Q) One of my diabetic patients read about finerenone in The New York Times. Apparently, it’s the “newest cure for albuminuria”! Is this just hype, or do the trials on this medication really show progress against kidney disease? Should I buy stock in the company?

Albuminuria (> 500 mg/d) associated with diabetic nephropathy and other glomerular diseases increases patient risk for chronic kidney disease (CKD) and its progression to end-stage renal disease (ESRD). Reduction of albuminuria has been shown to slow the progression of CKD.

Renin-angiotensin-aldosterone system (RAAS) blockers, such as ACE inhibitors or angiotensin receptor blockers, are considered firstline therapy to reduce albuminuria. Additional treatment modalities include diuretics, nondihydropyridine calcium channel blockers, ß-blockers, and aldosterone antagonist therapy. Limiting dietary sodium helps control blood pressure, thus slowing disease progression. In addition, some studies show that limiting phosphorus and protein (for the latter, intake of no more than 0.7 g/kg ideal body weight per day) may slow the progression of CKD. Unfortunately, despite these interventions, patients may still advance to ESRD.¹

The aldosterone and steroidal mineralocorticoid receptor antagonists (MRA) spironolactone and eplerenone have been found to reduce albuminuria when used in conjunction with RAAS blockade. However, patients using this combination are up to eight times more likely to experience hyperkalemia—a serious, potentially life-threatening adverse condition—than those not using an MRA.² The presence of hyperkalemia requires discontinuation of the RAAS blocker and the MRA, at least temporarily.

Finerenone, a nonsteroidal MRA with “greater receptor selectivity than spironolactone and better receptor affinity than eplerenone in vitro,” is in phase III trials for the treatment of systolic and diastolic dysfunction and reduction of morbidity and mortality associated with heart failure.² One study has already demonstrated that finerenone (5 to 10 mg/d) is at least as effective as spironolactone (25 mg/d) for heart failure patients.³

The Mineralocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN) found that finerenone at 10 to 20 mg/d was superior to spironolactone and eplerenone, partly due to the decreased incidence of hyperkalemia. However, it should be noted that the lower incidence of hyperkalemia may be attributable to the fact that 66% of the study participants had an estimated glomerular filtration rate (eGFR) greater than 60 mL/min and that potential participants with a serum potassium level of more than 4.8 mEq/L were not included in the study.²

Additional research is needed to confirm superiority of finerenone over spironolactone and eplerenone, in conjunction with RAAS blockers, in the treatment of albuminuria and hyperkalemia. Including subjects with lower eGFR (such as patients with stage IV CKD who are at higher risk for hyperkalemia) would give a better indication of finerenone’s efficacy. In the meantime, it’s probably too soon to corner the market on this stock! —SEB

Susan E. Brown, MS, ARNP, ACNP-BC, CCRN
Great River Nephrology, West Burlington, Iowa

References
1. Parikh SV, Haddad NJ, Hebert LA. Retarding progression of kidney disease. In: Johnson RJ, Feehally J, Floege J, eds. Comprehensive Clinical Nephrology. 5th ed. Philadelphia, PA: Saunders; 2015:931-940.
2. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314(9):884-894.
3. Kolkhof P, Delbeck M, Kretschmer A, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist, protects from rat cardiorenal injury. J Cardiovasc Pharmacol. 2014;64(1):69-78.

Q) One of my diabetic patients read about finerenone in The New York Times. Apparently, it’s the “newest cure for albuminuria”! Is this just hype, or do the trials on this medication really show progress against kidney disease? Should I buy stock in the company?

Albuminuria (> 500 mg/d) associated with diabetic nephropathy and other glomerular diseases increases patient risk for chronic kidney disease (CKD) and its progression to end-stage renal disease (ESRD). Reduction of albuminuria has been shown to slow the progression of CKD.

Renin-angiotensin-aldosterone system (RAAS) blockers, such as ACE inhibitors or angiotensin receptor blockers, are considered firstline therapy to reduce albuminuria. Additional treatment modalities include diuretics, nondihydropyridine calcium channel blockers, ß-blockers, and aldosterone antagonist therapy. Limiting dietary sodium helps control blood pressure, thus slowing disease progression. In addition, some studies show that limiting phosphorus and protein (for the latter, intake of no more than 0.7 g/kg ideal body weight per day) may slow the progression of CKD. Unfortunately, despite these interventions, patients may still advance to ESRD.¹

The aldosterone and steroidal mineralocorticoid receptor antagonists (MRA) spironolactone and eplerenone have been found to reduce albuminuria when used in conjunction with RAAS blockade. However, patients using this combination are up to eight times more likely to experience hyperkalemia—a serious, potentially life-threatening adverse condition—than those not using an MRA.² The presence of hyperkalemia requires discontinuation of the RAAS blocker and the MRA, at least temporarily.

Finerenone, a nonsteroidal MRA with “greater receptor selectivity than spironolactone and better receptor affinity than eplerenone in vitro,” is in phase III trials for the treatment of systolic and diastolic dysfunction and reduction of morbidity and mortality associated with heart failure.² One study has already demonstrated that finerenone (5 to 10 mg/d) is at least as effective as spironolactone (25 mg/d) for heart failure patients.³

The Mineralocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN) found that finerenone at 10 to 20 mg/d was superior to spironolactone and eplerenone, partly due to the decreased incidence of hyperkalemia. However, it should be noted that the lower incidence of hyperkalemia may be attributable to the fact that 66% of the study participants had an estimated glomerular filtration rate (eGFR) greater than 60 mL/min and that potential participants with a serum potassium level of more than 4.8 mEq/L were not included in the study.²

Additional research is needed to confirm superiority of finerenone over spironolactone and eplerenone, in conjunction with RAAS blockers, in the treatment of albuminuria and hyperkalemia. Including subjects with lower eGFR (such as patients with stage IV CKD who are at higher risk for hyperkalemia) would give a better indication of finerenone’s efficacy. In the meantime, it’s probably too soon to corner the market on this stock! —SEB

Susan E. Brown, MS, ARNP, ACNP-BC, CCRN
Great River Nephrology, West Burlington, Iowa

References
1. Parikh SV, Haddad NJ, Hebert LA. Retarding progression of kidney disease. In: Johnson RJ, Feehally J, Floege J, eds. Comprehensive Clinical Nephrology. 5th ed. Philadelphia, PA: Saunders; 2015:931-940.
2. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314(9):884-894.
3. Kolkhof P, Delbeck M, Kretschmer A, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist, protects from rat cardiorenal injury. J Cardiovasc Pharmacol. 2014;64(1):69-78.

Q) One of my diabetic patients read about finerenone in The New York Times. Apparently, it’s the “newest cure for albuminuria”! Is this just hype, or do the trials on this medication really show progress against kidney disease? Should I buy stock in the company?

Albuminuria (> 500 mg/d) associated with diabetic nephropathy and other glomerular diseases increases patient risk for chronic kidney disease (CKD) and its progression to end-stage renal disease (ESRD). Reduction of albuminuria has been shown to slow the progression of CKD.

Renin-angiotensin-aldosterone system (RAAS) blockers, such as ACE inhibitors or angiotensin receptor blockers, are considered firstline therapy to reduce albuminuria. Additional treatment modalities include diuretics, nondihydropyridine calcium channel blockers, ß-blockers, and aldosterone antagonist therapy. Limiting dietary sodium helps control blood pressure, thus slowing disease progression. In addition, some studies show that limiting phosphorus and protein (for the latter, intake of no more than 0.7 g/kg ideal body weight per day) may slow the progression of CKD. Unfortunately, despite these interventions, patients may still advance to ESRD.¹

The aldosterone and steroidal mineralocorticoid receptor antagonists (MRA) spironolactone and eplerenone have been found to reduce albuminuria when used in conjunction with RAAS blockade. However, patients using this combination are up to eight times more likely to experience hyperkalemia—a serious, potentially life-threatening adverse condition—than those not using an MRA.² The presence of hyperkalemia requires discontinuation of the RAAS blocker and the MRA, at least temporarily.

Finerenone, a nonsteroidal MRA with “greater receptor selectivity than spironolactone and better receptor affinity than eplerenone in vitro,” is in phase III trials for the treatment of systolic and diastolic dysfunction and reduction of morbidity and mortality associated with heart failure.² One study has already demonstrated that finerenone (5 to 10 mg/d) is at least as effective as spironolactone (25 mg/d) for heart failure patients.³

The Mineralocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN) found that finerenone at 10 to 20 mg/d was superior to spironolactone and eplerenone, partly due to the decreased incidence of hyperkalemia. However, it should be noted that the lower incidence of hyperkalemia may be attributable to the fact that 66% of the study participants had an estimated glomerular filtration rate (eGFR) greater than 60 mL/min and that potential participants with a serum potassium level of more than 4.8 mEq/L were not included in the study.²

Additional research is needed to confirm superiority of finerenone over spironolactone and eplerenone, in conjunction with RAAS blockers, in the treatment of albuminuria and hyperkalemia. Including subjects with lower eGFR (such as patients with stage IV CKD who are at higher risk for hyperkalemia) would give a better indication of finerenone’s efficacy. In the meantime, it’s probably too soon to corner the market on this stock! —SEB

Susan E. Brown, MS, ARNP, ACNP-BC, CCRN
Great River Nephrology, West Burlington, Iowa

References
1. Parikh SV, Haddad NJ, Hebert LA. Retarding progression of kidney disease. In: Johnson RJ, Feehally J, Floege J, eds. Comprehensive Clinical Nephrology. 5th ed. Philadelphia, PA: Saunders; 2015:931-940.
2. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314(9):884-894.
3. Kolkhof P, Delbeck M, Kretschmer A, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist, protects from rat cardiorenal injury. J Cardiovasc Pharmacol. 2014;64(1):69-78.

Q) I see patients with diabetes, hypertension, chronic kidney disease (CKD), obesity ... often all within the same patient! I keep hearing that the DASH diet is best for these patients. Is this true? Do you have any suggestions (or handouts) for teaching good eating habits in a 15-minute office visit?

It is always nice to focus on what patients can do, rather than what they can’t. Patients with diabetes, kidney disease, heart disease, and obesity hear a lot of “can’t” messages, making “can” messages particularly important to emphasize.

Healthy diets for diabetes, heart, and kidney patients include foods low in trans and saturated fats and sodium. Not all CKD patients are required to follow a low-potassium diet; dietary restrictions are based on laboratory values, medications, and other factors. As we know, adding an ACE inhibitor or an angiotensin receptor blocker (ARB) to the treatment regimen can cause an elevation in serum potassium.

For adults with CKD, it is recommended that sodium intake be restricted to < 2,000 mg/d.⁴ And in this population, salt substitutes are not recommended, since they often contain large amounts of potassium chloride, which increases risk for hyperkalemia.⁵ Other ­spices (eg, garlic, pepper, lemon) are better substitutes for salt.

The late Paul Prudhomme, an award-winning chef from New Orleans, struggled with obesity and health issues for years. He developed wonderful, kidney-friendly spices free of salt and potassium. His line of spices, Magic Seasoning Blends, is sold in many grocery stores. You can recommend them without worry.

Studies have shown that the usual Western diet (which features an abundance of processed foods, fats, and sugars) contributes to kidney disease.⁶ The DASH (Dietary Approaches to Stop Hypertension) diet, developed by cardio experts, replaces these foods with healthier alternatives.

Recent research has shown that the DASH diet does, in fact, slow the progression of kidney disease.⁷ It also lowers blood pressure and decreases kidney stone formation, which are risk factors for kidney disease.

So, the DASH diet is protective for your patients (from both a kidney and a cardiac standpoint)—but how do you explain this in a 15-minute office visit?

Here are a few quick tips:
• Increase fruit and vegetable intake to include all colors on your plate (and no, tan is not really a color)
• If you eat meat, the cooking method should start with “B” (ie, bake, boil, broil, barbeque [without salty sauce]) ... Note that “fried” does not start with “B”!
• Use a smaller plate and you will not eat as much
• Use technology in your favor. There are great apps and downloads you can recommend (see Table). —CC

Christine Corbett, MSN, APRN, FNP-BC, CNN-NP
Kansas City Veterans Affairs, Kansas City, Missouri

References
4. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;(3):1-150.
5. National Kidney Disease Education Program. Potassium: tips for people with chronic kidney disease (CKD). www.niddk.nih.gov/health-information/health-communication-programs/nkdep/a-z/nutrition-potassium/Documents/nutrition-potassium-508.pdf. Accessed June 20, 2016.
6. Odermatt A. The Western-style diet: a major risk factor for impaired kidney function and chronic kidney disease. Am J Physiol Renal Physiol. 2011;301(5):F919-F931.
7. Steiber A. DASH-style diet effective in preventing, delaying CKD progression. Renal and Urology News. 2012.

Q) I see patients with diabetes, hypertension, chronic kidney disease (CKD), obesity ... often all within the same patient! I keep hearing that the DASH diet is best for these patients. Is this true? Do you have any suggestions (or handouts) for teaching good eating habits in a 15-minute office visit?

It is always nice to focus on what patients can do, rather than what they can’t. Patients with diabetes, kidney disease, heart disease, and obesity hear a lot of “can’t” messages, making “can” messages particularly important to emphasize.

Healthy diets for diabetes, heart, and kidney patients include foods low in trans and saturated fats and sodium. Not all CKD patients are required to follow a low-potassium diet; dietary restrictions are based on laboratory values, medications, and other factors. As we know, adding an ACE inhibitor or an angiotensin receptor blocker (ARB) to the treatment regimen can cause an elevation in serum potassium.

For adults with CKD, it is recommended that sodium intake be restricted to < 2,000 mg/d.⁴ And in this population, salt substitutes are not recommended, since they often contain large amounts of potassium chloride, which increases risk for hyperkalemia.⁵ Other ­spices (eg, garlic, pepper, lemon) are better substitutes for salt.

The late Paul Prudhomme, an award-winning chef from New Orleans, struggled with obesity and health issues for years. He developed wonderful, kidney-friendly spices free of salt and potassium. His line of spices, Magic Seasoning Blends, is sold in many grocery stores. You can recommend them without worry.

Studies have shown that the usual Western diet (which features an abundance of processed foods, fats, and sugars) contributes to kidney disease.⁶ The DASH (Dietary Approaches to Stop Hypertension) diet, developed by cardio experts, replaces these foods with healthier alternatives.

Recent research has shown that the DASH diet does, in fact, slow the progression of kidney disease.⁷ It also lowers blood pressure and decreases kidney stone formation, which are risk factors for kidney disease.

So, the DASH diet is protective for your patients (from both a kidney and a cardiac standpoint)—but how do you explain this in a 15-minute office visit?

Here are a few quick tips:
• Increase fruit and vegetable intake to include all colors on your plate (and no, tan is not really a color)
• If you eat meat, the cooking method should start with “B” (ie, bake, boil, broil, barbeque [without salty sauce]) ... Note that “fried” does not start with “B”!
• Use a smaller plate and you will not eat as much
• Use technology in your favor. There are great apps and downloads you can recommend (see Table). —CC

Christine Corbett, MSN, APRN, FNP-BC, CNN-NP
Kansas City Veterans Affairs, Kansas City, Missouri

References
4. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;(3):1-150.
5. National Kidney Disease Education Program. Potassium: tips for people with chronic kidney disease (CKD). www.niddk.nih.gov/health-information/health-communication-programs/nkdep/a-z/nutrition-potassium/Documents/nutrition-potassium-508.pdf. Accessed June 20, 2016.
6. Odermatt A. The Western-style diet: a major risk factor for impaired kidney function and chronic kidney disease. Am J Physiol Renal Physiol. 2011;301(5):F919-F931.
7. Steiber A. DASH-style diet effective in preventing, delaying CKD progression. Renal and Urology News. 2012.

Q) I see patients with diabetes, hypertension, chronic kidney disease (CKD), obesity ... often all within the same patient! I keep hearing that the DASH diet is best for these patients. Is this true? Do you have any suggestions (or handouts) for teaching good eating habits in a 15-minute office visit?

It is always nice to focus on what patients can do, rather than what they can’t. Patients with diabetes, kidney disease, heart disease, and obesity hear a lot of “can’t” messages, making “can” messages particularly important to emphasize.

Healthy diets for diabetes, heart, and kidney patients include foods low in trans and saturated fats and sodium. Not all CKD patients are required to follow a low-potassium diet; dietary restrictions are based on laboratory values, medications, and other factors. As we know, adding an ACE inhibitor or an angiotensin receptor blocker (ARB) to the treatment regimen can cause an elevation in serum potassium.

For adults with CKD, it is recommended that sodium intake be restricted to < 2,000 mg/d.⁴ And in this population, salt substitutes are not recommended, since they often contain large amounts of potassium chloride, which increases risk for hyperkalemia.⁵ Other ­spices (eg, garlic, pepper, lemon) are better substitutes for salt.

The late Paul Prudhomme, an award-winning chef from New Orleans, struggled with obesity and health issues for years. He developed wonderful, kidney-friendly spices free of salt and potassium. His line of spices, Magic Seasoning Blends, is sold in many grocery stores. You can recommend them without worry.

Studies have shown that the usual Western diet (which features an abundance of processed foods, fats, and sugars) contributes to kidney disease.⁶ The DASH (Dietary Approaches to Stop Hypertension) diet, developed by cardio experts, replaces these foods with healthier alternatives.

Recent research has shown that the DASH diet does, in fact, slow the progression of kidney disease.⁷ It also lowers blood pressure and decreases kidney stone formation, which are risk factors for kidney disease.

So, the DASH diet is protective for your patients (from both a kidney and a cardiac standpoint)—but how do you explain this in a 15-minute office visit?

Here are a few quick tips:
• Increase fruit and vegetable intake to include all colors on your plate (and no, tan is not really a color)
• If you eat meat, the cooking method should start with “B” (ie, bake, boil, broil, barbeque [without salty sauce]) ... Note that “fried” does not start with “B”!
• Use a smaller plate and you will not eat as much
• Use technology in your favor. There are great apps and downloads you can recommend (see Table). —CC

Christine Corbett, MSN, APRN, FNP-BC, CNN-NP
Kansas City Veterans Affairs, Kansas City, Missouri

References
4. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;(3):1-150.
5. National Kidney Disease Education Program. Potassium: tips for people with chronic kidney disease (CKD). www.niddk.nih.gov/health-information/health-communication-programs/nkdep/a-z/nutrition-potassium/Documents/nutrition-potassium-508.pdf. Accessed June 20, 2016.
6. Odermatt A. The Western-style diet: a major risk factor for impaired kidney function and chronic kidney disease. Am J Physiol Renal Physiol. 2011;301(5):F919-F931.
7. Steiber A. DASH-style diet effective in preventing, delaying CKD progression. Renal and Urology News. 2012.

PRACTICE CHANGER
Consider treating patients with acute low back pain with naproxen only, as adding cyclobenzaprine or oxycodone/acetaminophen to scheduled naproxen increases adverse effects and does not improve functional assessment at seven days or three months.

Strength of Recommendation
B: Based on a high-quality, randomized controlled trial (RCT).¹

A 46-year-old man presents to the emergency department (ED) with low back pain (LBP) after helping a friend move a couch three days ago. He denies any direct trauma to his back and describes the pain as a “spasm” in his lumbar spinal region with no radicular symptoms. The pain worsens with prolonged standing and position changes. He has tried acetaminophen with no benefit. You diagnose a lumbar muscular strain. What medications should you prescribe to help relieve his LBP and improve his overall function?

Acute LBP prompts nearly 2.7 million ED visits in the United States each year.² It leads to persistent subjective impairment and con­tinued analgesic use at seven days (impairment, 70%; analgesic use, 69%) and three months (48% and 46%, respectively) after ED discharge.³ Systematic reviews show that monotherapy with NSAIDs or muscle relaxants is more effective than placebo for pain relief.^4,5 A secondary analysis of patients (N = 715) from a prospective cohort study showed worse functioning at six months in those who were prescribed opiates for LBP than in those who were not.⁶

Monotherapy or combination therapy for LBP?
Because medications used for LBP have different mechanisms of action, clinicians frequently combine them in an attempt to improve symptoms and function.² Current evidence on combination therapy shows mixed results. A large RCT (N = 867) showed that the combination of cyclobenzaprine and ibuprofen led to lower subjective pain intensity, but it did not result in self-reported pain improvement, compared to cyclobenz­a­prine alone. However, a small RCT (N = 40) demonstrated im­­proved LBP and spasm with naprozen plus cyclobenzaprine, compared to naproxen alone.^7,8

This study sought to determine the benefit of treating acute LBP with cyclobenzaprine or oxycodone/acetaminophen in combination with an NSAID, compared to treatment with an NSAID alone.

Continue for the study summary >>

STUDY SUMMARY
Adding second pain reliever provided no significant benefit
This double-blinded RCT enrolled 323 adults presenting to an ED with two weeks or less of nontraumatic, nonradicular LBP.¹ Subjects had a score of > 5 on the Roland-Morris Disability Questionnaire (RMDQ), which measures functional impairment due to LBP (range, 0-24). Patients were excluded if they had radicular pain radiating below the gluteal folds, direct trauma to the back within the previous month, pain lasting > 2 wk, a recent history of multiple LBP episodes per month, or a history of opioid use.

All subjects received 10 days’ worth of naproxen (500 mg bid). They were then randomized to receive either oxycodone/acetaminophen (5 mg/325 mg), cyclobenzaprine (5 mg), or placebo, with instructions to take one to two tablets as needed every eight hours for 10 days. All patients also received a 10-minute educational session emphasizing the role of nonpharmacologic interventions.

The primary outcome was change in the RMDQ between ED discharge and a phone call seven days later; a 5-point improvement in the RMDQ was considered clinically significant. Secondary outcomes included subjective description of worst pain, frequency of LBP, frequency of analgesic use, satisfaction with treatment, median number of days to return to work and usual activities, need for follow-up health care visits, and opioid use. Investigators also asked about any adverse effects.

At seven days, reported RMDQ scores had improved by 9.8 points in patients taking naproxen plus placebo, 10.1 points in those receiving naproxen plus cyclobenzaprine, and 11.1 points in those using naproxen plus oxycodone/acetaminophen. There were no statistically significant between-group differences for placebo vs cyclobenzaprine or oxycodone/acetaminophen (0.3 points and 1.3 points, respectively) or cyclobenzaprine vs oxycodone/acetaminophen (0.9 points).

Secondary outcomes. At seven days, there was no significant difference between study groups in subjective pain assessment, frequency of LBP, or use of as-needed medications in the prior 24 hours. There was also no difference in the median number of days to return to work or need for follow-up health care visits.

Among patients who took more than one dose of the study medication, those who took oxycodone/acetaminophen were more likely to describe their worst pain in the last 24 hours as mild/none, compared to patients taking placebo (number needed to treat, 6). About 72% of all subjects reported that they would choose the same treatment option again, with no difference between groups. At three months, there was no difference between groups in subjective pain assessment, frequency of LBP, use of as-needed medications, or opioid use during the previous 72 hours.

Adverse effects, including drowsiness, dizziness, stomach ir­ritation, and nausea or vomiting, were more common in the oxy­codone/acetaminophen and the cyclobenzaprine treatment groups, with a number needed to harm of 5.3 and 7.8, respectively.

Continue for what's new >>

WHAT’S NEW
Second med adds nothing
This RCT found that adding cyclobenzaprine or oxycodone/aceta­minophen to naproxen for the treatment of nontraumatic, nonradicular acute LBP did not significantly improve functional assessment at seven days or three months after the initial ED visit. But it did increase adverse effects.

CAVEATS
Specific subset studied
This study was performed in a single urban ED and included a very specific subset of LBP patients, which limits the generalizability of the results. However, patients often present to primary care with similar LBP complaints, and the results of the study should reasonably apply to other settings.

The findings may not generalize to all NSAIDs, but there is no evidence to suggest that other NSAIDs would behave differently when combined with cyclobenzaprine or oxycodone/acetaminophen. In this analysis, only about one-third of patients used the as-needed medication more than once daily; another third used it intermittently or never.

CHALLENGES TO IMPLEMENTATION
Patients may expect more
Patients expect to receive prescriptions, and clinicians are inclined to write them if they believe doing so will help their patients. The evidence, however, does not demonstrate a benefit to these prescription-only medications for LBP.

REFERENCES
1. Friedman BW, Dym AA, Davitt M, et al. Naproxen with cyclobenzaprine, oxycodone/acetaminophen, or placebo for treating acute low back pain: a randomized clinical trial. JAMA. 2015;314:1572-1580.
2. Friedman BW, Chilstrom M, Bijur PE, et al. Diagnostic testing and treatment of low back pain in United States emergency departments: a national perspective. Spine (Phila Pa 1976). 2010;35:E1406-E1411.
3. Friedman BW, O’Mahony S, Mulvey L, et al. One-week and 3-month outcomes after an emergency department visit for undifferentiated musculoskeletal low back pain. Ann Emerg Med. 2012;59:128-133.
4. Roelofs PD, Deyo RA, Koes BW, et al. Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane review. Spine (Phila Pa 1976). 2008;33:1766-1774.
5. van Tulder MW, Touray T, Furlan AD, et al. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane collaboration. Spine (Phila Pa 1976). 2003;28:1978-1992.
6. Ashworth J, Green DJ, Dunn KM, et al. Opioid use among low back pain patients in primary care: is opioid prescription associated with disability at 6-month follow-up? Pain. 2013; 154:1038-1044.
7. Childers MK, Borenstein D, Brown RL, et al. Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial. Curr Med Res Opin. 2005;21:1485-1493.
8. Borenstein DG, Lacks S, Wiesel SW. Cyclobenzaprine and naproxen versus naproxen alone in the treatment of acute low back pain and muscle spasm. Clin Ther. 1990;12:125-131.

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.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(6):404-406.

PRACTICE CHANGER
Consider treating patients with acute low back pain with naproxen only, as adding cyclobenzaprine or oxycodone/acetaminophen to scheduled naproxen increases adverse effects and does not improve functional assessment at seven days or three months.

Strength of Recommendation
B: Based on a high-quality, randomized controlled trial (RCT).¹

A 46-year-old man presents to the emergency department (ED) with low back pain (LBP) after helping a friend move a couch three days ago. He denies any direct trauma to his back and describes the pain as a “spasm” in his lumbar spinal region with no radicular symptoms. The pain worsens with prolonged standing and position changes. He has tried acetaminophen with no benefit. You diagnose a lumbar muscular strain. What medications should you prescribe to help relieve his LBP and improve his overall function?

Acute LBP prompts nearly 2.7 million ED visits in the United States each year.² It leads to persistent subjective impairment and con­tinued analgesic use at seven days (impairment, 70%; analgesic use, 69%) and three months (48% and 46%, respectively) after ED discharge.³ Systematic reviews show that monotherapy with NSAIDs or muscle relaxants is more effective than placebo for pain relief.^4,5 A secondary analysis of patients (N = 715) from a prospective cohort study showed worse functioning at six months in those who were prescribed opiates for LBP than in those who were not.⁶

Monotherapy or combination therapy for LBP?
Because medications used for LBP have different mechanisms of action, clinicians frequently combine them in an attempt to improve symptoms and function.² Current evidence on combination therapy shows mixed results. A large RCT (N = 867) showed that the combination of cyclobenzaprine and ibuprofen led to lower subjective pain intensity, but it did not result in self-reported pain improvement, compared to cyclobenz­a­prine alone. However, a small RCT (N = 40) demonstrated im­­proved LBP and spasm with naprozen plus cyclobenzaprine, compared to naproxen alone.^7,8

This study sought to determine the benefit of treating acute LBP with cyclobenzaprine or oxycodone/acetaminophen in combination with an NSAID, compared to treatment with an NSAID alone.

Continue for the study summary >>

STUDY SUMMARY
Adding second pain reliever provided no significant benefit
This double-blinded RCT enrolled 323 adults presenting to an ED with two weeks or less of nontraumatic, nonradicular LBP.¹ Subjects had a score of > 5 on the Roland-Morris Disability Questionnaire (RMDQ), which measures functional impairment due to LBP (range, 0-24). Patients were excluded if they had radicular pain radiating below the gluteal folds, direct trauma to the back within the previous month, pain lasting > 2 wk, a recent history of multiple LBP episodes per month, or a history of opioid use.

All subjects received 10 days’ worth of naproxen (500 mg bid). They were then randomized to receive either oxycodone/acetaminophen (5 mg/325 mg), cyclobenzaprine (5 mg), or placebo, with instructions to take one to two tablets as needed every eight hours for 10 days. All patients also received a 10-minute educational session emphasizing the role of nonpharmacologic interventions.

