidence.
• Identify local leaders who can convince colleagues of the evidence. Distribute evidence summaries or guidelines with references to major articles that support each recommendation.
• Work with clinical practice committees to establish new standards of care within the hospital. Establish hospital care paths to dictate and support local standards of care. Measure individual physician performance and offer feedback with the goal of reducing utilization.
• National societies should recommend that insurance companies remove inappropriate financial incentives. If companies deny payment for inappropriate testing, physicians will stop ordering it. Even requirements for preauthorization of tests should reduce utilization. The Choosing Wisely campaign (www.choosingwisely.org) would be a good place to start.

Guidelines and practice advisories issued by several medical societies, including the American Society of Anesthesiologists,¹ American Heart Association (AHA) and American College of Cardiology (ACC),² and Society of General Internal Medicine,³ advise against routine preoperative testing for patients undergoing low-risk surgical procedures. Such testing often includes routine blood chemistry, complete blood cell counts, measures of the clotting system, and cardiac stress testing.

See related article

In this issue of the Cleveland Clinic Journal of Medicine, Dr. Nathan Houchens reviews the evidence against these measures.⁴

Despite a substantial body of evidence going back more than 2 decades that includes prospective randomized controlled trials,^5–10 physicians continue to order unnecessary, ineffective, and costly tests in the perioperative period.¹¹ The process of abandoning current medical practice—a phenomenon known as medical reversal¹²—often takes years,¹³ because it is more difficult to convince physicians to discontinue a current behavior than to implement a new one.¹⁴ The study of what makes physicians accept new therapies and abandon old ones began more than half a century ago.¹⁵

More recently, Cabana et al¹⁶ created a framework to understand why physicians do not follow clinical practice guidelines. Among the reasons are lack of familiarity or agreement with the contents of the guideline, lack of outcome expectancy, inertia of previous practice, and external barriers to implementation.

It is harder to convince physicians to discontinue a current behavior than to implement a new one

The rapid proliferation of guidelines in the past 20 years has led to numerous conflicting recommendations, many of which are based primarily on expert opinion.¹⁷ Guidelines based solely on randomized trials have also come under fire.^18,19

In the case of preoperative testing, the recommendations are generally evidence-based and consistent. Why then do physicians appear to disregard the evidence? We propose several reasons why they might do so.

SOME PHYSICIANS ARE UNFAMILIAR WITH THE EVIDENCE

The complexity of the evidence summarized in guidelines has increased exponentially in the last decade, but physician time to assess the evidence has not increased. For example, the number of references in the executive summary of the ACC/AHA perioperative guidelines increased from 96 in 2002 to 252 in 2014. Most of the recommendations are backed by substantial amounts of high-quality evidence. For example, there are 17 prospective and 13 retrospective studies demonstrating that routine testing with the prothrombin time and the partial thromboplastin time is not helpful in asymptomatic patients.²⁰

Although compliance with medical evidence varies among specialties,²¹ most physicians do not have time to keep up with the ever-increasing amount of information. Specifically in the area of cardiac risk assessment, there has been a rapid proliferation of tests that can be used to assess cardiac risk.^22–28 In a Harris Interactive survey from 2008, physicians reported not applying medical evidence routinely. One-third believed they would do it more if they had the time.²⁹ Without information technology support to provide medical information at the point of care,³⁰ especially in small practices, using evidence may not be practical. Simply making the information available online and not promoting it actively does not improve utilization.³¹

As a consequence, physicians continue to order unnecessary tests, even though they may not feel confident interpreting the results.³²

PHYSICIANS MAY NOT BELIEVE THE EVIDENCE

A lack of transparency in evidence-based guidelines and, sometimes, a lack of flexibility and relevance to clinical practice are important barriers to physicians’ acceptance of and adherence to evidence-based clinical practice guidelines.³⁰

Most physicians do not have time to keep up with the ever-increasing amount of information

Even experts who write guidelines may not be swayed by the evidence. For example, a randomized prospective trial of almost 6,000 patients reported that coronary artery revascularization before elective major vascular surgery does not affect long-term mortality rates.³³ Based on this study, the 2014 ACC/AHA guidelines² advised against revascularization before noncardiac surgery exclusively to reduce perioperative cardiac events. Yet the same guidelines do recommend assessing for myocardial ischemia in patients with elevated risk and poor or unknown functional capacity, using a pharmacologic stress test. Based on the extent of the stress test abnormalities, coronary angiography and revascularization are then suggested for patients willing to undergo coronary artery bypass grafting (CABG) or percutaneous coronary intervention.²

