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Postinflammatory erythema
The troubling, frustrating part of acne: the persistent acne scars that are often a prolonged battle for most of our patients. We have many techniques to deal with postinflammatory hyperpigmentation (PIH). However, postinflammatory erythema (PIE), the erythematous scars often seen in acne and other inflammatory skin conditions, is not well understood. And despite its pervasive nature, very little data exist that identify its etiology and effective treatment options.
Inflammatory acne scars are not all the same. PIH, often seen with Fitzpatrick skin types III-VI, is related to brown spots, not red spots. Hyperpigmentation is caused by an excess production of melanin. There are treatments for PIH in our armamentarium – such as microdermabrasion, chemical peels, hydroquinone, and vitamin C – that inhibit melanogenesis and blend the skin discoloration.
In contrast, PIE is characterized by pink, red, and sometimes purple-appearing vascular neogenesis seen most often with skin types I-III after an inflammatory skin condition resolves, and is often seen in cystic acne.
The term postinflammatory erythema was initially introduced in the dermatology literature in 2013 by Bae-Harboe et al. to describe erythema often seen after the resolution of inflammatory acne or other inflammatory skin conditions.1 It is not to be confused with the erythema and telangiectasias seen in erythematotelangiectatic rosacea, which is a separate entity.
In my practice, microneedling has also been effective in reducing PIE. Although this may seem counterintuitive because of the bleeding associated with the microneedling process, microneedling-induced skin tissue injury and neocollagenesis have been clinically shown to improve the abnormal vascular proliferation that occurs in PIE. Similar techniques can be used with fractional resurfacing lasers. However, no studies have specifically evaluated the erythematous component of acne scars treated with fractionated lasers.
Topical preparations containing brimonidine (Mirvaso), azelaic acid, and green tea, as well as oral nicotinamide, can have a temporary effect on reducing skin erythema.
However, very little data or clinical studies are available on treatments for PIE, and there are no well-studied preparations with long-term efficacy data. Studies are needed to provide better clinical guidelines for treatment methods and alternatives to treatments, including topical and systemic medications.
References
1. J Clin Aesthet Dermatol. 2013 Sep;6(9):46-7.
2. J Am Acad Dermatol. 2009 May;60(5):801-7.
Dr. Talakoub and Dr. Wesley are co-contributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected].
The troubling, frustrating part of acne: the persistent acne scars that are often a prolonged battle for most of our patients. We have many techniques to deal with postinflammatory hyperpigmentation (PIH). However, postinflammatory erythema (PIE), the erythematous scars often seen in acne and other inflammatory skin conditions, is not well understood. And despite its pervasive nature, very little data exist that identify its etiology and effective treatment options.
Inflammatory acne scars are not all the same. PIH, often seen with Fitzpatrick skin types III-VI, is related to brown spots, not red spots. Hyperpigmentation is caused by an excess production of melanin. There are treatments for PIH in our armamentarium – such as microdermabrasion, chemical peels, hydroquinone, and vitamin C – that inhibit melanogenesis and blend the skin discoloration.
In contrast, PIE is characterized by pink, red, and sometimes purple-appearing vascular neogenesis seen most often with skin types I-III after an inflammatory skin condition resolves, and is often seen in cystic acne.
The term postinflammatory erythema was initially introduced in the dermatology literature in 2013 by Bae-Harboe et al. to describe erythema often seen after the resolution of inflammatory acne or other inflammatory skin conditions.1 It is not to be confused with the erythema and telangiectasias seen in erythematotelangiectatic rosacea, which is a separate entity.
In my practice, microneedling has also been effective in reducing PIE. Although this may seem counterintuitive because of the bleeding associated with the microneedling process, microneedling-induced skin tissue injury and neocollagenesis have been clinically shown to improve the abnormal vascular proliferation that occurs in PIE. Similar techniques can be used with fractional resurfacing lasers. However, no studies have specifically evaluated the erythematous component of acne scars treated with fractionated lasers.
Topical preparations containing brimonidine (Mirvaso), azelaic acid, and green tea, as well as oral nicotinamide, can have a temporary effect on reducing skin erythema.
However, very little data or clinical studies are available on treatments for PIE, and there are no well-studied preparations with long-term efficacy data. Studies are needed to provide better clinical guidelines for treatment methods and alternatives to treatments, including topical and systemic medications.
References
1. J Clin Aesthet Dermatol. 2013 Sep;6(9):46-7.
2. J Am Acad Dermatol. 2009 May;60(5):801-7.
Dr. Talakoub and Dr. Wesley are co-contributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected].