The primary outcome was change in the RMDQ between ED discharge and a phone call seven days later; a 5-point improvement in the RMDQ was considered clinically significant. Secondary outcomes included subjective description of worst pain, frequency of LBP, frequency of analgesic use, satisfaction with treatment, median number of days to return to work and usual activities, need for follow-up health care visits, and opioid use. Investigators also asked about any adverse effects.

At seven days, reported RMDQ scores had improved by 9.8 points in patients taking naproxen plus placebo, 10.1 points in those receiving naproxen plus cyclobenzaprine, and 11.1 points in those using naproxen plus oxycodone/acetaminophen. There were no statistically significant between-group differences for placebo vs cyclobenzaprine or oxycodone/acetaminophen (0.3 points and 1.3 points, respectively) or cyclobenzaprine vs oxycodone/acetaminophen (0.9 points).

Secondary outcomes. At seven days, there was no significant difference between study groups in subjective pain assessment, frequency of LBP, or use of as-needed medications in the prior 24 hours. There was also no difference in the median number of days to return to work or need for follow-up health care visits.

Among patients who took more than one dose of the study medication, those who took oxycodone/acetaminophen were more likely to describe their worst pain in the last 24 hours as mild/none, compared to patients taking placebo (number needed to treat, 6). About 72% of all subjects reported that they would choose the same treatment option again, with no difference between groups. At three months, there was no difference between groups in subjective pain assessment, frequency of LBP, use of as-needed medications, or opioid use during the previous 72 hours.

Adverse effects, including drowsiness, dizziness, stomach ir­ritation, and nausea or vomiting, were more common in the oxy­codone/acetaminophen and the cyclobenzaprine treatment groups, with a number needed to harm of 5.3 and 7.8, respectively.

Continue for what's new >>

WHAT’S NEW
Second med adds nothing
This RCT found that adding cyclobenzaprine or oxycodone/aceta­minophen to naproxen for the treatment of nontraumatic, nonradicular acute LBP did not significantly improve functional assessment at seven days or three months after the initial ED visit. But it did increase adverse effects.

CAVEATS
Specific subset studied
This study was performed in a single urban ED and included a very specific subset of LBP patients, which limits the generalizability of the results. However, patients often present to primary care with similar LBP complaints, and the results of the study should reasonably apply to other settings.

The findings may not generalize to all NSAIDs, but there is no evidence to suggest that other NSAIDs would behave differently when combined with cyclobenzaprine or oxycodone/acetaminophen. In this analysis, only about one-third of patients used the as-needed medication more than once daily; another third used it intermittently or never.

CHALLENGES TO IMPLEMENTATION
Patients may expect more
Patients expect to receive prescriptions, and clinicians are inclined to write them if they believe doing so will help their patients. The evidence, however, does not demonstrate a benefit to these prescription-only medications for LBP.

REFERENCES
1. Friedman BW, Dym AA, Davitt M, et al. Naproxen with cyclobenzaprine, oxycodone/acetaminophen, or placebo for treating acute low back pain: a randomized clinical trial. JAMA. 2015;314:1572-1580.
2. Friedman BW, Chilstrom M, Bijur PE, et al. Diagnostic testing and treatment of low back pain in United States emergency departments: a national perspective. Spine (Phila Pa 1976). 2010;35:E1406-E1411.
3. Friedman BW, O’Mahony S, Mulvey L, et al. One-week and 3-month outcomes after an emergency department visit for undifferentiated musculoskeletal low back pain. Ann Emerg Med. 2012;59:128-133.
4. Roelofs PD, Deyo RA, Koes BW, et al. Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane review. Spine (Phila Pa 1976). 2008;33:1766-1774.
5. van Tulder MW, Touray T, Furlan AD, et al. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane collaboration. Spine (Phila Pa 1976). 2003;28:1978-1992.
6. Ashworth J, Green DJ, Dunn KM, et al. Opioid use among low back pain patients in primary care: is opioid prescription associated with disability at 6-month follow-up? Pain. 2013; 154:1038-1044.
7. Childers MK, Borenstein D, Brown RL, et al. Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial. Curr Med Res Opin. 2005;21:1485-1493.
8. Borenstein DG, Lacks S, Wiesel SW. Cyclobenzaprine and naproxen versus naproxen alone in the treatment of acute low back pain and muscle spasm. Clin Ther. 1990;12:125-131.

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.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(6):404-406.

PRACTICE CHANGER
Consider treating patients with acute low back pain with naproxen only, as adding cyclobenzaprine or oxycodone/acetaminophen to scheduled naproxen increases adverse effects and does not improve functional assessment at seven days or three months.

Strength of Recommendation
B: Based on a high-quality, randomized controlled trial (RCT).¹

A 46-year-old man presents to the emergency department (ED) with low back pain (LBP) after helping a friend move a couch three days ago. He denies any direct trauma to his back and describes the pain as a “spasm” in his lumbar spinal region with no radicular symptoms. The pain worsens with prolonged standing and position changes. He has tried acetaminophen with no benefit. You diagnose a lumbar muscular strain. What medications should you prescribe to help relieve his LBP and improve his overall function?

Acute LBP prompts nearly 2.7 million ED visits in the United States each year.² It leads to persistent subjective impairment and con­tinued analgesic use at seven days (impairment, 70%; analgesic use, 69%) and three months (48% and 46%, respectively) after ED discharge.³ Systematic reviews show that monotherapy with NSAIDs or muscle relaxants is more effective than placebo for pain relief.^4,5 A secondary analysis of patients (N = 715) from a prospective cohort study showed worse functioning at six months in those who were prescribed opiates for LBP than in those who were not.⁶

Monotherapy or combination therapy for LBP?
Because medications used for LBP have different mechanisms of action, clinicians frequently combine them in an attempt to improve symptoms and function.² Current evidence on combination therapy shows mixed results. A large RCT (N = 867) showed that the combination of cyclobenzaprine and ibuprofen led to lower subjective pain intensity, but it did not result in self-reported pain improvement, compared to cyclobenz­a­prine alone. However, a small RCT (N = 40) demonstrated im­­proved LBP and spasm with naprozen plus cyclobenzaprine, compared to naproxen alone.^7,8

This study sought to determine the benefit of treating acute LBP with cyclobenzaprine or oxycodone/acetaminophen in combination with an NSAID, compared to treatment with an NSAID alone.

Continue for the study summary >>

STUDY SUMMARY
Adding second pain reliever provided no significant benefit
This double-blinded RCT enrolled 323 adults presenting to an ED with two weeks or less of nontraumatic, nonradicular LBP.¹ Subjects had a score of > 5 on the Roland-Morris Disability Questionnaire (RMDQ), which measures functional impairment due to LBP (range, 0-24). Patients were excluded if they had radicular pain radiating below the gluteal folds, direct trauma to the back within the previous month, pain lasting > 2 wk, a recent history of multiple LBP episodes per month, or a history of opioid use.

All subjects received 10 days’ worth of naproxen (500 mg bid). They were then randomized to receive either oxycodone/acetaminophen (5 mg/325 mg), cyclobenzaprine (5 mg), or placebo, with instructions to take one to two tablets as needed every eight hours for 10 days. All patients also received a 10-minute educational session emphasizing the role of nonpharmacologic interventions.

The primary outcome was change in the RMDQ between ED discharge and a phone call seven days later; a 5-point improvement in the RMDQ was considered clinically significant. Secondary outcomes included subjective description of worst pain, frequency of LBP, frequency of analgesic use, satisfaction with treatment, median number of days to return to work and usual activities, need for follow-up health care visits, and opioid use. Investigators also asked about any adverse effects.

At seven days, reported RMDQ scores had improved by 9.8 points in patients taking naproxen plus placebo, 10.1 points in those receiving naproxen plus cyclobenzaprine, and 11.1 points in those using naproxen plus oxycodone/acetaminophen. There were no statistically significant between-group differences for placebo vs cyclobenzaprine or oxycodone/acetaminophen (0.3 points and 1.3 points, respectively) or cyclobenzaprine vs oxycodone/acetaminophen (0.9 points).

Secondary outcomes. At seven days, there was no significant difference between study groups in subjective pain assessment, frequency of LBP, or use of as-needed medications in the prior 24 hours. There was also no difference in the median number of days to return to work or need for follow-up health care visits.

Among patients who took more than one dose of the study medication, those who took oxycodone/acetaminophen were more likely to describe their worst pain in the last 24 hours as mild/none, compared to patients taking placebo (number needed to treat, 6). About 72% of all subjects reported that they would choose the same treatment option again, with no difference between groups. At three months, there was no difference between groups in subjective pain assessment, frequency of LBP, use of as-needed medications, or opioid use during the previous 72 hours.

Adverse effects, including drowsiness, dizziness, stomach ir­ritation, and nausea or vomiting, were more common in the oxy­codone/acetaminophen and the cyclobenzaprine treatment groups, with a number needed to harm of 5.3 and 7.8, respectively.

Continue for what's new >>

WHAT’S NEW
Second med adds nothing
This RCT found that adding cyclobenzaprine or oxycodone/aceta­minophen to naproxen for the treatment of nontraumatic, nonradicular acute LBP did not significantly improve functional assessment at seven days or three months after the initial ED visit. But it did increase adverse effects.

CAVEATS
Specific subset studied
This study was performed in a single urban ED and included a very specific subset of LBP patients, which limits the generalizability of the results. However, patients often present to primary care with similar LBP complaints, and the results of the study should reasonably apply to other settings.

The findings may not generalize to all NSAIDs, but there is no evidence to suggest that other NSAIDs would behave differently when combined with cyclobenzaprine or oxycodone/acetaminophen. In this analysis, only about one-third of patients used the as-needed medication more than once daily; another third used it intermittently or never.

CHALLENGES TO IMPLEMENTATION
Patients may expect more
Patients expect to receive prescriptions, and clinicians are inclined to write them if they believe doing so will help their patients. The evidence, however, does not demonstrate a benefit to these prescription-only medications for LBP.

REFERENCES
1. Friedman BW, Dym AA, Davitt M, et al. Naproxen with cyclobenzaprine, oxycodone/acetaminophen, or placebo for treating acute low back pain: a randomized clinical trial. JAMA. 2015;314:1572-1580.
2. Friedman BW, Chilstrom M, Bijur PE, et al. Diagnostic testing and treatment of low back pain in United States emergency departments: a national perspective. Spine (Phila Pa 1976). 2010;35:E1406-E1411.
3. Friedman BW, O’Mahony S, Mulvey L, et al. One-week and 3-month outcomes after an emergency department visit for undifferentiated musculoskeletal low back pain. Ann Emerg Med. 2012;59:128-133.
4. Roelofs PD, Deyo RA, Koes BW, et al. Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane review. Spine (Phila Pa 1976). 2008;33:1766-1774.
5. van Tulder MW, Touray T, Furlan AD, et al. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane collaboration. Spine (Phila Pa 1976). 2003;28:1978-1992.
6. Ashworth J, Green DJ, Dunn KM, et al. Opioid use among low back pain patients in primary care: is opioid prescription associated with disability at 6-month follow-up? Pain. 2013; 154:1038-1044.
7. Childers MK, Borenstein D, Brown RL, et al. Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial. Curr Med Res Opin. 2005;21:1485-1493.
8. Borenstein DG, Lacks S, Wiesel SW. Cyclobenzaprine and naproxen versus naproxen alone in the treatment of acute low back pain and muscle spasm. Clin Ther. 1990;12:125-131.

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.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(6):404-406.

LONDON – One of the largest studies of pregnancy outcomes after bisphosphonate exposure has found no evidence for major teratogenic effects in women with inflammatory diseases and glucocorticoid-induced osteoporosis and women with bone diseases.

However, the investigators for the French case-control study did find higher rates of neonatal complications and spontaneous abortion among infants of mothers with systemic inflammatory diseases and bisphosphonate use, but the results could be the result of confounding because of the severity of underlying disease and exposure to other medications.

“I think if a women is worried about bisphosphonate exposure during pregnancy, this study can bring her some reassuring news,” although it does not necessarily mean that bisphosphonates are safe during pregnancy, first author Aurélien Sokal said in an interview at the European Congress of Rheumatology. He is a medical student at Beaujon Hospital, Clichy, France, but conducted the study with colleagues during his time in training in the rheumatology department at Paris-Sud University.

“Very little is known about the effect of bisphosphonates on pregnancy outcomes and fetal development,” Mr. Sokal said, and they are feared for possible teratogenic effects in pregnancy because of their long half-life in bone – where they can be released even 1 year after their administration – as well as their ability to cross the placenta and high affinity for high-turnover bones, such as those in a growing fetus. He also noted that abnormalities in bone length, low birth weights, and bone diseases have been observed in rats exposed to bisphosphonates during gestation.

The study compared 23 patients with inflammatory diseases and bisphosphonate exposure during pregnancy against 92 controls with inflammatory diseases but no exposure, and 16 with bone diseases and exposure to bisphosphonates against 64 healthy controls with no underlying disease or bisphosphonate use. The patients came from a database assembled by the French Reference Center of Teratogenic Agents (CRAT) in Paris that has collected information since 1975 on patients referred for any drug exposure during pregnancy and followed their care through the end of pregnancy. The 39 patients who were exposed to bisphosphonates took the drugs during 1987-2014 within the 6 weeks preceding (n = 6) or during pregnancy (n = 33). They had a mean age of 33 years.

Systemic inflammatory diseases

The systemic inflammatory diseases found in women in the study included systemic lupus erythematosus (SLE), rheumatoid arthritis, antiphospholipid syndrome, systemic vasculitis, and other diseases. Of the 23 cases with systemic inflammatory diseases, 16 took risedronate, 5 took alendronate, 1 took etidronate, and the bisphosphonate was unknown in 1. Bisphosphonate exposure occurred before pregnancy in 2, during the first trimester in 21, second trimester in 4, third trimester in 4, and in all trimesters in 1.

Other types of medications were used significantly more often by patients with systemic inflammatory diseases than by controls: steroids (78% vs. 47%), methotrexate (26% vs. 5%), colchicine (17% vs. 2%), proton pump inhibitors (22% vs. 5%), and reproductive hormones (17% vs. 2%). Controls took antimalarials significantly more often (50% vs. 22%).

Voluntary abortions occurred at a similar rate in both exposed and unexposed women (12% vs. 9%), whereas significantly more therapeutic pregnancy terminations occurred among women exposed to bisphosphonates (17% vs. 1%). Live births occurred in 94% of the remaining exposed pregnant women, compared with 80% of controls.

Newborns were delivered at a mean of 38 weeks in both cases and controls, and there were no differences in birth weight, length, or rate of congenital malformation (9% vs. 2%).

The two malformations in neonates from exposed women had an uncertain link to bisphosphonates. One involved a neonate with severe malformative syndrome and advanced bone maturation who had a mother with SLE and was exposed to multiple drugs, including mycophenolate mofetil. The other neonate had ductus arteriosus, inguinal hernia, and negative otoacoustic emission; the baby’s mother had Crohn’s disease but had not taken known teratogenic drugs.

Two neonatal malformations among control women involved one neonate with severe malformative syndrome who had a mother with SLE but who was without exposure to known teratogenic drugs, and another with convulsant encephalopathy whose mother had systemic sclerosis and took pentoxifylline, cisapride, dihydroergocryptine, and colchicine.

However, cases had a 25% rate of neonatal complications, compared with a significantly lower 5% in controls. No infants had hypocalcemia.

Bone diseases

The 16 women with bone diseases included 9 with osteoporosis, 3 with malignancy, and 4 with miscellaneous bone conditions. A total of 5 received intravenous bisphosphonates and 11 received oral drugs (9 alendronate, 2 other). Most received a bisphosphonate in the first trimester (9 patients), but also 4 received it before pregnancy and 3 in the second trimester. More pregnancy terminations (voluntary or therapeutic) occurred among women with bone disease when compared with controls (19% vs. 3%), but the difference was not statistically significant. However in the remaining patients, live births occurred significantly less often in cases than in controls (69% vs. 100%). Birth weight, length, gestational age at birth, and the rates of congenital malformation and neonatal complications were otherwise similar.

The results of the study fall in line with those from the two major previous controlled studies on 24 women (Reprod Toxicol. 2006 Nov;22:578-9) and 21 women (Bone. 2009 Mar;44:428-30). Another series of 10 bisphosphonate-exposed pregnancies described 2 malformations, including 1 ventricular septal defect and 1 kidney and cardiac malformation (Autoimmun Rev. 2010 Jun;9:547-52). Another single case report described a neonate with bilateral talipes equinovarus (J Bone Miner Res. 2004 Oct;19:1742-5). A literature review of 78 cases of bisphosphonate exposure during or prior to pregnancy reported three malformations (Hormones [Athens]. 2011 Oct-Dec;10:280-91).

The study is ongoing and continues to collect data on the follow-up of children, Mr. Sokal said.

The study had no specific funding, and none of the investigators had disclosures to report.

[email protected]

LONDON – One of the largest studies of pregnancy outcomes after bisphosphonate exposure has found no evidence for major teratogenic effects in women with inflammatory diseases and glucocorticoid-induced osteoporosis and women with bone diseases.

However, the investigators for the French case-control study did find higher rates of neonatal complications and spontaneous abortion among infants of mothers with systemic inflammatory diseases and bisphosphonate use, but the results could be the result of confounding because of the severity of underlying disease and exposure to other medications.

“I think if a women is worried about bisphosphonate exposure during pregnancy, this study can bring her some reassuring news,” although it does not necessarily mean that bisphosphonates are safe during pregnancy, first author Aurélien Sokal said in an interview at the European Congress of Rheumatology. He is a medical student at Beaujon Hospital, Clichy, France, but conducted the study with colleagues during his time in training in the rheumatology department at Paris-Sud University.

“Very little is known about the effect of bisphosphonates on pregnancy outcomes and fetal development,” Mr. Sokal said, and they are feared for possible teratogenic effects in pregnancy because of their long half-life in bone – where they can be released even 1 year after their administration – as well as their ability to cross the placenta and high affinity for high-turnover bones, such as those in a growing fetus. He also noted that abnormalities in bone length, low birth weights, and bone diseases have been observed in rats exposed to bisphosphonates during gestation.

The study compared 23 patients with inflammatory diseases and bisphosphonate exposure during pregnancy against 92 controls with inflammatory diseases but no exposure, and 16 with bone diseases and exposure to bisphosphonates against 64 healthy controls with no underlying disease or bisphosphonate use. The patients came from a database assembled by the French Reference Center of Teratogenic Agents (CRAT) in Paris that has collected information since 1975 on patients referred for any drug exposure during pregnancy and followed their care through the end of pregnancy. The 39 patients who were exposed to bisphosphonates took the drugs during 1987-2014 within the 6 weeks preceding (n = 6) or during pregnancy (n = 33). They had a mean age of 33 years.

Systemic inflammatory diseases

The systemic inflammatory diseases found in women in the study included systemic lupus erythematosus (SLE), rheumatoid arthritis, antiphospholipid syndrome, systemic vasculitis, and other diseases. Of the 23 cases with systemic inflammatory diseases, 16 took risedronate, 5 took alendronate, 1 took etidronate, and the bisphosphonate was unknown in 1. Bisphosphonate exposure occurred before pregnancy in 2, during the first trimester in 21, second trimester in 4, third trimester in 4, and in all trimesters in 1.

Other types of medications were used significantly more often by patients with systemic inflammatory diseases than by controls: steroids (78% vs. 47%), methotrexate (26% vs. 5%), colchicine (17% vs. 2%), proton pump inhibitors (22% vs. 5%), and reproductive hormones (17% vs. 2%). Controls took antimalarials significantly more often (50% vs. 22%).

Voluntary abortions occurred at a similar rate in both exposed and unexposed women (12% vs. 9%), whereas significantly more therapeutic pregnancy terminations occurred among women exposed to bisphosphonates (17% vs. 1%). Live births occurred in 94% of the remaining exposed pregnant women, compared with 80% of controls.

Newborns were delivered at a mean of 38 weeks in both cases and controls, and there were no differences in birth weight, length, or rate of congenital malformation (9% vs. 2%).

The two malformations in neonates from exposed women had an uncertain link to bisphosphonates. One involved a neonate with severe malformative syndrome and advanced bone maturation who had a mother with SLE and was exposed to multiple drugs, including mycophenolate mofetil. The other neonate had ductus arteriosus, inguinal hernia, and negative otoacoustic emission; the baby’s mother had Crohn’s disease but had not taken known teratogenic drugs.

Two neonatal malformations among control women involved one neonate with severe malformative syndrome who had a mother with SLE but who was without exposure to known teratogenic drugs, and another with convulsant encephalopathy whose mother had systemic sclerosis and took pentoxifylline, cisapride, dihydroergocryptine, and colchicine.

However, cases had a 25% rate of neonatal complications, compared with a significantly lower 5% in controls. No infants had hypocalcemia.

Bone diseases

The 16 women with bone diseases included 9 with osteoporosis, 3 with malignancy, and 4 with miscellaneous bone conditions. A total of 5 received intravenous bisphosphonates and 11 received oral drugs (9 alendronate, 2 other). Most received a bisphosphonate in the first trimester (9 patients), but also 4 received it before pregnancy and 3 in the second trimester. More pregnancy terminations (voluntary or therapeutic) occurred among women with bone disease when compared with controls (19% vs. 3%), but the difference was not statistically significant. However in the remaining patients, live births occurred significantly less often in cases than in controls (69% vs. 100%). Birth weight, length, gestational age at birth, and the rates of congenital malformation and neonatal complications were otherwise similar.

The results of the study fall in line with those from the two major previous controlled studies on 24 women (Reprod Toxicol. 2006 Nov;22:578-9) and 21 women (Bone. 2009 Mar;44:428-30). Another series of 10 bisphosphonate-exposed pregnancies described 2 malformations, including 1 ventricular septal defect and 1 kidney and cardiac malformation (Autoimmun Rev. 2010 Jun;9:547-52). Another single case report described a neonate with bilateral talipes equinovarus (J Bone Miner Res. 2004 Oct;19:1742-5). A literature review of 78 cases of bisphosphonate exposure during or prior to pregnancy reported three malformations (Hormones [Athens]. 2011 Oct-Dec;10:280-91).

The study is ongoing and continues to collect data on the follow-up of children, Mr. Sokal said.

The study had no specific funding, and none of the investigators had disclosures to report.

[email protected]

LONDON – One of the largest studies of pregnancy outcomes after bisphosphonate exposure has found no evidence for major teratogenic effects in women with inflammatory diseases and glucocorticoid-induced osteoporosis and women with bone diseases.

However, the investigators for the French case-control study did find higher rates of neonatal complications and spontaneous abortion among infants of mothers with systemic inflammatory diseases and bisphosphonate use, but the results could be the result of confounding because of the severity of underlying disease and exposure to other medications.

“I think if a women is worried about bisphosphonate exposure during pregnancy, this study can bring her some reassuring news,” although it does not necessarily mean that bisphosphonates are safe during pregnancy, first author Aurélien Sokal said in an interview at the European Congress of Rheumatology. He is a medical student at Beaujon Hospital, Clichy, France, but conducted the study with colleagues during his time in training in the rheumatology department at Paris-Sud University.

“Very little is known about the effect of bisphosphonates on pregnancy outcomes and fetal development,” Mr. Sokal said, and they are feared for possible teratogenic effects in pregnancy because of their long half-life in bone – where they can be released even 1 year after their administration – as well as their ability to cross the placenta and high affinity for high-turnover bones, such as those in a growing fetus. He also noted that abnormalities in bone length, low birth weights, and bone diseases have been observed in rats exposed to bisphosphonates during gestation.

The study compared 23 patients with inflammatory diseases and bisphosphonate exposure during pregnancy against 92 controls with inflammatory diseases but no exposure, and 16 with bone diseases and exposure to bisphosphonates against 64 healthy controls with no underlying disease or bisphosphonate use. The patients came from a database assembled by the French Reference Center of Teratogenic Agents (CRAT) in Paris that has collected information since 1975 on patients referred for any drug exposure during pregnancy and followed their care through the end of pregnancy. The 39 patients who were exposed to bisphosphonates took the drugs during 1987-2014 within the 6 weeks preceding (n = 6) or during pregnancy (n = 33). They had a mean age of 33 years.

Systemic inflammatory diseases

The systemic inflammatory diseases found in women in the study included systemic lupus erythematosus (SLE), rheumatoid arthritis, antiphospholipid syndrome, systemic vasculitis, and other diseases. Of the 23 cases with systemic inflammatory diseases, 16 took risedronate, 5 took alendronate, 1 took etidronate, and the bisphosphonate was unknown in 1. Bisphosphonate exposure occurred before pregnancy in 2, during the first trimester in 21, second trimester in 4, third trimester in 4, and in all trimesters in 1.

Other types of medications were used significantly more often by patients with systemic inflammatory diseases than by controls: steroids (78% vs. 47%), methotrexate (26% vs. 5%), colchicine (17% vs. 2%), proton pump inhibitors (22% vs. 5%), and reproductive hormones (17% vs. 2%). Controls took antimalarials significantly more often (50% vs. 22%).

Voluntary abortions occurred at a similar rate in both exposed and unexposed women (12% vs. 9%), whereas significantly more therapeutic pregnancy terminations occurred among women exposed to bisphosphonates (17% vs. 1%). Live births occurred in 94% of the remaining exposed pregnant women, compared with 80% of controls.

Newborns were delivered at a mean of 38 weeks in both cases and controls, and there were no differences in birth weight, length, or rate of congenital malformation (9% vs. 2%).

The two malformations in neonates from exposed women had an uncertain link to bisphosphonates. One involved a neonate with severe malformative syndrome and advanced bone maturation who had a mother with SLE and was exposed to multiple drugs, including mycophenolate mofetil. The other neonate had ductus arteriosus, inguinal hernia, and negative otoacoustic emission; the baby’s mother had Crohn’s disease but had not taken known teratogenic drugs.

Two neonatal malformations among control women involved one neonate with severe malformative syndrome who had a mother with SLE but who was without exposure to known teratogenic drugs, and another with convulsant encephalopathy whose mother had systemic sclerosis and took pentoxifylline, cisapride, dihydroergocryptine, and colchicine.

However, cases had a 25% rate of neonatal complications, compared with a significantly lower 5% in controls. No infants had hypocalcemia.

Bone diseases

The 16 women with bone diseases included 9 with osteoporosis, 3 with malignancy, and 4 with miscellaneous bone conditions. A total of 5 received intravenous bisphosphonates and 11 received oral drugs (9 alendronate, 2 other). Most received a bisphosphonate in the first trimester (9 patients), but also 4 received it before pregnancy and 3 in the second trimester. More pregnancy terminations (voluntary or therapeutic) occurred among women with bone disease when compared with controls (19% vs. 3%), but the difference was not statistically significant. However in the remaining patients, live births occurred significantly less often in cases than in controls (69% vs. 100%). Birth weight, length, gestational age at birth, and the rates of congenital malformation and neonatal complications were otherwise similar.

The results of the study fall in line with those from the two major previous controlled studies on 24 women (Reprod Toxicol. 2006 Nov;22:578-9) and 21 women (Bone. 2009 Mar;44:428-30). Another series of 10 bisphosphonate-exposed pregnancies described 2 malformations, including 1 ventricular septal defect and 1 kidney and cardiac malformation (Autoimmun Rev. 2010 Jun;9:547-52). Another single case report described a neonate with bilateral talipes equinovarus (J Bone Miner Res. 2004 Oct;19:1742-5). A literature review of 78 cases of bisphosphonate exposure during or prior to pregnancy reported three malformations (Hormones [Athens]. 2011 Oct-Dec;10:280-91).

The study is ongoing and continues to collect data on the follow-up of children, Mr. Sokal said.

The study had no specific funding, and none of the investigators had disclosures to report.

[email protected]

NEW ORLEANS – If the yardstick for measuring the cost-effectiveness of an operation or a medical treatment is that it costs less than $50,000 for each quality-adjusted life-year gained, then weight-loss surgery as a treatment for type 2 diabetes is cost-effective.

However, more long-term follow-up is needed to determine the true value of metabolic or bariatric surgery such as gastric bypass, compared with medical treatment for type 2 diabetes. Studies of bariatric surgery in the nondiabetic population found it was most cost-effective in the following scenarios: in women; in the morbidly obese vs. the moderately obese; in patients with obesity-related comorbidities including diabetes; when the procedures were performed laparoscopically; and when the studies themselves received industry support.