The 2014 European Society of Cardiology and European Society of Anaesthesiology guidelines directly recommend revascularization before high-risk surgery, depending on the extent of a stress-induced perfusion defect.³⁴ This recommendation relies on data from the Coronary Artery Surgery Study registry, which included almost 25,000 patients who underwent coronary angiography from 1975 through 1979. At a mean follow-up of 4.1 years, 1,961 patients underwent high-risk surgery. In this observational cohort, patients who underwent CABG had a lower risk of death and myocardial infarction after surgery.³⁵ The reliance of medical societies³⁴ on data that are more than 30 years old—when operative mortality rates and the treatment of coronary artery disease have changed substantially in the interim and despite the fact that this study did not test whether preoperative revascularization can reduce postoperative mortality—reflects a certain resistance to accept the results of the more recent and relevant randomized trial.³³

Other physicians may also prefer to rely on selective data or to simply defer to guidelines that support their beliefs. Some physicians find that evidence-based guidelines are impractical and rigid and reduce their autonomy.³⁶ For many physicians, trials that use surrogate end points and short-term outcomes are not sufficiently compelling to make them abandon current practice.³⁷ Finally, when members of the guideline committees have financial associations with the pharmaceutical industry, or when corporations interested in the outcomes provide financial support for a trial’s development, the likelihood of a recommendation being trusted and used by physicians is drastically reduced.³⁸

PRACTICING DEFENSIVELY

Even if physicians are familiar with the evidence and believe it, they may choose not to act on it. One reason is fear of litigation.

In court, attorneys can use guidelines as well as articles from medical journals as both exculpatory and inculpatory evidence. But they more frequently rely on the standard of care, or what most physicians would do under similar circumstances. If a patient has a bad outcome, such as a perioperative myocardial infarction or life-threatening bleeding, the defendant may assert that testing was unwarranted because guidelines do not recommend it or because the probability of such an outcome was low. However, because the outcome occurred, the jury may not believe that the probability was low enough not to consider, especially if expert witnesses testify that the standard of care would be to order the test.

In areas of controversy, physicians generally believe that erring on the side of more testing is more defensible in court.³⁹ Indeed, following established practice traditions, learned during residency,^11,40 may absolve physicians in negligence claims if the way medical care was delivered is supported by recognized and respected physicians.⁴¹

Even physicians who write the guidelines may be unswayed by the evidence

As a consequence, physicians prefer to practice the same way their peers do rather than follow the evidence. Unfortunately, the more procedures physicians perform for low-risk patients, the more likely these tests will become accepted as the legal standard of care.⁴² In this vicious circle, the new standard of care can increase the risk of litigation for others.⁴³ Although unnecessary testing that leads to harmful invasive tests or procedures can also result in malpractice litigation, physicians may not consider this possibility.

FINANCIAL INCENTIVES

The threat of malpractice litigation provides a negative financial incentive to keep performing unnecessary tests, but there are a number of positive incentives as well.

First, physicians often feel compelled to order tests when they believe that physicians referring the patients want the tests done, or when they fear that not completing the tests could delay or cancel the scheduled surgery.⁴⁰ Refusing to order the test could result in a loss of future referrals. In contrast, ordering tests allows them to meet expectations, preserve trust, and appear more valuable to referring physicians and their patients.

Insurance companies are complicit in these practices. Paying for unnecessary tests can create direct financial incentives for physicians or institutions that own on-site laboratories or diagnostic imaging equipment. Evidence shows that under those circumstances physicians do order more tests. Self-referral and referral to facilities where physicians have a financial interest is associated with increased healthcare costs.⁴⁴ In addition to direct revenues for the tests performed, physicians may also bill for test interpretation, follow-up visits, and additional procedures generated from test results.

This may be one explanation why the ordering of cardiac tests (stress testing, echocardiography, vascular ultrasonography) by US physicians varies widely from state to state.⁴⁵

RECOMMENDATIONS TO REDUCE INAPPROPRIATE TESTING

To counter these influences, we propose a multifaceted intervention that includes the following:

• Establish preoperative clinics staffed by experts. Despite the large volume of potentially relevant evidence, the number of articles directly supporting or refuting preoperative laboratory testing is small enough that physicians who routinely engage in preoperative assessment should easily master the evidence.
• Identify local leaders who can convince colleagues of the evidence. Distribute evidence summaries or guidelines with references to major articles that support each recommendation.
• Work with clinical practice committees to establish new standards of care within the hospital. Establish hospital care paths to dictate and support local standards of care. Measure individual physician performance and offer feedback with the goal of reducing utilization.
• National societies should recommend that insurance companies remove inappropriate financial incentives. If companies deny payment for inappropriate testing, physicians will stop ordering it. Even requirements for preauthorization of tests should reduce utilization. The Choosing Wisely campaign (www.choosingwisely.org) would be a good place to start.