Study authors Mary Relling

(left) and Chengcheng Liu

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).

The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.

Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.

The researchers reported these findings in the Journal of Clinical Oncology.

“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”

The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.

To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.

The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.

The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10⁻⁹).

Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.

“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”

The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.

The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).

In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.

The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:

• Older age (HR=1.1 per year; P<0.001)
• Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
• High-dose (≥240,000 U/m²) asparaginase regimens (HR=3.2; P<0.001).
  

Study authors Mary Relling

(left) and Chengcheng Liu

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).

The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.

Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.

The researchers reported these findings in the Journal of Clinical Oncology.

“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”

The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.

To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.

The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.

The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10⁻⁹).

Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.

“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”

The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.

The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).

In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.

The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:

• Older age (HR=1.1 per year; P<0.001)
• Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
• High-dose (≥240,000 U/m²) asparaginase regimens (HR=3.2; P<0.001).
  

Study authors Mary Relling

(left) and Chengcheng Liu

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).

The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.

Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.

The researchers reported these findings in the Journal of Clinical Oncology.

“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”

The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.

To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.

The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.

The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10⁻⁹).

Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.

“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”

The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.

The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).

In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.

The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:

• Older age (HR=1.1 per year; P<0.001)
• Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
• High-dose (≥240,000 U/m²) asparaginase regimens (HR=3.2; P<0.001).
  

Illustrative Case

A 55-year-old man with hypertension and stage 3 chronic kidney disease (CKD) comes in to your office for routine care. His blood pressure is 135/85 mm Hg, and he is presently taking lisinopril 40 mg daily. Should you increase his antihypertensive regimen?

Hypertension is common and leads to significant morbidity and mortality, but pharmacologic treatment reduces incidence of stroke by 35% to 40%, myocardial infarction (MI) by 15% to 25%, and heart failure by up to 64%.^2-4 Specific blood pressure targets for defined populations continue to be studied.

In patients with diabetes, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial found that more intensive BP targets did not reduce the rate of major CV events, but the study may have been underpowered.⁵ The members of The Eighth Joint National Committee recommended treating patients over age 60 years to BP goals <150/90 mm Hg.⁶ This was based on evidence from 6 randomized controlled trials (RCTs),^7-12 but there remains debate—even among the members of the Committee—as to appropriate BP goals in patients of any age without CV disease who have BP measurements of 140-159/90-99 mm Hg.¹³

Study Summary

Treating to SBP <120 mm Hg lowers mortality

The Systolic Blood Pressure Intervention Trial (SPRINT) was a multicenter RCT designed to determine if treating to lower SBP targets in non-diabetic patients at high risk for CV events improves outcomes as compared to standard care. Patients were at least 50 years of age with SBP of 130 to 180 mm Hg and were at increased CV risk as defined by clinical or subclinical CV disease other than stroke, CKD with glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m², 10-year risk of CV disease >15% on Framingham risk score, or age ≥75 years of age. Patients with diabetes; prior stroke; polycystic kidney disease; significant proteinuria within the past 6 months; symptomatic heart failure within the past 6 months; or left ventricular ejection fraction <35% were excluded.¹

Patients (N=9361) were randomly assigned to an SBP target <120 mm Hg in the intensive group or <140 mm Hg in the standard treatment group, in an open-label design. Allocation was concealed. The study protocol encouraged, but did not require, the use of thiazide-type diuretics, loop diuretics (for those with advanced renal disease), angiotensin-converting enzyme inhibitors or angiotensin receptor blocker agents, calcium channel blockers, and beta-blockers. Clinicians could add other agents as needed. All major classes of antihypertensives were used.

Medication dosing adjustments were based on the average of 3 BP measurements taken with an automated measurement system (Omron Healthcare, Model 907) with the patient seated after 5 minutes of quiet rest. Target SBP in the standard therapy group was 135 to 139 mm Hg. Medication dosages were lowered if SBP was <130 mm Hg at a single visit or <135 mm Hg at 2 consecutive visits.¹

The primary composite outcome included the first occurrence of MI, acute coronary syndrome, stroke, heart failure, or death from CV causes. Secondary outcomes were the individual components of the primary composite outcome, death from any cause, and the composite of the primary outcome or death from any cause.¹

In a group of 1000 patients, an estimated 16 patients will benefit from intensive BP treatment, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.

Study halted early. The study was stopped early due to significantly lower rates of the primary outcome in the intensive therapy group vs the standard therapy group (1.65% per year vs 2.19% per year, respectively, hazard ratio [HR] with intensive treatment=0.75; 95% confidence interval [CI], 0.64-0.89; P<.001). The resulting median follow-up time was 3.26 years.¹ This corresponds to a 25% lower relative risk of the primary outcome, with a decrease in event rates from 6.8% to 5.2% over the trial period. All-cause mortality was also lower in the intensive therapy group: 3.4% vs 4.5% (HR=0.73; 95% CI, 0.60-0.90; P=.003).

The number needed to treat (NNT) over 3.26 years to prevent a primary outcome event, death from any cause, and death from CV causes was 61, 90, and 172, respectively. Serious adverse events occurred more frequently in the intensive therapy group than in the standard therapy group (38.3% vs 37.1%; HR=1.04; P=.25) with a number needed to harm (NNH) of 46 over the study period.¹ (When looking at serious adverse events identified as likely associated with the intervention, rates were 4.7% vs 2.5%, respectively [P<.001].) Hypotension, syncope, electrolyte abnormalities, and acute kidney injury/acute renal failure reached statistical significance. The incidence of bradycardia and injurious falls was higher in the intensive treatment group, but did not reach statistical significance. In the subgroup of patients ≥75 years of age, 48% in each study group experienced a serious adverse event.¹

Throughout the study, mean SBP was 121.5 mm Hg in the intensive therapy group and 134.6 mm Hg in the standard treatment group. This required an average of one additional BP medication in the intensive therapy group (2.8 vs 1.8, respectively).¹

What’s New

Lower SBP produces mortality benefits in those under, and over, age 75

This trial builds on a body of evidence that shows the advantages of lowering SBP to <150 mm Hg^7,11,12 by demonstrating benefits, including lower all-cause mortality, for lower SBP targets in non-diabetic patients at high risk of CV disease. The SPRINT trial also showed that the benefits of intensive therapy remained true in a subgroup of patients ≥75 years of age.

The incidence of the primary outcome in the cohort ≥75 years of age receiving intensive therapy was 7.7% vs 10.9% for those receiving standard therapy (HR=0.67; 95% CI, 0.51-0.86; NNT=31). All-cause mortality was also lower in the intensive therapy group than in the standard therapy group among patients ≥75 years of age: 5.5% vs 8.04% (HR=0.68; 95% CI, 0.50-0.92; NNT=38).¹

Caveats

Many do not benefit from—or are harmed by—increased medication

Identifying patients most likely to benefit from more intensive blood pressure targets remains challenging.

The absolute risk reduction for the primary outcome is 1.6%, meaning 98.4% of patients receiving more intensive treatment will not benefit. In a group of 1000 patients, an estimated 16 patients will benefit, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.¹⁴ The difference between how BP was measured in this trial (an average of 3 readings after the patient had rested for 5 minutes) and that which occurs typically in clinical practice could potentially lead to overtreatment in practice.

Also, reducing antihypertensive therapies when the SBP was about 130 to 135 mm Hg in the standard therapy group likely exaggerated the difference in outcomes between the intensive and standard therapy groups, and is neither routine nor recommended in clinical practice.⁶ Finally, the trial specifically studied non-diabetic patients at high risk of CV disease ≥50 years of age, limiting generalizability to other populations.

Challenges to implementation

Who will benefit/who can achieve intensive SBP goals?

Identifying patients most likely to benefit from more intensive BP targets remains challenging. The SPRINT trial showed a mortality benefit, but at a cost of increased morbidity.^1,14 In particular, caution should be exercised in the subgroup of patients ≥75 years. Despite a lower NNT than the rest of the study population, serious adverse events happened more frequently. Also, this particular cohort of volunteers may not be representative of those ≥75 years of age in the general population.

Additionally, achieving intensive SBP goals can be challenging. In the SPRINT trial, only half of the intensive target group achieved an SBP <120 mm Hg.¹ And in a 2011-12 National Health and Nutrition Examination Survey, only 52% of patients in the general population achieved a BP target <140/90 mm Hg.¹⁵ Lower morbidity and mortality should remain the ultimate goals to the management of hypertension, requiring physicians to carefully assess an individual patient’s likelihood of benefit vs harm.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative Case

A 55-year-old man with hypertension and stage 3 chronic kidney disease (CKD) comes in to your office for routine care. His blood pressure is 135/85 mm Hg, and he is presently taking lisinopril 40 mg daily. Should you increase his antihypertensive regimen?

Hypertension is common and leads to significant morbidity and mortality, but pharmacologic treatment reduces incidence of stroke by 35% to 40%, myocardial infarction (MI) by 15% to 25%, and heart failure by up to 64%.^2-4 Specific blood pressure targets for defined populations continue to be studied.

In patients with diabetes, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial found that more intensive BP targets did not reduce the rate of major CV events, but the study may have been underpowered.⁵ The members of The Eighth Joint National Committee recommended treating patients over age 60 years to BP goals <150/90 mm Hg.⁶ This was based on evidence from 6 randomized controlled trials (RCTs),^7-12 but there remains debate—even among the members of the Committee—as to appropriate BP goals in patients of any age without CV disease who have BP measurements of 140-159/90-99 mm Hg.¹³

Study Summary

Treating to SBP <120 mm Hg lowers mortality

The Systolic Blood Pressure Intervention Trial (SPRINT) was a multicenter RCT designed to determine if treating to lower SBP targets in non-diabetic patients at high risk for CV events improves outcomes as compared to standard care. Patients were at least 50 years of age with SBP of 130 to 180 mm Hg and were at increased CV risk as defined by clinical or subclinical CV disease other than stroke, CKD with glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m², 10-year risk of CV disease >15% on Framingham risk score, or age ≥75 years of age. Patients with diabetes; prior stroke; polycystic kidney disease; significant proteinuria within the past 6 months; symptomatic heart failure within the past 6 months; or left ventricular ejection fraction <35% were excluded.¹

Patients (N=9361) were randomly assigned to an SBP target <120 mm Hg in the intensive group or <140 mm Hg in the standard treatment group, in an open-label design. Allocation was concealed. The study protocol encouraged, but did not require, the use of thiazide-type diuretics, loop diuretics (for those with advanced renal disease), angiotensin-converting enzyme inhibitors or angiotensin receptor blocker agents, calcium channel blockers, and beta-blockers. Clinicians could add other agents as needed. All major classes of antihypertensives were used.

Medication dosing adjustments were based on the average of 3 BP measurements taken with an automated measurement system (Omron Healthcare, Model 907) with the patient seated after 5 minutes of quiet rest. Target SBP in the standard therapy group was 135 to 139 mm Hg. Medication dosages were lowered if SBP was <130 mm Hg at a single visit or <135 mm Hg at 2 consecutive visits.¹

The primary composite outcome included the first occurrence of MI, acute coronary syndrome, stroke, heart failure, or death from CV causes. Secondary outcomes were the individual components of the primary composite outcome, death from any cause, and the composite of the primary outcome or death from any cause.¹

In a group of 1000 patients, an estimated 16 patients will benefit from intensive BP treatment, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.

Study halted early. The study was stopped early due to significantly lower rates of the primary outcome in the intensive therapy group vs the standard therapy group (1.65% per year vs 2.19% per year, respectively, hazard ratio [HR] with intensive treatment=0.75; 95% confidence interval [CI], 0.64-0.89; P<.001). The resulting median follow-up time was 3.26 years.¹ This corresponds to a 25% lower relative risk of the primary outcome, with a decrease in event rates from 6.8% to 5.2% over the trial period. All-cause mortality was also lower in the intensive therapy group: 3.4% vs 4.5% (HR=0.73; 95% CI, 0.60-0.90; P=.003).