In people with diabetes, the results were similar. “Diabetes metabolic surgery is more cost-effective early in the course of type 2 diabetes compared to later in the course, when performed laparoscopically, and again when the study received support from industry,” reported Dr. William H. Herman, professor of epidemiology and internal medicine at the University of Michigan School of Public Health in Ann Arbor and director of the Michigan Center for Diabetes Translational Research.

He reviewed 11 economic analyses of bariatric surgery and concluded that all exceeded the benchmark for cost-effectiveness based on the cost per quality-adjusted life-year (QALY) gained. Six studies evaluated the general population of obese people and found that the cost-effectiveness ratios ranged from $1,600 to $44,000 per QALY gained. The remaining five studies involved obese patients with type 2 diabetes, two of which reported cost-effectiveness ratios of $2,000 to $23,000 per QALY gained; and the remaining three studies actually reporting a cost-savings. “In other words, the money spent on these interventions was more than recouped in the savings resulting from reduced downstream medical costs,” Dr. Herman reported at the American Diabetes Association scientific sessions.

The studies that found gastric bypass cost-saving in diabetes are noteworthy, Dr. Herman said. “If an intervention is more effective and less costly than a comparator intervention, then it is cost-saving, and that really is an unusual finding in health or medicine; perhaps 10% or 15% of interventions turn out to be cost-saving,” he said. “These are interventions that we want to adopt and put into practice pretty much without question.”

By the same measure, if an intervention is more costly and less effective, it’s easy to dismiss “out of hand,” Dr. Herman said. However, interpreting some of the studies he evaluated was more nuanced. “The problem occurs when a new treatment is both more effective but more costly, which was the case with two of the five analyses of metabolic surgery, and all of the analysis of bariatric surgery in the nondiabetic population,” he said

While gastric bypass surgery for type 2 diabetes is a good value, Dr. Herman added a few caveats. “When one looks at other interventions in similar categories, metformin for diabetes prevention has recently been shown to be cost-saving,” he said. He also said surgery is more cost-effective than marginally cost-effective interventions like intensive glycemic management for people with newly diagnosed type 2 diabetes or retinal screening every year vs. every 2 years.

One key issue with the existing evidence on cost-effectiveness of metabolic surgery for type 2 diabetes that Dr. Herman elucidated is how the studies accounted for participants lost to follow-up. “We know that a patient lost to follow-up may have a less favorable outcome than one who returns for follow-up,” he said. There are two ways studies can account for lost patients: the available-case analysis, which assumes that the patients lost to follow-up have the same rates of remission; and the attrition-adjusted available case follow-up, which uses a worst-case imputation. “I would argue that to account for attrition bias, remission rates calculated using the cases available for follow-up should be adjusted using worst-case imputation,” Dr. Herman said.

He pointed out another limitation when calculating the value of gastric bypass surgery for type 2 diabetes: “There are no randomized clinical trials of metabolic surgery that describe its long-term impact on diabetes treatments, complications, comorbidities, and survival. And it really is going be very important to get these data to confirm the cost-effectiveness of metabolic surgery.”

Among the shortcomings of the existing literature he noted are the assumptions that treatment-related adverse events are self-limited, that body mass index (BMI) achieved up to 5 years after surgery will remain stable, and that diabetes will not relapse. “The data are pretty good now on reversal, remission, hernia repair, and those sorts of things, but we need to look at longer downstream costs associated with surgery, including the need for cholecystectomy, joint replacements, and nutritional deficiencies that may occur and do clearly have financial implications,” he said.

At the same time, the analyses on gastric bypass surgery for type 2 diabetes could be more favorable if they account for improvements in health-related quality-of-life and rely less on cross-sectional data. Dr. Herman said, “I would argue that using cross-sectional data to estimate changes in health-related quality of life as a function of BMI underestimates the improvements on health-related quality-of-life associated with weight loss and will in fact underestimate the cost utility of interventions for obesity treatment,” he said.

Dr. Herman added, “Clearly the evidence to date suggests that metabolic surgery is cost-effective, but I’ll be more assured when I see longer-term follow-up.”

Dr. Herman has no financial relationships to disclose.

NEW ORLEANS – If the yardstick for measuring the cost-effectiveness of an operation or a medical treatment is that it costs less than $50,000 for each quality-adjusted life-year gained, then weight-loss surgery as a treatment for type 2 diabetes is cost-effective.

However, more long-term follow-up is needed to determine the true value of metabolic or bariatric surgery such as gastric bypass, compared with medical treatment for type 2 diabetes. Studies of bariatric surgery in the nondiabetic population found it was most cost-effective in the following scenarios: in women; in the morbidly obese vs. the moderately obese; in patients with obesity-related comorbidities including diabetes; when the procedures were performed laparoscopically; and when the studies themselves received industry support.

In people with diabetes, the results were similar. “Diabetes metabolic surgery is more cost-effective early in the course of type 2 diabetes compared to later in the course, when performed laparoscopically, and again when the study received support from industry,” reported Dr. William H. Herman, professor of epidemiology and internal medicine at the University of Michigan School of Public Health in Ann Arbor and director of the Michigan Center for Diabetes Translational Research.

He reviewed 11 economic analyses of bariatric surgery and concluded that all exceeded the benchmark for cost-effectiveness based on the cost per quality-adjusted life-year (QALY) gained. Six studies evaluated the general population of obese people and found that the cost-effectiveness ratios ranged from $1,600 to $44,000 per QALY gained. The remaining five studies involved obese patients with type 2 diabetes, two of which reported cost-effectiveness ratios of $2,000 to $23,000 per QALY gained; and the remaining three studies actually reporting a cost-savings. “In other words, the money spent on these interventions was more than recouped in the savings resulting from reduced downstream medical costs,” Dr. Herman reported at the American Diabetes Association scientific sessions.

The studies that found gastric bypass cost-saving in diabetes are noteworthy, Dr. Herman said. “If an intervention is more effective and less costly than a comparator intervention, then it is cost-saving, and that really is an unusual finding in health or medicine; perhaps 10% or 15% of interventions turn out to be cost-saving,” he said. “These are interventions that we want to adopt and put into practice pretty much without question.”

By the same measure, if an intervention is more costly and less effective, it’s easy to dismiss “out of hand,” Dr. Herman said. However, interpreting some of the studies he evaluated was more nuanced. “The problem occurs when a new treatment is both more effective but more costly, which was the case with two of the five analyses of metabolic surgery, and all of the analysis of bariatric surgery in the nondiabetic population,” he said

While gastric bypass surgery for type 2 diabetes is a good value, Dr. Herman added a few caveats. “When one looks at other interventions in similar categories, metformin for diabetes prevention has recently been shown to be cost-saving,” he said. He also said surgery is more cost-effective than marginally cost-effective interventions like intensive glycemic management for people with newly diagnosed type 2 diabetes or retinal screening every year vs. every 2 years.

One key issue with the existing evidence on cost-effectiveness of metabolic surgery for type 2 diabetes that Dr. Herman elucidated is how the studies accounted for participants lost to follow-up. “We know that a patient lost to follow-up may have a less favorable outcome than one who returns for follow-up,” he said. There are two ways studies can account for lost patients: the available-case analysis, which assumes that the patients lost to follow-up have the same rates of remission; and the attrition-adjusted available case follow-up, which uses a worst-case imputation. “I would argue that to account for attrition bias, remission rates calculated using the cases available for follow-up should be adjusted using worst-case imputation,” Dr. Herman said.

He pointed out another limitation when calculating the value of gastric bypass surgery for type 2 diabetes: “There are no randomized clinical trials of metabolic surgery that describe its long-term impact on diabetes treatments, complications, comorbidities, and survival. And it really is going be very important to get these data to confirm the cost-effectiveness of metabolic surgery.”

Among the shortcomings of the existing literature he noted are the assumptions that treatment-related adverse events are self-limited, that body mass index (BMI) achieved up to 5 years after surgery will remain stable, and that diabetes will not relapse. “The data are pretty good now on reversal, remission, hernia repair, and those sorts of things, but we need to look at longer downstream costs associated with surgery, including the need for cholecystectomy, joint replacements, and nutritional deficiencies that may occur and do clearly have financial implications,” he said.

At the same time, the analyses on gastric bypass surgery for type 2 diabetes could be more favorable if they account for improvements in health-related quality-of-life and rely less on cross-sectional data. Dr. Herman said, “I would argue that using cross-sectional data to estimate changes in health-related quality of life as a function of BMI underestimates the improvements on health-related quality-of-life associated with weight loss and will in fact underestimate the cost utility of interventions for obesity treatment,” he said.

Dr. Herman added, “Clearly the evidence to date suggests that metabolic surgery is cost-effective, but I’ll be more assured when I see longer-term follow-up.”

Dr. Herman has no financial relationships to disclose.

NEW ORLEANS – If the yardstick for measuring the cost-effectiveness of an operation or a medical treatment is that it costs less than $50,000 for each quality-adjusted life-year gained, then weight-loss surgery as a treatment for type 2 diabetes is cost-effective.

However, more long-term follow-up is needed to determine the true value of metabolic or bariatric surgery such as gastric bypass, compared with medical treatment for type 2 diabetes. Studies of bariatric surgery in the nondiabetic population found it was most cost-effective in the following scenarios: in women; in the morbidly obese vs. the moderately obese; in patients with obesity-related comorbidities including diabetes; when the procedures were performed laparoscopically; and when the studies themselves received industry support.

In people with diabetes, the results were similar. “Diabetes metabolic surgery is more cost-effective early in the course of type 2 diabetes compared to later in the course, when performed laparoscopically, and again when the study received support from industry,” reported Dr. William H. Herman, professor of epidemiology and internal medicine at the University of Michigan School of Public Health in Ann Arbor and director of the Michigan Center for Diabetes Translational Research.

He reviewed 11 economic analyses of bariatric surgery and concluded that all exceeded the benchmark for cost-effectiveness based on the cost per quality-adjusted life-year (QALY) gained. Six studies evaluated the general population of obese people and found that the cost-effectiveness ratios ranged from $1,600 to $44,000 per QALY gained. The remaining five studies involved obese patients with type 2 diabetes, two of which reported cost-effectiveness ratios of $2,000 to $23,000 per QALY gained; and the remaining three studies actually reporting a cost-savings. “In other words, the money spent on these interventions was more than recouped in the savings resulting from reduced downstream medical costs,” Dr. Herman reported at the American Diabetes Association scientific sessions.

The studies that found gastric bypass cost-saving in diabetes are noteworthy, Dr. Herman said. “If an intervention is more effective and less costly than a comparator intervention, then it is cost-saving, and that really is an unusual finding in health or medicine; perhaps 10% or 15% of interventions turn out to be cost-saving,” he said. “These are interventions that we want to adopt and put into practice pretty much without question.”

By the same measure, if an intervention is more costly and less effective, it’s easy to dismiss “out of hand,” Dr. Herman said. However, interpreting some of the studies he evaluated was more nuanced. “The problem occurs when a new treatment is both more effective but more costly, which was the case with two of the five analyses of metabolic surgery, and all of the analysis of bariatric surgery in the nondiabetic population,” he said

While gastric bypass surgery for type 2 diabetes is a good value, Dr. Herman added a few caveats. “When one looks at other interventions in similar categories, metformin for diabetes prevention has recently been shown to be cost-saving,” he said. He also said surgery is more cost-effective than marginally cost-effective interventions like intensive glycemic management for people with newly diagnosed type 2 diabetes or retinal screening every year vs. every 2 years.

One key issue with the existing evidence on cost-effectiveness of metabolic surgery for type 2 diabetes that Dr. Herman elucidated is how the studies accounted for participants lost to follow-up. “We know that a patient lost to follow-up may have a less favorable outcome than one who returns for follow-up,” he said. There are two ways studies can account for lost patients: the available-case analysis, which assumes that the patients lost to follow-up have the same rates of remission; and the attrition-adjusted available case follow-up, which uses a worst-case imputation. “I would argue that to account for attrition bias, remission rates calculated using the cases available for follow-up should be adjusted using worst-case imputation,” Dr. Herman said.

He pointed out another limitation when calculating the value of gastric bypass surgery for type 2 diabetes: “There are no randomized clinical trials of metabolic surgery that describe its long-term impact on diabetes treatments, complications, comorbidities, and survival. And it really is going be very important to get these data to confirm the cost-effectiveness of metabolic surgery.”

Among the shortcomings of the existing literature he noted are the assumptions that treatment-related adverse events are self-limited, that body mass index (BMI) achieved up to 5 years after surgery will remain stable, and that diabetes will not relapse. “The data are pretty good now on reversal, remission, hernia repair, and those sorts of things, but we need to look at longer downstream costs associated with surgery, including the need for cholecystectomy, joint replacements, and nutritional deficiencies that may occur and do clearly have financial implications,” he said.

At the same time, the analyses on gastric bypass surgery for type 2 diabetes could be more favorable if they account for improvements in health-related quality-of-life and rely less on cross-sectional data. Dr. Herman said, “I would argue that using cross-sectional data to estimate changes in health-related quality of life as a function of BMI underestimates the improvements on health-related quality-of-life associated with weight loss and will in fact underestimate the cost utility of interventions for obesity treatment,” he said.

Dr. Herman added, “Clearly the evidence to date suggests that metabolic surgery is cost-effective, but I’ll be more assured when I see longer-term follow-up.”

Dr. Herman has no financial relationships to disclose.

Supreme Court justices have deadlocked on whether protections for undocumented immigrants can be expanded under an executive order by the President.

In a June 23 decision, justices were equally divided on the constitutionality of two of President Obama’s immigration policies: the Deferred Action for Parents of Americans and Lawful Permanent Residents (DAPA) and an expanded version of the Deferred Action for Childhood Arrivals (DACA). The former protects undocumented immigrants who are parents of U.S. citizens from deportation, if they meet certain criteria. The second extends work authorization under the original DACA program from 2 years to 3 years and broadens age requirements.

whitehouse.gov

The 4-to-4 split decision in Texas v. United States mean the policies remain blocked by the lower court, and the expanded programs will not go forward anytime soon. The decision does not affect original DACA, which protects from deportation undocumented immigrants brought to the United States as children and offers access to work authorization.

President Obama expressed disappointment at the lack of agreement, saying the tie vote underscores the need for nine justices on the court.

“As disappointing as it was to be challenged for taking the kind of action that other administrations have taken, the country was looking to the Supreme Court to resolve the important legal questions raised in this case,” President Obama said during a June 23 press conference. “Today, the Supreme Court was unable to reach a decision ... it means the expanded set of common sense deferred action policies that I announced 2 years ago cannot go forward at this stage until there is a ninth justice on the court to break the tie.”

Texas Attorney General Ken Paxton was satisfied with the decision, calling it a victory for the state plaintiffs.

“Today’s decision keeps in place what we have maintained from the very start: one person, even a president, cannot unilaterally change the law,” Mr. Paxton said in a statement. “This is a major setback to President Obama’s attempts to expand executive power, and a victory for those who believe in the separation of powers and the rule of law.”

Texas was 1 of 26 states that sued over DAPA and expanded DACA. The states argued the president does not have the authority to issue the new immigration policies, and that the programs violate the Constitution as well as the Administrative Procedure Act for notice-and-comment rule making. Justices heard oral arguments April 18.

Immigration advocates were worried that if expanded DACA were struck down, a similar fate would follow for the original DACA policy. As it stands, undocumented immigrants who benefit from deportation protection and work authorization under original DACA, including undocumented medical students, will not be affected by the Supreme Court decision.

Marielena Hincapié, executive director for the National Immigration Law Center, vowed to continue fighting for the policies to take effect.

“Immigrants and allies fought for and won these significant policy victories, which would have brought much-needed emotional and economic stability to millions of our community members, and we will not sit back,” she said in a statement. “We urge the Department of Justice to seek a rehearing for when a ninth justice is confirmed for the Supreme Court.”

Federation for American Immigration Reform President Dan Stein said the split decision upholds the rule of law and helps preserve the balance of power in the United States.

“By ruling in favor of the federal court’s injunction, half of the nation’s Supreme Court Justices have shown that they have deep concerns about this president’s attempt at a power grab by his efforts to amend federal laws from the Oval Office,” Mr. Stein said in a statement.

Texas v. United States will be sent back to U.S. District Court Judge Andrew Hanen in Texas who will hear the case on its merits. The case could wind its way back to the U.S. Supreme Court for a rehearing after a ninth justice is confirmed.

[email protected]

On Twitter @legal_med

Supreme Court justices have deadlocked on whether protections for undocumented immigrants can be expanded under an executive order by the President.

In a June 23 decision, justices were equally divided on the constitutionality of two of President Obama’s immigration policies: the Deferred Action for Parents of Americans and Lawful Permanent Residents (DAPA) and an expanded version of the Deferred Action for Childhood Arrivals (DACA). The former protects undocumented immigrants who are parents of U.S. citizens from deportation, if they meet certain criteria. The second extends work authorization under the original DACA program from 2 years to 3 years and broadens age requirements.

whitehouse.gov

The 4-to-4 split decision in Texas v. United States mean the policies remain blocked by the lower court, and the expanded programs will not go forward anytime soon. The decision does not affect original DACA, which protects from deportation undocumented immigrants brought to the United States as children and offers access to work authorization.

President Obama expressed disappointment at the lack of agreement, saying the tie vote underscores the need for nine justices on the court.

“As disappointing as it was to be challenged for taking the kind of action that other administrations have taken, the country was looking to the Supreme Court to resolve the important legal questions raised in this case,” President Obama said during a June 23 press conference. “Today, the Supreme Court was unable to reach a decision ... it means the expanded set of common sense deferred action policies that I announced 2 years ago cannot go forward at this stage until there is a ninth justice on the court to break the tie.”

Texas Attorney General Ken Paxton was satisfied with the decision, calling it a victory for the state plaintiffs.

“Today’s decision keeps in place what we have maintained from the very start: one person, even a president, cannot unilaterally change the law,” Mr. Paxton said in a statement. “This is a major setback to President Obama’s attempts to expand executive power, and a victory for those who believe in the separation of powers and the rule of law.”

Texas was 1 of 26 states that sued over DAPA and expanded DACA. The states argued the president does not have the authority to issue the new immigration policies, and that the programs violate the Constitution as well as the Administrative Procedure Act for notice-and-comment rule making. Justices heard oral arguments April 18.

Immigration advocates were worried that if expanded DACA were struck down, a similar fate would follow for the original DACA policy. As it stands, undocumented immigrants who benefit from deportation protection and work authorization under original DACA, including undocumented medical students, will not be affected by the Supreme Court decision.

Marielena Hincapié, executive director for the National Immigration Law Center, vowed to continue fighting for the policies to take effect.

“Immigrants and allies fought for and won these significant policy victories, which would have brought much-needed emotional and economic stability to millions of our community members, and we will not sit back,” she said in a statement. “We urge the Department of Justice to seek a rehearing for when a ninth justice is confirmed for the Supreme Court.”

Federation for American Immigration Reform President Dan Stein said the split decision upholds the rule of law and helps preserve the balance of power in the United States.

“By ruling in favor of the federal court’s injunction, half of the nation’s Supreme Court Justices have shown that they have deep concerns about this president’s attempt at a power grab by his efforts to amend federal laws from the Oval Office,” Mr. Stein said in a statement.

Texas v. United States will be sent back to U.S. District Court Judge Andrew Hanen in Texas who will hear the case on its merits. The case could wind its way back to the U.S. Supreme Court for a rehearing after a ninth justice is confirmed.

[email protected]

On Twitter @legal_med

Supreme Court justices have deadlocked on whether protections for undocumented immigrants can be expanded under an executive order by the President.

In a June 23 decision, justices were equally divided on the constitutionality of two of President Obama’s immigration policies: the Deferred Action for Parents of Americans and Lawful Permanent Residents (DAPA) and an expanded version of the Deferred Action for Childhood Arrivals (DACA). The former protects undocumented immigrants who are parents of U.S. citizens from deportation, if they meet certain criteria. The second extends work authorization under the original DACA program from 2 years to 3 years and broadens age requirements.

whitehouse.gov

The 4-to-4 split decision in Texas v. United States mean the policies remain blocked by the lower court, and the expanded programs will not go forward anytime soon. The decision does not affect original DACA, which protects from deportation undocumented immigrants brought to the United States as children and offers access to work authorization.

President Obama expressed disappointment at the lack of agreement, saying the tie vote underscores the need for nine justices on the court.

“As disappointing as it was to be challenged for taking the kind of action that other administrations have taken, the country was looking to the Supreme Court to resolve the important legal questions raised in this case,” President Obama said during a June 23 press conference. “Today, the Supreme Court was unable to reach a decision ... it means the expanded set of common sense deferred action policies that I announced 2 years ago cannot go forward at this stage until there is a ninth justice on the court to break the tie.”

Texas Attorney General Ken Paxton was satisfied with the decision, calling it a victory for the state plaintiffs.

“Today’s decision keeps in place what we have maintained from the very start: one person, even a president, cannot unilaterally change the law,” Mr. Paxton said in a statement. “This is a major setback to President Obama’s attempts to expand executive power, and a victory for those who believe in the separation of powers and the rule of law.”

Texas was 1 of 26 states that sued over DAPA and expanded DACA. The states argued the president does not have the authority to issue the new immigration policies, and that the programs violate the Constitution as well as the Administrative Procedure Act for notice-and-comment rule making. Justices heard oral arguments April 18.

Immigration advocates were worried that if expanded DACA were struck down, a similar fate would follow for the original DACA policy. As it stands, undocumented immigrants who benefit from deportation protection and work authorization under original DACA, including undocumented medical students, will not be affected by the Supreme Court decision.

Marielena Hincapié, executive director for the National Immigration Law Center, vowed to continue fighting for the policies to take effect.

“Immigrants and allies fought for and won these significant policy victories, which would have brought much-needed emotional and economic stability to millions of our community members, and we will not sit back,” she said in a statement. “We urge the Department of Justice to seek a rehearing for when a ninth justice is confirmed for the Supreme Court.”

Federation for American Immigration Reform President Dan Stein said the split decision upholds the rule of law and helps preserve the balance of power in the United States.

“By ruling in favor of the federal court’s injunction, half of the nation’s Supreme Court Justices have shown that they have deep concerns about this president’s attempt at a power grab by his efforts to amend federal laws from the Oval Office,” Mr. Stein said in a statement.

Texas v. United States will be sent back to U.S. District Court Judge Andrew Hanen in Texas who will hear the case on its merits. The case could wind its way back to the U.S. Supreme Court for a rehearing after a ninth justice is confirmed.

[email protected]

On Twitter @legal_med

Truly, the right to bear firearms is not something that should be in the domain of the psychiatrist, but in our current landscape, it’s fallen into our realm. Personally, (as opposed to professionally), it seems to me that there is no reason that someone needs to own an assault weapon, and Americans somehow survived without them for 10 years from 1994 to 2004 during a national ban on assault weapons, inspired in part by the massacre of children in a 1989 mass shooting at a Stockton, Calif., school, followed in 1993 by a street shooting where eight people were killed in San Francisco.

A CNN poll conducted in 1993 revealed that 73% of those polled opposed the manufacture, sale, or possession of assault weapons, and back then, the politics of gun control were less partisan: Former Republican President Ronald Reagan supported legislation to make them illegal. The ban on assault weapons expired in 2004, and mass shooters have been able to obtain these weapons legally and have used them for many of the highly publicized massacres we read about, now several times a year.

What shocks me is that we manufacture these weapons to allow for rapid and efficient discharge, we make these firearms easily accessible to anyone who wants them in more than 40 states, and then we are surprised when people use them to do exactly what they were designed to do: kill lots of people quickly. Those who oppose bans on these weapons insist that terrorists will find other ways: They will use illegal weapons, bombs made from pressure cookers, biologic agents, or explosives. They may be right; that doesn’t mean our government needs to make it easy for gunmen to massacre innocent people.

Until recently, the discussion about mass murder somehow pitted mental illness against gun control, so like it or not, psychiatry was pulled into the discussion of mass murder. Does this make sense? Very little of gun violence takes the form of these highly publicized mass murders – perhaps 1%. But if you’ve turned on CNN lately, they get a lot of air time, while the deaths of countless others – dozens a day in our gun-drenched cities – are now just part of the routine risks of life. If you hold your definition of mass murders to the deaths of four victims in a public place, then most mass murders are what we see in the news: Aurora, Newtown, Fort Hood, Isla Vista, and the list goes on. Of those shooters, roughly half had some history of some kind of mental illness. If you enlarge the definition, as some do, to include any shooting where four or more victims die, then the association with mental illness drops. Many of these killings are domestic and gang violence, or deaths that occur during the commission of another crime.

Overall, it is estimated that less than 10% of gun murders are caused by mental illness, and the politically correct mantra of the time is to point out that people with mental illness are more likely to be the victims of violence than to perpetrate it. Finally, most gun deaths are suicides and not homicides – a distinction not made by CNN.

Despite the staggering rise in gun deaths in our country, and the clear link between gun availability and gun deaths, our federal legislators are stuck; no new gun legislation has passed. Our Congress has made the quiet statement after Newtown that the National Rifle Association (NRA) is remarkably powerful, and perhaps the story was over when we decided that killing children is acceptable. If that’s not enough, Congress was not propelled to action when one of their own was shot in the head during a massacre.

If I feel frustrated and let off steam by tweeting, how awful former U.S. Rep. Gabby Giffords must feel that her former colleagues have not embraced her advocacy actions with Americans for Responsible Solutions.

Over the last week, we’ve seen Sen. Chris Murphy (D-Conn.) stage a 15-hour filibuster on two gun safety amendments. One would close the terror gap; the other sought to expand background checks for firearms purchases. Both measures failed, as did two other gun control measures in the Senate. We’ve also seen House Democrats conduct a sit-in in an effort to force gun control votes. We can’t even agree that those under FBI surveillance for terrorist activities and those on a no-fly list should not be allowed to purchase firearms of any type, including assault rifles. The response is that the right to own guns is protected by the Constitution and can’t be denied without a judicial process.

In the case of those with mental illnesses, individual states do not allow for such protections. In New York, the NYSAFE Act allows that patients can be reported to the state, then placed on the National Instant Criminal Background Check System, to prevent gun purchases if a therapist believes a patient is at risk of violence. There needs to be no dangerous act and no history of hospitalization to set this in motion, just a therapist’s belief. And all patients who are involuntarily hospitalized in New York are placed in the database.

California is different with its efforts to keep guns from those with mental disorders: Anyone brought in for a psychiatric evaluation by law enforcement or involuntarily hospitalized from an ER on what is commonly known as a “5150 hold,” loses the right to own a gun for 5 years. There is no hearing at that point, and those who are later released at the commitment hearing do not get their gun rights back.

In Maryland, where I live, the restrictions are a mixed bag: Anyone who remains in a psychiatric hospital for more than 30 days, voluntarily or otherwise and without regard to dangerousness, loses his right to own a gun. In addition, more recent legislation has added that at commitment hearings, the administrative law judge determines whether the patient may retain gun rights based on an assessment of his dangerousness toward others.

Each state is different, but for psychiatric patients who are lawful gun owners, seeking help can be a mixed bag, and they certainly do not get the national civil rights protections that we afford terror suspects. Does the fear of losing the right to bear arms play into a hunter’s decision to seek mental health care? It’s hard to imagine that it would not. While we advocate for decreasing stigma and getting care for those who need help, we also erect barriers and increase stigma in this odd mixed-message public health endeavor.

Given the vocal nature of gun control advocates, it’s hard not to wonder whether the unwillingness of Congress to pass laws that might make us safer is about the will of the people or the dollar amount that legislatures receive from the NRA. I am sure there are readers who disagree with me and feel that more guns in the hands of “good guys” make us all safer, but I continue to find it interesting that mental illness does not cause mass murder – at least not with the numbers we see in the United States – in countries with stricter gun control.

Those who advocate for gun rights remain unconcerned about the high incidence of guns and suicide. Many believe that people should have the right to take their own lives, and if a gun were not available, another means would be found. In some cases, there is no doubt that this is true. In others, we worry that an easily accessible gun in the hands of a suicidal person has a very high rate of mortality, and there is no room for second thoughts or chances after an impulsive decision.