The troubling, frustrating part of acne: the persistent acne scars that are often a prolonged battle for most of our patients. We have many techniques to deal with postinflammatory hyperpigmentation (PIH). However, postinflammatory erythema (PIE), the erythematous scars often seen in acne and other inflammatory skin conditions, is not well understood. And despite its pervasive nature, very little data exist that identify its etiology and effective treatment options.
Inflammatory acne scars are not all the same. PIH, often seen with Fitzpatrick skin types III-VI, is related to brown spots, not red spots. Hyperpigmentation is caused by an excess production of melanin. There are treatments for PIH in our armamentarium – such as microdermabrasion, chemical peels, hydroquinone, and vitamin C – that inhibit melanogenesis and blend the skin discoloration.
In contrast, PIE is characterized by pink, red, and sometimes purple-appearing vascular neogenesis seen most often with skin types I-III after an inflammatory skin condition resolves, and is often seen in cystic acne.
The term postinflammatory erythema was initially introduced in the dermatology literature in 2013 by Bae-Harboe et al. to describe erythema often seen after the resolution of inflammatory acne or other inflammatory skin conditions.1 It is not to be confused with the erythema and telangiectasias seen in erythematotelangiectatic rosacea, which is a separate entity.
In my practice, microneedling has also been effective in reducing PIE. Although this may seem counterintuitive because of the bleeding associated with the microneedling process, microneedling-induced skin tissue injury and neocollagenesis have been clinically shown to improve the abnormal vascular proliferation that occurs in PIE. Similar techniques can be used with fractional resurfacing lasers. However, no studies have specifically evaluated the erythematous component of acne scars treated with fractionated lasers.
Topical preparations containing brimonidine (Mirvaso), azelaic acid, and green tea, as well as oral nicotinamide, can have a temporary effect on reducing skin erythema.
However, very little data or clinical studies are available on treatments for PIE, and there are no well-studied preparations with long-term efficacy data. Studies are needed to provide better clinical guidelines for treatment methods and alternatives to treatments, including topical and systemic medications.
References
1. J Clin Aesthet Dermatol. 2013 Sep;6(9):46-7.
2. J Am Acad Dermatol. 2009 May;60(5):801-7.
Dr. Talakoub and Dr. Wesley are co-contributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected].
Delayed ICU Transfer Affects Mortality and Length of Stay
Clinical Question: Can an objective measurement of critical illness inform intensive care unit (ICU) transfer timeliness?
Background: Early intervention has shown mortality benefit in many critical illness syndromes, yet heterogeneity in timing of ICU transfer exists. Previous studies examining ICU transfer timeliness have mostly focused on subjective criteria.
Study Design: Retrospective observational cohort study.
Setting: Medical-surgical units at five hospitals including the University of Chicago and NorthShore University HealthSystem in Illinois.
Synopsis: All medical-surgical ward patients between November 2008 and January 2013 were scored using eCART, a previously validated objective scoring system, to decide when transfer was appropriate. Of those, 3,789 patients reached the predetermined threshold for critical illness. Transfers more than six hours after crossing the threshold were considered delayed. Patients with delayed transfer had a statistically significant increase in length of stay (LOS) and in-hospital mortality (33.2% versus 24.5%; P < 0.001), and the mortality increase was linear, with a 3% increase in odds for each one hour of further transfer delay (P < 0.001). The rate of change of eCART score did influence time of transfer, and the authors suggest that rapid changes were more likely to be recognized. They postulate that routine implementation of eCART or similar objective scoring may lead to earlier recognition of necessary ICU transfer and thus improve mortality and LOS, and they suggest this as a topic for future trials.
Bottom Line: Delayed ICU transfer negatively affects LOS and in-hospital mortality. Objective criteria may identify more appropriate timing of transfer. Clinical trials to investigate this are warranted.
Citation: Churpek MM, Wendlandt B, Zadravecz FJ, Adhikari R, Winslow C, Edelson DP. Association between intensive care unit transfer delay and hospital mortality: a multicenter investigation [published online ahead of print June 28, 2016]. J Hosp Med. doi:10.1002/jhm.2630.
Short Take
Intranasal Live Attenuated Influenza Vaccine Not Recommended
The Centers for Disease Control and Prevention recommends against use of the nasal spray live attenuated influenza vaccine. This is based on data showing poor effectiveness in prior years.