The number needed to treat (NNT) over 3.26 years to prevent a primary outcome event, death from any cause, and death from CV causes was 61, 90, and 172, respectively. Serious adverse events occurred more frequently in the intensive therapy group than in the standard therapy group (38.3% vs 37.1%; HR=1.04; P=.25) with a number needed to harm (NNH) of 46 over the study period.¹ (When looking at serious adverse events identified as likely associated with the intervention, rates were 4.7% vs 2.5%, respectively [P<.001].) Hypotension, syncope, electrolyte abnormalities, and acute kidney injury/acute renal failure reached statistical significance. The incidence of bradycardia and injurious falls was higher in the intensive treatment group, but did not reach statistical significance. In the subgroup of patients ≥75 years of age, 48% in each study group experienced a serious adverse event.¹

Throughout the study, mean SBP was 121.5 mm Hg in the intensive therapy group and 134.6 mm Hg in the standard treatment group. This required an average of one additional BP medication in the intensive therapy group (2.8 vs 1.8, respectively).¹

What’s New

Lower SBP produces mortality benefits in those under, and over, age 75

This trial builds on a body of evidence that shows the advantages of lowering SBP to <150 mm Hg^7,11,12 by demonstrating benefits, including lower all-cause mortality, for lower SBP targets in non-diabetic patients at high risk of CV disease. The SPRINT trial also showed that the benefits of intensive therapy remained true in a subgroup of patients ≥75 years of age.

The incidence of the primary outcome in the cohort ≥75 years of age receiving intensive therapy was 7.7% vs 10.9% for those receiving standard therapy (HR=0.67; 95% CI, 0.51-0.86; NNT=31). All-cause mortality was also lower in the intensive therapy group than in the standard therapy group among patients ≥75 years of age: 5.5% vs 8.04% (HR=0.68; 95% CI, 0.50-0.92; NNT=38).¹

Caveats

Many do not benefit from—or are harmed by—increased medication

Identifying patients most likely to benefit from more intensive blood pressure targets remains challenging.

The absolute risk reduction for the primary outcome is 1.6%, meaning 98.4% of patients receiving more intensive treatment will not benefit. In a group of 1000 patients, an estimated 16 patients will benefit, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.¹⁴ The difference between how BP was measured in this trial (an average of 3 readings after the patient had rested for 5 minutes) and that which occurs typically in clinical practice could potentially lead to overtreatment in practice.

Also, reducing antihypertensive therapies when the SBP was about 130 to 135 mm Hg in the standard therapy group likely exaggerated the difference in outcomes between the intensive and standard therapy groups, and is neither routine nor recommended in clinical practice.⁶ Finally, the trial specifically studied non-diabetic patients at high risk of CV disease ≥50 years of age, limiting generalizability to other populations.

Challenges to implementation

Who will benefit/who can achieve intensive SBP goals?

Identifying patients most likely to benefit from more intensive BP targets remains challenging. The SPRINT trial showed a mortality benefit, but at a cost of increased morbidity.^1,14 In particular, caution should be exercised in the subgroup of patients ≥75 years. Despite a lower NNT than the rest of the study population, serious adverse events happened more frequently. Also, this particular cohort of volunteers may not be representative of those ≥75 years of age in the general population.

Additionally, achieving intensive SBP goals can be challenging. In the SPRINT trial, only half of the intensive target group achieved an SBP <120 mm Hg.¹ And in a 2011-12 National Health and Nutrition Examination Survey, only 52% of patients in the general population achieved a BP target <140/90 mm Hg.¹⁵ Lower morbidity and mortality should remain the ultimate goals to the management of hypertension, requiring physicians to carefully assess an individual patient’s likelihood of benefit vs harm.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative Case

A 55-year-old man with hypertension and stage 3 chronic kidney disease (CKD) comes in to your office for routine care. His blood pressure is 135/85 mm Hg, and he is presently taking lisinopril 40 mg daily. Should you increase his antihypertensive regimen?

Hypertension is common and leads to significant morbidity and mortality, but pharmacologic treatment reduces incidence of stroke by 35% to 40%, myocardial infarction (MI) by 15% to 25%, and heart failure by up to 64%.^2-4 Specific blood pressure targets for defined populations continue to be studied.

In patients with diabetes, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial found that more intensive BP targets did not reduce the rate of major CV events, but the study may have been underpowered.⁵ The members of The Eighth Joint National Committee recommended treating patients over age 60 years to BP goals <150/90 mm Hg.⁶ This was based on evidence from 6 randomized controlled trials (RCTs),^7-12 but there remains debate—even among the members of the Committee—as to appropriate BP goals in patients of any age without CV disease who have BP measurements of 140-159/90-99 mm Hg.¹³

Study Summary

Treating to SBP <120 mm Hg lowers mortality

The Systolic Blood Pressure Intervention Trial (SPRINT) was a multicenter RCT designed to determine if treating to lower SBP targets in non-diabetic patients at high risk for CV events improves outcomes as compared to standard care. Patients were at least 50 years of age with SBP of 130 to 180 mm Hg and were at increased CV risk as defined by clinical or subclinical CV disease other than stroke, CKD with glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m², 10-year risk of CV disease >15% on Framingham risk score, or age ≥75 years of age. Patients with diabetes; prior stroke; polycystic kidney disease; significant proteinuria within the past 6 months; symptomatic heart failure within the past 6 months; or left ventricular ejection fraction <35% were excluded.¹

Patients (N=9361) were randomly assigned to an SBP target <120 mm Hg in the intensive group or <140 mm Hg in the standard treatment group, in an open-label design. Allocation was concealed. The study protocol encouraged, but did not require, the use of thiazide-type diuretics, loop diuretics (for those with advanced renal disease), angiotensin-converting enzyme inhibitors or angiotensin receptor blocker agents, calcium channel blockers, and beta-blockers. Clinicians could add other agents as needed. All major classes of antihypertensives were used.

Medication dosing adjustments were based on the average of 3 BP measurements taken with an automated measurement system (Omron Healthcare, Model 907) with the patient seated after 5 minutes of quiet rest. Target SBP in the standard therapy group was 135 to 139 mm Hg. Medication dosages were lowered if SBP was <130 mm Hg at a single visit or <135 mm Hg at 2 consecutive visits.¹

The primary composite outcome included the first occurrence of MI, acute coronary syndrome, stroke, heart failure, or death from CV causes. Secondary outcomes were the individual components of the primary composite outcome, death from any cause, and the composite of the primary outcome or death from any cause.¹

In a group of 1000 patients, an estimated 16 patients will benefit from intensive BP treatment, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.

Study halted early. The study was stopped early due to significantly lower rates of the primary outcome in the intensive therapy group vs the standard therapy group (1.65% per year vs 2.19% per year, respectively, hazard ratio [HR] with intensive treatment=0.75; 95% confidence interval [CI], 0.64-0.89; P<.001). The resulting median follow-up time was 3.26 years.¹ This corresponds to a 25% lower relative risk of the primary outcome, with a decrease in event rates from 6.8% to 5.2% over the trial period. All-cause mortality was also lower in the intensive therapy group: 3.4% vs 4.5% (HR=0.73; 95% CI, 0.60-0.90; P=.003).

The number needed to treat (NNT) over 3.26 years to prevent a primary outcome event, death from any cause, and death from CV causes was 61, 90, and 172, respectively. Serious adverse events occurred more frequently in the intensive therapy group than in the standard therapy group (38.3% vs 37.1%; HR=1.04; P=.25) with a number needed to harm (NNH) of 46 over the study period.¹ (When looking at serious adverse events identified as likely associated with the intervention, rates were 4.7% vs 2.5%, respectively [P<.001].) Hypotension, syncope, electrolyte abnormalities, and acute kidney injury/acute renal failure reached statistical significance. The incidence of bradycardia and injurious falls was higher in the intensive treatment group, but did not reach statistical significance. In the subgroup of patients ≥75 years of age, 48% in each study group experienced a serious adverse event.¹

Throughout the study, mean SBP was 121.5 mm Hg in the intensive therapy group and 134.6 mm Hg in the standard treatment group. This required an average of one additional BP medication in the intensive therapy group (2.8 vs 1.8, respectively).¹

What’s New

Lower SBP produces mortality benefits in those under, and over, age 75

This trial builds on a body of evidence that shows the advantages of lowering SBP to <150 mm Hg^7,11,12 by demonstrating benefits, including lower all-cause mortality, for lower SBP targets in non-diabetic patients at high risk of CV disease. The SPRINT trial also showed that the benefits of intensive therapy remained true in a subgroup of patients ≥75 years of age.

The incidence of the primary outcome in the cohort ≥75 years of age receiving intensive therapy was 7.7% vs 10.9% for those receiving standard therapy (HR=0.67; 95% CI, 0.51-0.86; NNT=31). All-cause mortality was also lower in the intensive therapy group than in the standard therapy group among patients ≥75 years of age: 5.5% vs 8.04% (HR=0.68; 95% CI, 0.50-0.92; NNT=38).¹

Caveats

Many do not benefit from—or are harmed by—increased medication

Identifying patients most likely to benefit from more intensive blood pressure targets remains challenging.

The absolute risk reduction for the primary outcome is 1.6%, meaning 98.4% of patients receiving more intensive treatment will not benefit. In a group of 1000 patients, an estimated 16 patients will benefit, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.¹⁴ The difference between how BP was measured in this trial (an average of 3 readings after the patient had rested for 5 minutes) and that which occurs typically in clinical practice could potentially lead to overtreatment in practice.

Also, reducing antihypertensive therapies when the SBP was about 130 to 135 mm Hg in the standard therapy group likely exaggerated the difference in outcomes between the intensive and standard therapy groups, and is neither routine nor recommended in clinical practice.⁶ Finally, the trial specifically studied non-diabetic patients at high risk of CV disease ≥50 years of age, limiting generalizability to other populations.

Challenges to implementation

Who will benefit/who can achieve intensive SBP goals?

Identifying patients most likely to benefit from more intensive BP targets remains challenging. The SPRINT trial showed a mortality benefit, but at a cost of increased morbidity.^1,14 In particular, caution should be exercised in the subgroup of patients ≥75 years. Despite a lower NNT than the rest of the study population, serious adverse events happened more frequently. Also, this particular cohort of volunteers may not be representative of those ≥75 years of age in the general population.

Additionally, achieving intensive SBP goals can be challenging. In the SPRINT trial, only half of the intensive target group achieved an SBP <120 mm Hg.¹ And in a 2011-12 National Health and Nutrition Examination Survey, only 52% of patients in the general population achieved a BP target <140/90 mm Hg.¹⁵ Lower morbidity and mortality should remain the ultimate goals to the management of hypertension, requiring physicians to carefully assess an individual patient’s likelihood of benefit vs harm.

ACKNOWLEDGEMENT 
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

The US Preventive Services Task Force made 8 recommendations in 2015 that family physicians should implement in their practices (TABLE 1¹). The conditions addressed are high blood pressure, abnormal blood glucose, breast cancer, depression, and tobacco use. The Task Force also issued 13 “I” statements (TABLE 2¹) reflecting insufficient evidence to recommend for or against a particular intervention—once again underscoring the inadequate evidence base for many commonly-accepted practices aimed at prevention. Four such interventions were targeted toward children.

High blood pressure: Verify before starting treatment

The Task Force continues to give strong backing to the practice of screening for high blood pressure (HBP) and treating those with HBP to prevent cardiovascular and renal disease. The new recommendation, however, recognizes there is significant over-diagnosis of this condition and advises that, before starting treatment, HBP found with office measurement be confirmed with either ambulatory blood pressure monitoring or home blood pressure monitoring. This topic was covered in more depth in a recent Practice Alert.²

Since cardiovascular disease is the leading cause of death in the United States and much of this mortality is preventable, the Task Force also has recommendations in place for screening and treatment of other risks for cardiovascular disease, including obesity, hyperlipidemia, elevated blood glucose (discussed below), and tobacco use.¹

Blood glucose: Focus is now on overweight/obese individuals

The Task Force’s new recommendation for diabetes screening differs from the one made in 2008, which recommended screening for type 2 diabetes (T2DM) only in adults with hypertension. The Task Force now recommends screening for abnormal blood glucose in all obese and overweight adults between the ages of 40 and 70. The Task Force analysis is detailed³ and will be the subject of the next Practice Alert, with only the highlights described here.

The recommendation is limited to overweight and obese adults because they are most likely to have abnormal blood glucose and to benefit from interventions. Screening can be done by measuring fasting blood glucose levels, performing a glucose tolerance test, or measuring glycated hemoglobin levels. The optimal screening frequency is unknown but suggested to be every 3 years. Refer patients with abnormal screen results to an intensive behavioral counseling program that promotes healthy eating and physical activity. Those with T2DM should also receive these services and consider pharmacotherapy.

The Task Force examined the potential of electronic nicotine delivery systems for smoking cessation and concluded that the evidence was insufficient to make a recommendation.

Breast cancer: Mammography advice is age dependent

The Task Force breast cancer screening recommendations, first proposed in 2015 and finalized in early 2016, essentially reaffirm those made in 2009. Women ages 50 through 74 should be screened with mammography every 2 years, and individuals younger than age 50 should make a decision to receive screening—or not—based on the known benefits and risks of mammography at their age and their personal risks and preferences.