Psychiatry has been lassoed here – guns are our domain whether we want them to be or not – and we already are starting to see patients who want us to advocate for their right to retain their firearms. While I can’t imagine taking on the responsibility or liability of saying my patient (or anyone else) is safe with a firearm, there may be moments where it seems there is little choice, especially when a firearm is required for the patient’s employment. In the meantime, I keep hoping our legislators will wake up and come to their senses.

Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care,” forthcoming from Johns Hopkins University Press in fall 2016.

Truly, the right to bear firearms is not something that should be in the domain of the psychiatrist, but in our current landscape, it’s fallen into our realm. Personally, (as opposed to professionally), it seems to me that there is no reason that someone needs to own an assault weapon, and Americans somehow survived without them for 10 years from 1994 to 2004 during a national ban on assault weapons, inspired in part by the massacre of children in a 1989 mass shooting at a Stockton, Calif., school, followed in 1993 by a street shooting where eight people were killed in San Francisco.

A CNN poll conducted in 1993 revealed that 73% of those polled opposed the manufacture, sale, or possession of assault weapons, and back then, the politics of gun control were less partisan: Former Republican President Ronald Reagan supported legislation to make them illegal. The ban on assault weapons expired in 2004, and mass shooters have been able to obtain these weapons legally and have used them for many of the highly publicized massacres we read about, now several times a year.

What shocks me is that we manufacture these weapons to allow for rapid and efficient discharge, we make these firearms easily accessible to anyone who wants them in more than 40 states, and then we are surprised when people use them to do exactly what they were designed to do: kill lots of people quickly. Those who oppose bans on these weapons insist that terrorists will find other ways: They will use illegal weapons, bombs made from pressure cookers, biologic agents, or explosives. They may be right; that doesn’t mean our government needs to make it easy for gunmen to massacre innocent people.

Until recently, the discussion about mass murder somehow pitted mental illness against gun control, so like it or not, psychiatry was pulled into the discussion of mass murder. Does this make sense? Very little of gun violence takes the form of these highly publicized mass murders – perhaps 1%. But if you’ve turned on CNN lately, they get a lot of air time, while the deaths of countless others – dozens a day in our gun-drenched cities – are now just part of the routine risks of life. If you hold your definition of mass murders to the deaths of four victims in a public place, then most mass murders are what we see in the news: Aurora, Newtown, Fort Hood, Isla Vista, and the list goes on. Of those shooters, roughly half had some history of some kind of mental illness. If you enlarge the definition, as some do, to include any shooting where four or more victims die, then the association with mental illness drops. Many of these killings are domestic and gang violence, or deaths that occur during the commission of another crime.

Overall, it is estimated that less than 10% of gun murders are caused by mental illness, and the politically correct mantra of the time is to point out that people with mental illness are more likely to be the victims of violence than to perpetrate it. Finally, most gun deaths are suicides and not homicides – a distinction not made by CNN.

Despite the staggering rise in gun deaths in our country, and the clear link between gun availability and gun deaths, our federal legislators are stuck; no new gun legislation has passed. Our Congress has made the quiet statement after Newtown that the National Rifle Association (NRA) is remarkably powerful, and perhaps the story was over when we decided that killing children is acceptable. If that’s not enough, Congress was not propelled to action when one of their own was shot in the head during a massacre.

If I feel frustrated and let off steam by tweeting, how awful former U.S. Rep. Gabby Giffords must feel that her former colleagues have not embraced her advocacy actions with Americans for Responsible Solutions.

Over the last week, we’ve seen Sen. Chris Murphy (D-Conn.) stage a 15-hour filibuster on two gun safety amendments. One would close the terror gap; the other sought to expand background checks for firearms purchases. Both measures failed, as did two other gun control measures in the Senate. We’ve also seen House Democrats conduct a sit-in in an effort to force gun control votes. We can’t even agree that those under FBI surveillance for terrorist activities and those on a no-fly list should not be allowed to purchase firearms of any type, including assault rifles. The response is that the right to own guns is protected by the Constitution and can’t be denied without a judicial process.

In the case of those with mental illnesses, individual states do not allow for such protections. In New York, the NYSAFE Act allows that patients can be reported to the state, then placed on the National Instant Criminal Background Check System, to prevent gun purchases if a therapist believes a patient is at risk of violence. There needs to be no dangerous act and no history of hospitalization to set this in motion, just a therapist’s belief. And all patients who are involuntarily hospitalized in New York are placed in the database.

California is different with its efforts to keep guns from those with mental disorders: Anyone brought in for a psychiatric evaluation by law enforcement or involuntarily hospitalized from an ER on what is commonly known as a “5150 hold,” loses the right to own a gun for 5 years. There is no hearing at that point, and those who are later released at the commitment hearing do not get their gun rights back.

In Maryland, where I live, the restrictions are a mixed bag: Anyone who remains in a psychiatric hospital for more than 30 days, voluntarily or otherwise and without regard to dangerousness, loses his right to own a gun. In addition, more recent legislation has added that at commitment hearings, the administrative law judge determines whether the patient may retain gun rights based on an assessment of his dangerousness toward others.

Each state is different, but for psychiatric patients who are lawful gun owners, seeking help can be a mixed bag, and they certainly do not get the national civil rights protections that we afford terror suspects. Does the fear of losing the right to bear arms play into a hunter’s decision to seek mental health care? It’s hard to imagine that it would not. While we advocate for decreasing stigma and getting care for those who need help, we also erect barriers and increase stigma in this odd mixed-message public health endeavor.

Given the vocal nature of gun control advocates, it’s hard not to wonder whether the unwillingness of Congress to pass laws that might make us safer is about the will of the people or the dollar amount that legislatures receive from the NRA. I am sure there are readers who disagree with me and feel that more guns in the hands of “good guys” make us all safer, but I continue to find it interesting that mental illness does not cause mass murder – at least not with the numbers we see in the United States – in countries with stricter gun control.

Those who advocate for gun rights remain unconcerned about the high incidence of guns and suicide. Many believe that people should have the right to take their own lives, and if a gun were not available, another means would be found. In some cases, there is no doubt that this is true. In others, we worry that an easily accessible gun in the hands of a suicidal person has a very high rate of mortality, and there is no room for second thoughts or chances after an impulsive decision.

Psychiatry has been lassoed here – guns are our domain whether we want them to be or not – and we already are starting to see patients who want us to advocate for their right to retain their firearms. While I can’t imagine taking on the responsibility or liability of saying my patient (or anyone else) is safe with a firearm, there may be moments where it seems there is little choice, especially when a firearm is required for the patient’s employment. In the meantime, I keep hoping our legislators will wake up and come to their senses.

Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care,” forthcoming from Johns Hopkins University Press in fall 2016.

Truly, the right to bear firearms is not something that should be in the domain of the psychiatrist, but in our current landscape, it’s fallen into our realm. Personally, (as opposed to professionally), it seems to me that there is no reason that someone needs to own an assault weapon, and Americans somehow survived without them for 10 years from 1994 to 2004 during a national ban on assault weapons, inspired in part by the massacre of children in a 1989 mass shooting at a Stockton, Calif., school, followed in 1993 by a street shooting where eight people were killed in San Francisco.

A CNN poll conducted in 1993 revealed that 73% of those polled opposed the manufacture, sale, or possession of assault weapons, and back then, the politics of gun control were less partisan: Former Republican President Ronald Reagan supported legislation to make them illegal. The ban on assault weapons expired in 2004, and mass shooters have been able to obtain these weapons legally and have used them for many of the highly publicized massacres we read about, now several times a year.

What shocks me is that we manufacture these weapons to allow for rapid and efficient discharge, we make these firearms easily accessible to anyone who wants them in more than 40 states, and then we are surprised when people use them to do exactly what they were designed to do: kill lots of people quickly. Those who oppose bans on these weapons insist that terrorists will find other ways: They will use illegal weapons, bombs made from pressure cookers, biologic agents, or explosives. They may be right; that doesn’t mean our government needs to make it easy for gunmen to massacre innocent people.

Until recently, the discussion about mass murder somehow pitted mental illness against gun control, so like it or not, psychiatry was pulled into the discussion of mass murder. Does this make sense? Very little of gun violence takes the form of these highly publicized mass murders – perhaps 1%. But if you’ve turned on CNN lately, they get a lot of air time, while the deaths of countless others – dozens a day in our gun-drenched cities – are now just part of the routine risks of life. If you hold your definition of mass murders to the deaths of four victims in a public place, then most mass murders are what we see in the news: Aurora, Newtown, Fort Hood, Isla Vista, and the list goes on. Of those shooters, roughly half had some history of some kind of mental illness. If you enlarge the definition, as some do, to include any shooting where four or more victims die, then the association with mental illness drops. Many of these killings are domestic and gang violence, or deaths that occur during the commission of another crime.

Overall, it is estimated that less than 10% of gun murders are caused by mental illness, and the politically correct mantra of the time is to point out that people with mental illness are more likely to be the victims of violence than to perpetrate it. Finally, most gun deaths are suicides and not homicides – a distinction not made by CNN.

Despite the staggering rise in gun deaths in our country, and the clear link between gun availability and gun deaths, our federal legislators are stuck; no new gun legislation has passed. Our Congress has made the quiet statement after Newtown that the National Rifle Association (NRA) is remarkably powerful, and perhaps the story was over when we decided that killing children is acceptable. If that’s not enough, Congress was not propelled to action when one of their own was shot in the head during a massacre.

If I feel frustrated and let off steam by tweeting, how awful former U.S. Rep. Gabby Giffords must feel that her former colleagues have not embraced her advocacy actions with Americans for Responsible Solutions.

Over the last week, we’ve seen Sen. Chris Murphy (D-Conn.) stage a 15-hour filibuster on two gun safety amendments. One would close the terror gap; the other sought to expand background checks for firearms purchases. Both measures failed, as did two other gun control measures in the Senate. We’ve also seen House Democrats conduct a sit-in in an effort to force gun control votes. We can’t even agree that those under FBI surveillance for terrorist activities and those on a no-fly list should not be allowed to purchase firearms of any type, including assault rifles. The response is that the right to own guns is protected by the Constitution and can’t be denied without a judicial process.

In the case of those with mental illnesses, individual states do not allow for such protections. In New York, the NYSAFE Act allows that patients can be reported to the state, then placed on the National Instant Criminal Background Check System, to prevent gun purchases if a therapist believes a patient is at risk of violence. There needs to be no dangerous act and no history of hospitalization to set this in motion, just a therapist’s belief. And all patients who are involuntarily hospitalized in New York are placed in the database.

California is different with its efforts to keep guns from those with mental disorders: Anyone brought in for a psychiatric evaluation by law enforcement or involuntarily hospitalized from an ER on what is commonly known as a “5150 hold,” loses the right to own a gun for 5 years. There is no hearing at that point, and those who are later released at the commitment hearing do not get their gun rights back.

In Maryland, where I live, the restrictions are a mixed bag: Anyone who remains in a psychiatric hospital for more than 30 days, voluntarily or otherwise and without regard to dangerousness, loses his right to own a gun. In addition, more recent legislation has added that at commitment hearings, the administrative law judge determines whether the patient may retain gun rights based on an assessment of his dangerousness toward others.

Each state is different, but for psychiatric patients who are lawful gun owners, seeking help can be a mixed bag, and they certainly do not get the national civil rights protections that we afford terror suspects. Does the fear of losing the right to bear arms play into a hunter’s decision to seek mental health care? It’s hard to imagine that it would not. While we advocate for decreasing stigma and getting care for those who need help, we also erect barriers and increase stigma in this odd mixed-message public health endeavor.

Given the vocal nature of gun control advocates, it’s hard not to wonder whether the unwillingness of Congress to pass laws that might make us safer is about the will of the people or the dollar amount that legislatures receive from the NRA. I am sure there are readers who disagree with me and feel that more guns in the hands of “good guys” make us all safer, but I continue to find it interesting that mental illness does not cause mass murder – at least not with the numbers we see in the United States – in countries with stricter gun control.

Those who advocate for gun rights remain unconcerned about the high incidence of guns and suicide. Many believe that people should have the right to take their own lives, and if a gun were not available, another means would be found. In some cases, there is no doubt that this is true. In others, we worry that an easily accessible gun in the hands of a suicidal person has a very high rate of mortality, and there is no room for second thoughts or chances after an impulsive decision.

Psychiatry has been lassoed here – guns are our domain whether we want them to be or not – and we already are starting to see patients who want us to advocate for their right to retain their firearms. While I can’t imagine taking on the responsibility or liability of saying my patient (or anyone else) is safe with a firearm, there may be moments where it seems there is little choice, especially when a firearm is required for the patient’s employment. In the meantime, I keep hoping our legislators will wake up and come to their senses.

Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care,” forthcoming from Johns Hopkins University Press in fall 2016.

United States health care is moving rapidly from volume- to value-based reimbursement. An essential part of this movement will be the development of alternative payment models where a specific bundle of care (colonoscopy), episode of care (a year of care for attributed Crohn’s patients), or ongoing care of a specialty-centric patient population (patients with cirrhosis) are covered within a contract that links health outcomes, quality of care, and payment together. Gastroenterologists are slowly becoming aware of these concepts. Primary care has its patient-centered medical home and now specialists have a patient-centric specialty practice where patient populations are cared for principally by a specialty practice within a well-defined care delivery structure. Previous columns have illustrated these concepts, and this month, Meier and colleagues provide an excellent definition and example of how practices can participate in this new world order.

John I Allen, M.D., MBA, AGAF, Special Section Editor

The Patient Protection and Affordable Care Act secures access to health insurance coverage for many previously uninsured individuals, while transforming the structure of health care delivery to promote high value care that is coordinated and patient-centered.¹ The development of innovative care delivery models is a key feature of this transformation. In turn, patient-centered medical homes (PCMHs) have proliferated in number, with PCMH-related pilot and demonstration projects spanning numerous federal agencies.²

Defining the patient-centered medical home

The concept of the PCMH predates the Patient Protection and Affordable Care Act, with its origins in the American Academy of Pediatrics’ 1967 discussion of the medical home. In 2007, a joint release by the American Academy of Family Physicians, the American Academy of Pediatrics, the American College of Physicians, and the American Osteopathic Association defined the PCMH as “an approach to providing comprehensive primary care for children, youth and adults.” Furthermore, the PCMH would serve as “a health care setting that facilitates partnerships between individual patients, and their personal physicians, and when appropriate, the patient’s family.” Several key principles underscore the PCMH model; the patient has a personal physician, and care is physician-directed at the level of the practice, oriented around the whole person, and coordinated to ensure the highest quality and safety of medical care. The PCMH facilitates enhanced access to care, and the payment structure incentivizes and compensates high-quality care delivery.³

Advent of the patient-centered specialty practice

In 2013 the National Committee for Quality Assurance (NCQA), which operates the Patient Centered Medical Home Recognition program, released a set of standards governing the recognition of the patient-centered specialty practice (PCSP).⁴ Similar to the PCMH model, the PCSP model places the patient at the center of care delivery. Key functions of the PCSP include placing the patient at the center of care, sharing of information, and coordinating across all practices (specialty and primary) for patients.⁵ The NCQA outlines six standards for PCSP recognition; these standards focus on planning, management, tracking and coordination of care, performance measurement, performance improvement, referrals, communication to patients, care access, and coordination and management for populations.⁵

Centering patient care in the specialty practice

With the release of the NCQA PCSP standards, provider groups and regulators should work to identify circumstances under which the PCSP might best operate as an effective model for the populations they serve. For example, in the case of mental illness that is both severe and persistent, the creation of a PCMH may disrupt existing patient-provider relationships, increase fragmentation of medical care, and position poorly equipped providers at the center of a care process that requires greater specialization.⁶

Drawing from this example, we suggest that select patient populations with advanced chronic liver disease may benefit from the development of patient-centered care models that operate such as a PCSP. This may include patients with compensated cirrhosis and other comorbid illnesses such as diabetes mellitus or depression, populations with active complications of portal hypertension, or patients who await or have received liver transplantation.^7,8 We suggest examining the potential value of this model in circumstances where the complexity of patient needs or the sensitivity and vulnerability of the patient circumstance may best be managed by an established, trusted, and specialized provider. In the case of patients with cirrhosis and substance abuse from alcohol, a hybrid specialty model that incorporates addiction medicine, social work, and psychiatry providers in addition to hepatologists and allied health providers may be warranted.⁷

Designing the patient-centered specialty practice for populations with cirrhosis and liver transplant recipients

Practices and providers should carefully assess the context for PCSP adoption, identifying whether the specialty care model will promote greater efficiency and quality than that realized in the absence of a PCSP model. The PCSP model should align with patient needs, considering factors such as cause of disease, disease stage, comorbidities and complications, and socioeconomic factors. Although the NCQA PCSP standards should guide model development, there are specific needs and complexities of cirrhosis and liver transplant populations that may prove highly relevant in identifying one or more ideal model designs. This may entail development of additional PCSP standards beyond what is recognized by NCQA.

Table 1 outlines key questions providers might address when considering the development of the PCSP in this patient population. We divide these questions into three main categories: 1) understanding the context for PCSP model adoption, 2) identifying opportunities to align the PCSP model with the specific needs of the patient population, and 3) selecting a model design. Incorporating careful consideration of the questions highlighted within each of these categories can help inform practitioners on the merits of various PCSP models.

Understanding the context for patient-centered specialty practice adoption

Drawing from Alakeson et al.,⁹ we suggest that providers embarking on PCSP model adoption first consider how the quality of care and strength of patient-provider relationships for the target population will improve. The selection of an appropriate patient population is a key determinant in the answer to this question. Focusing specifically on the cirrhosis population, the PCSP may need to be directed toward a disease stage (i.e., decompensated cirrhosis) where the specialist is the most frequent and continuous point of system access. Similarly, the PCSP might yield the greatest gains in quality when access is a function of requiring specialized knowledge in the day-to-day management of care delivery (i.e., compensated liver disease or long-term post liver transplant recipients).

The case for the PCSP may be particularly strong in instances where the primary care provider lacks sufficient knowledge to appropriately manage patient care. For example, treatment of mental and behavioral health conditions that are comorbid with cirrhosis may best be suited to a specialized and established care team that has secured patient trust. Many transplant centers in the United States have explicitly created teams in this regard in the context of regulatory requirements for being a transplant program.¹⁰

Identifying opportunities to align the patient-centered specialty practice model with the specific needs of the patient population

Liver transplant and cirrhosis patients exhibit variability in the cause of disease, with genetic, social-behavioral, and other causal mechanisms operating as factors in the expression of disease. Developing a model focused on reduction in the risk of need for transplant might differ from these former two examples in target population and specialist team. A relevant example is with hospital readmissions because multiple studies to date have documented at least a 20% frequency of re-hospitalization within 30 days of index readmission.^11,12 Although disease severity indicated by Model for End Stage Liver Disease score explains a significant amount of the variability in risk for readmission, there are other factors including frailty¹³ and complications from index hospitalization14 that also contribute to 30-day readmission. The use of case management and remote monitoring strategies for patients at risk for hospital readmission is likely to be included in a PCSP focused on reducing inpatient utilization.

Variability in the social and economic context surrounding a patient’s daily life should also factor into model design. In the case of Medicaid coverage, a well-designed model might address discontinuities in specific provider and service access arising from churning in Medicaid eligibility and coverage.

Selecting a model design

Three examples of specialty care medical home designs have been described in the literature including the integrated model concept and two variants of the partnership model design. The integrated model concept provides specialty and primary care in one location, whereas the partnership models include an on-site liaison at the specialty practice, either a nurse practitioner who provides some degree of care and is able to draw from the services from an off-site primary care physician or otherwise an on-site nurse care manager who serves as an information source and advocate.⁹

We suggest that selection of model design should consider the number of specialty and primary care providers required to construct a comprehensive care team and whether there is reasonable capacity for patients to access comprehensive care in multiple settings. Providing a spectrum of services through separately located but coordinated PCSP and PCMH care models may be practical for some target populations. In other instances, multisite care programs may place an undesirable and impractical burden on patients with complex needs or low health system literacy.

As the field of PCSP model development moves forward, we suggest that providers learn from shared discussions of experience. If appropriate, innovation and shared learning should inform the development of additional standards to ensure that PCSP development for cirrhosis and transplant patients adheres to meaningful quality standards. As is clear from discussion, cirrhosis and liver transplant patients are a diverse group with a range of needs that fall across a spectrum of complexity. The development of well-structured PCSP models may require a high degree of specialization, where model adaptation acknowledges how specific disease-based needs, clinical comorbidities, and external support networks vary across groups.

One suggestion for moving forward is to focus early efforts narrowly on small and highly complex patient groups where the expected value of PCSP is large. This may entail beginning with patient groups whose clinical complexity may otherwise disqualify them from participation in traditional patient-centered care model demonstrations and evaluations. An ideal target population would be patients with decompensated cirrhosis who are ineligible for liver transplantation on the basis of multimorbidity. In addition, specialty providers might consider partnering with state agencies or patient groups in the development, testing, and funding of such programs. These partnerships may help to identify target patient populations with potential to benefit from participation in demonstration projects that innovate through the use of new PCSP model designs.

References

1. Sheen, E., Dorn, S.D., Brill, J.V., et al. Health care reform and the road ahead for gastroenterology. Clin Gastroenterol Hepatol. 2012;10:1062-5.

2. Agency for Healthcare Research and Quality. PCMH activities across federal agencies (Table 1). Available at: http://www.pcmh.ahrq.gov/sites/default/files/attachments/federal-pcmh-activities-table-1.pdf. Accessed May 13, 2015.

3. AAP, AAFP, ACP, and AOA. Joint principles of the patient-centered medical home, March 2007. Available at: http://www.acponline.org/running_practice/delivery_and_payment_models/pcmh/demonstrations/jointprinc_05_17.pdf. Accessed November 24, 2015.

4. Huang, X. Rosenthal, M.B. Transforming specialty practice–the patient-centered medical neighborhood. N Engl J Med. 2014;370:1376-9.

5. National Committee of Quality Assurance. Patient-centered specialty practice recognition: white paper. 2013. Available at: http://www.ncqa.org/Portals/0/Newsroom/2013/PCSP%20Launch/PCSPR%202013%20White%20Paper%203.26.13%20formatted.pdf. Accessed November 24, 2015.

6. National Committee of Quality Assurance. Patient-centered specialty practice frequently asked questions. Available at: http://www.ncqa.org/Programs/Recognition/Practices/PatientCenteredSpecialtyPracticePCSP/PatientCenteredSpecialtyPracticeFAQs.aspx Accessed June 4, 2015.

6. Kanwal, F. Coordinating care in patients with cirrhosis. Clin Gastroenterol Hepatol. 2013;11:859-61.

7. Fortune, B.E., Golus, A., Barsky, C.L., et al. Linking a hepatology clinical service line to quality improvement. Clin Gastroenterol Hepatol. 2015;13:1391-5.

8. Alakeson, V., Frank, R.G., Katz, R.E. Specialty care medical homes for people with severe, persistent mental disorders. Health Affairs. 2010;29:867-73.

9. Talwalkar, J.A. Potential impacts of the Affordable Care Act on the clinical practice of hepatology. Hepatology. 2014;59:1681-7.

9. Volk, M.L., Tocco, R.S., Bazick, J., et al. Hospital readmissions among patients with decompensated cirrhosis. Am J Gastroenterol. 2012;107:247-52.

10. Berman, K., Tandra, S., Forssell, K., et al. Incidence and predictors of 30-day readmission among patients hospitalized for advanced liver disease. Clin Gastroenterol Hepatol. 2011;9:254-9.

11. Tapper, E.B., Finkelstein, D., Mittleman, M.A., et al. Standard assessments of frailty are validated predictors of mortality in hospitalized patients with cirrhosis. Hepatology. 2015;62:584-90.

12. Eappen, S., Lane, B.H., Rosenberg, B., et al. Relationship between occurrence of surgical complications and hospital finances. JAMA. 2013;309:1599-606.

Dr. Meier, Dr. Shah, and Dr. Talwalkar are in the department of health care policy and research, department of health sciences research; Dr. Talwalkar is also in the division of gastroenterology and hepatology and the William von Liebig Center for Transplantation and Regenerative Medicine; Mayo Clinic, Rochester, Minn.

United States health care is moving rapidly from volume- to value-based reimbursement. An essential part of this movement will be the development of alternative payment models where a specific bundle of care (colonoscopy), episode of care (a year of care for attributed Crohn’s patients), or ongoing care of a specialty-centric patient population (patients with cirrhosis) are covered within a contract that links health outcomes, quality of care, and payment together. Gastroenterologists are slowly becoming aware of these concepts. Primary care has its patient-centered medical home and now specialists have a patient-centric specialty practice where patient populations are cared for principally by a specialty practice within a well-defined care delivery structure. Previous columns have illustrated these concepts, and this month, Meier and colleagues provide an excellent definition and example of how practices can participate in this new world order.

John I Allen, M.D., MBA, AGAF, Special Section Editor

The Patient Protection and Affordable Care Act secures access to health insurance coverage for many previously uninsured individuals, while transforming the structure of health care delivery to promote high value care that is coordinated and patient-centered.¹ The development of innovative care delivery models is a key feature of this transformation. In turn, patient-centered medical homes (PCMHs) have proliferated in number, with PCMH-related pilot and demonstration projects spanning numerous federal agencies.²

Defining the patient-centered medical home

The concept of the PCMH predates the Patient Protection and Affordable Care Act, with its origins in the American Academy of Pediatrics’ 1967 discussion of the medical home. In 2007, a joint release by the American Academy of Family Physicians, the American Academy of Pediatrics, the American College of Physicians, and the American Osteopathic Association defined the PCMH as “an approach to providing comprehensive primary care for children, youth and adults.” Furthermore, the PCMH would serve as “a health care setting that facilitates partnerships between individual patients, and their personal physicians, and when appropriate, the patient’s family.” Several key principles underscore the PCMH model; the patient has a personal physician, and care is physician-directed at the level of the practice, oriented around the whole person, and coordinated to ensure the highest quality and safety of medical care. The PCMH facilitates enhanced access to care, and the payment structure incentivizes and compensates high-quality care delivery.³

Advent of the patient-centered specialty practice

In 2013 the National Committee for Quality Assurance (NCQA), which operates the Patient Centered Medical Home Recognition program, released a set of standards governing the recognition of the patient-centered specialty practice (PCSP).⁴ Similar to the PCMH model, the PCSP model places the patient at the center of care delivery. Key functions of the PCSP include placing the patient at the center of care, sharing of information, and coordinating across all practices (specialty and primary) for patients.⁵ The NCQA outlines six standards for PCSP recognition; these standards focus on planning, management, tracking and coordination of care, performance measurement, performance improvement, referrals, communication to patients, care access, and coordination and management for populations.⁵

Centering patient care in the specialty practice

With the release of the NCQA PCSP standards, provider groups and regulators should work to identify circumstances under which the PCSP might best operate as an effective model for the populations they serve. For example, in the case of mental illness that is both severe and persistent, the creation of a PCMH may disrupt existing patient-provider relationships, increase fragmentation of medical care, and position poorly equipped providers at the center of a care process that requires greater specialization.⁶

Drawing from this example, we suggest that select patient populations with advanced chronic liver disease may benefit from the development of patient-centered care models that operate such as a PCSP. This may include patients with compensated cirrhosis and other comorbid illnesses such as diabetes mellitus or depression, populations with active complications of portal hypertension, or patients who await or have received liver transplantation.^7,8 We suggest examining the potential value of this model in circumstances where the complexity of patient needs or the sensitivity and vulnerability of the patient circumstance may best be managed by an established, trusted, and specialized provider. In the case of patients with cirrhosis and substance abuse from alcohol, a hybrid specialty model that incorporates addiction medicine, social work, and psychiatry providers in addition to hepatologists and allied health providers may be warranted.⁷

Designing the patient-centered specialty practice for populations with cirrhosis and liver transplant recipients

Practices and providers should carefully assess the context for PCSP adoption, identifying whether the specialty care model will promote greater efficiency and quality than that realized in the absence of a PCSP model. The PCSP model should align with patient needs, considering factors such as cause of disease, disease stage, comorbidities and complications, and socioeconomic factors. Although the NCQA PCSP standards should guide model development, there are specific needs and complexities of cirrhosis and liver transplant populations that may prove highly relevant in identifying one or more ideal model designs. This may entail development of additional PCSP standards beyond what is recognized by NCQA.

Table 1 outlines key questions providers might address when considering the development of the PCSP in this patient population. We divide these questions into three main categories: 1) understanding the context for PCSP model adoption, 2) identifying opportunities to align the PCSP model with the specific needs of the patient population, and 3) selecting a model design. Incorporating careful consideration of the questions highlighted within each of these categories can help inform practitioners on the merits of various PCSP models.