Citation: ACIP votes down use of LAIV for 2016-2017 flu season [press release]. CDC website.
Clinical Question: Can an objective measurement of critical illness inform intensive care unit (ICU) transfer timeliness?
Background: Early intervention has shown mortality benefit in many critical illness syndromes, yet heterogeneity in timing of ICU transfer exists. Previous studies examining ICU transfer timeliness have mostly focused on subjective criteria.
Study Design: Retrospective observational cohort study.
Setting: Medical-surgical units at five hospitals including the University of Chicago and NorthShore University HealthSystem in Illinois.
Synopsis: All medical-surgical ward patients between November 2008 and January 2013 were scored using eCART, a previously validated objective scoring system, to decide when transfer was appropriate. Of those, 3,789 patients reached the predetermined threshold for critical illness. Transfers more than six hours after crossing the threshold were considered delayed. Patients with delayed transfer had a statistically significant increase in length of stay (LOS) and in-hospital mortality (33.2% versus 24.5%; P < 0.001), and the mortality increase was linear, with a 3% increase in odds for each one hour of further transfer delay (P < 0.001). The rate of change of eCART score did influence time of transfer, and the authors suggest that rapid changes were more likely to be recognized. They postulate that routine implementation of eCART or similar objective scoring may lead to earlier recognition of necessary ICU transfer and thus improve mortality and LOS, and they suggest this as a topic for future trials.
Bottom Line: Delayed ICU transfer negatively affects LOS and in-hospital mortality. Objective criteria may identify more appropriate timing of transfer. Clinical trials to investigate this are warranted.
Citation: Churpek MM, Wendlandt B, Zadravecz FJ, Adhikari R, Winslow C, Edelson DP. Association between intensive care unit transfer delay and hospital mortality: a multicenter investigation [published online ahead of print June 28, 2016]. J Hosp Med. doi:10.1002/jhm.2630.
Short Take
Intranasal Live Attenuated Influenza Vaccine Not Recommended
The Centers for Disease Control and Prevention recommends against use of the nasal spray live attenuated influenza vaccine. This is based on data showing poor effectiveness in prior years.
Citation: ACIP votes down use of LAIV for 2016-2017 flu season [press release]. CDC website.
Clinical Question: Can an objective measurement of critical illness inform intensive care unit (ICU) transfer timeliness?
Background: Early intervention has shown mortality benefit in many critical illness syndromes, yet heterogeneity in timing of ICU transfer exists. Previous studies examining ICU transfer timeliness have mostly focused on subjective criteria.
Study Design: Retrospective observational cohort study.
Setting: Medical-surgical units at five hospitals including the University of Chicago and NorthShore University HealthSystem in Illinois.
Synopsis: All medical-surgical ward patients between November 2008 and January 2013 were scored using eCART, a previously validated objective scoring system, to decide when transfer was appropriate. Of those, 3,789 patients reached the predetermined threshold for critical illness. Transfers more than six hours after crossing the threshold were considered delayed. Patients with delayed transfer had a statistically significant increase in length of stay (LOS) and in-hospital mortality (33.2% versus 24.5%; P < 0.001), and the mortality increase was linear, with a 3% increase in odds for each one hour of further transfer delay (P < 0.001). The rate of change of eCART score did influence time of transfer, and the authors suggest that rapid changes were more likely to be recognized. They postulate that routine implementation of eCART or similar objective scoring may lead to earlier recognition of necessary ICU transfer and thus improve mortality and LOS, and they suggest this as a topic for future trials.
Bottom Line: Delayed ICU transfer negatively affects LOS and in-hospital mortality. Objective criteria may identify more appropriate timing of transfer. Clinical trials to investigate this are warranted.
Citation: Churpek MM, Wendlandt B, Zadravecz FJ, Adhikari R, Winslow C, Edelson DP. Association between intensive care unit transfer delay and hospital mortality: a multicenter investigation [published online ahead of print June 28, 2016]. J Hosp Med. doi:10.1002/jhm.2630.
Short Take
Intranasal Live Attenuated Influenza Vaccine Not Recommended
The Centers for Disease Control and Prevention recommends against use of the nasal spray live attenuated influenza vaccine. This is based on data showing poor effectiveness in prior years.
Citation: ACIP votes down use of LAIV for 2016-2017 flu season [press release]. CDC website.
IV Fluid Can Save Lives in Hemodynamically Stable Patients with Sepsis
Clinical Question: Does increased fluid administration in patients with sepsis with intermediate lactate levels improve outcomes?