Insufficient evidence exists to make recommendations regarding mammography for women ages 75 and up, the use of digital breast tomosynthesis as a primary screening tool, and the use of any modality to augment screening in women with dense breasts who have normal mammogram results. Details of these recommendations were described in a Practice Alert last year.⁴

Depression: Use screening tools designed for specific patients

The 2015 updates on screening for depression essentially reconfirm the Task Force’s previous findings and recommendations on this topic. Screening for depression is recommended for all adults, including pregnant and postpartum women,⁵ and adolescents starting at age 12.⁶ Once again, the evidence is insufficient to make a recommendation on screening for depression in children younger than age 12.

Both recommendations emphasize the importance of follow-up steps after screening to ensure accurate diagnosis, adequate treatment, and appropriate follow-up. Treatment for adults and adolescents can include pharmacotherapy, cognitive-behavioral therapy, and/or psychosocial counseling. However, pharmacotherapy is not recommended for pregnant and breastfeeding women because of potential harms to the fetus and newborn.

The Task Force notes that screening all young children for autism spectrum disorder is problematic because of possible over-diagnosis and unclear benefits of early intervention.

The Task Force deems a number of screening tools acceptable. For adolescents, it suggests the Patient Health Questionnaire for Adolescents and the primary care version of the Beck Depression Inventory.⁶ For adults, the Task Force suggests the Patient Health Questionnaire, the Hospital Anxiety and Depression Scales, the Geriatric Depression Scale for older adults, and the Edinburgh Postnatal Depression Scale for postpartum and pregnant women.⁵

There is no known optimal frequency of screening or evidence on the value of repeated screening. The Task Force suggests one initial screen with repeated screening based on individual characteristics.

Tobacco use: Ask every adult patient about it

Preventing the harms from tobacco use is one of the most important and productive primary care interventions. The Task Force has affirmed its previous recommendation to ask all adults about tobacco use, encourage those that use tobacco to quit, and to offer behavioral and pharmacologic interventions to assist with quitting.⁷ The new recommendations emphasize the importance of smoking cessation during pregnancy; however, because of concern about the unknown potential harms from pharmacologic interventions, they advise only behavioral therapy to assist pregnant women to quit smoking.

The Task Force also examined the potential of electronic nicotine delivery systems for smoking cessation and concluded the evidence is insufficient to make a recommendation. It also concluded that the availability of other proven methods of smoking cessation make them the preferred alternatives.

Services with insufficient evidence

TABLE 2¹ lists the interventions that the Task Force studied this past year and found insufficient evidence to support a recommendation for or against. For adults, these “I” recommendations include screening for visual acuity disorders in older adults, screening for thyroid disorders, screening for iron deficiency anemia during pregnancy, and routinely providing iron supplementation during pregnancy.

The persistent inadequate evidence for the effectiveness of preventive services in infants and children was highlighted by the results of last year’s examination of 4 screening tests, all recommended by the American Academy of Pediatrics, but given an “I” recommendation by the Task Force. These included screening for autism spectrum disorder (ASD) in young children (18-30 months), iron deficiency anemia in children ages 6 to 24 months, depression in those ages 11 and younger, and speech and language delay and disorders in children ages 5 or younger. (Ages noted are from the Task Force.)

The Task Force is careful to emphasize that the statement about ASD screening refers to infants and children who appear normal and for whom no concerns of ASD have been raised by their parents. Screening all young children for this disorder is problematic, according to the Task Force, because of possible over-diagnosis and unclear benefits of early intervention.⁸

The US Preventive Services Task Force made 8 recommendations in 2015 that family physicians should implement in their practices (TABLE 1¹). The conditions addressed are high blood pressure, abnormal blood glucose, breast cancer, depression, and tobacco use. The Task Force also issued 13 “I” statements (TABLE 2¹) reflecting insufficient evidence to recommend for or against a particular intervention—once again underscoring the inadequate evidence base for many commonly-accepted practices aimed at prevention. Four such interventions were targeted toward children.

High blood pressure: Verify before starting treatment

The Task Force continues to give strong backing to the practice of screening for high blood pressure (HBP) and treating those with HBP to prevent cardiovascular and renal disease. The new recommendation, however, recognizes there is significant over-diagnosis of this condition and advises that, before starting treatment, HBP found with office measurement be confirmed with either ambulatory blood pressure monitoring or home blood pressure monitoring. This topic was covered in more depth in a recent Practice Alert.²

Since cardiovascular disease is the leading cause of death in the United States and much of this mortality is preventable, the Task Force also has recommendations in place for screening and treatment of other risks for cardiovascular disease, including obesity, hyperlipidemia, elevated blood glucose (discussed below), and tobacco use.¹

Blood glucose: Focus is now on overweight/obese individuals

The Task Force’s new recommendation for diabetes screening differs from the one made in 2008, which recommended screening for type 2 diabetes (T2DM) only in adults with hypertension. The Task Force now recommends screening for abnormal blood glucose in all obese and overweight adults between the ages of 40 and 70. The Task Force analysis is detailed³ and will be the subject of the next Practice Alert, with only the highlights described here.

The recommendation is limited to overweight and obese adults because they are most likely to have abnormal blood glucose and to benefit from interventions. Screening can be done by measuring fasting blood glucose levels, performing a glucose tolerance test, or measuring glycated hemoglobin levels. The optimal screening frequency is unknown but suggested to be every 3 years. Refer patients with abnormal screen results to an intensive behavioral counseling program that promotes healthy eating and physical activity. Those with T2DM should also receive these services and consider pharmacotherapy.

The Task Force examined the potential of electronic nicotine delivery systems for smoking cessation and concluded that the evidence was insufficient to make a recommendation.

Breast cancer: Mammography advice is age dependent

The Task Force breast cancer screening recommendations, first proposed in 2015 and finalized in early 2016, essentially reaffirm those made in 2009. Women ages 50 through 74 should be screened with mammography every 2 years, and individuals younger than age 50 should make a decision to receive screening—or not—based on the known benefits and risks of mammography at their age and their personal risks and preferences.

Insufficient evidence exists to make recommendations regarding mammography for women ages 75 and up, the use of digital breast tomosynthesis as a primary screening tool, and the use of any modality to augment screening in women with dense breasts who have normal mammogram results. Details of these recommendations were described in a Practice Alert last year.⁴

Depression: Use screening tools designed for specific patients

The 2015 updates on screening for depression essentially reconfirm the Task Force’s previous findings and recommendations on this topic. Screening for depression is recommended for all adults, including pregnant and postpartum women,⁵ and adolescents starting at age 12.⁶ Once again, the evidence is insufficient to make a recommendation on screening for depression in children younger than age 12.

Both recommendations emphasize the importance of follow-up steps after screening to ensure accurate diagnosis, adequate treatment, and appropriate follow-up. Treatment for adults and adolescents can include pharmacotherapy, cognitive-behavioral therapy, and/or psychosocial counseling. However, pharmacotherapy is not recommended for pregnant and breastfeeding women because of potential harms to the fetus and newborn.

The Task Force notes that screening all young children for autism spectrum disorder is problematic because of possible over-diagnosis and unclear benefits of early intervention.

The Task Force deems a number of screening tools acceptable. For adolescents, it suggests the Patient Health Questionnaire for Adolescents and the primary care version of the Beck Depression Inventory.⁶ For adults, the Task Force suggests the Patient Health Questionnaire, the Hospital Anxiety and Depression Scales, the Geriatric Depression Scale for older adults, and the Edinburgh Postnatal Depression Scale for postpartum and pregnant women.⁵

There is no known optimal frequency of screening or evidence on the value of repeated screening. The Task Force suggests one initial screen with repeated screening based on individual characteristics.

Tobacco use: Ask every adult patient about it

Preventing the harms from tobacco use is one of the most important and productive primary care interventions. The Task Force has affirmed its previous recommendation to ask all adults about tobacco use, encourage those that use tobacco to quit, and to offer behavioral and pharmacologic interventions to assist with quitting.⁷ The new recommendations emphasize the importance of smoking cessation during pregnancy; however, because of concern about the unknown potential harms from pharmacologic interventions, they advise only behavioral therapy to assist pregnant women to quit smoking.

The Task Force also examined the potential of electronic nicotine delivery systems for smoking cessation and concluded the evidence is insufficient to make a recommendation. It also concluded that the availability of other proven methods of smoking cessation make them the preferred alternatives.

Services with insufficient evidence

TABLE 2¹ lists the interventions that the Task Force studied this past year and found insufficient evidence to support a recommendation for or against. For adults, these “I” recommendations include screening for visual acuity disorders in older adults, screening for thyroid disorders, screening for iron deficiency anemia during pregnancy, and routinely providing iron supplementation during pregnancy.

The persistent inadequate evidence for the effectiveness of preventive services in infants and children was highlighted by the results of last year’s examination of 4 screening tests, all recommended by the American Academy of Pediatrics, but given an “I” recommendation by the Task Force. These included screening for autism spectrum disorder (ASD) in young children (18-30 months), iron deficiency anemia in children ages 6 to 24 months, depression in those ages 11 and younger, and speech and language delay and disorders in children ages 5 or younger. (Ages noted are from the Task Force.)

The Task Force is careful to emphasize that the statement about ASD screening refers to infants and children who appear normal and for whom no concerns of ASD have been raised by their parents. Screening all young children for this disorder is problematic, according to the Task Force, because of possible over-diagnosis and unclear benefits of early intervention.⁸

The US Preventive Services Task Force made 8 recommendations in 2015 that family physicians should implement in their practices (TABLE 1¹). The conditions addressed are high blood pressure, abnormal blood glucose, breast cancer, depression, and tobacco use. The Task Force also issued 13 “I” statements (TABLE 2¹) reflecting insufficient evidence to recommend for or against a particular intervention—once again underscoring the inadequate evidence base for many commonly-accepted practices aimed at prevention. Four such interventions were targeted toward children.

High blood pressure: Verify before starting treatment

The Task Force continues to give strong backing to the practice of screening for high blood pressure (HBP) and treating those with HBP to prevent cardiovascular and renal disease. The new recommendation, however, recognizes there is significant over-diagnosis of this condition and advises that, before starting treatment, HBP found with office measurement be confirmed with either ambulatory blood pressure monitoring or home blood pressure monitoring. This topic was covered in more depth in a recent Practice Alert.²

Since cardiovascular disease is the leading cause of death in the United States and much of this mortality is preventable, the Task Force also has recommendations in place for screening and treatment of other risks for cardiovascular disease, including obesity, hyperlipidemia, elevated blood glucose (discussed below), and tobacco use.¹

Blood glucose: Focus is now on overweight/obese individuals

The Task Force’s new recommendation for diabetes screening differs from the one made in 2008, which recommended screening for type 2 diabetes (T2DM) only in adults with hypertension. The Task Force now recommends screening for abnormal blood glucose in all obese and overweight adults between the ages of 40 and 70. The Task Force analysis is detailed³ and will be the subject of the next Practice Alert, with only the highlights described here.

The recommendation is limited to overweight and obese adults because they are most likely to have abnormal blood glucose and to benefit from interventions. Screening can be done by measuring fasting blood glucose levels, performing a glucose tolerance test, or measuring glycated hemoglobin levels. The optimal screening frequency is unknown but suggested to be every 3 years. Refer patients with abnormal screen results to an intensive behavioral counseling program that promotes healthy eating and physical activity. Those with T2DM should also receive these services and consider pharmacotherapy.

The Task Force examined the potential of electronic nicotine delivery systems for smoking cessation and concluded that the evidence was insufficient to make a recommendation.

Breast cancer: Mammography advice is age dependent

The Task Force breast cancer screening recommendations, first proposed in 2015 and finalized in early 2016, essentially reaffirm those made in 2009. Women ages 50 through 74 should be screened with mammography every 2 years, and individuals younger than age 50 should make a decision to receive screening—or not—based on the known benefits and risks of mammography at their age and their personal risks and preferences.

Insufficient evidence exists to make recommendations regarding mammography for women ages 75 and up, the use of digital breast tomosynthesis as a primary screening tool, and the use of any modality to augment screening in women with dense breasts who have normal mammogram results. Details of these recommendations were described in a Practice Alert last year.⁴

Depression: Use screening tools designed for specific patients

The 2015 updates on screening for depression essentially reconfirm the Task Force’s previous findings and recommendations on this topic. Screening for depression is recommended for all adults, including pregnant and postpartum women,⁵ and adolescents starting at age 12.⁶ Once again, the evidence is insufficient to make a recommendation on screening for depression in children younger than age 12.