Understanding the context for patient-centered specialty practice adoption

Drawing from Alakeson et al.,⁹ we suggest that providers embarking on PCSP model adoption first consider how the quality of care and strength of patient-provider relationships for the target population will improve. The selection of an appropriate patient population is a key determinant in the answer to this question. Focusing specifically on the cirrhosis population, the PCSP may need to be directed toward a disease stage (i.e., decompensated cirrhosis) where the specialist is the most frequent and continuous point of system access. Similarly, the PCSP might yield the greatest gains in quality when access is a function of requiring specialized knowledge in the day-to-day management of care delivery (i.e., compensated liver disease or long-term post liver transplant recipients).

The case for the PCSP may be particularly strong in instances where the primary care provider lacks sufficient knowledge to appropriately manage patient care. For example, treatment of mental and behavioral health conditions that are comorbid with cirrhosis may best be suited to a specialized and established care team that has secured patient trust. Many transplant centers in the United States have explicitly created teams in this regard in the context of regulatory requirements for being a transplant program.¹⁰

Identifying opportunities to align the patient-centered specialty practice model with the specific needs of the patient population

Liver transplant and cirrhosis patients exhibit variability in the cause of disease, with genetic, social-behavioral, and other causal mechanisms operating as factors in the expression of disease. Developing a model focused on reduction in the risk of need for transplant might differ from these former two examples in target population and specialist team. A relevant example is with hospital readmissions because multiple studies to date have documented at least a 20% frequency of re-hospitalization within 30 days of index readmission.^11,12 Although disease severity indicated by Model for End Stage Liver Disease score explains a significant amount of the variability in risk for readmission, there are other factors including frailty¹³ and complications from index hospitalization14 that also contribute to 30-day readmission. The use of case management and remote monitoring strategies for patients at risk for hospital readmission is likely to be included in a PCSP focused on reducing inpatient utilization.

Variability in the social and economic context surrounding a patient’s daily life should also factor into model design. In the case of Medicaid coverage, a well-designed model might address discontinuities in specific provider and service access arising from churning in Medicaid eligibility and coverage.

Selecting a model design

Three examples of specialty care medical home designs have been described in the literature including the integrated model concept and two variants of the partnership model design. The integrated model concept provides specialty and primary care in one location, whereas the partnership models include an on-site liaison at the specialty practice, either a nurse practitioner who provides some degree of care and is able to draw from the services from an off-site primary care physician or otherwise an on-site nurse care manager who serves as an information source and advocate.⁹

We suggest that selection of model design should consider the number of specialty and primary care providers required to construct a comprehensive care team and whether there is reasonable capacity for patients to access comprehensive care in multiple settings. Providing a spectrum of services through separately located but coordinated PCSP and PCMH care models may be practical for some target populations. In other instances, multisite care programs may place an undesirable and impractical burden on patients with complex needs or low health system literacy.

As the field of PCSP model development moves forward, we suggest that providers learn from shared discussions of experience. If appropriate, innovation and shared learning should inform the development of additional standards to ensure that PCSP development for cirrhosis and transplant patients adheres to meaningful quality standards. As is clear from discussion, cirrhosis and liver transplant patients are a diverse group with a range of needs that fall across a spectrum of complexity. The development of well-structured PCSP models may require a high degree of specialization, where model adaptation acknowledges how specific disease-based needs, clinical comorbidities, and external support networks vary across groups.

One suggestion for moving forward is to focus early efforts narrowly on small and highly complex patient groups where the expected value of PCSP is large. This may entail beginning with patient groups whose clinical complexity may otherwise disqualify them from participation in traditional patient-centered care model demonstrations and evaluations. An ideal target population would be patients with decompensated cirrhosis who are ineligible for liver transplantation on the basis of multimorbidity. In addition, specialty providers might consider partnering with state agencies or patient groups in the development, testing, and funding of such programs. These partnerships may help to identify target patient populations with potential to benefit from participation in demonstration projects that innovate through the use of new PCSP model designs.

References

1. Sheen, E., Dorn, S.D., Brill, J.V., et al. Health care reform and the road ahead for gastroenterology. Clin Gastroenterol Hepatol. 2012;10:1062-5.

2. Agency for Healthcare Research and Quality. PCMH activities across federal agencies (Table 1). Available at: http://www.pcmh.ahrq.gov/sites/default/files/attachments/federal-pcmh-activities-table-1.pdf. Accessed May 13, 2015.

3. AAP, AAFP, ACP, and AOA. Joint principles of the patient-centered medical home, March 2007. Available at: http://www.acponline.org/running_practice/delivery_and_payment_models/pcmh/demonstrations/jointprinc_05_17.pdf. Accessed November 24, 2015.

4. Huang, X. Rosenthal, M.B. Transforming specialty practice–the patient-centered medical neighborhood. N Engl J Med. 2014;370:1376-9.

5. National Committee of Quality Assurance. Patient-centered specialty practice recognition: white paper. 2013. Available at: http://www.ncqa.org/Portals/0/Newsroom/2013/PCSP%20Launch/PCSPR%202013%20White%20Paper%203.26.13%20formatted.pdf. Accessed November 24, 2015.

6. National Committee of Quality Assurance. Patient-centered specialty practice frequently asked questions. Available at: http://www.ncqa.org/Programs/Recognition/Practices/PatientCenteredSpecialtyPracticePCSP/PatientCenteredSpecialtyPracticeFAQs.aspx Accessed June 4, 2015.

6. Kanwal, F. Coordinating care in patients with cirrhosis. Clin Gastroenterol Hepatol. 2013;11:859-61.

7. Fortune, B.E., Golus, A., Barsky, C.L., et al. Linking a hepatology clinical service line to quality improvement. Clin Gastroenterol Hepatol. 2015;13:1391-5.

8. Alakeson, V., Frank, R.G., Katz, R.E. Specialty care medical homes for people with severe, persistent mental disorders. Health Affairs. 2010;29:867-73.

9. Talwalkar, J.A. Potential impacts of the Affordable Care Act on the clinical practice of hepatology. Hepatology. 2014;59:1681-7.

9. Volk, M.L., Tocco, R.S., Bazick, J., et al. Hospital readmissions among patients with decompensated cirrhosis. Am J Gastroenterol. 2012;107:247-52.

10. Berman, K., Tandra, S., Forssell, K., et al. Incidence and predictors of 30-day readmission among patients hospitalized for advanced liver disease. Clin Gastroenterol Hepatol. 2011;9:254-9.

11. Tapper, E.B., Finkelstein, D., Mittleman, M.A., et al. Standard assessments of frailty are validated predictors of mortality in hospitalized patients with cirrhosis. Hepatology. 2015;62:584-90.

12. Eappen, S., Lane, B.H., Rosenberg, B., et al. Relationship between occurrence of surgical complications and hospital finances. JAMA. 2013;309:1599-606.

Dr. Meier, Dr. Shah, and Dr. Talwalkar are in the department of health care policy and research, department of health sciences research; Dr. Talwalkar is also in the division of gastroenterology and hepatology and the William von Liebig Center for Transplantation and Regenerative Medicine; Mayo Clinic, Rochester, Minn.

United States health care is moving rapidly from volume- to value-based reimbursement. An essential part of this movement will be the development of alternative payment models where a specific bundle of care (colonoscopy), episode of care (a year of care for attributed Crohn’s patients), or ongoing care of a specialty-centric patient population (patients with cirrhosis) are covered within a contract that links health outcomes, quality of care, and payment together. Gastroenterologists are slowly becoming aware of these concepts. Primary care has its patient-centered medical home and now specialists have a patient-centric specialty practice where patient populations are cared for principally by a specialty practice within a well-defined care delivery structure. Previous columns have illustrated these concepts, and this month, Meier and colleagues provide an excellent definition and example of how practices can participate in this new world order.

John I Allen, M.D., MBA, AGAF, Special Section Editor

The Patient Protection and Affordable Care Act secures access to health insurance coverage for many previously uninsured individuals, while transforming the structure of health care delivery to promote high value care that is coordinated and patient-centered.¹ The development of innovative care delivery models is a key feature of this transformation. In turn, patient-centered medical homes (PCMHs) have proliferated in number, with PCMH-related pilot and demonstration projects spanning numerous federal agencies.²

Defining the patient-centered medical home

The concept of the PCMH predates the Patient Protection and Affordable Care Act, with its origins in the American Academy of Pediatrics’ 1967 discussion of the medical home. In 2007, a joint release by the American Academy of Family Physicians, the American Academy of Pediatrics, the American College of Physicians, and the American Osteopathic Association defined the PCMH as “an approach to providing comprehensive primary care for children, youth and adults.” Furthermore, the PCMH would serve as “a health care setting that facilitates partnerships between individual patients, and their personal physicians, and when appropriate, the patient’s family.” Several key principles underscore the PCMH model; the patient has a personal physician, and care is physician-directed at the level of the practice, oriented around the whole person, and coordinated to ensure the highest quality and safety of medical care. The PCMH facilitates enhanced access to care, and the payment structure incentivizes and compensates high-quality care delivery.³

Advent of the patient-centered specialty practice

In 2013 the National Committee for Quality Assurance (NCQA), which operates the Patient Centered Medical Home Recognition program, released a set of standards governing the recognition of the patient-centered specialty practice (PCSP).⁴ Similar to the PCMH model, the PCSP model places the patient at the center of care delivery. Key functions of the PCSP include placing the patient at the center of care, sharing of information, and coordinating across all practices (specialty and primary) for patients.⁵ The NCQA outlines six standards for PCSP recognition; these standards focus on planning, management, tracking and coordination of care, performance measurement, performance improvement, referrals, communication to patients, care access, and coordination and management for populations.⁵

Centering patient care in the specialty practice

With the release of the NCQA PCSP standards, provider groups and regulators should work to identify circumstances under which the PCSP might best operate as an effective model for the populations they serve. For example, in the case of mental illness that is both severe and persistent, the creation of a PCMH may disrupt existing patient-provider relationships, increase fragmentation of medical care, and position poorly equipped providers at the center of a care process that requires greater specialization.⁶

Drawing from this example, we suggest that select patient populations with advanced chronic liver disease may benefit from the development of patient-centered care models that operate such as a PCSP. This may include patients with compensated cirrhosis and other comorbid illnesses such as diabetes mellitus or depression, populations with active complications of portal hypertension, or patients who await or have received liver transplantation.^7,8 We suggest examining the potential value of this model in circumstances where the complexity of patient needs or the sensitivity and vulnerability of the patient circumstance may best be managed by an established, trusted, and specialized provider. In the case of patients with cirrhosis and substance abuse from alcohol, a hybrid specialty model that incorporates addiction medicine, social work, and psychiatry providers in addition to hepatologists and allied health providers may be warranted.⁷

Designing the patient-centered specialty practice for populations with cirrhosis and liver transplant recipients

Practices and providers should carefully assess the context for PCSP adoption, identifying whether the specialty care model will promote greater efficiency and quality than that realized in the absence of a PCSP model. The PCSP model should align with patient needs, considering factors such as cause of disease, disease stage, comorbidities and complications, and socioeconomic factors. Although the NCQA PCSP standards should guide model development, there are specific needs and complexities of cirrhosis and liver transplant populations that may prove highly relevant in identifying one or more ideal model designs. This may entail development of additional PCSP standards beyond what is recognized by NCQA.

Table 1 outlines key questions providers might address when considering the development of the PCSP in this patient population. We divide these questions into three main categories: 1) understanding the context for PCSP model adoption, 2) identifying opportunities to align the PCSP model with the specific needs of the patient population, and 3) selecting a model design. Incorporating careful consideration of the questions highlighted within each of these categories can help inform practitioners on the merits of various PCSP models.

Understanding the context for patient-centered specialty practice adoption

Drawing from Alakeson et al.,⁹ we suggest that providers embarking on PCSP model adoption first consider how the quality of care and strength of patient-provider relationships for the target population will improve. The selection of an appropriate patient population is a key determinant in the answer to this question. Focusing specifically on the cirrhosis population, the PCSP may need to be directed toward a disease stage (i.e., decompensated cirrhosis) where the specialist is the most frequent and continuous point of system access. Similarly, the PCSP might yield the greatest gains in quality when access is a function of requiring specialized knowledge in the day-to-day management of care delivery (i.e., compensated liver disease or long-term post liver transplant recipients).

The case for the PCSP may be particularly strong in instances where the primary care provider lacks sufficient knowledge to appropriately manage patient care. For example, treatment of mental and behavioral health conditions that are comorbid with cirrhosis may best be suited to a specialized and established care team that has secured patient trust. Many transplant centers in the United States have explicitly created teams in this regard in the context of regulatory requirements for being a transplant program.¹⁰

Identifying opportunities to align the patient-centered specialty practice model with the specific needs of the patient population

Liver transplant and cirrhosis patients exhibit variability in the cause of disease, with genetic, social-behavioral, and other causal mechanisms operating as factors in the expression of disease. Developing a model focused on reduction in the risk of need for transplant might differ from these former two examples in target population and specialist team. A relevant example is with hospital readmissions because multiple studies to date have documented at least a 20% frequency of re-hospitalization within 30 days of index readmission.^11,12 Although disease severity indicated by Model for End Stage Liver Disease score explains a significant amount of the variability in risk for readmission, there are other factors including frailty¹³ and complications from index hospitalization14 that also contribute to 30-day readmission. The use of case management and remote monitoring strategies for patients at risk for hospital readmission is likely to be included in a PCSP focused on reducing inpatient utilization.

Variability in the social and economic context surrounding a patient’s daily life should also factor into model design. In the case of Medicaid coverage, a well-designed model might address discontinuities in specific provider and service access arising from churning in Medicaid eligibility and coverage.

Selecting a model design

Three examples of specialty care medical home designs have been described in the literature including the integrated model concept and two variants of the partnership model design. The integrated model concept provides specialty and primary care in one location, whereas the partnership models include an on-site liaison at the specialty practice, either a nurse practitioner who provides some degree of care and is able to draw from the services from an off-site primary care physician or otherwise an on-site nurse care manager who serves as an information source and advocate.⁹

We suggest that selection of model design should consider the number of specialty and primary care providers required to construct a comprehensive care team and whether there is reasonable capacity for patients to access comprehensive care in multiple settings. Providing a spectrum of services through separately located but coordinated PCSP and PCMH care models may be practical for some target populations. In other instances, multisite care programs may place an undesirable and impractical burden on patients with complex needs or low health system literacy.

As the field of PCSP model development moves forward, we suggest that providers learn from shared discussions of experience. If appropriate, innovation and shared learning should inform the development of additional standards to ensure that PCSP development for cirrhosis and transplant patients adheres to meaningful quality standards. As is clear from discussion, cirrhosis and liver transplant patients are a diverse group with a range of needs that fall across a spectrum of complexity. The development of well-structured PCSP models may require a high degree of specialization, where model adaptation acknowledges how specific disease-based needs, clinical comorbidities, and external support networks vary across groups.

One suggestion for moving forward is to focus early efforts narrowly on small and highly complex patient groups where the expected value of PCSP is large. This may entail beginning with patient groups whose clinical complexity may otherwise disqualify them from participation in traditional patient-centered care model demonstrations and evaluations. An ideal target population would be patients with decompensated cirrhosis who are ineligible for liver transplantation on the basis of multimorbidity. In addition, specialty providers might consider partnering with state agencies or patient groups in the development, testing, and funding of such programs. These partnerships may help to identify target patient populations with potential to benefit from participation in demonstration projects that innovate through the use of new PCSP model designs.

References

1. Sheen, E., Dorn, S.D., Brill, J.V., et al. Health care reform and the road ahead for gastroenterology. Clin Gastroenterol Hepatol. 2012;10:1062-5.

2. Agency for Healthcare Research and Quality. PCMH activities across federal agencies (Table 1). Available at: http://www.pcmh.ahrq.gov/sites/default/files/attachments/federal-pcmh-activities-table-1.pdf. Accessed May 13, 2015.

3. AAP, AAFP, ACP, and AOA. Joint principles of the patient-centered medical home, March 2007. Available at: http://www.acponline.org/running_practice/delivery_and_payment_models/pcmh/demonstrations/jointprinc_05_17.pdf. Accessed November 24, 2015.

4. Huang, X. Rosenthal, M.B. Transforming specialty practice–the patient-centered medical neighborhood. N Engl J Med. 2014;370:1376-9.

5. National Committee of Quality Assurance. Patient-centered specialty practice recognition: white paper. 2013. Available at: http://www.ncqa.org/Portals/0/Newsroom/2013/PCSP%20Launch/PCSPR%202013%20White%20Paper%203.26.13%20formatted.pdf. Accessed November 24, 2015.

6. National Committee of Quality Assurance. Patient-centered specialty practice frequently asked questions. Available at: http://www.ncqa.org/Programs/Recognition/Practices/PatientCenteredSpecialtyPracticePCSP/PatientCenteredSpecialtyPracticeFAQs.aspx Accessed June 4, 2015.

6. Kanwal, F. Coordinating care in patients with cirrhosis. Clin Gastroenterol Hepatol. 2013;11:859-61.

7. Fortune, B.E., Golus, A., Barsky, C.L., et al. Linking a hepatology clinical service line to quality improvement. Clin Gastroenterol Hepatol. 2015;13:1391-5.

8. Alakeson, V., Frank, R.G., Katz, R.E. Specialty care medical homes for people with severe, persistent mental disorders. Health Affairs. 2010;29:867-73.

9. Talwalkar, J.A. Potential impacts of the Affordable Care Act on the clinical practice of hepatology. Hepatology. 2014;59:1681-7.

9. Volk, M.L., Tocco, R.S., Bazick, J., et al. Hospital readmissions among patients with decompensated cirrhosis. Am J Gastroenterol. 2012;107:247-52.

10. Berman, K., Tandra, S., Forssell, K., et al. Incidence and predictors of 30-day readmission among patients hospitalized for advanced liver disease. Clin Gastroenterol Hepatol. 2011;9:254-9.

11. Tapper, E.B., Finkelstein, D., Mittleman, M.A., et al. Standard assessments of frailty are validated predictors of mortality in hospitalized patients with cirrhosis. Hepatology. 2015;62:584-90.

12. Eappen, S., Lane, B.H., Rosenberg, B., et al. Relationship between occurrence of surgical complications and hospital finances. JAMA. 2013;309:1599-606.

Dr. Meier, Dr. Shah, and Dr. Talwalkar are in the department of health care policy and research, department of health sciences research; Dr. Talwalkar is also in the division of gastroenterology and hepatology and the William von Liebig Center for Transplantation and Regenerative Medicine; Mayo Clinic, Rochester, Minn.

The clinical management of transgender and gender nonconforming youth is a growing area in pediatric endocrinology and adolescent medicine with multiple questions and challenges. One of the many challenges relates to the decision-making process for transitioning to the self-identified gender. Many medical and ethical aspects surround this issue. What are the risks in delaying transition until adulthood? Can clinicians correctly diagnose gender dysphoria in childhood and adolescence? Are children and adolescents capable of making life-changing decisions? What are the long-term psychological and medical consequences of puberty suppression and cross-sex hormones? Each of these questions may pose a conundrum for patients, families, and clinicians to consider.

What are the risks of delaying transition until adulthood?

Available studies report the incidence of mental health problems among transgender and gender nonconforming youth are higher than the incidence in cisgender youth.¹ This is especially true if they are unable to live as the gender with which they identify. de Vries et al. showed that transgender adults going through transition had worse baseline mental health problems than did transgender adolescents going through transition.² This makes sense, as transgender adults are less likely to have been living as their gender identity, compared with transgender adolescents. This exposes them to longer periods of gender dysphoria and to harassment and discrimination. There are medical risks as well. Some surgical procedures are much more difficult to perform on a fully mature adult. For example, breast removal surgery for a transmale who has fully developed breasts may result in significant scarring, which could have been avoided if the surgery was done when the patient was younger with smaller breasts.³ Furthermore, the secondary sex characteristics that develop during puberty can be much more difficult to remove in adulthood. These characteristics may result in an appearance that can provoke abuse and harassment. Patients can avoid this by the use of hormone blockers at an early age, which would prevent the development of the undesired secondary sex characteristics.

Can gender dysphoria be diagnosed at an early age?

Because of the risks associated with pubertal suppression and cross-sex hormones, there is a concern about making the right diagnosis. Past studies have reported that among children exhibiting gender dysphoria, about 10%-25% will continue to have gender dysphoria after the onset of puberty.^4,5 Because of this low rate of children with persistent gender dysphoria, many feel that making the diagnosis at such a young age, especially if the diagnosis is incorrect, will put them through unnecessary risks.

One potential treatment for some prepubertal children with gender dysphoria is social transition; for example, using the preferred name and pronouns, change of clothing and hairstyle, and so on. This is reversible; however, there are no studies documenting the psychosocial outcomes of children whose gender dysphoria desists in adolescence. Furthermore, the use of pubertal blockers does not begin until the patient reaches Tanner Stage 2,^6,7 and the use of cross-sex hormones typically does not begin until age 16 years old. This allows time for the child to work with a mental health therapist to confirm their gender identity. Finally, children who have gender dysphoria beginning at puberty or persisting after puberty generally have persistent gender dysphoria in adulthood.³

What are the medical risks with pubertal suppression and cross-sex hormones?

One of the risks for puberty suppression with a gonadotropin-releasing hormone agonist (GnRHa) – such as leuprolide – is reduced bone mineral density (BMD).⁷ Most bone accretion occurs during adolescence and cannot be recovered in adulthood. There are no studies on how GnRHa may affect BMD in transgender children and adolescents. The best evidence comes from GnRHa treatment of central precocious puberty in children, which has mixed results. Some studies show that GnRHa may lead to lower BMD,⁸ whereas other studies showed no difference in BMD between those treated with GnRHa versus those who were not,^9,10 especially after resumption of puberty.

What are the medical risks of using cross-sex hormones?

Likewise, use of cross-sex hormones – like estrogen and testosterone – is not risk free. The most likely risks with estrogen are venous thromboembolic events including pulmonary emboli, blood clots, gallstones, elevated liver enzymes, weight gain, and high cholesterol. Polycythemia, weight gain, acne, male pattern baldness, and sleep apnea are risks associated with testosterone use.⁷ Additionally, use of these hormones can induce infertility, and this is not always reversible.⁶ Furthermore, there are some studies in animal and human models that highlight the importance of sex hormones in organizing the brain during the critical period of adolescence.¹¹ There is some concern that pubertal suppression or the use of cross-sex hormones for transition during this time may disrupt this process. However, one prospective study showed that adolescents who received pubertal suppression and cross-sex hormones had no psychopathology as adults and even had improved mental health outcomes.¹² Nevertheless, this is only one study and further studies should confirm that pubertal suppression and sex reassignment are beneficial to the patient.

Can children and adolescents make complex, life-changing decisions?

The ethical issues of managing gender dysphoria in children and adolescents are the avoidance of harm – in both treatment and delaying treatment until the patient is older – and determining if children and adolescents are capable of making important decisions. Many would argue that children are not capable of making complex, life-changing decisions. For example, we wouldn’t expect an 8-year-old recently diagnosed with cancer to decide whether to proceed with treatment, knowing the potential side effects. Nevertheless, the recommended treatment for children is social transition. This process is reversible with little psychological and medical consequences.

However, adolescence can cloud the issue. Depending on the state, teenagers can obtain care for sexually transmitted infections (STIs) and contraception services without parental consent. Prevention of the spread of STIs and unwanted pregnancy are the primary rationales behind this, as adolescents are less likely to obtain these services if doing so required parental consent.¹³ However, underlying this rationale is the belief that adolescents are capable of making some complex decisions. Although the treatment of STIs or preventing unwanted pregnancy is not as complex as pubertal suppression or use of cross-sex hormones, the consequences of foregoing medical care of STIs (for example, the possibility of infertility due to pelvic inflammatory disease) or unexpected pregnancy are also life-changing.

One also must remember that not all adolescents reach their developmental milestones at the same age. A 14-year-old may have cognitive and executive functioning advanced for their age whereas an 18-year-old may lack these skills. Because of this variation, an interdisciplinary team including clinicians and behavioral/mental health experts should help individuals through the process of characterizing their self-identified gender identity and support their eventual transition using, as indicated for each individual, pubertal suppression, cross-sex hormones, and, ultimately, surgery.

The treatment of gender dysphoria in children and adolescents is characterized by ethical, medical, and psychosocial dilemmas. Long-term data are not available to determine the optimal age for transition for each individual. Despite the long-term risks, some children and adolescents are capable of making some important decisions. Furthermore, some treatment recommendations for children and adolescents who have gender dysphoria are reversible. At the end of the day, clinicians must combine the limited evidence with their experience to make the best judgment on how to proceed. Most important of all, they should allow the child to lead because he/she is the best judge of his/her gender identity.

References:

1. Institute of Medicine (U.S.) Committee on Lesbian, Gay, Bisexual, and Transgender Health Issues and Research Gaps and Opportunities. The Health of Lesbian, Gay, Bisexual, and Transgender People: Building a Foundation for Better Understanding. (Washington, D.C.: National Academies Press, 2011).

2. Psychiatry Res. 2011 Apr 30;186(2-3):414-8.

3. Nat Rev Endocrinol. 2011 May 17;7(8):466-72.

4. Dev Psychol. 2008 Jan;44(1):34-45.

5. J Adolesc Health. 2015 Oct;57(4):367-73.

6. J Clin Endocrinol Metab. 2009 Sep;94(9):3132-54.

7. The World Professional Association for Transgender Health. Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People. 2011; 7th ed.

8. J Clin Endocrinol Metab. 2008 Jan;93(1):190-5.

9. J Clin Endocrinol Metab. 2010 Jan;95(1):109-17.

10. Clinics (Sao Paulo). 2012;67(6):591-6.

11. Front Neuroendocrinol. 2005 Oct-Dec;26(3-4):163-74.

12. Pediatrics. 2014 Oct;134(4):696-704.

13. Arch Pediatr Adolesc Med. 2000;154(9):885-92.

Dr. Montano is an adolescent medicine fellow at Children’s Hospital of Pittsburgh of UPMC and a postdoctoral fellow in the department of pediatrics at the University of Pittsburgh. Email him at [email protected].

The clinical management of transgender and gender nonconforming youth is a growing area in pediatric endocrinology and adolescent medicine with multiple questions and challenges. One of the many challenges relates to the decision-making process for transitioning to the self-identified gender. Many medical and ethical aspects surround this issue. What are the risks in delaying transition until adulthood? Can clinicians correctly diagnose gender dysphoria in childhood and adolescence? Are children and adolescents capable of making life-changing decisions? What are the long-term psychological and medical consequences of puberty suppression and cross-sex hormones? Each of these questions may pose a conundrum for patients, families, and clinicians to consider.

What are the risks of delaying transition until adulthood?

Available studies report the incidence of mental health problems among transgender and gender nonconforming youth are higher than the incidence in cisgender youth.¹ This is especially true if they are unable to live as the gender with which they identify. de Vries et al. showed that transgender adults going through transition had worse baseline mental health problems than did transgender adolescents going through transition.² This makes sense, as transgender adults are less likely to have been living as their gender identity, compared with transgender adolescents. This exposes them to longer periods of gender dysphoria and to harassment and discrimination. There are medical risks as well. Some surgical procedures are much more difficult to perform on a fully mature adult. For example, breast removal surgery for a transmale who has fully developed breasts may result in significant scarring, which could have been avoided if the surgery was done when the patient was younger with smaller breasts.³ Furthermore, the secondary sex characteristics that develop during puberty can be much more difficult to remove in adulthood. These characteristics may result in an appearance that can provoke abuse and harassment. Patients can avoid this by the use of hormone blockers at an early age, which would prevent the development of the undesired secondary sex characteristics.

Can gender dysphoria be diagnosed at an early age?

Because of the risks associated with pubertal suppression and cross-sex hormones, there is a concern about making the right diagnosis. Past studies have reported that among children exhibiting gender dysphoria, about 10%-25% will continue to have gender dysphoria after the onset of puberty.^4,5 Because of this low rate of children with persistent gender dysphoria, many feel that making the diagnosis at such a young age, especially if the diagnosis is incorrect, will put them through unnecessary risks.