Background: The Surviving Sepsis Campaign bundle, which improves ED mortality, targets patients with hypotension or lactate levels >4 mmol/L. No similar optimal treatment strategy exists for less severe sepsis patients even though such patients are more common in hospitalized populations.
Study Design: Retrospective study of a quality improvement bundle.
Setting: 21 community-based hospitals in the Kaiser Permanente Northern California system.
Synopsis: This study evaluated implementation of a treatment bundle for 18,122 hemodynamically stable sepsis patients presenting to the ED with lactate levels between 2 and 4 mmol/L during the 12 months prior to and after bundle implementation. The bundle included antibiotic administration within three hours, repeated lactate levels within four hours, and 30 mL/kg or ≥2 L of intravenous fluids within three hours of initial lactate result. Patients with kidney disease and/or heart failure were separately evaluated because of the perceived risk of fluid administration.
Treatment after bundle implementation was associated with an adjusted hospital mortality odds ratio of 0.81 (95% CI, 0.66–0.99; P = 0.04). Significant reductions in hospital mortality were observed in patients with heart failure and/or kidney disease (P < 0.01) but not without (P > 0.4). This correlated with increased fluid administration in patients with heart failure and/or kidney disease following bundle implementation. This is not a randomized controlled study, which invites biases and confounding.
Bottom Line: Increased fluid administration improved mortality in patients with kidney disease and heart failure presenting with sepsis.
Reference: Liu V, Morehouse JW, Marelich GP, et al. Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. Am J Respir Crit Care Med. 2016;193(11):1264-1270.
Short Take
New Framework for Learners’ Clinical Reasoning
A qualitative study involving 37 emergency medicine residents found that clinical reasoning through individual cases progresses from case framing (phase 1) to pattern recognition (phase 2), then self-monitoring (phase 3).
Citation: Adams E, Goyder C, Heneghan C, Brand L, Ajjawi R. Clinical reasoning of junior doctors in emergency medicine: a grounded theory study [published online ahead of print June 23, 2016]. Emerg Med J. doi:10.1136/emermed-2015-205650.
Clinical Question: Does increased fluid administration in patients with sepsis with intermediate lactate levels improve outcomes?
Background: The Surviving Sepsis Campaign bundle, which improves ED mortality, targets patients with hypotension or lactate levels >4 mmol/L. No similar optimal treatment strategy exists for less severe sepsis patients even though such patients are more common in hospitalized populations.
Study Design: Retrospective study of a quality improvement bundle.
Setting: 21 community-based hospitals in the Kaiser Permanente Northern California system.
Synopsis: This study evaluated implementation of a treatment bundle for 18,122 hemodynamically stable sepsis patients presenting to the ED with lactate levels between 2 and 4 mmol/L during the 12 months prior to and after bundle implementation. The bundle included antibiotic administration within three hours, repeated lactate levels within four hours, and 30 mL/kg or ≥2 L of intravenous fluids within three hours of initial lactate result. Patients with kidney disease and/or heart failure were separately evaluated because of the perceived risk of fluid administration.
Treatment after bundle implementation was associated with an adjusted hospital mortality odds ratio of 0.81 (95% CI, 0.66–0.99; P = 0.04). Significant reductions in hospital mortality were observed in patients with heart failure and/or kidney disease (P < 0.01) but not without (P > 0.4). This correlated with increased fluid administration in patients with heart failure and/or kidney disease following bundle implementation. This is not a randomized controlled study, which invites biases and confounding.
Bottom Line: Increased fluid administration improved mortality in patients with kidney disease and heart failure presenting with sepsis.
Reference: Liu V, Morehouse JW, Marelich GP, et al. Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. Am J Respir Crit Care Med. 2016;193(11):1264-1270.
Short Take
New Framework for Learners’ Clinical Reasoning
A qualitative study involving 37 emergency medicine residents found that clinical reasoning through individual cases progresses from case framing (phase 1) to pattern recognition (phase 2), then self-monitoring (phase 3).
Citation: Adams E, Goyder C, Heneghan C, Brand L, Ajjawi R. Clinical reasoning of junior doctors in emergency medicine: a grounded theory study [published online ahead of print June 23, 2016]. Emerg Med J. doi:10.1136/emermed-2015-205650.
Clinical Question: Does increased fluid administration in patients with sepsis with intermediate lactate levels improve outcomes?