Both recommendations emphasize the importance of follow-up steps after screening to ensure accurate diagnosis, adequate treatment, and appropriate follow-up. Treatment for adults and adolescents can include pharmacotherapy, cognitive-behavioral therapy, and/or psychosocial counseling. However, pharmacotherapy is not recommended for pregnant and breastfeeding women because of potential harms to the fetus and newborn.

The Task Force notes that screening all young children for autism spectrum disorder is problematic because of possible over-diagnosis and unclear benefits of early intervention.

The Task Force deems a number of screening tools acceptable. For adolescents, it suggests the Patient Health Questionnaire for Adolescents and the primary care version of the Beck Depression Inventory.⁶ For adults, the Task Force suggests the Patient Health Questionnaire, the Hospital Anxiety and Depression Scales, the Geriatric Depression Scale for older adults, and the Edinburgh Postnatal Depression Scale for postpartum and pregnant women.⁵

There is no known optimal frequency of screening or evidence on the value of repeated screening. The Task Force suggests one initial screen with repeated screening based on individual characteristics.

Tobacco use: Ask every adult patient about it

Preventing the harms from tobacco use is one of the most important and productive primary care interventions. The Task Force has affirmed its previous recommendation to ask all adults about tobacco use, encourage those that use tobacco to quit, and to offer behavioral and pharmacologic interventions to assist with quitting.⁷ The new recommendations emphasize the importance of smoking cessation during pregnancy; however, because of concern about the unknown potential harms from pharmacologic interventions, they advise only behavioral therapy to assist pregnant women to quit smoking.

The Task Force also examined the potential of electronic nicotine delivery systems for smoking cessation and concluded the evidence is insufficient to make a recommendation. It also concluded that the availability of other proven methods of smoking cessation make them the preferred alternatives.

Services with insufficient evidence

TABLE 2¹ lists the interventions that the Task Force studied this past year and found insufficient evidence to support a recommendation for or against. For adults, these “I” recommendations include screening for visual acuity disorders in older adults, screening for thyroid disorders, screening for iron deficiency anemia during pregnancy, and routinely providing iron supplementation during pregnancy.

The persistent inadequate evidence for the effectiveness of preventive services in infants and children was highlighted by the results of last year’s examination of 4 screening tests, all recommended by the American Academy of Pediatrics, but given an “I” recommendation by the Task Force. These included screening for autism spectrum disorder (ASD) in young children (18-30 months), iron deficiency anemia in children ages 6 to 24 months, depression in those ages 11 and younger, and speech and language delay and disorders in children ages 5 or younger. (Ages noted are from the Task Force.)

The Task Force is careful to emphasize that the statement about ASD screening refers to infants and children who appear normal and for whom no concerns of ASD have been raised by their parents. Screening all young children for this disorder is problematic, according to the Task Force, because of possible over-diagnosis and unclear benefits of early intervention.⁸

Neither saxagliptin nor sitagliptin, the two oral DPP-4 inhibitors most commonly used as antihyperglycemic medications, raised the risk of hospitalization for heart failure in a large population-based cohort study that analyzed data from a Food and Drug Administration surveillance program.

The report was published online April 25 in Annals of Internal Medicine.

The cardiovascular safety of DPP-4 inhibitors is controversial: Several postmarketing studies have produced conflicting results, particularly with regard to HF risk. “Patients with diabetes have a higher HF risk than those without, so any antihyperglycemic agent that modifies the risk warrants further examination,” said Sengwee Toh, Sc.D., a pharmacoepidemiologist in the department of population medicine, Harvard Medical School and Harvard Pilgrim Health Institute, Boston, and his associates.

They compared rates of HF among demographically and geographically diverse patients who initiated antidiabetic medications during a 7-year period in routine clinical settings. The study population included 78,553 adults who initiated saxagliptin and 298,124 who initiated sitagliptin, who were compared with patients who initiated pioglitazone, second-generation sulfonylureas, or long-acting insulins. Mean follow-up was 7-9 months.

There was no evidence of an increased risk of hospitalization for HF among new users of saxagliptin or sitagliptin. The hazard ratios for developing HF were 0.83 for saxagliptin vs. sitagliptin, 0.63 for saxagliptin vs. pioglitazone, 0.69 for saxagliptin vs. sulfonylureas, and 0.61 for saxagliptin vs. insulin. Similarly, the hazard ratios for developing HF were 0.74 for sitagliptin vs. pioglitazone, 0.86 for sitagliptin vs. sulfonylureas, and 0.71 for sitagliptin vs. insulin.

These results were consistent across sensitivity analyses and subgroup analyses that categorized patients by whether or not they had preexisting cardiovascular disease and whether or not they had a history of prior HF, the investigators said (Ann Intern Med. 2016 April 25. doi:10.7326/M15-2568).

However, this was an observational study with a relatively short follow-up. “Well-designed randomized trials with hospitalization for HF as the main endpoint or observational studies that address the limitations of our study will help provide more definitive evidence on the topic,” Dr. Toh and his associates said.

This study was supported by the FDA. Dr. Toh reported having no relevant financial disclosures; one of his associates reported receiving personal fees from Novartis unrelated to this work.

Neither saxagliptin nor sitagliptin, the two oral DPP-4 inhibitors most commonly used as antihyperglycemic medications, raised the risk of hospitalization for heart failure in a large population-based cohort study that analyzed data from a Food and Drug Administration surveillance program.

The report was published online April 25 in Annals of Internal Medicine.

The cardiovascular safety of DPP-4 inhibitors is controversial: Several postmarketing studies have produced conflicting results, particularly with regard to HF risk. “Patients with diabetes have a higher HF risk than those without, so any antihyperglycemic agent that modifies the risk warrants further examination,” said Sengwee Toh, Sc.D., a pharmacoepidemiologist in the department of population medicine, Harvard Medical School and Harvard Pilgrim Health Institute, Boston, and his associates.

They compared rates of HF among demographically and geographically diverse patients who initiated antidiabetic medications during a 7-year period in routine clinical settings. The study population included 78,553 adults who initiated saxagliptin and 298,124 who initiated sitagliptin, who were compared with patients who initiated pioglitazone, second-generation sulfonylureas, or long-acting insulins. Mean follow-up was 7-9 months.

There was no evidence of an increased risk of hospitalization for HF among new users of saxagliptin or sitagliptin. The hazard ratios for developing HF were 0.83 for saxagliptin vs. sitagliptin, 0.63 for saxagliptin vs. pioglitazone, 0.69 for saxagliptin vs. sulfonylureas, and 0.61 for saxagliptin vs. insulin. Similarly, the hazard ratios for developing HF were 0.74 for sitagliptin vs. pioglitazone, 0.86 for sitagliptin vs. sulfonylureas, and 0.71 for sitagliptin vs. insulin.

These results were consistent across sensitivity analyses and subgroup analyses that categorized patients by whether or not they had preexisting cardiovascular disease and whether or not they had a history of prior HF, the investigators said (Ann Intern Med. 2016 April 25. doi:10.7326/M15-2568).

However, this was an observational study with a relatively short follow-up. “Well-designed randomized trials with hospitalization for HF as the main endpoint or observational studies that address the limitations of our study will help provide more definitive evidence on the topic,” Dr. Toh and his associates said.

This study was supported by the FDA. Dr. Toh reported having no relevant financial disclosures; one of his associates reported receiving personal fees from Novartis unrelated to this work.

Neither saxagliptin nor sitagliptin, the two oral DPP-4 inhibitors most commonly used as antihyperglycemic medications, raised the risk of hospitalization for heart failure in a large population-based cohort study that analyzed data from a Food and Drug Administration surveillance program.

The report was published online April 25 in Annals of Internal Medicine.

The cardiovascular safety of DPP-4 inhibitors is controversial: Several postmarketing studies have produced conflicting results, particularly with regard to HF risk. “Patients with diabetes have a higher HF risk than those without, so any antihyperglycemic agent that modifies the risk warrants further examination,” said Sengwee Toh, Sc.D., a pharmacoepidemiologist in the department of population medicine, Harvard Medical School and Harvard Pilgrim Health Institute, Boston, and his associates.

They compared rates of HF among demographically and geographically diverse patients who initiated antidiabetic medications during a 7-year period in routine clinical settings. The study population included 78,553 adults who initiated saxagliptin and 298,124 who initiated sitagliptin, who were compared with patients who initiated pioglitazone, second-generation sulfonylureas, or long-acting insulins. Mean follow-up was 7-9 months.

There was no evidence of an increased risk of hospitalization for HF among new users of saxagliptin or sitagliptin. The hazard ratios for developing HF were 0.83 for saxagliptin vs. sitagliptin, 0.63 for saxagliptin vs. pioglitazone, 0.69 for saxagliptin vs. sulfonylureas, and 0.61 for saxagliptin vs. insulin. Similarly, the hazard ratios for developing HF were 0.74 for sitagliptin vs. pioglitazone, 0.86 for sitagliptin vs. sulfonylureas, and 0.71 for sitagliptin vs. insulin.

These results were consistent across sensitivity analyses and subgroup analyses that categorized patients by whether or not they had preexisting cardiovascular disease and whether or not they had a history of prior HF, the investigators said (Ann Intern Med. 2016 April 25. doi:10.7326/M15-2568).

However, this was an observational study with a relatively short follow-up. “Well-designed randomized trials with hospitalization for HF as the main endpoint or observational studies that address the limitations of our study will help provide more definitive evidence on the topic,” Dr. Toh and his associates said.

This study was supported by the FDA. Dr. Toh reported having no relevant financial disclosures; one of his associates reported receiving personal fees from Novartis unrelated to this work.

VANCOUVER—Once-daily treatment with 80 mg of valbenazine reduces tardive dyskinesia severity, according to research presented at the 68th Annual Meeting of the American Academy of Neurology. The drug appears to be well tolerated and raises no notable safety concerns.

Tardive dyskinesia is characterized by abnormal, involuntary movements of the tongue, lips, face, trunk, and limbs. The movement disorder occurs in patients with chronic exposure to dopamine-receptor blocking agents (eg, antipsychotics) and often persists after drug discontinuation. No FDA-approved medications for the treatment of tardive dyskinesia are available.

Robert A. Hauser, MD, Professor of Neurology, Molecular Pharmacology, and Physiology at the University of South Florida Morsani College of Medicine in Tampa, and colleagues conducted a randomized, double-blind, placebo-controlled phase III trial of valbenazine, a highly selective inhibitor of vesicular monoamine transporter type 2, for the treatment of tardive dyskinesia. Earlier studies had suggested the drug's safety and efficacy.

The investigators enrolled patients with schizophrenia, schizoaffective disorder, or mood disorders into the study. Participants had moderate or severe tardive dyskinesia and a DSM-IV diagnosis of neuroleptic-induced tardive dyskinesia for at least three months prior to screening. In all, 78 patients were randomized to placebo, 76 were randomized to 40 mg/day of valbenazine, and 80 were randomized to 80 mg/day of valbenazine. The treatment period lasted for six weeks, and participants underwent evaluations at week 2, week 4, and week 6.

The study's primary efficacy end point was change from baseline to week 6 on the Abnormal Involuntary Movement Scale (AIMS), as assessed by blinded central video raters. AIMS examinations were filmed, and scoring was performed by consensus of pairs of central raters who were blinded to treatment arm and study video sequence. The secondary efficacy end point was Clinical Global Impression of Change for Tardive Dyskinesia (CGI-TD) mean score at week 6, as assessed by site investigators.

The population's mean age was 56. About 54% of patients were male, and two-thirds of subjects had schizophrenia or schizoaffective disorder. The population's mean AIMS score at baseline was 10.1.

At week 6, AIMS score improved by 0.1 points, compared with baseline, for patients receiving placebo.

Participants receiving 80 mg/day of valbenazine had an improvement of 3.2 points, compared with baseline, and this result was highly statistically significant. In addition, patients receiving 40 mg/day of valbenazine had an improvement of 1.9 points, compared with baseline. The investigators observed a trend toward improvement in CGI-TD scores for patients receiving valbenazine.

The rates of adverse events were similar between groups. Treatment-emergent adverse events occurred in 45% of the placebo group, 39% of the valbenazine 40 mg group, and 49% of the valbenazine 80 mg group. The most common adverse event was somnolence. The rate of discontinuations due to adverse events was "strikingly low" and similar across groups, said Dr. Hauser. Three serious adverse events occurred in the placebo group, four in the valbenazine 40 mg group, and six in the 80 mg group. One patient receiving 80 mg/day of valbenazine died, and the site investigator and data safety monitoring board judged the event unlikely related to study medication. Participants' psychiatric status remained stable.