One potential treatment for some prepubertal children with gender dysphoria is social transition; for example, using the preferred name and pronouns, change of clothing and hairstyle, and so on. This is reversible; however, there are no studies documenting the psychosocial outcomes of children whose gender dysphoria desists in adolescence. Furthermore, the use of pubertal blockers does not begin until the patient reaches Tanner Stage 2,^6,7 and the use of cross-sex hormones typically does not begin until age 16 years old. This allows time for the child to work with a mental health therapist to confirm their gender identity. Finally, children who have gender dysphoria beginning at puberty or persisting after puberty generally have persistent gender dysphoria in adulthood.³

What are the medical risks with pubertal suppression and cross-sex hormones?

One of the risks for puberty suppression with a gonadotropin-releasing hormone agonist (GnRHa) – such as leuprolide – is reduced bone mineral density (BMD).⁷ Most bone accretion occurs during adolescence and cannot be recovered in adulthood. There are no studies on how GnRHa may affect BMD in transgender children and adolescents. The best evidence comes from GnRHa treatment of central precocious puberty in children, which has mixed results. Some studies show that GnRHa may lead to lower BMD,⁸ whereas other studies showed no difference in BMD between those treated with GnRHa versus those who were not,^9,10 especially after resumption of puberty.

What are the medical risks of using cross-sex hormones?

Likewise, use of cross-sex hormones – like estrogen and testosterone – is not risk free. The most likely risks with estrogen are venous thromboembolic events including pulmonary emboli, blood clots, gallstones, elevated liver enzymes, weight gain, and high cholesterol. Polycythemia, weight gain, acne, male pattern baldness, and sleep apnea are risks associated with testosterone use.⁷ Additionally, use of these hormones can induce infertility, and this is not always reversible.⁶ Furthermore, there are some studies in animal and human models that highlight the importance of sex hormones in organizing the brain during the critical period of adolescence.¹¹ There is some concern that pubertal suppression or the use of cross-sex hormones for transition during this time may disrupt this process. However, one prospective study showed that adolescents who received pubertal suppression and cross-sex hormones had no psychopathology as adults and even had improved mental health outcomes.¹² Nevertheless, this is only one study and further studies should confirm that pubertal suppression and sex reassignment are beneficial to the patient.

Can children and adolescents make complex, life-changing decisions?

The ethical issues of managing gender dysphoria in children and adolescents are the avoidance of harm – in both treatment and delaying treatment until the patient is older – and determining if children and adolescents are capable of making important decisions. Many would argue that children are not capable of making complex, life-changing decisions. For example, we wouldn’t expect an 8-year-old recently diagnosed with cancer to decide whether to proceed with treatment, knowing the potential side effects. Nevertheless, the recommended treatment for children is social transition. This process is reversible with little psychological and medical consequences.

However, adolescence can cloud the issue. Depending on the state, teenagers can obtain care for sexually transmitted infections (STIs) and contraception services without parental consent. Prevention of the spread of STIs and unwanted pregnancy are the primary rationales behind this, as adolescents are less likely to obtain these services if doing so required parental consent.¹³ However, underlying this rationale is the belief that adolescents are capable of making some complex decisions. Although the treatment of STIs or preventing unwanted pregnancy is not as complex as pubertal suppression or use of cross-sex hormones, the consequences of foregoing medical care of STIs (for example, the possibility of infertility due to pelvic inflammatory disease) or unexpected pregnancy are also life-changing.

One also must remember that not all adolescents reach their developmental milestones at the same age. A 14-year-old may have cognitive and executive functioning advanced for their age whereas an 18-year-old may lack these skills. Because of this variation, an interdisciplinary team including clinicians and behavioral/mental health experts should help individuals through the process of characterizing their self-identified gender identity and support their eventual transition using, as indicated for each individual, pubertal suppression, cross-sex hormones, and, ultimately, surgery.

The treatment of gender dysphoria in children and adolescents is characterized by ethical, medical, and psychosocial dilemmas. Long-term data are not available to determine the optimal age for transition for each individual. Despite the long-term risks, some children and adolescents are capable of making some important decisions. Furthermore, some treatment recommendations for children and adolescents who have gender dysphoria are reversible. At the end of the day, clinicians must combine the limited evidence with their experience to make the best judgment on how to proceed. Most important of all, they should allow the child to lead because he/she is the best judge of his/her gender identity.

References:

1. Institute of Medicine (U.S.) Committee on Lesbian, Gay, Bisexual, and Transgender Health Issues and Research Gaps and Opportunities. The Health of Lesbian, Gay, Bisexual, and Transgender People: Building a Foundation for Better Understanding. (Washington, D.C.: National Academies Press, 2011).

2. Psychiatry Res. 2011 Apr 30;186(2-3):414-8.

3. Nat Rev Endocrinol. 2011 May 17;7(8):466-72.

4. Dev Psychol. 2008 Jan;44(1):34-45.

5. J Adolesc Health. 2015 Oct;57(4):367-73.

6. J Clin Endocrinol Metab. 2009 Sep;94(9):3132-54.

7. The World Professional Association for Transgender Health. Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People. 2011; 7th ed.

8. J Clin Endocrinol Metab. 2008 Jan;93(1):190-5.

9. J Clin Endocrinol Metab. 2010 Jan;95(1):109-17.

10. Clinics (Sao Paulo). 2012;67(6):591-6.

11. Front Neuroendocrinol. 2005 Oct-Dec;26(3-4):163-74.

12. Pediatrics. 2014 Oct;134(4):696-704.

13. Arch Pediatr Adolesc Med. 2000;154(9):885-92.

Dr. Montano is an adolescent medicine fellow at Children’s Hospital of Pittsburgh of UPMC and a postdoctoral fellow in the department of pediatrics at the University of Pittsburgh. Email him at [email protected].

The clinical management of transgender and gender nonconforming youth is a growing area in pediatric endocrinology and adolescent medicine with multiple questions and challenges. One of the many challenges relates to the decision-making process for transitioning to the self-identified gender. Many medical and ethical aspects surround this issue. What are the risks in delaying transition until adulthood? Can clinicians correctly diagnose gender dysphoria in childhood and adolescence? Are children and adolescents capable of making life-changing decisions? What are the long-term psychological and medical consequences of puberty suppression and cross-sex hormones? Each of these questions may pose a conundrum for patients, families, and clinicians to consider.

What are the risks of delaying transition until adulthood?

Available studies report the incidence of mental health problems among transgender and gender nonconforming youth are higher than the incidence in cisgender youth.¹ This is especially true if they are unable to live as the gender with which they identify. de Vries et al. showed that transgender adults going through transition had worse baseline mental health problems than did transgender adolescents going through transition.² This makes sense, as transgender adults are less likely to have been living as their gender identity, compared with transgender adolescents. This exposes them to longer periods of gender dysphoria and to harassment and discrimination. There are medical risks as well. Some surgical procedures are much more difficult to perform on a fully mature adult. For example, breast removal surgery for a transmale who has fully developed breasts may result in significant scarring, which could have been avoided if the surgery was done when the patient was younger with smaller breasts.³ Furthermore, the secondary sex characteristics that develop during puberty can be much more difficult to remove in adulthood. These characteristics may result in an appearance that can provoke abuse and harassment. Patients can avoid this by the use of hormone blockers at an early age, which would prevent the development of the undesired secondary sex characteristics.

Can gender dysphoria be diagnosed at an early age?

Because of the risks associated with pubertal suppression and cross-sex hormones, there is a concern about making the right diagnosis. Past studies have reported that among children exhibiting gender dysphoria, about 10%-25% will continue to have gender dysphoria after the onset of puberty.^4,5 Because of this low rate of children with persistent gender dysphoria, many feel that making the diagnosis at such a young age, especially if the diagnosis is incorrect, will put them through unnecessary risks.

One potential treatment for some prepubertal children with gender dysphoria is social transition; for example, using the preferred name and pronouns, change of clothing and hairstyle, and so on. This is reversible; however, there are no studies documenting the psychosocial outcomes of children whose gender dysphoria desists in adolescence. Furthermore, the use of pubertal blockers does not begin until the patient reaches Tanner Stage 2,^6,7 and the use of cross-sex hormones typically does not begin until age 16 years old. This allows time for the child to work with a mental health therapist to confirm their gender identity. Finally, children who have gender dysphoria beginning at puberty or persisting after puberty generally have persistent gender dysphoria in adulthood.³

What are the medical risks with pubertal suppression and cross-sex hormones?

One of the risks for puberty suppression with a gonadotropin-releasing hormone agonist (GnRHa) – such as leuprolide – is reduced bone mineral density (BMD).⁷ Most bone accretion occurs during adolescence and cannot be recovered in adulthood. There are no studies on how GnRHa may affect BMD in transgender children and adolescents. The best evidence comes from GnRHa treatment of central precocious puberty in children, which has mixed results. Some studies show that GnRHa may lead to lower BMD,⁸ whereas other studies showed no difference in BMD between those treated with GnRHa versus those who were not,^9,10 especially after resumption of puberty.

What are the medical risks of using cross-sex hormones?

Likewise, use of cross-sex hormones – like estrogen and testosterone – is not risk free. The most likely risks with estrogen are venous thromboembolic events including pulmonary emboli, blood clots, gallstones, elevated liver enzymes, weight gain, and high cholesterol. Polycythemia, weight gain, acne, male pattern baldness, and sleep apnea are risks associated with testosterone use.⁷ Additionally, use of these hormones can induce infertility, and this is not always reversible.⁶ Furthermore, there are some studies in animal and human models that highlight the importance of sex hormones in organizing the brain during the critical period of adolescence.¹¹ There is some concern that pubertal suppression or the use of cross-sex hormones for transition during this time may disrupt this process. However, one prospective study showed that adolescents who received pubertal suppression and cross-sex hormones had no psychopathology as adults and even had improved mental health outcomes.¹² Nevertheless, this is only one study and further studies should confirm that pubertal suppression and sex reassignment are beneficial to the patient.

Can children and adolescents make complex, life-changing decisions?

The ethical issues of managing gender dysphoria in children and adolescents are the avoidance of harm – in both treatment and delaying treatment until the patient is older – and determining if children and adolescents are capable of making important decisions. Many would argue that children are not capable of making complex, life-changing decisions. For example, we wouldn’t expect an 8-year-old recently diagnosed with cancer to decide whether to proceed with treatment, knowing the potential side effects. Nevertheless, the recommended treatment for children is social transition. This process is reversible with little psychological and medical consequences.

However, adolescence can cloud the issue. Depending on the state, teenagers can obtain care for sexually transmitted infections (STIs) and contraception services without parental consent. Prevention of the spread of STIs and unwanted pregnancy are the primary rationales behind this, as adolescents are less likely to obtain these services if doing so required parental consent.¹³ However, underlying this rationale is the belief that adolescents are capable of making some complex decisions. Although the treatment of STIs or preventing unwanted pregnancy is not as complex as pubertal suppression or use of cross-sex hormones, the consequences of foregoing medical care of STIs (for example, the possibility of infertility due to pelvic inflammatory disease) or unexpected pregnancy are also life-changing.

One also must remember that not all adolescents reach their developmental milestones at the same age. A 14-year-old may have cognitive and executive functioning advanced for their age whereas an 18-year-old may lack these skills. Because of this variation, an interdisciplinary team including clinicians and behavioral/mental health experts should help individuals through the process of characterizing their self-identified gender identity and support their eventual transition using, as indicated for each individual, pubertal suppression, cross-sex hormones, and, ultimately, surgery.

The treatment of gender dysphoria in children and adolescents is characterized by ethical, medical, and psychosocial dilemmas. Long-term data are not available to determine the optimal age for transition for each individual. Despite the long-term risks, some children and adolescents are capable of making some important decisions. Furthermore, some treatment recommendations for children and adolescents who have gender dysphoria are reversible. At the end of the day, clinicians must combine the limited evidence with their experience to make the best judgment on how to proceed. Most important of all, they should allow the child to lead because he/she is the best judge of his/her gender identity.

References:

1. Institute of Medicine (U.S.) Committee on Lesbian, Gay, Bisexual, and Transgender Health Issues and Research Gaps and Opportunities. The Health of Lesbian, Gay, Bisexual, and Transgender People: Building a Foundation for Better Understanding. (Washington, D.C.: National Academies Press, 2011).

2. Psychiatry Res. 2011 Apr 30;186(2-3):414-8.

3. Nat Rev Endocrinol. 2011 May 17;7(8):466-72.

4. Dev Psychol. 2008 Jan;44(1):34-45.

5. J Adolesc Health. 2015 Oct;57(4):367-73.

6. J Clin Endocrinol Metab. 2009 Sep;94(9):3132-54.

7. The World Professional Association for Transgender Health. Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People. 2011; 7th ed.

8. J Clin Endocrinol Metab. 2008 Jan;93(1):190-5.

9. J Clin Endocrinol Metab. 2010 Jan;95(1):109-17.

10. Clinics (Sao Paulo). 2012;67(6):591-6.

11. Front Neuroendocrinol. 2005 Oct-Dec;26(3-4):163-74.

12. Pediatrics. 2014 Oct;134(4):696-704.

13. Arch Pediatr Adolesc Med. 2000;154(9):885-92.

Dr. Montano is an adolescent medicine fellow at Children’s Hospital of Pittsburgh of UPMC and a postdoctoral fellow in the department of pediatrics at the University of Pittsburgh. Email him at [email protected].

FLORENCE, ITALY – The 2016 revision of the European Society of Cardiology’s guidelines for diagnosing and treating acute and chronic heart failure highlights the extent to which thinking in the field has changed during the past 4 years, since the prior edition in 2012.

The new European guidelines, unveiled by the ESC’s Heart Failure Association during the group’s annual meeting, also underscore the great dependence that many new approaches have on expert opinion rather than what’s become the keystone of guidelines writing, evidence-based medicine. Frequent reliance on consensus decisions rather than indisputable proof from controlled trials defines what some U.S. specialists see as a divide as wide as the Atlantic between the European and U.S. approaches to guideline writing.

Mitchel L. Zoler/Frontline Medical News

“The guidelines from the ESC are articulated very well; they made their recommendations very clear. But a lot is consensus driven, without new data,” said Dr. Mariell L. Jessup, who serves as both vice chair of the panel currently revising the U.S. heart failure guidelines – expected out later in 2016 – and was also the sole American representative on the panel that produced the ESC guidelines. “The ESC guidelines make clear all the things that need to happen to patients. I hope it will result in better patient care. We are clearly not doing a good job in heart failure. We not only don’t have evidence-based treatments, but people often don’t do a good job [caring for heart failure patients] and they die in the hospital all the time.”

Dr. Javed Butler, another member of the U.S. guidelines panel and professor and chief of cardiology at Stony Brook (N.Y.) University, called the U.S. and European divide a “philosophical perspective of evidence-based medicine.

“U.S. physicians should read the ESC guidelines and make up their own minds. The ESC guidelines are excellent and give you perspective. But U.S. regulatory and payment issues will be driven by U.S. guidelines,” Dr. Butler said in an interview.

Mitchel L. Zoler/Frontline Medical News

But despite their limitations and the limited weight that the ESC guidelines carry for U.S. practice, they have many redeeming features, noted Dr. Mandeep R. Mehra, medical director of the Heart and Vascular Center at Brigham and Women’s Hospital in Boston. The 2016 ESC guidelines “are extraordinarily clear, very practical, and very concise. They are very usable, and provide a fantastic algorithm for managing patients with heart failure with reduced ejection fraction [HFrEF],” he said while discussing the guidelines during the meeting.

U.S. and Europe largely agree on sacubitril/valsartan and ivabradine

Clearly the greatest area of U.S. and European agreement was in the adoption by both guidelines groups of sacubitril/valsartan (Entresto) and ivabradine (Corlanor) as important new components of the basic drug formula for treating patients with HFrEF. In fact, the U.S. guideline writers saw these two additions as so important and timely that they issued a “focused update” in May to the existing, 2013 U.S. heart failure guidelines, and timed release of this update to occur on May 20, 2016, a day before release of the ESC guidelines. But as Dr. Butler noted, this was more of a temporal harmonization than a substantive one, because even here, in a very evidence-based change, the U.S. guidelines for using sacubitril/valsartan differed subtly but importantly from the ESC version.

The U.S. focused update says that treatment of patients with stage C (symptomatic heart failure with structural heart disease) HFrEF should receive treatment with sacubitril/valsartan (also know as an angiotensin receptor neprilysin inhibitor, or ARNI), an ACE inhibitor, or an angiotensin receptor blocker (ARB), as well as evidence-based treatment with a beta-blocker and with a mineralocorticoid receptor antagonist (MRA). A subsequent recommendation in the U.S. focused update said that HFrEF patients with chronic symptoms and New York Heart Association class II or III disease should switch from a stable, tolerated regimen with either an ACE inhibitor or ARB to treatment with sacubitril/valsartan.

Courtesy Stony Brook University

In contrast, the new European guideline for sacubitril/valsartan recommends starting patients on this combination formulation only after first demonstrating that patients tolerated treatment with an ACE inhibitor or ARB for at least 30 days and determining that patients remained symptomatic while on one of these treatments. In short, the U.S. guideline gives a green light to starting patients with newly diagnosed, symptomatic HFrEF on sacubitril/valsartan immediately, while the European guideline only sanctions sacubitril/valsartan to start after a patient has spent at least 30 days settling into a multidrug regimen featuring an ACE inhibitor or an ARB when an ACE inhibitor isn’t well tolerated.

“The European guidelines are closely related to the study population enrolled in the PARADIGM-HF trial,” the pivotal trial that showed superiority of sacubitril/valsartan to an ACE inhibitor (N Engl J Med. 2014;371:993-1004), noted Dr. Butler in an interview. “The U.S. guidelines interpreted [the PARADIGM-HF] results in the best interests of a larger patient population. The European guidelines are far more proscriptive in replicating the clinical criteria of the trial. In some patients the sequence of starting a MRA and sacubitril/valsartan matters, but in other patients it is less important.”

Dr. Frank Ruschitzka, a coauthor of the ESC guidelines, said that the reason for the more cautious ESC approach was lack of widespread familiarity with sacubitril/valsartan treatment among cardiologists.

Mitchel L. Zoler/Frontline Medical News

The ESC guidelines on using sacubitril/valsartan “replicated the PARADIGM-HF trial. We have no data right now that it is justifiable to put a [treatment-naive] patient on sacubitril/valsartan to begin with. Another difference between the U.S. and ESC guidelines is when to start a MRA,” said Dr. Ruschitzka, professor and head of cardiology at the Heart Center of the University Hospital in Zurich. “It makes a lot of sense to me to start sacubitril/valsartan early. The PARADIGM trial was positive, but no one has a feel for how to use sacubitril/valsartan. Should we give it to everyone? We said replicate the trial, and gain experience using the drug. We want to bring a life-saving drug to patients, but this is the approach we took. We need more data.”

Dr. Jessup noted that a lot of uncertainty also exists among U.S. clinicians about when to start sacubitril/valsartan. “It’s not been clear which patients to put on sacubitril/valsartan. No guidelines had been out on using it” until mid-May, and “the cost of sacubitril/valsartan is daunting. I have received calls from many people who ask whom am I supposed to use sacubitril/valsartan on? It took years and years to get people to [routinely] start patients on an ACE inhibitor and a beta-blocker, and now we’re telling them to do something else. In my practice it’s a 30-minute conversation with each patient that you need to first stop your ACE inhibitor, and then they often get denied coverage by their insurer,” said Dr. Jessup, professor of medicine at the University of Pennsylvania in Philadelphia. She expressed hope that coverage issues will diminish now that clear guidelines are out endorsing a key role for sacubitril/valsartan.

Mitchel L. Zoler/Frontline Medical News

“We now all have started sacubitril/valsartan on patients” without first starting them on an ACE inhibitor, “but we all need to get a sense of what we can get away with” when using this drug, noted Dr. JoAnn Lindenfeld, professor and director of heart failure and transplant at Vanderbilt University in Nashville.

At least one European cardiologist was skeptical of just how proscriptive the ESC guideline for sacubitril/valsartan will be in actual practice.

“The best treatment [for symptomatic HFrEF] is sacubitril/valsartan, a beta-blocker, and a MRA,” said Dr. John J.V. McMurray, professor of cardiology at Glasgow University and lead investigator for the PARADIGM-HF pivotal trial for sacubitril/valsartan. “The treatment sequence advocated in the guidelines – treat with an ACE inhibitor first and if patients remain symptomatic change to sacubitril/valsartan – is evidence-based medicine. As a guidelines writer and as a promoter of evidence-based medicine, this is absolutely the correct approach. But as a practicing physician I’d go straight for sacubitril/valsartan. Otherwise you’re wasting everybody’s time starting with an ACE inhibitor and then waiting a month to switch,” Dr. McMurray said in an interview.

Mitchel L. Zoler/Frontline Medical News

“It’s pointless to wait. We saw results within 30 days of starting sacubitril/valsartan, so it’s a theoretical risk to wait. Very few patients will become completely asymptomatic on an ACE inhibitor. Everyone who entered PARADIGM-HF was at New York Heart Association class II or higher, and at the time of randomization only a handful of patients were in New York Heart Association class I. Very few patients get to class I. That tells you it’s pretty uncommon for a heart failure patient to become truly asymptomatic with ACE inhibitor treatment. The main problem is that you are inconveniencing everybody with more blood tests and more clinic visits by waiting to start sacubitril/valsartan, said Dr. McMurray, who was not a member of the panel that wrote the new ESC guidelines.

Even less separates the new U.S. focused update and the ESC guidelines for using ivabradine. Both agree on starting the drug on HFrEF patients who remain symptomatic and with a left ventricular ejection fraction of 35% or less despite being on guideline-directed therapy including titration to a maximum beta-blocker dosage and with a persistent heart rate of at least 70 beats/min. The goal of ivabradine treatment is to further reduce heart rate beyond what’s achieved by a maximal beta-blocker dosage.

Perhaps the biggest questions about ivabradine have been why it took so long to enter the U.S. guidelines, and why it is listed in both the U.S. and ESC guidelines as a level II recommendation. Results from the pivotal trial that supported ivabradine’s use in HFrEF patients, SHIFT, first appeared in 2010 (Lancet. 2010 Sep 11;376[9744]:875-95).

Dr. Butler chalked up the drug’s slow entry into U.S. guidelines as the result of a lack of initiative by ivabradine’s initial developer, Servier. “SHIFT did not have any U.S. sites, and Servier never sought Food and Drug Administration approval,” he noted. “Amgen acquired the U.S. rights to ivabradine in 2013,” and the drug received FDA approval in April 2015, Dr. Butler noted, in explaining the drug’s U.S. timeline. As to why its use is a level II recommendation, he noted that the evidence for efficacy came only from the SHIFT trial, questions exist whether the beta-blocker dosages were fully optimized in all patients in this trial, and the benefit was limited to a reduction in heart failure hospitalizations but not in mortality. “I think that patients with persistent heart failure symptoms [and a persistently elevated heart rate] should get ivabradine,” but these caveats limit it to a class II level recommendation, Dr. Butler said.

“There were questions about ivabradine’s benefit in reducing heart failure hospitalization but not mortality, and questions about whether it would benefit patients if their beta-blocker dosage was adequately up titrated. There were also questions about which heart failure patients to use it on,” noted Dr. Lindenfeld, a member of the panel that wrote the U.S. focused update. These concerns in part help explain the delay to integrating ivabradine into U.S. practice guidelines, she said in an interview, but added that additional data and analysis published during the past 3 or so years have clarified ivabradine’s potentially useful role in treating selected HFrEF patients.

New ESC guidelines based on expert opinion

The sections on sacubitril/valsartan and ivabradine occupy a mere 2 pages among more than 55 pages of text and charts that spell out the ESC’s current vision of how physicians should diagnose and manage heart failure patients. While much of what carried over from prior editions of the guidelines is rooted in evidence, many of the new approaches advocated rely on expert opinion or new interpretations of existing data. Here are some of the notable changes and highlights of the 2016 ESC recommendations:

• Heart failure diagnosis. The new ESC guidelines streamline the diagnostic process, which now focuses on five key elements: The patient’s history, physical examination, ECG, serum level of either brain natriuretic peptide (BNP) or N-terminal(NT)-proBNP, and echocardiography. The guidelines specify threshold levels of BNP and NT-proBNP that can effectively rule out heart failure, a BNP level of at least 35 pg/mL or a NT-proBNP level of at least 125 pg/mL.

Mitchel L. Zoler/Frontline Medical News

“The diagnostic minimum levels of BNP and NT-proBNP were designed to rule out heart failure. They both have a high negative predictive value, but at these levels their positive predictive value is low,” explained Dr. Adriaan A. Voors, cochair of the ESC’s guideline-writing panel and professor of cardiology at the University of Groningen, the Netherlands.

But while these levels might be effective for reliable rule out of heart failure, they could mean a large number of patients would qualify for an echocardiographic assessment.

“If we used the ESC’s natriuretic peptide cutoffs, there would be a clear concern about overuse of echo. It’s a cost-effectiveness issue. You wind up doing a lot of echos that will be normal. Echocardiography is very safe, but each echo costs about $400-$500,” commented Dr. Butler.

“The results from the STOP-HF and PONTIAC studies showed that BNP levels can identify people at increased risk for developing heart failure who need more intensive assessment and could also potentially benefit from more attention to heart failure prevention. I suspect the full U.S. guideline update will address this issue, but we have not yet finalized our decisions,” he added.

• Heart failure classification. The new ESC guidelines created a new heart failure category, midrange ejection fraction, that the writing panel positioned squarely between the two more classic heart failure subgroups, HFrEF and heart failure with preserved ejection fraction (HFpEF). The definition of each of the three subgroups depends on left ventricular ejection fraction as determined by echocardiography: A LVEF of less than 40% defined HFrEF, a LVEF of 40%-49% defined heart failure with midrange ejection fraction (HFmrEF), and a LVEF of 50% or higher defined HFpEF. Diagnostic confirmation of both HFmrEF and HFpEF also requires that patients fulfill certain criteria of structural or functional heart abnormalities.

Mitchel L. Zoler/Frontline Medical News

The category of HFmrEF was created “to stimulate research into how to best manage these patients,” explained Dr. Piotr Ponikowski, chair of the ESC guidelines writing panel. For the time being, it remains a category with only theoretical importance as nothing is known to suggest that management of patients with HFmrEF should in any way differ from patients with HFpEF.

• Acute heart failure. Perhaps the most revolutionary element of the new guidelines is the detailed map they provide to managing patients who present with acute decompensated heart failure and the underlying principles cited to justify this radically different approach.

“The acute heart failure section was completely rewritten,” noted Dr. Ponikowski, professor of heart diseases at the Medical University in Wroclaw, Poland. “We don’t yet have evidence-based treatments” to apply to acute heart failure patients, he admitted, “however we strongly recommend the concept that the shorter the better. Shorten the time of diagnosis and for therapeutic decisions. We have borrowed from acute coronary syndrome. Don’t keep patients in the emergency department for another couple of hours just to see if they will respond. We must be aware that we need to do our best to shorten diagnosis and treatment decisions. Time is an issue. Manage a patient’s congestion and impaired peripheral perfusion within a time frame of 1-2 hours.”

The concept that acute heart failure must be quickly managed as an emergency condition similar to acute coronary syndrome first appeared as a European practice recommendation in 2015, a consensus statement from the European Heart Failure Association and two other collaborating organizations (Eur Heart J. 2015 Aug 7;36[30]:1958-66).

Mitchel L. Zoler/Frontline Medical News

“In 2015, the consensus paper talked about how to handle acute heart failure patients in the emergency department. Now, we have focused on defining the patients’ phenotype and how to categorize their treatment options. We built on the 2015 statement, but the algorithms we now have are original to 2016; they were not in the 2015 paper,” said Dr. Veli-Pekka Harjola, a member of the 2015 consensus group and 2016 guidelines panel who spearheaded writing the acute heart failure section of the new ESC guidelines.

An additional new and notable feature of this section in the 2016 guidelines is its creation of an acronym, CHAMP, designed to guide the management of patients with acute heart failure. CHAMP stands for acute Coronary syndrome, Hypertension emergency, Arrhythmia, acute Mechanical cause, and Pulmonary embolism. The CHAMP acronym’s purpose is to “focus attention on these five specific, potential causes of acute heart failure, life-threatening conditions that need immediate treatment,” explained Dr. Ponikowski.

“CHAMP emphasizes the most critical causes of acute heart failure,” added Dr. Harjola, a cardiologist at Helsinki University Central Hospital. “We created this new acronym” to help clinicians keep in mind what to look for in a patient presenting with acute heart failure.