Background: The Surviving Sepsis Campaign bundle, which improves ED mortality, targets patients with hypotension or lactate levels >4 mmol/L. No similar optimal treatment strategy exists for less severe sepsis patients even though such patients are more common in hospitalized populations.
Study Design: Retrospective study of a quality improvement bundle.
Setting: 21 community-based hospitals in the Kaiser Permanente Northern California system.
Synopsis: This study evaluated implementation of a treatment bundle for 18,122 hemodynamically stable sepsis patients presenting to the ED with lactate levels between 2 and 4 mmol/L during the 12 months prior to and after bundle implementation. The bundle included antibiotic administration within three hours, repeated lactate levels within four hours, and 30 mL/kg or ≥2 L of intravenous fluids within three hours of initial lactate result. Patients with kidney disease and/or heart failure were separately evaluated because of the perceived risk of fluid administration.
Treatment after bundle implementation was associated with an adjusted hospital mortality odds ratio of 0.81 (95% CI, 0.66–0.99; P = 0.04). Significant reductions in hospital mortality were observed in patients with heart failure and/or kidney disease (P < 0.01) but not without (P > 0.4). This correlated with increased fluid administration in patients with heart failure and/or kidney disease following bundle implementation. This is not a randomized controlled study, which invites biases and confounding.
Bottom Line: Increased fluid administration improved mortality in patients with kidney disease and heart failure presenting with sepsis.
Reference: Liu V, Morehouse JW, Marelich GP, et al. Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. Am J Respir Crit Care Med. 2016;193(11):1264-1270.
Short Take
New Framework for Learners’ Clinical Reasoning
A qualitative study involving 37 emergency medicine residents found that clinical reasoning through individual cases progresses from case framing (phase 1) to pattern recognition (phase 2), then self-monitoring (phase 3).
Citation: Adams E, Goyder C, Heneghan C, Brand L, Ajjawi R. Clinical reasoning of junior doctors in emergency medicine: a grounded theory study [published online ahead of print June 23, 2016]. Emerg Med J. doi:10.1136/emermed-2015-205650.
Epinephrine-Induced Takotsubo Cardiomyopathy
Takotsubo cardiomyopathy (TCM) is a transient left ventricular (LV) wall motion abnormality often associated with acute medical illnesses, catastrophic life events, and intense physical or emotional stress.1,2 Takotsubo cardiomyopathy also is known as stress-induced transient cardiomyopathy, apical ballooning syndrome, ampulla cardiomyopathy, and broken heart syndrome. The first reported case occurred in 1990 in Japan and accounts for 2% of all suspected acute coronary syndromes. Postmenopausal women seem to be at a higher risk for developing the disease, as about 90% of takotsubo cardiomyopathy occurs in postmenopausal women.3
Diagnosis of TCM is difficult, and there is an ongoing debate about the diagnostic criteria. The Mayo Clinic proposed the following criteria: (1) transient hypokinesis, akinesis, or dyskinesis of the LV mid-segments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often but not always present; (2) absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (3) new electrocardiographic abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin; and (4) absence of pheochromocytoma and myocarditis.4
Depending on the part of the LV involved, TCM can be classified into apical ballooning variant (most common), an inverted or reverse takotsubo variant (basal akinesis with hyper dynamic apex), or a midventricular takotsubo variant.5
Several investigators have proposed the role of catecholamine in the pathogeneses of TCM.6,7 Previous case reports have shown that the clinical circumstances with elevated catecholamine can result in TCM.8,9 The authors recently encountered a case of a patient who developed apical ballooning TCM after an inadvertent injection of a high dose of epinephrine.
Case Report
A 60-year-old man with a history of hypertension, alcohol abuse, tobacco use, non-Hodgkin lymphoma, and recently diagnosed squamous cell carcinoma of the right glossopalatine fossa was admitted to the chemotherapy infusion clinic at the Kansas City VAMC to receive his first dose of cetuximab. Forty-five minutes after starting the test-dose infusion, the patient developed shortness of breath along with hives on his trunk and extremities. His blood pressure was 80/50 mm Hg; heart rate, 100 bpm; 16 breaths per minute respiration rate; and oxygen saturation by pulse oximetry was 90% on ambient air. The patient reported no chest pain, and a cardiac examination was unremarkable without wheezing on lung auscultation.
A clinical diagnosis of acute anaphylaxis reaction was considered; the test dose of cetuximab was discontinued, and the patient was given 50 mg of diphenhydramine, followed by an inadvertent administration of 1 mg of epinephrine intravenously (recommended dose 0.1 mg). After 3 minutes of administration of the medication, the patient’s blood pressure increased to190/110 with a pulse rate of 120 bpm.