A second phase III study of valbenazine is currently under way, said Dr. Hauser. Given the observed dose response and the drug's tolerability, it would be worthwhile to investigate higher doses of valbenazine, he concluded.

—Erik Greb

VANCOUVER—Once-daily treatment with 80 mg of valbenazine reduces tardive dyskinesia severity, according to research presented at the 68th Annual Meeting of the American Academy of Neurology. The drug appears to be well tolerated and raises no notable safety concerns.

Tardive dyskinesia is characterized by abnormal, involuntary movements of the tongue, lips, face, trunk, and limbs. The movement disorder occurs in patients with chronic exposure to dopamine-receptor blocking agents (eg, antipsychotics) and often persists after drug discontinuation. No FDA-approved medications for the treatment of tardive dyskinesia are available.

Robert A. Hauser, MD, Professor of Neurology, Molecular Pharmacology, and Physiology at the University of South Florida Morsani College of Medicine in Tampa, and colleagues conducted a randomized, double-blind, placebo-controlled phase III trial of valbenazine, a highly selective inhibitor of vesicular monoamine transporter type 2, for the treatment of tardive dyskinesia. Earlier studies had suggested the drug's safety and efficacy.

The investigators enrolled patients with schizophrenia, schizoaffective disorder, or mood disorders into the study. Participants had moderate or severe tardive dyskinesia and a DSM-IV diagnosis of neuroleptic-induced tardive dyskinesia for at least three months prior to screening. In all, 78 patients were randomized to placebo, 76 were randomized to 40 mg/day of valbenazine, and 80 were randomized to 80 mg/day of valbenazine. The treatment period lasted for six weeks, and participants underwent evaluations at week 2, week 4, and week 6.

The study's primary efficacy end point was change from baseline to week 6 on the Abnormal Involuntary Movement Scale (AIMS), as assessed by blinded central video raters. AIMS examinations were filmed, and scoring was performed by consensus of pairs of central raters who were blinded to treatment arm and study video sequence. The secondary efficacy end point was Clinical Global Impression of Change for Tardive Dyskinesia (CGI-TD) mean score at week 6, as assessed by site investigators.

The population's mean age was 56. About 54% of patients were male, and two-thirds of subjects had schizophrenia or schizoaffective disorder. The population's mean AIMS score at baseline was 10.1.

At week 6, AIMS score improved by 0.1 points, compared with baseline, for patients receiving placebo.

Participants receiving 80 mg/day of valbenazine had an improvement of 3.2 points, compared with baseline, and this result was highly statistically significant. In addition, patients receiving 40 mg/day of valbenazine had an improvement of 1.9 points, compared with baseline. The investigators observed a trend toward improvement in CGI-TD scores for patients receiving valbenazine.

The rates of adverse events were similar between groups. Treatment-emergent adverse events occurred in 45% of the placebo group, 39% of the valbenazine 40 mg group, and 49% of the valbenazine 80 mg group. The most common adverse event was somnolence. The rate of discontinuations due to adverse events was "strikingly low" and similar across groups, said Dr. Hauser. Three serious adverse events occurred in the placebo group, four in the valbenazine 40 mg group, and six in the 80 mg group. One patient receiving 80 mg/day of valbenazine died, and the site investigator and data safety monitoring board judged the event unlikely related to study medication. Participants' psychiatric status remained stable.

A second phase III study of valbenazine is currently under way, said Dr. Hauser. Given the observed dose response and the drug's tolerability, it would be worthwhile to investigate higher doses of valbenazine, he concluded.

—Erik Greb

VANCOUVER—Once-daily treatment with 80 mg of valbenazine reduces tardive dyskinesia severity, according to research presented at the 68th Annual Meeting of the American Academy of Neurology. The drug appears to be well tolerated and raises no notable safety concerns.

Tardive dyskinesia is characterized by abnormal, involuntary movements of the tongue, lips, face, trunk, and limbs. The movement disorder occurs in patients with chronic exposure to dopamine-receptor blocking agents (eg, antipsychotics) and often persists after drug discontinuation. No FDA-approved medications for the treatment of tardive dyskinesia are available.

Robert A. Hauser, MD, Professor of Neurology, Molecular Pharmacology, and Physiology at the University of South Florida Morsani College of Medicine in Tampa, and colleagues conducted a randomized, double-blind, placebo-controlled phase III trial of valbenazine, a highly selective inhibitor of vesicular monoamine transporter type 2, for the treatment of tardive dyskinesia. Earlier studies had suggested the drug's safety and efficacy.

The investigators enrolled patients with schizophrenia, schizoaffective disorder, or mood disorders into the study. Participants had moderate or severe tardive dyskinesia and a DSM-IV diagnosis of neuroleptic-induced tardive dyskinesia for at least three months prior to screening. In all, 78 patients were randomized to placebo, 76 were randomized to 40 mg/day of valbenazine, and 80 were randomized to 80 mg/day of valbenazine. The treatment period lasted for six weeks, and participants underwent evaluations at week 2, week 4, and week 6.

The study's primary efficacy end point was change from baseline to week 6 on the Abnormal Involuntary Movement Scale (AIMS), as assessed by blinded central video raters. AIMS examinations were filmed, and scoring was performed by consensus of pairs of central raters who were blinded to treatment arm and study video sequence. The secondary efficacy end point was Clinical Global Impression of Change for Tardive Dyskinesia (CGI-TD) mean score at week 6, as assessed by site investigators.

The population's mean age was 56. About 54% of patients were male, and two-thirds of subjects had schizophrenia or schizoaffective disorder. The population's mean AIMS score at baseline was 10.1.

At week 6, AIMS score improved by 0.1 points, compared with baseline, for patients receiving placebo.

Participants receiving 80 mg/day of valbenazine had an improvement of 3.2 points, compared with baseline, and this result was highly statistically significant. In addition, patients receiving 40 mg/day of valbenazine had an improvement of 1.9 points, compared with baseline. The investigators observed a trend toward improvement in CGI-TD scores for patients receiving valbenazine.

The rates of adverse events were similar between groups. Treatment-emergent adverse events occurred in 45% of the placebo group, 39% of the valbenazine 40 mg group, and 49% of the valbenazine 80 mg group. The most common adverse event was somnolence. The rate of discontinuations due to adverse events was "strikingly low" and similar across groups, said Dr. Hauser. Three serious adverse events occurred in the placebo group, four in the valbenazine 40 mg group, and six in the 80 mg group. One patient receiving 80 mg/day of valbenazine died, and the site investigator and data safety monitoring board judged the event unlikely related to study medication. Participants' psychiatric status remained stable.

A second phase III study of valbenazine is currently under way, said Dr. Hauser. Given the observed dose response and the drug's tolerability, it would be worthwhile to investigate higher doses of valbenazine, he concluded.

—Erik Greb

VANCOUVER—Among people with multiple sclerosis (MS) and chronic demyelinating optic neuropathy, clemastine fumarate reduces visual evoked potential latency delay, a putative biomarker for remyelination, according to a phase II study presented at the 68th Annual Meeting of the American Academy of Neurology.

"This is the first randomized controlled trial documenting efficacy for a candidate remyelinating agent in MS," said Ari Green, MD, Assistant Clinical Director of the Multiple Sclerosis Center at the University of California San Francisco (UCSF), and colleagues.

Ari Green, MD

Investigators at UCSF identified clemastine fumarate, an antihistamine that is available over the counter, as a potential remyelinating agent using an in vitro micropillar screen. In an animal model, the agent led to robust remyelination and appeared to protect axons, said Dr. Green.

To assess the efficacy of clemastine fumarate for remyelination in patients with MS and chronic optic neuropathy, Dr. Green and colleagues conducted a double-blind, randomized, placebo-controlled, crossover study.

They enrolled 50 participants who had a delay in transmission time greater than 118 ms in at least one eye. Patients had an average age of 40, Expanded Disability Status Scale score of 2.1, and disease duration of 5.1 years. The study period was 150 days.

Patients were grouped into two treatment arms. For the first treatment period, 25 patients received oral clemastine fumarate and 25 patients received placebo twice daily. The primary efficacy end point was change in latency delay on visual evoked potential.

Visual evoked potential latency delay was reduced by 1.9 ms per eye for the period on treatment. A strong trend for improvement of the secondary end point of low contrast visual acuity also was observed. Clemastine treatment was associated with mild worsening of fatigue on the Multidimensional Assessment of Fatigue, however.

Among patients who first received clemastine, the treatment effect was sustained "even into the second epoch, suggesting that we were in fact having a remyelinating effect, and not just a transient effect on ion channels," Dr. Green said.

Larger studies are needed before doctors can recommend clemastine fumarate for people with MS, Dr. Green said. New medications are in development, and researchers aim to improve the targeting and reduce the side effects from these drugs.

"While the improvement in vision appears modest, this study is promising because it is the first time a drug has been shown to possibly reverse the damage done by MS," said Dr. Green. "Findings are preliminary, but this study provides a framework for future MS repair studies and will hopefully herald discoveries that will enhance the brain's innate capacity for repair."

—Jake Remaly

VANCOUVER—Among people with multiple sclerosis (MS) and chronic demyelinating optic neuropathy, clemastine fumarate reduces visual evoked potential latency delay, a putative biomarker for remyelination, according to a phase II study presented at the 68th Annual Meeting of the American Academy of Neurology.

"This is the first randomized controlled trial documenting efficacy for a candidate remyelinating agent in MS," said Ari Green, MD, Assistant Clinical Director of the Multiple Sclerosis Center at the University of California San Francisco (UCSF), and colleagues.

Ari Green, MD

Investigators at UCSF identified clemastine fumarate, an antihistamine that is available over the counter, as a potential remyelinating agent using an in vitro micropillar screen. In an animal model, the agent led to robust remyelination and appeared to protect axons, said Dr. Green.

To assess the efficacy of clemastine fumarate for remyelination in patients with MS and chronic optic neuropathy, Dr. Green and colleagues conducted a double-blind, randomized, placebo-controlled, crossover study.

They enrolled 50 participants who had a delay in transmission time greater than 118 ms in at least one eye. Patients had an average age of 40, Expanded Disability Status Scale score of 2.1, and disease duration of 5.1 years. The study period was 150 days.

Patients were grouped into two treatment arms. For the first treatment period, 25 patients received oral clemastine fumarate and 25 patients received placebo twice daily. The primary efficacy end point was change in latency delay on visual evoked potential.

Visual evoked potential latency delay was reduced by 1.9 ms per eye for the period on treatment. A strong trend for improvement of the secondary end point of low contrast visual acuity also was observed. Clemastine treatment was associated with mild worsening of fatigue on the Multidimensional Assessment of Fatigue, however.

Among patients who first received clemastine, the treatment effect was sustained "even into the second epoch, suggesting that we were in fact having a remyelinating effect, and not just a transient effect on ion channels," Dr. Green said.

Larger studies are needed before doctors can recommend clemastine fumarate for people with MS, Dr. Green said. New medications are in development, and researchers aim to improve the targeting and reduce the side effects from these drugs.

"While the improvement in vision appears modest, this study is promising because it is the first time a drug has been shown to possibly reverse the damage done by MS," said Dr. Green. "Findings are preliminary, but this study provides a framework for future MS repair studies and will hopefully herald discoveries that will enhance the brain's innate capacity for repair."

—Jake Remaly

VANCOUVER—Among people with multiple sclerosis (MS) and chronic demyelinating optic neuropathy, clemastine fumarate reduces visual evoked potential latency delay, a putative biomarker for remyelination, according to a phase II study presented at the 68th Annual Meeting of the American Academy of Neurology.

"This is the first randomized controlled trial documenting efficacy for a candidate remyelinating agent in MS," said Ari Green, MD, Assistant Clinical Director of the Multiple Sclerosis Center at the University of California San Francisco (UCSF), and colleagues.

Ari Green, MD

Investigators at UCSF identified clemastine fumarate, an antihistamine that is available over the counter, as a potential remyelinating agent using an in vitro micropillar screen. In an animal model, the agent led to robust remyelination and appeared to protect axons, said Dr. Green.

To assess the efficacy of clemastine fumarate for remyelination in patients with MS and chronic optic neuropathy, Dr. Green and colleagues conducted a double-blind, randomized, placebo-controlled, crossover study.

They enrolled 50 participants who had a delay in transmission time greater than 118 ms in at least one eye. Patients had an average age of 40, Expanded Disability Status Scale score of 2.1, and disease duration of 5.1 years. The study period was 150 days.