U.S. cardiologists find things to like in what the Europeans say about managing acute heart failure, as well as aspects to question.

“It makes no sense not to aggressively treat a patient who arrives at an emergency department with acute heart failure. But there is a difference between acute MI or stroke and acute heart failure,” said Dr. Butler. “In acute MI there is the ruptured plaque and thrombus that blocks a coronary artery. In stroke there is a thrombus. These are diseases with a specific onset and treatment target. But with acute heart failure we don’t have a thrombus to treat; we don’t have a specific target. What we’ve learned from studying implanted devices [such as CardioMems] is that the congestion that causes acute heart failure can start 2-3 weeks before a patient develops acute decompensated heart failure and goes to the hospital. We have not found a specific pathophysiologic abnormality in the patient with acute heart failure that is any different from chronic heart failure. This begs the question: If a patient who presents with acute heart failure has a congestion process that’s been going on for 2 or 3 weeks what difference will another 3 hours make? Do we need to replicate the concept of an acute stroke team or acute MI response for acute heart failure?”

Dr. Butler stressed that additional data are expected soon that may help clarify this issue.

“Some large outcome trials in patients with acute heart failure are now underway, one testing serelaxin treatment, another testing ularitide treatment, that are also testing the hypothesis that rapid treatment with these drugs can produce more end-organ protection, stop damage to the heart, kidney and liver, and lead to better long-term outcomes. Until we have those data, the jury is still out” on the benefit patients gain from rapid treatment of acute heart failure. “Until then, it’s not that the data say don’t treat acute heart failure patients aggressively. But we have not yet proven it is similar to treating an acute MI or stroke,” said Dr. Butler.

Mitchel L. Zoler/Frontline Medical News

“U.S. guidelines have tended to stay away from areas where there are no evidence-based data. To their credit, the Europeans will take on something like acute heart failure where we don’t have an adequate evidence base. Despite that, they provide guidelines, which is important because clinicians need guidance even when the evidence is not very good, when the guideline is based mostly on experience and expert consensus.” commented Dr. William T. Abraham, professor and director of cardiovascular medicine at the Ohio State University Wexner Medical Center in Columbus.

“It’s absolutely appropriate to think of acute heart failure as an emergency situation. We know from high-sensitivity troponin assays that troponin levels are increased in 90% of patients who present with acute decompensated heart failure. So most acute heart failure patients are losing heart muscle cells and we should treat them like we treat acute coronary syndrome. Time matters in acute heart failure; time is heart muscle. Treatment needs to break the hemodynamic and neurohormonal storm of acute decompensated heart failure; get the patient stabilized; improve vital organ perfusion, including within the heart; and shift the myocardial oxygen supply and demand equation so myocardial necrosis stops. All of this is important, and study results suggest it’s the correct approach. I’m not sure study results prove it, but studies that have looked at the time course of treatment for acute heart failure showed that early initiation of treatment – within the first 6 hours of onset – compared with 12-24 hours of onset makes a difference in outcomes,” Dr. Abraham said in an interview.

But a major limitation to the potential efficacy of a rapidly initiated management strategy is that few interventions currently exist with proven benefits for acute heart failure patients.

For the time being, rapid intervention means using diuretics relatively quickly and, if there is an indication for treating with a vasoactive medication, using that quickly too. “The rapid approach is really more relevant to the future; it’s relevant to the design of future acute heart failure treatment trials. That is where this early treatment paradigm is important,” as it could potentially apply to new, more effective treatments of the future rather than to the marginally effective treatments now available, Dr. Abraham said.

“For a long we time haven’t pushed how quickly we should act when implementing guideline-directed treatment” for patients with acute heart failure, noted Dr. Mehra. “The CHAMP approach is interesting, and the ESC guidelines are a very interesting move in the direction” of faster action. “They speak to the period of time during which one should act. Hopefully this will help the science of acute decompensated heart failure move forward.”

But for other U.S. experts the issue again pivots on the lack of evidence.

“There is nothing new” about managing acute heart failure, said Dr. Jessup. “The ESC guideline was articulated very well; they made their recommendations very clear. But a lot is consensus driven. There are no new data. The problem with acute heart failure is that the recommendations are what we think clinicians should do. CHAMP is a nice acronym; it’s packaged better, but there are not any new data.”

Comorbidities

A dramatic contrast distinguishes the extent to which the ESC guidelines highlight comorbidities, compared with prevailing U.S. guidelines. The new ESC guidelines highlight and discuss with some detail 16 distinct comorbidities for clinicians to keep in mind when managing heart failure patients, compared with three comorbidities (atrial fibrillation, anemia, and depression) discussed with similar detail in the 2013 U.S. guidelines.

Mitchel L. Zoler/Frontline Medical News

“We are targeting comorbidities to personalize medicine, by subgrouping [heart failure] patients into groups that need to receive special attention,” explained Dr. Stefan D. Anker, a coauthor on the ESC guidelines. “We care about comorbidities because they make the diagnosis of heart failure difficult. They aggravate symptoms and contribute to additional hospitalizations. They interfere with [heart failure] treatment, and because comorbidities have led to exclusions of heart failure patients from trials, we lack evidence of treatment efficacy in patients with certain comorbidities,” said Dr. Anker, a professor of innovative clinical trials at the Medical University in Göttingen, Germany.

“The comorbidity discussion in the ESC guidelines is extremely important,” commented Dr. Abraham. “It supports the need for a multidimensional approach to heart failure patients. A cardiologist may not have all the resources to manage all the comorbidities [a heart failure patient might have]. This is why having a sleep medicine specialist, a diabetes specialist, a nephrologist, etc., involved as part of a heart failure management team can be very valuable. We need to involve subspecialists in managing the comorbidities of heart failure because they clearly have an impact on patient outcome.”

But Dr. Butler had a somewhat different take on how comorbidity management fits into the broader picture of heart failure management.

“There is no doubt that heart failure worsens other comorbidities and other comorbidities worsen heart failure. The relationship is bidirectional between heart failure and chronic obstructive pulmonary disease, liver disease, depression, sleep apnea, renal disease, lung disease, diabetes, etc. The problem is that treating a comorbidity does not necessarily translate into improved heart failure outcomes. Comorbidities are important for heart failure patients and worsen their heart failure outcomes. However, management of a comorbidity should be done primarily for the sake of improving the comorbidity. If you treat depression, for example, and it does not improve a patient’s heart failure, that doesn’t mean you shouldn’t have treated the depression. It just means that we don’t have good data that it will improve heart failure.”

Another limitation from a U.S. perspective is what role treatment of various comorbidities can play in benefiting heart failure patients and how compelling the evidence is for this. Dr. Butler gave as an example the problem with treating iron deficiency in heart failure patients who do not have anemia, a strategy endorsed in the ESC guidelines as a level IIa recommendation.

“The data regarding improved exercise capacity from treatment with intravenous ferric carboxymaltose is pretty convincing,” he said. But patients have benefited from this treatment only with improved function and quality of life, and not with improved survival or fewer hospitalizations.

“Is treating patients to improve their function and help them feel better enough?” Dr. Butler asked. “In other diseases it is. In gastrointestinal disease, if a drug helps patients feel better you approve the drug. We value improved functional capacity for patients with pulmonary hypertension, angina, and peripheral vascular disease. All these indications have drugs approved for improving functional capacity and quality of life. But for heart failure the bar has been set higher. There is a lot of interest in changing this” for heart failure.

“There is interest in running a study of ferric carboxymaltose for heart failure with a mortality endpoint. In the meantime, the impact on improving functional capacity is compelling, and it will be interesting to see what happens in the U.S. guidelines. Currently, in U.S. practice if a heart failure patient has iron-deficiency anemia you treat with intravenous iron replacement and the treatment gets reimbursed without a problem. But if the heart failure patient has iron deficiency without anemia then reimbursement for the cost of iron supplementation can be a problem,” Dr. Butler noted. This may change only if the experts who write the next U.S. heart failure guidelines decide to change the rules of what constitutes a useful heart failure treatment, he said.

Dr. Butler has been a consultant to Novartis and Amgen and several other companies. Dr. Jessup had no disclosures. Dr. Mehra has been a consultant to Teva, Johnson & Johnson, Boston Scientific, and St. Jude. Dr. Ruschitzka has been a consultant to Novartis, Servier, Sanofi, Cardiorentis, Heartware, and St. Jude. Dr. McMurray has received research support from Novartis and Amgen. Dr. Lindenfeld has been a consultant to Novartis, Abbott, Janssen, Relypsa, and Resmed. Dr. Voors has been a consultant to Novartis, Amgen, Servier, and several other drug companies. Dr. Ponikowski has been a consultant to Amgen, Novartis, Servier, and several other drug companies. Dr. Harjola has been a consultant to Novartis, Servier, Bayer, Boehringer Ingelheim, Pfizer, and Resmed. Dr. Abraham has been a consultant to Amgen, Novartis, and several device companies. Dr. Anker has been a consultant to Novartis, Servier, and several other companies.

[email protected]

On Twitter @mitchelzoler

FLORENCE, ITALY – The 2016 revision of the European Society of Cardiology’s guidelines for diagnosing and treating acute and chronic heart failure highlights the extent to which thinking in the field has changed during the past 4 years, since the prior edition in 2012.

The new European guidelines, unveiled by the ESC’s Heart Failure Association during the group’s annual meeting, also underscore the great dependence that many new approaches have on expert opinion rather than what’s become the keystone of guidelines writing, evidence-based medicine. Frequent reliance on consensus decisions rather than indisputable proof from controlled trials defines what some U.S. specialists see as a divide as wide as the Atlantic between the European and U.S. approaches to guideline writing.

Mitchel L. Zoler/Frontline Medical News

“The guidelines from the ESC are articulated very well; they made their recommendations very clear. But a lot is consensus driven, without new data,” said Dr. Mariell L. Jessup, who serves as both vice chair of the panel currently revising the U.S. heart failure guidelines – expected out later in 2016 – and was also the sole American representative on the panel that produced the ESC guidelines. “The ESC guidelines make clear all the things that need to happen to patients. I hope it will result in better patient care. We are clearly not doing a good job in heart failure. We not only don’t have evidence-based treatments, but people often don’t do a good job [caring for heart failure patients] and they die in the hospital all the time.”

Dr. Javed Butler, another member of the U.S. guidelines panel and professor and chief of cardiology at Stony Brook (N.Y.) University, called the U.S. and European divide a “philosophical perspective of evidence-based medicine.

“U.S. physicians should read the ESC guidelines and make up their own minds. The ESC guidelines are excellent and give you perspective. But U.S. regulatory and payment issues will be driven by U.S. guidelines,” Dr. Butler said in an interview.

Mitchel L. Zoler/Frontline Medical News

But despite their limitations and the limited weight that the ESC guidelines carry for U.S. practice, they have many redeeming features, noted Dr. Mandeep R. Mehra, medical director of the Heart and Vascular Center at Brigham and Women’s Hospital in Boston. The 2016 ESC guidelines “are extraordinarily clear, very practical, and very concise. They are very usable, and provide a fantastic algorithm for managing patients with heart failure with reduced ejection fraction [HFrEF],” he said while discussing the guidelines during the meeting.

U.S. and Europe largely agree on sacubitril/valsartan and ivabradine

Clearly the greatest area of U.S. and European agreement was in the adoption by both guidelines groups of sacubitril/valsartan (Entresto) and ivabradine (Corlanor) as important new components of the basic drug formula for treating patients with HFrEF. In fact, the U.S. guideline writers saw these two additions as so important and timely that they issued a “focused update” in May to the existing, 2013 U.S. heart failure guidelines, and timed release of this update to occur on May 20, 2016, a day before release of the ESC guidelines. But as Dr. Butler noted, this was more of a temporal harmonization than a substantive one, because even here, in a very evidence-based change, the U.S. guidelines for using sacubitril/valsartan differed subtly but importantly from the ESC version.

The U.S. focused update says that treatment of patients with stage C (symptomatic heart failure with structural heart disease) HFrEF should receive treatment with sacubitril/valsartan (also know as an angiotensin receptor neprilysin inhibitor, or ARNI), an ACE inhibitor, or an angiotensin receptor blocker (ARB), as well as evidence-based treatment with a beta-blocker and with a mineralocorticoid receptor antagonist (MRA). A subsequent recommendation in the U.S. focused update said that HFrEF patients with chronic symptoms and New York Heart Association class II or III disease should switch from a stable, tolerated regimen with either an ACE inhibitor or ARB to treatment with sacubitril/valsartan.

Courtesy Stony Brook University

In contrast, the new European guideline for sacubitril/valsartan recommends starting patients on this combination formulation only after first demonstrating that patients tolerated treatment with an ACE inhibitor or ARB for at least 30 days and determining that patients remained symptomatic while on one of these treatments. In short, the U.S. guideline gives a green light to starting patients with newly diagnosed, symptomatic HFrEF on sacubitril/valsartan immediately, while the European guideline only sanctions sacubitril/valsartan to start after a patient has spent at least 30 days settling into a multidrug regimen featuring an ACE inhibitor or an ARB when an ACE inhibitor isn’t well tolerated.

“The European guidelines are closely related to the study population enrolled in the PARADIGM-HF trial,” the pivotal trial that showed superiority of sacubitril/valsartan to an ACE inhibitor (N Engl J Med. 2014;371:993-1004), noted Dr. Butler in an interview. “The U.S. guidelines interpreted [the PARADIGM-HF] results in the best interests of a larger patient population. The European guidelines are far more proscriptive in replicating the clinical criteria of the trial. In some patients the sequence of starting a MRA and sacubitril/valsartan matters, but in other patients it is less important.”

Dr. Frank Ruschitzka, a coauthor of the ESC guidelines, said that the reason for the more cautious ESC approach was lack of widespread familiarity with sacubitril/valsartan treatment among cardiologists.

Mitchel L. Zoler/Frontline Medical News

The ESC guidelines on using sacubitril/valsartan “replicated the PARADIGM-HF trial. We have no data right now that it is justifiable to put a [treatment-naive] patient on sacubitril/valsartan to begin with. Another difference between the U.S. and ESC guidelines is when to start a MRA,” said Dr. Ruschitzka, professor and head of cardiology at the Heart Center of the University Hospital in Zurich. “It makes a lot of sense to me to start sacubitril/valsartan early. The PARADIGM trial was positive, but no one has a feel for how to use sacubitril/valsartan. Should we give it to everyone? We said replicate the trial, and gain experience using the drug. We want to bring a life-saving drug to patients, but this is the approach we took. We need more data.”

Dr. Jessup noted that a lot of uncertainty also exists among U.S. clinicians about when to start sacubitril/valsartan. “It’s not been clear which patients to put on sacubitril/valsartan. No guidelines had been out on using it” until mid-May, and “the cost of sacubitril/valsartan is daunting. I have received calls from many people who ask whom am I supposed to use sacubitril/valsartan on? It took years and years to get people to [routinely] start patients on an ACE inhibitor and a beta-blocker, and now we’re telling them to do something else. In my practice it’s a 30-minute conversation with each patient that you need to first stop your ACE inhibitor, and then they often get denied coverage by their insurer,” said Dr. Jessup, professor of medicine at the University of Pennsylvania in Philadelphia. She expressed hope that coverage issues will diminish now that clear guidelines are out endorsing a key role for sacubitril/valsartan.

Mitchel L. Zoler/Frontline Medical News

“We now all have started sacubitril/valsartan on patients” without first starting them on an ACE inhibitor, “but we all need to get a sense of what we can get away with” when using this drug, noted Dr. JoAnn Lindenfeld, professor and director of heart failure and transplant at Vanderbilt University in Nashville.

At least one European cardiologist was skeptical of just how proscriptive the ESC guideline for sacubitril/valsartan will be in actual practice.

“The best treatment [for symptomatic HFrEF] is sacubitril/valsartan, a beta-blocker, and a MRA,” said Dr. John J.V. McMurray, professor of cardiology at Glasgow University and lead investigator for the PARADIGM-HF pivotal trial for sacubitril/valsartan. “The treatment sequence advocated in the guidelines – treat with an ACE inhibitor first and if patients remain symptomatic change to sacubitril/valsartan – is evidence-based medicine. As a guidelines writer and as a promoter of evidence-based medicine, this is absolutely the correct approach. But as a practicing physician I’d go straight for sacubitril/valsartan. Otherwise you’re wasting everybody’s time starting with an ACE inhibitor and then waiting a month to switch,” Dr. McMurray said in an interview.

Mitchel L. Zoler/Frontline Medical News

“It’s pointless to wait. We saw results within 30 days of starting sacubitril/valsartan, so it’s a theoretical risk to wait. Very few patients will become completely asymptomatic on an ACE inhibitor. Everyone who entered PARADIGM-HF was at New York Heart Association class II or higher, and at the time of randomization only a handful of patients were in New York Heart Association class I. Very few patients get to class I. That tells you it’s pretty uncommon for a heart failure patient to become truly asymptomatic with ACE inhibitor treatment. The main problem is that you are inconveniencing everybody with more blood tests and more clinic visits by waiting to start sacubitril/valsartan, said Dr. McMurray, who was not a member of the panel that wrote the new ESC guidelines.

Even less separates the new U.S. focused update and the ESC guidelines for using ivabradine. Both agree on starting the drug on HFrEF patients who remain symptomatic and with a left ventricular ejection fraction of 35% or less despite being on guideline-directed therapy including titration to a maximum beta-blocker dosage and with a persistent heart rate of at least 70 beats/min. The goal of ivabradine treatment is to further reduce heart rate beyond what’s achieved by a maximal beta-blocker dosage.

Perhaps the biggest questions about ivabradine have been why it took so long to enter the U.S. guidelines, and why it is listed in both the U.S. and ESC guidelines as a level II recommendation. Results from the pivotal trial that supported ivabradine’s use in HFrEF patients, SHIFT, first appeared in 2010 (Lancet. 2010 Sep 11;376[9744]:875-95).

Dr. Butler chalked up the drug’s slow entry into U.S. guidelines as the result of a lack of initiative by ivabradine’s initial developer, Servier. “SHIFT did not have any U.S. sites, and Servier never sought Food and Drug Administration approval,” he noted. “Amgen acquired the U.S. rights to ivabradine in 2013,” and the drug received FDA approval in April 2015, Dr. Butler noted, in explaining the drug’s U.S. timeline. As to why its use is a level II recommendation, he noted that the evidence for efficacy came only from the SHIFT trial, questions exist whether the beta-blocker dosages were fully optimized in all patients in this trial, and the benefit was limited to a reduction in heart failure hospitalizations but not in mortality. “I think that patients with persistent heart failure symptoms [and a persistently elevated heart rate] should get ivabradine,” but these caveats limit it to a class II level recommendation, Dr. Butler said.

“There were questions about ivabradine’s benefit in reducing heart failure hospitalization but not mortality, and questions about whether it would benefit patients if their beta-blocker dosage was adequately up titrated. There were also questions about which heart failure patients to use it on,” noted Dr. Lindenfeld, a member of the panel that wrote the U.S. focused update. These concerns in part help explain the delay to integrating ivabradine into U.S. practice guidelines, she said in an interview, but added that additional data and analysis published during the past 3 or so years have clarified ivabradine’s potentially useful role in treating selected HFrEF patients.

New ESC guidelines based on expert opinion

The sections on sacubitril/valsartan and ivabradine occupy a mere 2 pages among more than 55 pages of text and charts that spell out the ESC’s current vision of how physicians should diagnose and manage heart failure patients. While much of what carried over from prior editions of the guidelines is rooted in evidence, many of the new approaches advocated rely on expert opinion or new interpretations of existing data. Here are some of the notable changes and highlights of the 2016 ESC recommendations:

• Heart failure diagnosis. The new ESC guidelines streamline the diagnostic process, which now focuses on five key elements: The patient’s history, physical examination, ECG, serum level of either brain natriuretic peptide (BNP) or N-terminal(NT)-proBNP, and echocardiography. The guidelines specify threshold levels of BNP and NT-proBNP that can effectively rule out heart failure, a BNP level of at least 35 pg/mL or a NT-proBNP level of at least 125 pg/mL.

Mitchel L. Zoler/Frontline Medical News

“The diagnostic minimum levels of BNP and NT-proBNP were designed to rule out heart failure. They both have a high negative predictive value, but at these levels their positive predictive value is low,” explained Dr. Adriaan A. Voors, cochair of the ESC’s guideline-writing panel and professor of cardiology at the University of Groningen, the Netherlands.

But while these levels might be effective for reliable rule out of heart failure, they could mean a large number of patients would qualify for an echocardiographic assessment.

“If we used the ESC’s natriuretic peptide cutoffs, there would be a clear concern about overuse of echo. It’s a cost-effectiveness issue. You wind up doing a lot of echos that will be normal. Echocardiography is very safe, but each echo costs about $400-$500,” commented Dr. Butler.

“The results from the STOP-HF and PONTIAC studies showed that BNP levels can identify people at increased risk for developing heart failure who need more intensive assessment and could also potentially benefit from more attention to heart failure prevention. I suspect the full U.S. guideline update will address this issue, but we have not yet finalized our decisions,” he added.

• Heart failure classification. The new ESC guidelines created a new heart failure category, midrange ejection fraction, that the writing panel positioned squarely between the two more classic heart failure subgroups, HFrEF and heart failure with preserved ejection fraction (HFpEF). The definition of each of the three subgroups depends on left ventricular ejection fraction as determined by echocardiography: A LVEF of less than 40% defined HFrEF, a LVEF of 40%-49% defined heart failure with midrange ejection fraction (HFmrEF), and a LVEF of 50% or higher defined HFpEF. Diagnostic confirmation of both HFmrEF and HFpEF also requires that patients fulfill certain criteria of structural or functional heart abnormalities.

Mitchel L. Zoler/Frontline Medical News

The category of HFmrEF was created “to stimulate research into how to best manage these patients,” explained Dr. Piotr Ponikowski, chair of the ESC guidelines writing panel. For the time being, it remains a category with only theoretical importance as nothing is known to suggest that management of patients with HFmrEF should in any way differ from patients with HFpEF.

• Acute heart failure. Perhaps the most revolutionary element of the new guidelines is the detailed map they provide to managing patients who present with acute decompensated heart failure and the underlying principles cited to justify this radically different approach.

“The acute heart failure section was completely rewritten,” noted Dr. Ponikowski, professor of heart diseases at the Medical University in Wroclaw, Poland. “We don’t yet have evidence-based treatments” to apply to acute heart failure patients, he admitted, “however we strongly recommend the concept that the shorter the better. Shorten the time of diagnosis and for therapeutic decisions. We have borrowed from acute coronary syndrome. Don’t keep patients in the emergency department for another couple of hours just to see if they will respond. We must be aware that we need to do our best to shorten diagnosis and treatment decisions. Time is an issue. Manage a patient’s congestion and impaired peripheral perfusion within a time frame of 1-2 hours.”

The concept that acute heart failure must be quickly managed as an emergency condition similar to acute coronary syndrome first appeared as a European practice recommendation in 2015, a consensus statement from the European Heart Failure Association and two other collaborating organizations (Eur Heart J. 2015 Aug 7;36[30]:1958-66).

Mitchel L. Zoler/Frontline Medical News

“In 2015, the consensus paper talked about how to handle acute heart failure patients in the emergency department. Now, we have focused on defining the patients’ phenotype and how to categorize their treatment options. We built on the 2015 statement, but the algorithms we now have are original to 2016; they were not in the 2015 paper,” said Dr. Veli-Pekka Harjola, a member of the 2015 consensus group and 2016 guidelines panel who spearheaded writing the acute heart failure section of the new ESC guidelines.

An additional new and notable feature of this section in the 2016 guidelines is its creation of an acronym, CHAMP, designed to guide the management of patients with acute heart failure. CHAMP stands for acute Coronary syndrome, Hypertension emergency, Arrhythmia, acute Mechanical cause, and Pulmonary embolism. The CHAMP acronym’s purpose is to “focus attention on these five specific, potential causes of acute heart failure, life-threatening conditions that need immediate treatment,” explained Dr. Ponikowski.

“CHAMP emphasizes the most critical causes of acute heart failure,” added Dr. Harjola, a cardiologist at Helsinki University Central Hospital. “We created this new acronym” to help clinicians keep in mind what to look for in a patient presenting with acute heart failure.

U.S. cardiologists find things to like in what the Europeans say about managing acute heart failure, as well as aspects to question.

“It makes no sense not to aggressively treat a patient who arrives at an emergency department with acute heart failure. But there is a difference between acute MI or stroke and acute heart failure,” said Dr. Butler. “In acute MI there is the ruptured plaque and thrombus that blocks a coronary artery. In stroke there is a thrombus. These are diseases with a specific onset and treatment target. But with acute heart failure we don’t have a thrombus to treat; we don’t have a specific target. What we’ve learned from studying implanted devices [such as CardioMems] is that the congestion that causes acute heart failure can start 2-3 weeks before a patient develops acute decompensated heart failure and goes to the hospital. We have not found a specific pathophysiologic abnormality in the patient with acute heart failure that is any different from chronic heart failure. This begs the question: If a patient who presents with acute heart failure has a congestion process that’s been going on for 2 or 3 weeks what difference will another 3 hours make? Do we need to replicate the concept of an acute stroke team or acute MI response for acute heart failure?”

Dr. Butler stressed that additional data are expected soon that may help clarify this issue.

“Some large outcome trials in patients with acute heart failure are now underway, one testing serelaxin treatment, another testing ularitide treatment, that are also testing the hypothesis that rapid treatment with these drugs can produce more end-organ protection, stop damage to the heart, kidney and liver, and lead to better long-term outcomes. Until we have those data, the jury is still out” on the benefit patients gain from rapid treatment of acute heart failure. “Until then, it’s not that the data say don’t treat acute heart failure patients aggressively. But we have not yet proven it is similar to treating an acute MI or stroke,” said Dr. Butler.

Mitchel L. Zoler/Frontline Medical News

“U.S. guidelines have tended to stay away from areas where there are no evidence-based data. To their credit, the Europeans will take on something like acute heart failure where we don’t have an adequate evidence base. Despite that, they provide guidelines, which is important because clinicians need guidance even when the evidence is not very good, when the guideline is based mostly on experience and expert consensus.” commented Dr. William T. Abraham, professor and director of cardiovascular medicine at the Ohio State University Wexner Medical Center in Columbus.

“It’s absolutely appropriate to think of acute heart failure as an emergency situation. We know from high-sensitivity troponin assays that troponin levels are increased in 90% of patients who present with acute decompensated heart failure. So most acute heart failure patients are losing heart muscle cells and we should treat them like we treat acute coronary syndrome. Time matters in acute heart failure; time is heart muscle. Treatment needs to break the hemodynamic and neurohormonal storm of acute decompensated heart failure; get the patient stabilized; improve vital organ perfusion, including within the heart; and shift the myocardial oxygen supply and demand equation so myocardial necrosis stops. All of this is important, and study results suggest it’s the correct approach. I’m not sure study results prove it, but studies that have looked at the time course of treatment for acute heart failure showed that early initiation of treatment – within the first 6 hours of onset – compared with 12-24 hours of onset makes a difference in outcomes,” Dr. Abraham said in an interview.

But a major limitation to the potential efficacy of a rapidly initiated management strategy is that few interventions currently exist with proven benefits for acute heart failure patients.

For the time being, rapid intervention means using diuretics relatively quickly and, if there is an indication for treating with a vasoactive medication, using that quickly too. “The rapid approach is really more relevant to the future; it’s relevant to the design of future acute heart failure treatment trials. That is where this early treatment paradigm is important,” as it could potentially apply to new, more effective treatments of the future rather than to the marginally effective treatments now available, Dr. Abraham said.

“For a long we time haven’t pushed how quickly we should act when implementing guideline-directed treatment” for patients with acute heart failure, noted Dr. Mehra. “The CHAMP approach is interesting, and the ESC guidelines are a very interesting move in the direction” of faster action. “They speak to the period of time during which one should act. Hopefully this will help the science of acute decompensated heart failure move forward.”

But for other U.S. experts the issue again pivots on the lack of evidence.

“There is nothing new” about managing acute heart failure, said Dr. Jessup. “The ESC guideline was articulated very well; they made their recommendations very clear. But a lot is consensus driven. There are no new data. The problem with acute heart failure is that the recommendations are what we think clinicians should do. CHAMP is a nice acronym; it’s packaged better, but there are not any new data.”

Comorbidities

A dramatic contrast distinguishes the extent to which the ESC guidelines highlight comorbidities, compared with prevailing U.S. guidelines. The new ESC guidelines highlight and discuss with some detail 16 distinct comorbidities for clinicians to keep in mind when managing heart failure patients, compared with three comorbidities (atrial fibrillation, anemia, and depression) discussed with similar detail in the 2013 U.S. guidelines.

Mitchel L. Zoler/Frontline Medical News

“We are targeting comorbidities to personalize medicine, by subgrouping [heart failure] patients into groups that need to receive special attention,” explained Dr. Stefan D. Anker, a coauthor on the ESC guidelines. “We care about comorbidities because they make the diagnosis of heart failure difficult. They aggravate symptoms and contribute to additional hospitalizations. They interfere with [heart failure] treatment, and because comorbidities have led to exclusions of heart failure patients from trials, we lack evidence of treatment efficacy in patients with certain comorbidities,” said Dr. Anker, a professor of innovative clinical trials at the Medical University in Göttingen, Germany.

“The comorbidity discussion in the ESC guidelines is extremely important,” commented Dr. Abraham. “It supports the need for a multidimensional approach to heart failure patients. A cardiologist may not have all the resources to manage all the comorbidities [a heart failure patient might have]. This is why having a sleep medicine specialist, a diabetes specialist, a nephrologist, etc., involved as part of a heart failure management team can be very valuable. We need to involve subspecialists in managing the comorbidities of heart failure because they clearly have an impact on patient outcome.”

But Dr. Butler had a somewhat different take on how comorbidity management fits into the broader picture of heart failure management.

“There is no doubt that heart failure worsens other comorbidities and other comorbidities worsen heart failure. The relationship is bidirectional between heart failure and chronic obstructive pulmonary disease, liver disease, depression, sleep apnea, renal disease, lung disease, diabetes, etc. The problem is that treating a comorbidity does not necessarily translate into improved heart failure outcomes. Comorbidities are important for heart failure patients and worsen their heart failure outcomes. However, management of a comorbidity should be done primarily for the sake of improving the comorbidity. If you treat depression, for example, and it does not improve a patient’s heart failure, that doesn’t mean you shouldn’t have treated the depression. It just means that we don’t have good data that it will improve heart failure.”

Another limitation from a U.S. perspective is what role treatment of various comorbidities can play in benefiting heart failure patients and how compelling the evidence is for this. Dr. Butler gave as an example the problem with treating iron deficiency in heart failure patients who do not have anemia, a strategy endorsed in the ESC guidelines as a level IIa recommendation.

“The data regarding improved exercise capacity from treatment with intravenous ferric carboxymaltose is pretty convincing,” he said. But patients have benefited from this treatment only with improved function and quality of life, and not with improved survival or fewer hospitalizations.

“Is treating patients to improve their function and help them feel better enough?” Dr. Butler asked. “In other diseases it is. In gastrointestinal disease, if a drug helps patients feel better you approve the drug. We value improved functional capacity for patients with pulmonary hypertension, angina, and peripheral vascular disease. All these indications have drugs approved for improving functional capacity and quality of life. But for heart failure the bar has been set higher. There is a lot of interest in changing this” for heart failure.

“There is interest in running a study of ferric carboxymaltose for heart failure with a mortality endpoint. In the meantime, the impact on improving functional capacity is compelling, and it will be interesting to see what happens in the U.S. guidelines. Currently, in U.S. practice if a heart failure patient has iron-deficiency anemia you treat with intravenous iron replacement and the treatment gets reimbursed without a problem. But if the heart failure patient has iron deficiency without anemia then reimbursement for the cost of iron supplementation can be a problem,” Dr. Butler noted. This may change only if the experts who write the next U.S. heart failure guidelines decide to change the rules of what constitutes a useful heart failure treatment, he said.

Dr. Butler has been a consultant to Novartis and Amgen and several other companies. Dr. Jessup had no disclosures. Dr. Mehra has been a consultant to Teva, Johnson & Johnson, Boston Scientific, and St. Jude. Dr. Ruschitzka has been a consultant to Novartis, Servier, Sanofi, Cardiorentis, Heartware, and St. Jude. Dr. McMurray has received research support from Novartis and Amgen. Dr. Lindenfeld has been a consultant to Novartis, Abbott, Janssen, Relypsa, and Resmed. Dr. Voors has been a consultant to Novartis, Amgen, Servier, and several other drug companies. Dr. Ponikowski has been a consultant to Amgen, Novartis, Servier, and several other drug companies. Dr. Harjola has been a consultant to Novartis, Servier, Bayer, Boehringer Ingelheim, Pfizer, and Resmed. Dr. Abraham has been a consultant to Amgen, Novartis, and several device companies. Dr. Anker has been a consultant to Novartis, Servier, and several other companies.

[email protected]

On Twitter @mitchelzoler

FLORENCE, ITALY – The 2016 revision of the European Society of Cardiology’s guidelines for diagnosing and treating acute and chronic heart failure highlights the extent to which thinking in the field has changed during the past 4 years, since the prior edition in 2012.

The new European guidelines, unveiled by the ESC’s Heart Failure Association during the group’s annual meeting, also underscore the great dependence that many new approaches have on expert opinion rather than what’s become the keystone of guidelines writing, evidence-based medicine. Frequent reliance on consensus decisions rather than indisputable proof from controlled trials defines what some U.S. specialists see as a divide as wide as the Atlantic between the European and U.S. approaches to guideline writing.

Mitchel L. Zoler/Frontline Medical News

“The guidelines from the ESC are articulated very well; they made their recommendations very clear. But a lot is consensus driven, without new data,” said Dr. Mariell L. Jessup, who serves as both vice chair of the panel currently revising the U.S. heart failure guidelines – expected out later in 2016 – and was also the sole American representative on the panel that produced the ESC guidelines. “The ESC guidelines make clear all the things that need to happen to patients. I hope it will result in better patient care. We are clearly not doing a good job in heart failure. We not only don’t have evidence-based treatments, but people often don’t do a good job [caring for heart failure patients] and they die in the hospital all the time.”

Dr. Javed Butler, another member of the U.S. guidelines panel and professor and chief of cardiology at Stony Brook (N.Y.) University, called the U.S. and European divide a “philosophical perspective of evidence-based medicine.

“U.S. physicians should read the ESC guidelines and make up their own minds. The ESC guidelines are excellent and give you perspective. But U.S. regulatory and payment issues will be driven by U.S. guidelines,” Dr. Butler said in an interview.

Mitchel L. Zoler/Frontline Medical News

But despite their limitations and the limited weight that the ESC guidelines carry for U.S. practice, they have many redeeming features, noted Dr. Mandeep R. Mehra, medical director of the Heart and Vascular Center at Brigham and Women’s Hospital in Boston. The 2016 ESC guidelines “are extraordinarily clear, very practical, and very concise. They are very usable, and provide a fantastic algorithm for managing patients with heart failure with reduced ejection fraction [HFrEF],” he said while discussing the guidelines during the meeting.

U.S. and Europe largely agree on sacubitril/valsartan and ivabradine

Clearly the greatest area of U.S. and European agreement was in the adoption by both guidelines groups of sacubitril/valsartan (Entresto) and ivabradine (Corlanor) as important new components of the basic drug formula for treating patients with HFrEF. In fact, the U.S. guideline writers saw these two additions as so important and timely that they issued a “focused update” in May to the existing, 2013 U.S. heart failure guidelines, and timed release of this update to occur on May 20, 2016, a day before release of the ESC guidelines. But as Dr. Butler noted, this was more of a temporal harmonization than a substantive one, because even here, in a very evidence-based change, the U.S. guidelines for using sacubitril/valsartan differed subtly but importantly from the ESC version.

The U.S. focused update says that treatment of patients with stage C (symptomatic heart failure with structural heart disease) HFrEF should receive treatment with sacubitril/valsartan (also know as an angiotensin receptor neprilysin inhibitor, or ARNI), an ACE inhibitor, or an angiotensin receptor blocker (ARB), as well as evidence-based treatment with a beta-blocker and with a mineralocorticoid receptor antagonist (MRA). A subsequent recommendation in the U.S. focused update said that HFrEF patients with chronic symptoms and New York Heart Association class II or III disease should switch from a stable, tolerated regimen with either an ACE inhibitor or ARB to treatment with sacubitril/valsartan.

Courtesy Stony Brook University

In contrast, the new European guideline for sacubitril/valsartan recommends starting patients on this combination formulation only after first demonstrating that patients tolerated treatment with an ACE inhibitor or ARB for at least 30 days and determining that patients remained symptomatic while on one of these treatments. In short, the U.S. guideline gives a green light to starting patients with newly diagnosed, symptomatic HFrEF on sacubitril/valsartan immediately, while the European guideline only sanctions sacubitril/valsartan to start after a patient has spent at least 30 days settling into a multidrug regimen featuring an ACE inhibitor or an ARB when an ACE inhibitor isn’t well tolerated.

“The European guidelines are closely related to the study population enrolled in the PARADIGM-HF trial,” the pivotal trial that showed superiority of sacubitril/valsartan to an ACE inhibitor (N Engl J Med. 2014;371:993-1004), noted Dr. Butler in an interview. “The U.S. guidelines interpreted [the PARADIGM-HF] results in the best interests of a larger patient population. The European guidelines are far more proscriptive in replicating the clinical criteria of the trial. In some patients the sequence of starting a MRA and sacubitril/valsartan matters, but in other patients it is less important.”

Dr. Frank Ruschitzka, a coauthor of the ESC guidelines, said that the reason for the more cautious ESC approach was lack of widespread familiarity with sacubitril/valsartan treatment among cardiologists.

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The ESC guidelines on using sacubitril/valsartan “replicated the PARADIGM-HF trial. We have no data right now that it is justifiable to put a [treatment-naive] patient on sacubitril/valsartan to begin with. Another difference between the U.S. and ESC guidelines is when to start a MRA,” said Dr. Ruschitzka, professor and head of cardiology at the Heart Center of the University Hospital in Zurich. “It makes a lot of sense to me to start sacubitril/valsartan early. The PARADIGM trial was positive, but no one has a feel for how to use sacubitril/valsartan. Should we give it to everyone? We said replicate the trial, and gain experience using the drug. We want to bring a life-saving drug to patients, but this is the approach we took. We need more data.”

Dr. Jessup noted that a lot of uncertainty also exists among U.S. clinicians about when to start sacubitril/valsartan. “It’s not been clear which patients to put on sacubitril/valsartan. No guidelines had been out on using it” until mid-May, and “the cost of sacubitril/valsartan is daunting. I have received calls from many people who ask whom am I supposed to use sacubitril/valsartan on? It took years and years to get people to [routinely] start patients on an ACE inhibitor and a beta-blocker, and now we’re telling them to do something else. In my practice it’s a 30-minute conversation with each patient that you need to first stop your ACE inhibitor, and then they often get denied coverage by their insurer,” said Dr. Jessup, professor of medicine at the University of Pennsylvania in Philadelphia. She expressed hope that coverage issues will diminish now that clear guidelines are out endorsing a key role for sacubitril/valsartan.

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“We now all have started sacubitril/valsartan on patients” without first starting them on an ACE inhibitor, “but we all need to get a sense of what we can get away with” when using this drug, noted Dr. JoAnn Lindenfeld, professor and director of heart failure and transplant at Vanderbilt University in Nashville.

At least one European cardiologist was skeptical of just how proscriptive the ESC guideline for sacubitril/valsartan will be in actual practice.

“The best treatment [for symptomatic HFrEF] is sacubitril/valsartan, a beta-blocker, and a MRA,” said Dr. John J.V. McMurray, professor of cardiology at Glasgow University and lead investigator for the PARADIGM-HF pivotal trial for sacubitril/valsartan. “The treatment sequence advocated in the guidelines – treat with an ACE inhibitor first and if patients remain symptomatic change to sacubitril/valsartan – is evidence-based medicine. As a guidelines writer and as a promoter of evidence-based medicine, this is absolutely the correct approach. But as a practicing physician I’d go straight for sacubitril/valsartan. Otherwise you’re wasting everybody’s time starting with an ACE inhibitor and then waiting a month to switch,” Dr. McMurray said in an interview.

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“It’s pointless to wait. We saw results within 30 days of starting sacubitril/valsartan, so it’s a theoretical risk to wait. Very few patients will become completely asymptomatic on an ACE inhibitor. Everyone who entered PARADIGM-HF was at New York Heart Association class II or higher, and at the time of randomization only a handful of patients were in New York Heart Association class I. Very few patients get to class I. That tells you it’s pretty uncommon for a heart failure patient to become truly asymptomatic with ACE inhibitor treatment. The main problem is that you are inconveniencing everybody with more blood tests and more clinic visits by waiting to start sacubitril/valsartan, said Dr. McMurray, who was not a member of the panel that wrote the new ESC guidelines.

Even less separates the new U.S. focused update and the ESC guidelines for using ivabradine. Both agree on starting the drug on HFrEF patients who remain symptomatic and with a left ventricular ejection fraction of 35% or less despite being on guideline-directed therapy including titration to a maximum beta-blocker dosage and with a persistent heart rate of at least 70 beats/min. The goal of ivabradine treatment is to further reduce heart rate beyond what’s achieved by a maximal beta-blocker dosage.

Perhaps the biggest questions about ivabradine have been why it took so long to enter the U.S. guidelines, and why it is listed in both the U.S. and ESC guidelines as a level II recommendation. Results from the pivotal trial that supported ivabradine’s use in HFrEF patients, SHIFT, first appeared in 2010 (Lancet. 2010 Sep 11;376[9744]:875-95).

Dr. Butler chalked up the drug’s slow entry into U.S. guidelines as the result of a lack of initiative by ivabradine’s initial developer, Servier. “SHIFT did not have any U.S. sites, and Servier never sought Food and Drug Administration approval,” he noted. “Amgen acquired the U.S. rights to ivabradine in 2013,” and the drug received FDA approval in April 2015, Dr. Butler noted, in explaining the drug’s U.S. timeline. As to why its use is a level II recommendation, he noted that the evidence for efficacy came only from the SHIFT trial, questions exist whether the beta-blocker dosages were fully optimized in all patients in this trial, and the benefit was limited to a reduction in heart failure hospitalizations but not in mortality. “I think that patients with persistent heart failure symptoms [and a persistently elevated heart rate] should get ivabradine,” but these caveats limit it to a class II level recommendation, Dr. Butler said.

“There were questions about ivabradine’s benefit in reducing heart failure hospitalization but not mortality, and questions about whether it would benefit patients if their beta-blocker dosage was adequately up titrated. There were also questions about which heart failure patients to use it on,” noted Dr. Lindenfeld, a member of the panel that wrote the U.S. focused update. These concerns in part help explain the delay to integrating ivabradine into U.S. practice guidelines, she said in an interview, but added that additional data and analysis published during the past 3 or so years have clarified ivabradine’s potentially useful role in treating selected HFrEF patients.

New ESC guidelines based on expert opinion

The sections on sacubitril/valsartan and ivabradine occupy a mere 2 pages among more than 55 pages of text and charts that spell out the ESC’s current vision of how physicians should diagnose and manage heart failure patients. While much of what carried over from prior editions of the guidelines is rooted in evidence, many of the new approaches advocated rely on expert opinion or new interpretations of existing data. Here are some of the notable changes and highlights of the 2016 ESC recommendations:

• Heart failure diagnosis. The new ESC guidelines streamline the diagnostic process, which now focuses on five key elements: The patient’s history, physical examination, ECG, serum level of either brain natriuretic peptide (BNP) or N-terminal(NT)-proBNP, and echocardiography. The guidelines specify threshold levels of BNP and NT-proBNP that can effectively rule out heart failure, a BNP level of at least 35 pg/mL or a NT-proBNP level of at least 125 pg/mL.

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“The diagnostic minimum levels of BNP and NT-proBNP were designed to rule out heart failure. They both have a high negative predictive value, but at these levels their positive predictive value is low,” explained Dr. Adriaan A. Voors, cochair of the ESC’s guideline-writing panel and professor of cardiology at the University of Groningen, the Netherlands.

But while these levels might be effective for reliable rule out of heart failure, they could mean a large number of patients would qualify for an echocardiographic assessment.

“If we used the ESC’s natriuretic peptide cutoffs, there would be a clear concern about overuse of echo. It’s a cost-effectiveness issue. You wind up doing a lot of echos that will be normal. Echocardiography is very safe, but each echo costs about $400-$500,” commented Dr. Butler.

“The results from the STOP-HF and PONTIAC studies showed that BNP levels can identify people at increased risk for developing heart failure who need more intensive assessment and could also potentially benefit from more attention to heart failure prevention. I suspect the full U.S. guideline update will address this issue, but we have not yet finalized our decisions,” he added.

• Heart failure classification. The new ESC guidelines created a new heart failure category, midrange ejection fraction, that the writing panel positioned squarely between the two more classic heart failure subgroups, HFrEF and heart failure with preserved ejection fraction (HFpEF). The definition of each of the three subgroups depends on left ventricular ejection fraction as determined by echocardiography: A LVEF of less than 40% defined HFrEF, a LVEF of 40%-49% defined heart failure with midrange ejection fraction (HFmrEF), and a LVEF of 50% or higher defined HFpEF. Diagnostic confirmation of both HFmrEF and HFpEF also requires that patients fulfill certain criteria of structural or functional heart abnormalities.

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The category of HFmrEF was created “to stimulate research into how to best manage these patients,” explained Dr. Piotr Ponikowski, chair of the ESC guidelines writing panel. For the time being, it remains a category with only theoretical importance as nothing is known to suggest that management of patients with HFmrEF should in any way differ from patients with HFpEF.

• Acute heart failure. Perhaps the most revolutionary element of the new guidelines is the detailed map they provide to managing patients who present with acute decompensated heart failure and the underlying principles cited to justify this radically different approach.

“The acute heart failure section was completely rewritten,” noted Dr. Ponikowski, professor of heart diseases at the Medical University in Wroclaw, Poland. “We don’t yet have evidence-based treatments” to apply to acute heart failure patients, he admitted, “however we strongly recommend the concept that the shorter the better. Shorten the time of diagnosis and for therapeutic decisions. We have borrowed from acute coronary syndrome. Don’t keep patients in the emergency department for another couple of hours just to see if they will respond. We must be aware that we need to do our best to shorten diagnosis and treatment decisions. Time is an issue. Manage a patient’s congestion and impaired peripheral perfusion within a time frame of 1-2 hours.”

The concept that acute heart failure must be quickly managed as an emergency condition similar to acute coronary syndrome first appeared as a European practice recommendation in 2015, a consensus statement from the European Heart Failure Association and two other collaborating organizations (Eur Heart J. 2015 Aug 7;36[30]:1958-66).

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“In 2015, the consensus paper talked about how to handle acute heart failure patients in the emergency department. Now, we have focused on defining the patients’ phenotype and how to categorize their treatment options. We built on the 2015 statement, but the algorithms we now have are original to 2016; they were not in the 2015 paper,” said Dr. Veli-Pekka Harjola, a member of the 2015 consensus group and 2016 guidelines panel who spearheaded writing the acute heart failure section of the new ESC guidelines.

An additional new and notable feature of this section in the 2016 guidelines is its creation of an acronym, CHAMP, designed to guide the management of patients with acute heart failure. CHAMP stands for acute Coronary syndrome, Hypertension emergency, Arrhythmia, acute Mechanical cause, and Pulmonary embolism. The CHAMP acronym’s purpose is to “focus attention on these five specific, potential causes of acute heart failure, life-threatening conditions that need immediate treatment,” explained Dr. Ponikowski.

“CHAMP emphasizes the most critical causes of acute heart failure,” added Dr. Harjola, a cardiologist at Helsinki University Central Hospital. “We created this new acronym” to help clinicians keep in mind what to look for in a patient presenting with acute heart failure.

U.S. cardiologists find things to like in what the Europeans say about managing acute heart failure, as well as aspects to question.

“It makes no sense not to aggressively treat a patient who arrives at an emergency department with acute heart failure. But there is a difference between acute MI or stroke and acute heart failure,” said Dr. Butler. “In acute MI there is the ruptured plaque and thrombus that blocks a coronary artery. In stroke there is a thrombus. These are diseases with a specific onset and treatment target. But with acute heart failure we don’t have a thrombus to treat; we don’t have a specific target. What we’ve learned from studying implanted devices [such as CardioMems] is that the congestion that causes acute heart failure can start 2-3 weeks before a patient develops acute decompensated heart failure and goes to the hospital. We have not found a specific pathophysiologic abnormality in the patient with acute heart failure that is any different from chronic heart failure. This begs the question: If a patient who presents with acute heart failure has a congestion process that’s been going on for 2 or 3 weeks what difference will another 3 hours make? Do we need to replicate the concept of an acute stroke team or acute MI response for acute heart failure?”

Dr. Butler stressed that additional data are expected soon that may help clarify this issue.

“Some large outcome trials in patients with acute heart failure are now underway, one testing serelaxin treatment, another testing ularitide treatment, that are also testing the hypothesis that rapid treatment with these drugs can produce more end-organ protection, stop damage to the heart, kidney and liver, and lead to better long-term outcomes. Until we have those data, the jury is still out” on the benefit patients gain from rapid treatment of acute heart failure. “Until then, it’s not that the data say don’t treat acute heart failure patients aggressively. But we have not yet proven it is similar to treating an acute MI or stroke,” said Dr. Butler.

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“U.S. guidelines have tended to stay away from areas where there are no evidence-based data. To their credit, the Europeans will take on something like acute heart failure where we don’t have an adequate evidence base. Despite that, they provide guidelines, which is important because clinicians need guidance even when the evidence is not very good, when the guideline is based mostly on experience and expert consensus.” commented Dr. William T. Abraham, professor and director of cardiovascular medicine at the Ohio State University Wexner Medical Center in Columbus.

“It’s absolutely appropriate to think of acute heart failure as an emergency situation. We know from high-sensitivity troponin assays that troponin levels are increased in 90% of patients who present with acute decompensated heart failure. So most acute heart failure patients are losing heart muscle cells and we should treat them like we treat acute coronary syndrome. Time matters in acute heart failure; time is heart muscle. Treatment needs to break the hemodynamic and neurohormonal storm of acute decompensated heart failure; get the patient stabilized; improve vital organ perfusion, including within the heart; and shift the myocardial oxygen supply and demand equation so myocardial necrosis stops. All of this is important, and study results suggest it’s the correct approach. I’m not sure study results prove it, but studies that have looked at the time course of treatment for acute heart failure showed that early initiation of treatment – within the first 6 hours of onset – compared with 12-24 hours of onset makes a difference in outcomes,” Dr. Abraham said in an interview.

But a major limitation to the potential efficacy of a rapidly initiated management strategy is that few interventions currently exist with proven benefits for acute heart failure patients.

For the time being, rapid intervention means using diuretics relatively quickly and, if there is an indication for treating with a vasoactive medication, using that quickly too. “The rapid approach is really more relevant to the future; it’s relevant to the design of future acute heart failure treatment trials. That is where this early treatment paradigm is important,” as it could potentially apply to new, more effective treatments of the future rather than to the marginally effective treatments now available, Dr. Abraham said.

“For a long we time haven’t pushed how quickly we should act when implementing guideline-directed treatment” for patients with acute heart failure, noted Dr. Mehra. “The CHAMP approach is interesting, and the ESC guidelines are a very interesting move in the direction” of faster action. “They speak to the period of time during which one should act. Hopefully this will help the science of acute decompensated heart failure move forward.”

But for other U.S. experts the issue again pivots on the lack of evidence.

“There is nothing new” about managing acute heart failure, said Dr. Jessup. “The ESC guideline was articulated very well; they made their recommendations very clear. But a lot is consensus driven. There are no new data. The problem with acute heart failure is that the recommendations are what we think clinicians should do. CHAMP is a nice acronym; it’s packaged better, but there are not any new data.”

Comorbidities

A dramatic contrast distinguishes the extent to which the ESC guidelines highlight comorbidities, compared with prevailing U.S. guidelines. The new ESC guidelines highlight and discuss with some detail 16 distinct comorbidities for clinicians to keep in mind when managing heart failure patients, compared with three comorbidities (atrial fibrillation, anemia, and depression) discussed with similar detail in the 2013 U.S. guidelines.

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“We are targeting comorbidities to personalize medicine, by subgrouping [heart failure] patients into groups that need to receive special attention,” explained Dr. Stefan D. Anker, a coauthor on the ESC guidelines. “We care about comorbidities because they make the diagnosis of heart failure difficult. They aggravate symptoms and contribute to additional hospitalizations. They interfere with [heart failure] treatment, and because comorbidities have led to exclusions of heart failure patients from trials, we lack evidence of treatment efficacy in patients with certain comorbidities,” said Dr. Anker, a professor of innovative clinical trials at the Medical University in Göttingen, Germany.

“The comorbidity discussion in the ESC guidelines is extremely important,” commented Dr. Abraham. “It supports the need for a multidimensional approach to heart failure patients. A cardiologist may not have all the resources to manage all the comorbidities [a heart failure patient might have]. This is why having a sleep medicine specialist, a diabetes specialist, a nephrologist, etc., involved as part of a heart failure management team can be very valuable. We need to involve subspecialists in managing the comorbidities of heart failure because they clearly have an impact on patient outcome.”

But Dr. Butler had a somewhat different take on how comorbidity management fits into the broader picture of heart failure management.

“There is no doubt that heart failure worsens other comorbidities and other comorbidities worsen heart failure. The relationship is bidirectional between heart failure and chronic obstructive pulmonary disease, liver disease, depression, sleep apnea, renal disease, lung disease, diabetes, etc. The problem is that treating a comorbidity does not necessarily translate into improved heart failure outcomes. Comorbidities are important for heart failure patients and worsen their heart failure outcomes. However, management of a comorbidity should be done primarily for the sake of improving the comorbidity. If you treat depression, for example, and it does not improve a patient’s heart failure, that doesn’t mean you shouldn’t have treated the depression. It just means that we don’t have good data that it will improve heart failure.”

Another limitation from a U.S. perspective is what role treatment of various comorbidities can play in benefiting heart failure patients and how compelling the evidence is for this. Dr. Butler gave as an example the problem with treating iron deficiency in heart failure patients who do not have anemia, a strategy endorsed in the ESC guidelines as a level IIa recommendation.

“The data regarding improved exercise capacity from treatment with intravenous ferric carboxymaltose is pretty convincing,” he said. But patients have benefited from this treatment only with improved function and quality of life, and not with improved survival or fewer hospitalizations.

“Is treating patients to improve their function and help them feel better enough?” Dr. Butler asked. “In other diseases it is. In gastrointestinal disease, if a drug helps patients feel better you approve the drug. We value improved functional capacity for patients with pulmonary hypertension, angina, and peripheral vascular disease. All these indications have drugs approved for improving functional capacity and quality of life. But for heart failure the bar has been set higher. There is a lot of interest in changing this” for heart failure.

“There is interest in running a study of ferric carboxymaltose for heart failure with a mortality endpoint. In the meantime, the impact on improving functional capacity is compelling, and it will be interesting to see what happens in the U.S. guidelines. Currently, in U.S. practice if a heart failure patient has iron-deficiency anemia you treat with intravenous iron replacement and the treatment gets reimbursed without a problem. But if the heart failure patient has iron deficiency without anemia then reimbursement for the cost of iron supplementation can be a problem,” Dr. Butler noted. This may change only if the experts who write the next U.S. heart failure guidelines decide to change the rules of what constitutes a useful heart failure treatment, he said.

Dr. Butler has been a consultant to Novartis and Amgen and several other companies. Dr. Jessup had no disclosures. Dr. Mehra has been a consultant to Teva, Johnson & Johnson, Boston Scientific, and St. Jude. Dr. Ruschitzka has been a consultant to Novartis, Servier, Sanofi, Cardiorentis, Heartware, and St. Jude. Dr. McMurray has received research support from Novartis and Amgen. Dr. Lindenfeld has been a consultant to Novartis, Abbott, Janssen, Relypsa, and Resmed. Dr. Voors has been a consultant to Novartis, Amgen, Servier, and several other drug companies. Dr. Ponikowski has been a consultant to Amgen, Novartis, Servier, and several other drug companies. Dr. Harjola has been a consultant to Novartis, Servier, Bayer, Boehringer Ingelheim, Pfizer, and Resmed. Dr. Abraham has been a consultant to Amgen, Novartis, and several device companies. Dr. Anker has been a consultant to Novartis, Servier, and several other companies.

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