Patients were grouped into two treatment arms. For the first treatment period, 25 patients received oral clemastine fumarate and 25 patients received placebo twice daily. The primary efficacy end point was change in latency delay on visual evoked potential.

Visual evoked potential latency delay was reduced by 1.9 ms per eye for the period on treatment. A strong trend for improvement of the secondary end point of low contrast visual acuity also was observed. Clemastine treatment was associated with mild worsening of fatigue on the Multidimensional Assessment of Fatigue, however.

Among patients who first received clemastine, the treatment effect was sustained "even into the second epoch, suggesting that we were in fact having a remyelinating effect, and not just a transient effect on ion channels," Dr. Green said.

Larger studies are needed before doctors can recommend clemastine fumarate for people with MS, Dr. Green said. New medications are in development, and researchers aim to improve the targeting and reduce the side effects from these drugs.

"While the improvement in vision appears modest, this study is promising because it is the first time a drug has been shown to possibly reverse the damage done by MS," said Dr. Green. "Findings are preliminary, but this study provides a framework for future MS repair studies and will hopefully herald discoveries that will enhance the brain's innate capacity for repair."

—Jake Remaly

Surveillance of CDNK2A mutation carriers detected most pancreatic ductal carcinoma in situ (PDAC) at a resectable stage, while the surveillance benefit was lower for those with familial prostate cancer.

Among 178 CDKN2A mutation carriers, PDAC was detected in 13 (7.3%), 9 of whom underwent surgery. Compared with previously reported rates of 15%-20% for symptomatic PDAC, this 70% resection rate represents a substantial increase. The 5-year survival rate of 24% for screen-detected PDAC was higher than 4%-7% reported for symptomatic sporadic PDAC. Among individuals with familial prostate cancer (FPC), 13 of 214 individuals (6.1%) underwent surgery, but with a higher proportion of precursor lesions detected, just four high-risk lesions (1.9% of screened FPC patients) were removed.

Whether surveillance improved prognosis for FPC families was difficult to determine, according to the investigators. The yield of PDAC was low at 0.9%, as was the yield of relevant precursor lesions (grade 3 PanIN and high-grade IPMN) at 1.9%.

“However, if surgical removal of multifocal grade 2 PanIN and multifocal BD-IPMNs is regarded as beneficial, the diagnostic yield increases to 3.7% (eight of 214 patients), and surveillance of FPC might also be considered effective,” wrote Dr. Hans Vasen, professor in the department of gastroenterology and hepatology at the Leiden University Medical Center, the Netherlands, and colleagues. “The value of surveillance of FPC is still not clear, and the main effect seems to be prevention of PDAC by removal of” precursor lesions, they added (J Clin Oncol. 2016 Apr 25. doi: 10.1200/JCO.2015.64.0730).

The retrospective evaluation of an ongoing prospective follow-up study included 411 high-risk individuals: 178 with CDKN2A mutations, 214 with familial pancreatic cancer, and 19 with BRCA1/2 or PALB2 mutations. The study was conducted at three expert centers in Marburg, Germany; Leiden, the Netherlands; and Madrid.

In the BRCA1/2 and PALB2 mutation cohort, one individual (3.8%) with a BRCA2 mutation developed PDAC and underwent surgery; 17 months after the surgery this patient died of liver metastasis. Two others underwent surgery for cystic lesions and are in good health at 10 and 21 months after surgery.

In the cohort of CDKN2A mutation carriers, the mean age at the start of surveillance was 56 years (range, 37-75) and the mean follow-up time was 53 months (range, 0-169): in total, 866 MRIs and 106 endoscopic ultrasounds were conducted. In the FPC group, the mean age was 48 years (range, 27-81), and the mean follow up was 2.8 years (range, 0-10.8): 618 MRIs and 402 endoscopic ultrasounds were conducted. Among BRCA1/2 and PALB2 mutation carriers, the mean age was 52.6 years (range, 25-70), and the mean follow up was 32.7 months (range, 1-119).

Surveillance of CDNK2A mutation carriers detected most pancreatic ductal carcinoma in situ (PDAC) at a resectable stage, while the surveillance benefit was lower for those with familial prostate cancer.

Among 178 CDKN2A mutation carriers, PDAC was detected in 13 (7.3%), 9 of whom underwent surgery. Compared with previously reported rates of 15%-20% for symptomatic PDAC, this 70% resection rate represents a substantial increase. The 5-year survival rate of 24% for screen-detected PDAC was higher than 4%-7% reported for symptomatic sporadic PDAC. Among individuals with familial prostate cancer (FPC), 13 of 214 individuals (6.1%) underwent surgery, but with a higher proportion of precursor lesions detected, just four high-risk lesions (1.9% of screened FPC patients) were removed.

Whether surveillance improved prognosis for FPC families was difficult to determine, according to the investigators. The yield of PDAC was low at 0.9%, as was the yield of relevant precursor lesions (grade 3 PanIN and high-grade IPMN) at 1.9%.

“However, if surgical removal of multifocal grade 2 PanIN and multifocal BD-IPMNs is regarded as beneficial, the diagnostic yield increases to 3.7% (eight of 214 patients), and surveillance of FPC might also be considered effective,” wrote Dr. Hans Vasen, professor in the department of gastroenterology and hepatology at the Leiden University Medical Center, the Netherlands, and colleagues. “The value of surveillance of FPC is still not clear, and the main effect seems to be prevention of PDAC by removal of” precursor lesions, they added (J Clin Oncol. 2016 Apr 25. doi: 10.1200/JCO.2015.64.0730).

The retrospective evaluation of an ongoing prospective follow-up study included 411 high-risk individuals: 178 with CDKN2A mutations, 214 with familial pancreatic cancer, and 19 with BRCA1/2 or PALB2 mutations. The study was conducted at three expert centers in Marburg, Germany; Leiden, the Netherlands; and Madrid.

In the BRCA1/2 and PALB2 mutation cohort, one individual (3.8%) with a BRCA2 mutation developed PDAC and underwent surgery; 17 months after the surgery this patient died of liver metastasis. Two others underwent surgery for cystic lesions and are in good health at 10 and 21 months after surgery.

In the cohort of CDKN2A mutation carriers, the mean age at the start of surveillance was 56 years (range, 37-75) and the mean follow-up time was 53 months (range, 0-169): in total, 866 MRIs and 106 endoscopic ultrasounds were conducted. In the FPC group, the mean age was 48 years (range, 27-81), and the mean follow up was 2.8 years (range, 0-10.8): 618 MRIs and 402 endoscopic ultrasounds were conducted. Among BRCA1/2 and PALB2 mutation carriers, the mean age was 52.6 years (range, 25-70), and the mean follow up was 32.7 months (range, 1-119).

Surveillance of CDNK2A mutation carriers detected most pancreatic ductal carcinoma in situ (PDAC) at a resectable stage, while the surveillance benefit was lower for those with familial prostate cancer.

Among 178 CDKN2A mutation carriers, PDAC was detected in 13 (7.3%), 9 of whom underwent surgery. Compared with previously reported rates of 15%-20% for symptomatic PDAC, this 70% resection rate represents a substantial increase. The 5-year survival rate of 24% for screen-detected PDAC was higher than 4%-7% reported for symptomatic sporadic PDAC. Among individuals with familial prostate cancer (FPC), 13 of 214 individuals (6.1%) underwent surgery, but with a higher proportion of precursor lesions detected, just four high-risk lesions (1.9% of screened FPC patients) were removed.

Whether surveillance improved prognosis for FPC families was difficult to determine, according to the investigators. The yield of PDAC was low at 0.9%, as was the yield of relevant precursor lesions (grade 3 PanIN and high-grade IPMN) at 1.9%.

“However, if surgical removal of multifocal grade 2 PanIN and multifocal BD-IPMNs is regarded as beneficial, the diagnostic yield increases to 3.7% (eight of 214 patients), and surveillance of FPC might also be considered effective,” wrote Dr. Hans Vasen, professor in the department of gastroenterology and hepatology at the Leiden University Medical Center, the Netherlands, and colleagues. “The value of surveillance of FPC is still not clear, and the main effect seems to be prevention of PDAC by removal of” precursor lesions, they added (J Clin Oncol. 2016 Apr 25. doi: 10.1200/JCO.2015.64.0730).

The retrospective evaluation of an ongoing prospective follow-up study included 411 high-risk individuals: 178 with CDKN2A mutations, 214 with familial pancreatic cancer, and 19 with BRCA1/2 or PALB2 mutations. The study was conducted at three expert centers in Marburg, Germany; Leiden, the Netherlands; and Madrid.

In the BRCA1/2 and PALB2 mutation cohort, one individual (3.8%) with a BRCA2 mutation developed PDAC and underwent surgery; 17 months after the surgery this patient died of liver metastasis. Two others underwent surgery for cystic lesions and are in good health at 10 and 21 months after surgery.

In the cohort of CDKN2A mutation carriers, the mean age at the start of surveillance was 56 years (range, 37-75) and the mean follow-up time was 53 months (range, 0-169): in total, 866 MRIs and 106 endoscopic ultrasounds were conducted. In the FPC group, the mean age was 48 years (range, 27-81), and the mean follow up was 2.8 years (range, 0-10.8): 618 MRIs and 402 endoscopic ultrasounds were conducted. Among BRCA1/2 and PALB2 mutation carriers, the mean age was 52.6 years (range, 25-70), and the mean follow up was 32.7 months (range, 1-119).

Firearms are the most common means of suicide in the United States, accounting for approximately 20,000 adult deaths annually,1 which is approximately two-thirds of the more than 32,000 gun-related fatalities each year in the United States. Of approximately 3,000 American children who are shot to death annually, one-third are suicides.^1-4

Firearms are dangerous; it has been documented that even guns obtained for recreation or protection increase the risk of suicide, homicide, or injury.^2,3 This problem has become a public health concern.^3-8 Because most suicide attempts with firearms are fatal, psychiatrists have an interest in reducing such outcomes.^1-8

Risk factors for suicide by firearm
Easy availability of a gun in the home, with ammunition present—especially a gun that is kept loaded and not locked up—is the one of the biggest risk factors for suicide by firearms.⁴ Unrestricted, quick access allows people who are impulsive little time to reconsider suicide. The risk presented by easy availability is magnified by dangerous concomitant intoxication (see below), distress, and lack of supervision (of children).

Alcohol consumption is associated with suicide. Approximately one-fourth of the people who commit suicide are intoxicated at the time of death.⁹ Alcohol use, especially binge drinking, is observed in an even larger percentage of suicide attempts than individuals using guns while sober.

Female sex. In recent years, gun use by women has increased, along with firearm-related suicide. Simply having a gun at home greatly increases the suicide rate for women.^2-4

People with a history of high impulsivity, impaired judgment, violence, or psychiatric and neurologic disorders places people at greater risk of shooting themselves, especially those with depression, suicidal ideation, substance abuse, psychosis, or dementia.⁴

Older age, particularly men who live alone, increases the risk of suicide by firearms, especially in the context of chronic pain or other health problems. Gunfire is the most common means of suicide among geriatric patients of both sexes.⁸

Lethality. In general, suicide attempts with guns are more likely to be fatal than overdosing, poisoning, or self-mutilation.^1,2 Most self-inflicted gunshot wounds result in death, usually on the day of the shooting.^1,2

Evidence about these risk factors has led the American Medical Association and other health care groups to encourage physicians—in particular, psychiatric clinicians who focus on suicide prevention—to counsel patients about gun safety.

What can you do to minimize risk?
Gun-related inquiry and counsel by psychiatrists can benefit patients and their family.⁴ Be aware, however, of restrictions on such discussions by health care providers in some states (Box).¹⁰

Ask about the presence of firearms in the home. Our advice and our “doctor’s orders” are a means to promote health; suggestions in the context of a supportive physician-patient relationship could result in compliance.^3,4 Firearm-focused discussions might be uncomfortable or unpopular but are critical for preventing suicide. Openly discussing such issues with our patients could avoid tragedies.⁴ Involving family or significant others in these interventions also might be helpful.

Ask about access to and storage of firearms. Simply talking about gun safety is helpful.⁴ Seeking information about gun usage is especially called for in psychiatric practices that treat patients with suicidal ideation, depression, substance abuse, and cognitive impairment.⁸ Discuss firearm availability with patients who have a history of substance use, impulsivity, anger, or violence, or who have a brain disorder or neurologic condition. Talking about firearms with patients and educating them about safety is indicated whenever you observe a risk factor for suicide.

Advise safe storage. Aim to have the entire family agree to a safety policy. Guns should be kept unloaded and not stored with ammunition (eg, keep guns in the attic and ammunition in the basement), which might diminish the risk of (1) an impulsive shooting and (2) a planned attempt by giving people time to consider options other than suicide. Firearm safety includes locking ammunition and weapons in a safe and applying trigger locks. Try to get patients and their family to plan for compliance with such recommendations whenever possible.

Guide dialogue and educate patients about handling guns safely. Be sure that patients know that most firearm deaths that happen inside a home are suicide.^2-4 Advise patients, and their family, that firearms should not be handled while intoxicated.⁴ Encourage families to remove gun access from members who are suicidal, depressed, abusing pharmaceuticals or using illicit drugs, and those in distress or with a significant mental or neurologic illness.

In such circumstances, institute a protective plan to prevent shootings. This can be time-limited, or might include removing guns or ammunition from the home or deactivating firing mechanisms, etc. For safety reasons, some families do not keep ammunition in their home.

Additionally, firearms in the hands of children ought to include close monitoring by a responsible, sober adult. Keeping guns in locked storage is especially important for preventing suicide in children. Despite suicide being less frequent among younger people than in adults, taking steps to avoid 1,000 child suicides each year in the United States is a valuable intervention.

Conclusion
Specific inquiry, overt discussion, and face-to-face counseling about gun safety can be a life-saving aspect of psychiatric intervention. With such recommendations and education, psychiatrists can play a productive role in reducing firearm-related suicide.

Firearms are the most common means of suicide in the United States, accounting for approximately 20,000 adult deaths annually,1 which is approximately two-thirds of the more than 32,000 gun-related fatalities each year in the United States. Of approximately 3,000 American children who are shot to death annually, one-third are suicides.^1-4

Firearms are dangerous; it has been documented that even guns obtained for recreation or protection increase the risk of suicide, homicide, or injury.^2,3 This problem has become a public health concern.^3-8 Because most suicide attempts with firearms are fatal, psychiatrists have an interest in reducing such outcomes.^1-8

Risk factors for suicide by firearm
Easy availability of a gun in the home, with ammunition present—especially a gun that is kept loaded and not locked up—is the one of the biggest risk factors for suicide by firearms.⁴ Unrestricted, quick access allows people who are impulsive little time to reconsider suicide. The risk presented by easy availability is magnified by dangerous concomitant intoxication (see below), distress, and lack of supervision (of children).

Alcohol consumption is associated with suicide. Approximately one-fourth of the people who commit suicide are intoxicated at the time of death.⁹ Alcohol use, especially binge drinking, is observed in an even larger percentage of suicide attempts than individuals using guns while sober.

Female sex. In recent years, gun use by women has increased, along with firearm-related suicide. Simply having a gun at home greatly increases the suicide rate for women.^2-4

People with a history of high impulsivity, impaired judgment, violence, or psychiatric and neurologic disorders places people at greater risk of shooting themselves, especially those with depression, suicidal ideation, substance abuse, psychosis, or dementia.⁴

Older age, particularly men who live alone, increases the risk of suicide by firearms, especially in the context of chronic pain or other health problems. Gunfire is the most common means of suicide among geriatric patients of both sexes.⁸

Lethality. In general, suicide attempts with guns are more likely to be fatal than overdosing, poisoning, or self-mutilation.^1,2 Most self-inflicted gunshot wounds result in death, usually on the day of the shooting.^1,2

Evidence about these risk factors has led the American Medical Association and other health care groups to encourage physicians—in particular, psychiatric clinicians who focus on suicide prevention—to counsel patients about gun safety.

What can you do to minimize risk?
Gun-related inquiry and counsel by psychiatrists can benefit patients and their family.⁴ Be aware, however, of restrictions on such discussions by health care providers in some states (Box).¹⁰

Ask about the presence of firearms in the home. Our advice and our “doctor’s orders” are a means to promote health; suggestions in the context of a supportive physician-patient relationship could result in compliance.^3,4 Firearm-focused discussions might be uncomfortable or unpopular but are critical for preventing suicide. Openly discussing such issues with our patients could avoid tragedies.⁴ Involving family or significant others in these interventions also might be helpful.

Ask about access to and storage of firearms. Simply talking about gun safety is helpful.⁴ Seeking information about gun usage is especially called for in psychiatric practices that treat patients with suicidal ideation, depression, substance abuse, and cognitive impairment.⁸ Discuss firearm availability with patients who have a history of substance use, impulsivity, anger, or violence, or who have a brain disorder or neurologic condition. Talking about firearms with patients and educating them about safety is indicated whenever you observe a risk factor for suicide.

Advise safe storage. Aim to have the entire family agree to a safety policy. Guns should be kept unloaded and not stored with ammunition (eg, keep guns in the attic and ammunition in the basement), which might diminish the risk of (1) an impulsive shooting and (2) a planned attempt by giving people time to consider options other than suicide. Firearm safety includes locking ammunition and weapons in a safe and applying trigger locks. Try to get patients and their family to plan for compliance with such recommendations whenever possible.

Guide dialogue and educate patients about handling guns safely. Be sure that patients know that most firearm deaths that happen inside a home are suicide.^2-4 Advise patients, and their family, that firearms should not be handled while intoxicated.⁴ Encourage families to remove gun access from members who are suicidal, depressed, abusing pharmaceuticals or using illicit drugs, and those in distress or with a significant mental or neurologic illness.

In such circumstances, institute a protective plan to prevent shootings. This can be time-limited, or might include removing guns or ammunition from the home or deactivating firing mechanisms, etc. For safety reasons, some families do not keep ammunition in their home.

Additionally, firearms in the hands of children ought to include close monitoring by a responsible, sober adult. Keeping guns in locked storage is especially important for preventing suicide in children. Despite suicide being less frequent among younger people than in adults, taking steps to avoid 1,000 child suicides each year in the United States is a valuable intervention.

Conclusion
Specific inquiry, overt discussion, and face-to-face counseling about gun safety can be a life-saving aspect of psychiatric intervention. With such recommendations and education, psychiatrists can play a productive role in reducing firearm-related suicide.

Firearms are the most common means of suicide in the United States, accounting for approximately 20,000 adult deaths annually,1 which is approximately two-thirds of the more than 32,000 gun-related fatalities each year in the United States. Of approximately 3,000 American children who are shot to death annually, one-third are suicides.^1-4

Firearms are dangerous; it has been documented that even guns obtained for recreation or protection increase the risk of suicide, homicide, or injury.^2,3 This problem has become a public health concern.^3-8 Because most suicide attempts with firearms are fatal, psychiatrists have an interest in reducing such outcomes.^1-8

Risk factors for suicide by firearm
Easy availability of a gun in the home, with ammunition present—especially a gun that is kept loaded and not locked up—is the one of the biggest risk factors for suicide by firearms.⁴ Unrestricted, quick access allows people who are impulsive little time to reconsider suicide. The risk presented by easy availability is magnified by dangerous concomitant intoxication (see below), distress, and lack of supervision (of children).

Alcohol consumption is associated with suicide. Approximately one-fourth of the people who commit suicide are intoxicated at the time of death.⁹ Alcohol use, especially binge drinking, is observed in an even larger percentage of suicide attempts than individuals using guns while sober.

Female sex. In recent years, gun use by women has increased, along with firearm-related suicide. Simply having a gun at home greatly increases the suicide rate for women.^2-4

People with a history of high impulsivity, impaired judgment, violence, or psychiatric and neurologic disorders places people at greater risk of shooting themselves, especially those with depression, suicidal ideation, substance abuse, psychosis, or dementia.⁴

Older age, particularly men who live alone, increases the risk of suicide by firearms, especially in the context of chronic pain or other health problems. Gunfire is the most common means of suicide among geriatric patients of both sexes.⁸

Lethality. In general, suicide attempts with guns are more likely to be fatal than overdosing, poisoning, or self-mutilation.^1,2 Most self-inflicted gunshot wounds result in death, usually on the day of the shooting.^1,2

Evidence about these risk factors has led the American Medical Association and other health care groups to encourage physicians—in particular, psychiatric clinicians who focus on suicide prevention—to counsel patients about gun safety.

What can you do to minimize risk?
Gun-related inquiry and counsel by psychiatrists can benefit patients and their family.⁴ Be aware, however, of restrictions on such discussions by health care providers in some states (Box).¹⁰

Ask about the presence of firearms in the home. Our advice and our “doctor’s orders” are a means to promote health; suggestions in the context of a supportive physician-patient relationship could result in compliance.^3,4 Firearm-focused discussions might be uncomfortable or unpopular but are critical for preventing suicide. Openly discussing such issues with our patients could avoid tragedies.⁴ Involving family or significant others in these interventions also might be helpful.

Ask about access to and storage of firearms. Simply talking about gun safety is helpful.⁴ Seeking information about gun usage is especially called for in psychiatric practices that treat patients with suicidal ideation, depression, substance abuse, and cognitive impairment.⁸ Discuss firearm availability with patients who have a history of substance use, impulsivity, anger, or violence, or who have a brain disorder or neurologic condition. Talking about firearms with patients and educating them about safety is indicated whenever you observe a risk factor for suicide.

Advise safe storage. Aim to have the entire family agree to a safety policy. Guns should be kept unloaded and not stored with ammunition (eg, keep guns in the attic and ammunition in the basement), which might diminish the risk of (1) an impulsive shooting and (2) a planned attempt by giving people time to consider options other than suicide. Firearm safety includes locking ammunition and weapons in a safe and applying trigger locks. Try to get patients and their family to plan for compliance with such recommendations whenever possible.

Guide dialogue and educate patients about handling guns safely. Be sure that patients know that most firearm deaths that happen inside a home are suicide.^2-4 Advise patients, and their family, that firearms should not be handled while intoxicated.⁴ Encourage families to remove gun access from members who are suicidal, depressed, abusing pharmaceuticals or using illicit drugs, and those in distress or with a significant mental or neurologic illness.

In such circumstances, institute a protective plan to prevent shootings. This can be time-limited, or might include removing guns or ammunition from the home or deactivating firing mechanisms, etc. For safety reasons, some families do not keep ammunition in their home.

Additionally, firearms in the hands of children ought to include close monitoring by a responsible, sober adult. Keeping guns in locked storage is especially important for preventing suicide in children. Despite suicide being less frequent among younger people than in adults, taking steps to avoid 1,000 child suicides each year in the United States is a valuable intervention.

Conclusion
Specific inquiry, overt discussion, and face-to-face counseling about gun safety can be a life-saving aspect of psychiatric intervention. With such recommendations and education, psychiatrists can play a productive role in reducing firearm-related suicide.

According to a study by Ji et al published online on February 11 in the International Journal of Impotence Research, men with psoriasis may be more prone to erectile dysfunction (ED) than those without this skin disease, and their odds of sexual difficulties are even higher if they are depressed or have other health problems such as diabetes mellitus or high blood pressure.

The investigators evaluated 191 psoriasis patients and 191 healthy men. Of the 191 patients with psoriasis, 52.9% had symptoms of ED compared with 40.3% of the control group, reflecting an age-adjusted odds ratio of 1.965 in favor of the psoriasis group. A univariate analysis of the psoriasis cohort demonstrated that age, hypertension, hyperlipidemia, diabetes mellitus, and depressive symptoms were risk factors for ED. A multivariate logistic regression model indicated that increasing age, hypertension, hyperlipidemia, and depressive symptoms were independent risk factors for ED in those with psoriasis. More severe depressive symptoms increased the risk of ED, especially moderate to severe ED.

Ji et al noted that ED is a predictor of future cardiovascular disease; therefore, it is important to identify ED early in treatment to evaluate cardiovascular issues in psoriasis patients. They noted that screening of ED may become a part of routine care in the management of psoriasis patients.

What’s the issue?

Even though it was a small study from one location, it still sheds light on many important issues. Psoriasis and its comorbidities appear to increase the risk for ED. In addition, ED also may be an indicator of cardiovascular disease.

How will these data impact your evaluation of psoriasis patients?

We want to know your views! Tell us what you think.

According to a study by Ji et al published online on February 11 in the International Journal of Impotence Research, men with psoriasis may be more prone to erectile dysfunction (ED) than those without this skin disease, and their odds of sexual difficulties are even higher if they are depressed or have other health problems such as diabetes mellitus or high blood pressure.

The investigators evaluated 191 psoriasis patients and 191 healthy men. Of the 191 patients with psoriasis, 52.9% had symptoms of ED compared with 40.3% of the control group, reflecting an age-adjusted odds ratio of 1.965 in favor of the psoriasis group. A univariate analysis of the psoriasis cohort demonstrated that age, hypertension, hyperlipidemia, diabetes mellitus, and depressive symptoms were risk factors for ED. A multivariate logistic regression model indicated that increasing age, hypertension, hyperlipidemia, and depressive symptoms were independent risk factors for ED in those with psoriasis. More severe depressive symptoms increased the risk of ED, especially moderate to severe ED.

Ji et al noted that ED is a predictor of future cardiovascular disease; therefore, it is important to identify ED early in treatment to evaluate cardiovascular issues in psoriasis patients. They noted that screening of ED may become a part of routine care in the management of psoriasis patients.

What’s the issue?

Even though it was a small study from one location, it still sheds light on many important issues. Psoriasis and its comorbidities appear to increase the risk for ED. In addition, ED also may be an indicator of cardiovascular disease.

How will these data impact your evaluation of psoriasis patients?

We want to know your views! Tell us what you think.

According to a study by Ji et al published online on February 11 in the International Journal of Impotence Research, men with psoriasis may be more prone to erectile dysfunction (ED) than those without this skin disease, and their odds of sexual difficulties are even higher if they are depressed or have other health problems such as diabetes mellitus or high blood pressure.

The investigators evaluated 191 psoriasis patients and 191 healthy men. Of the 191 patients with psoriasis, 52.9% had symptoms of ED compared with 40.3% of the control group, reflecting an age-adjusted odds ratio of 1.965 in favor of the psoriasis group. A univariate analysis of the psoriasis cohort demonstrated that age, hypertension, hyperlipidemia, diabetes mellitus, and depressive symptoms were risk factors for ED. A multivariate logistic regression model indicated that increasing age, hypertension, hyperlipidemia, and depressive symptoms were independent risk factors for ED in those with psoriasis. More severe depressive symptoms increased the risk of ED, especially moderate to severe ED.

Ji et al noted that ED is a predictor of future cardiovascular disease; therefore, it is important to identify ED early in treatment to evaluate cardiovascular issues in psoriasis patients. They noted that screening of ED may become a part of routine care in the management of psoriasis patients.

What’s the issue?

Even though it was a small study from one location, it still sheds light on many important issues. Psoriasis and its comorbidities appear to increase the risk for ED. In addition, ED also may be an indicator of cardiovascular disease.

How will these data impact your evaluation of psoriasis patients?

We want to know your views! Tell us what you think.

Orthorexia nervosa, from the Greek orthos (straight, proper) and orexia (appetite), is a disorder in which a person demonstrates a pathological obsession not with weight loss but with a “pure” or healthy diet, which can contribute to significant dietary restriction and food-related obsessions. Although the disorder is not a formal diagnosis in DSM 5,¹ it is increasingly reported on college campuses and in medical practices, and has been the focus of media attention.

How common is orthorexia?
The precise prevalence of orthorexia nervosa is unknown; some authors have reported estimates as high as 21% of the general population² and 43.6% of medical students.³ The higher prevalence among medical students might be attributable to the increased focus on factors that can contribute to illnesses (eg, food and diet), and thus underscores the importance of screening for orthorexia symptoms among this population.

How do you identify the disorder?
Orthorexia nervosa was first described by Bratman,⁴ who observed that a subset of his eating disorder patients were overly obsessed with maintaining an extreme “healthy diet.” Although diagnostic criteria for orthorexia nervosa have not been established, Bratman proposed the following as symptoms indicative of the disorder:

• spending >3 hours a day thinking about a healthy diet
• worrying more about the perceived nutritional quality or “purity” of one’s food than the pleasure of eating it
• feeling guilty about straying from dietary beliefs
• having eating habits that isolate the affected person from others.

Given the focus on this disorder in the media and its presence in medical practice, it is important that you become familiar with the symptoms associated with orthorexia nervosa so you can provide necessary treatment. A patient’s answers to the following questions will aid the savvy clinician in identifying symptoms that suggest orthorexia nervosa⁵:

• Do you turn to healthy food as a primary source of happiness and meaning, even more so than spirituality? 
• Does your diet make you feel superior to other people?
• Does your diet interfere with your personal relationships (family, friends), or with your work? 
• Do you use pure foods as a “sword and shield” to ward off anxiety, not just about health problems but about everything that makes you feel insecure?
• Do foods help you feel in control more than really makes sense?
• Do you have to carry your diet to further and further extremes to provide the same “kick”?
• If you stray even minimally from your chosen diet, do you feel a compulsive need to cleanse?
• Has your interest in healthy food expanded past reasonable boundaries to become a kind of brain parasite, so to speak, controlling your life rather than furthering your goals?

No single item is indicative of orthorexia nervosa; however, this list represents a potential clinical picture of how the disorder presents.

Overlap with anorexia nervosa. Although overlap in symptom presentation between these 2 disorders can be significant (eg, diet rigidity can lead to malnutrition, even death), each has important distinguishing features. A low weight status or significant weight loss, or both, is a hallmark characteristic of anorexia nervosa; however, weight loss is not the primary goal in orthorexia nervosa (although extreme dietary restriction in orthorexia could contribute to weight loss). Additionally, a person with anorexia nervosa tends to be preoccupied with weight or shape; a person with orthorexia nervosa is obsessed with food quality and purity. Finally, people with orthorexia have an obsessive preoccupation with health, whereas those with anorexia are more consumed with a fear of fat or weight gain.

Multimodal treatment is indicated
Treating orthorexia typically includes a combination of interventions common to other eating disorders. These include cognitive-behavioral therapy, dietary and nutritional counseling, and medical management of any physical sequelae that result from extreme dietary restriction and malnutrition. Refer patients in whom you suspect orthorexia nervosa to a trained therapist and a dietician who have expertise in managing eating disorders.

It is encouraging to note that, with careful diagnosis and appropriate treatment, recovery from orthorexia is possible,⁶ and patients can achieve an improved quality of life.

Orthorexia nervosa, from the Greek orthos (straight, proper) and orexia (appetite), is a disorder in which a person demonstrates a pathological obsession not with weight loss but with a “pure” or healthy diet, which can contribute to significant dietary restriction and food-related obsessions. Although the disorder is not a formal diagnosis in DSM 5,¹ it is increasingly reported on college campuses and in medical practices, and has been the focus of media attention.

How common is orthorexia?
The precise prevalence of orthorexia nervosa is unknown; some authors have reported estimates as high as 21% of the general population² and 43.6% of medical students.³ The higher prevalence among medical students might be attributable to the increased focus on factors that can contribute to illnesses (eg, food and diet), and thus underscores the importance of screening for orthorexia symptoms among this population.

How do you identify the disorder?
Orthorexia nervosa was first described by Bratman,⁴ who observed that a subset of his eating disorder patients were overly obsessed with maintaining an extreme “healthy diet.” Although diagnostic criteria for orthorexia nervosa have not been established, Bratman proposed the following as symptoms indicative of the disorder:

• spending >3 hours a day thinking about a healthy diet
• worrying more about the perceived nutritional quality or “purity” of one’s food than the pleasure of eating it
• feeling guilty about straying from dietary beliefs
• having eating habits that isolate the affected person from others.

Given the focus on this disorder in the media and its presence in medical practice, it is important that you become familiar with the symptoms associated with orthorexia nervosa so you can provide necessary treatment. A patient’s answers to the following questions will aid the savvy clinician in identifying symptoms that suggest orthorexia nervosa⁵:

• Do you turn to healthy food as a primary source of happiness and meaning, even more so than spirituality? 
• Does your diet make you feel superior to other people?
• Does your diet interfere with your personal relationships (family, friends), or with your work? 
• Do you use pure foods as a “sword and shield” to ward off anxiety, not just about health problems but about everything that makes you feel insecure?
• Do foods help you feel in control more than really makes sense?
• Do you have to carry your diet to further and further extremes to provide the same “kick”?
• If you stray even minimally from your chosen diet, do you feel a compulsive need to cleanse?
• Has your interest in healthy food expanded past reasonable boundaries to become a kind of brain parasite, so to speak, controlling your life rather than furthering your goals?

No single item is indicative of orthorexia nervosa; however, this list represents a potential clinical picture of how the disorder presents.

Overlap with anorexia nervosa. Although overlap in symptom presentation between these 2 disorders can be significant (eg, diet rigidity can lead to malnutrition, even death), each has important distinguishing features. A low weight status or significant weight loss, or both, is a hallmark characteristic of anorexia nervosa; however, weight loss is not the primary goal in orthorexia nervosa (although extreme dietary restriction in orthorexia could contribute to weight loss). Additionally, a person with anorexia nervosa tends to be preoccupied with weight or shape; a person with orthorexia nervosa is obsessed with food quality and purity. Finally, people with orthorexia have an obsessive preoccupation with health, whereas those with anorexia are more consumed with a fear of fat or weight gain.

Multimodal treatment is indicated
Treating orthorexia typically includes a combination of interventions common to other eating disorders. These include cognitive-behavioral therapy, dietary and nutritional counseling, and medical management of any physical sequelae that result from extreme dietary restriction and malnutrition. Refer patients in whom you suspect orthorexia nervosa to a trained therapist and a dietician who have expertise in managing eating disorders.

It is encouraging to note that, with careful diagnosis and appropriate treatment, recovery from orthorexia is possible,⁶ and patients can achieve an improved quality of life.

Orthorexia nervosa, from the Greek orthos (straight, proper) and orexia (appetite), is a disorder in which a person demonstrates a pathological obsession not with weight loss but with a “pure” or healthy diet, which can contribute to significant dietary restriction and food-related obsessions. Although the disorder is not a formal diagnosis in DSM 5,¹ it is increasingly reported on college campuses and in medical practices, and has been the focus of media attention.

How common is orthorexia?
The precise prevalence of orthorexia nervosa is unknown; some authors have reported estimates as high as 21% of the general population² and 43.6% of medical students.³ The higher prevalence among medical students might be attributable to the increased focus on factors that can contribute to illnesses (eg, food and diet), and thus underscores the importance of screening for orthorexia symptoms among this population.

How do you identify the disorder?
Orthorexia nervosa was first described by Bratman,⁴ who observed that a subset of his eating disorder patients were overly obsessed with maintaining an extreme “healthy diet.” Although diagnostic criteria for orthorexia nervosa have not been established, Bratman proposed the following as symptoms indicative of the disorder:

• spending >3 hours a day thinking about a healthy diet
• worrying more about the perceived nutritional quality or “purity” of one’s food than the pleasure of eating it
• feeling guilty about straying from dietary beliefs
• having eating habits that isolate the affected person from others.

Given the focus on this disorder in the media and its presence in medical practice, it is important that you become familiar with the symptoms associated with orthorexia nervosa so you can provide necessary treatment. A patient’s answers to the following questions will aid the savvy clinician in identifying symptoms that suggest orthorexia nervosa⁵:

• Do you turn to healthy food as a primary source of happiness and meaning, even more so than spirituality? 
• Does your diet make you feel superior to other people?
• Does your diet interfere with your personal relationships (family, friends), or with your work? 
• Do you use pure foods as a “sword and shield” to ward off anxiety, not just about health problems but about everything that makes you feel insecure?
• Do foods help you feel in control more than really makes sense?
• Do you have to carry your diet to further and further extremes to provide the same “kick”?
• If you stray even minimally from your chosen diet, do you feel a compulsive need to cleanse?
• Has your interest in healthy food expanded past reasonable boundaries to become a kind of brain parasite, so to speak, controlling your life rather than furthering your goals?

No single item is indicative of orthorexia nervosa; however, this list represents a potential clinical picture of how the disorder presents.

Overlap with anorexia nervosa. Although overlap in symptom presentation between these 2 disorders can be significant (eg, diet rigidity can lead to malnutrition, even death), each has important distinguishing features. A low weight status or significant weight loss, or both, is a hallmark characteristic of anorexia nervosa; however, weight loss is not the primary goal in orthorexia nervosa (although extreme dietary restriction in orthorexia could contribute to weight loss). Additionally, a person with anorexia nervosa tends to be preoccupied with weight or shape; a person with orthorexia nervosa is obsessed with food quality and purity. Finally, people with orthorexia have an obsessive preoccupation with health, whereas those with anorexia are more consumed with a fear of fat or weight gain.

Multimodal treatment is indicated
Treating orthorexia typically includes a combination of interventions common to other eating disorders. These include cognitive-behavioral therapy, dietary and nutritional counseling, and medical management of any physical sequelae that result from extreme dietary restriction and malnutrition. Refer patients in whom you suspect orthorexia nervosa to a trained therapist and a dietician who have expertise in managing eating disorders.

It is encouraging to note that, with careful diagnosis and appropriate treatment, recovery from orthorexia is possible,⁶ and patients can achieve an improved quality of life.