An electrocardiogram (EKG) showed ST elevation in the precordial and inferior leads consistent with inferior and anterior myocardial injury (Figure 1). Pertinent laboratory studies revealed normal serum potassium (4.4 mEq/L), elevated serum glucose (219 mg/dL), and elevated troponin-I, (1.180 ng/mL; reference range 0-0.3 ng/mL). An emergent transthoracic echocardiogram showed a LV ejection fraction of 40% with akinesis involving the apical anterior, mid and distal anteroseptal, and anterolateral wall with no significant valvular abnormalities (Figures 2 and 3).
Given these echocardiographic findings, persistent EKG changes, and elevated troponin levels, an emergent coronary angiography along with left ventriculography was performed. The left ventriculogram demonstrated apical ballooning consistent with TCM (Figures 4 and 5). The left epicardial coronary arteries did not reveal any obstructive disease (Figure 6).
The subsequent hospital course was unremarkable, and the patient was discharged on guideline-directed medications for systolic dysfunction (ie, beta blockers and angiotensin-converting-enzyme inhibitors). Serum levels of epinephrine were not checked. A follow-up echocardiogram performed after 8 weeks showed complete recovery of the LV function (Figures 7a and 7b). The temporal sequence of events was highly suggestive of TCM, possibly due to the supratherapeutic dose of epinephrine.
Discussion
The pathogenesis of stress-induced cardiomyopathy is not fully understood. Various hypotheses have been suggested, including catecholamine excess, coronary vasospasm, microvascular dysfunction, and dynamic midcavity or LV outflow tract obstruction.1,10 The hypothesis implicating catecholamine excess in the pathogenesis of TCM is supported by animal studies.7 These studies suggest that catecholamines possibly play a role by “direct toxicity to myocardial cells” as evidenced by histologic findings of myofibrillar degeneration, contraction band necrosis, and leukocyte infiltration in harvested hearts from experimental animals and patients undergoing autopsy.7,11 Similarly, cultured cardiomyocytes exposed to high doses of epinephrine showed apoptic changes. Pretreatment of these cells with α- and β-adrenoreceptor blockers significantly attenuated these changes.7
However, myocardial necrosis alone cannot explain the entire picture, because most patients with TCM regain full recovery of LV function within several days of the event, and the degree of LV dysfunction is inconsistent with the mild elevations in cardiac 
The role of estrogen also has been implicated in the pathogenesis of TCM. From a prevalence standpoint, almost 90% of TCM occurs in postmenopausal women.11,12 Estrogen plays a critical role in protecting the myocardium, possibly by down regulating β-adrenergic receptors. Postmenopausal women who do not receive estrogen replacement therapy lose this protection and may be more vulnerable to the catecholamine surge that is associated with stress.11 Overall, the catecholamines play a central role in the pathogenesis. This case suggests that exogenous administration of epinephrine in suprapharmacologic doses can be sufficient to replicate the stressful situation and induce TCM.
Conclusion
The authors’ case report describes the induction of apical ballooning TCM by administration of supratherapeutic doses of epinephrine and supports the role of catecholamines in the pathophysiology of TCM. It is hoped that this report will help clinicians to suspect, recognize, and manage this disease and be aware of possible iatrogenic causes.
1. Komamura K, Fukui M, Iwasaku T, Hirotani S, Masuyama T. Takotsubo cardiomyopathy: pathophysiology, diagnosis and treatment. World J Cardiol. 2014;6(7):602-609.
2. Wittstein IS, Thiemann DR, Lima JAC, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352(6):539-548.
3. Parodi G, Del Pace S, Carrabba N, et al. Incidence, clinical findings, and outcome of women with left ventricular apical ballooning syndrome. Am J Cardiol. 2007;99(2):182-185.
4. Madhavan M, Prasad A. Proposed Mayo Clinic criteria for the diagnosis of Tako-Tsubo cardiomyopathy and long-term prognosis. Herz. 2010;35(4):240-243.
5. Kawai S, Kitabatake A, Tomoike H; Takotsubo Cardiomyopathy Group. Guidelines for diagnosis of takotsubo (ampulla) cardiomyopathy. Circ J. 2007;71(6):990-992.
6. Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE. Stress (Takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med. 2008;5(1):22-29.
7. Paur H, Wright PT, Sikkel MB, et al. High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation. 2012;126(6):697-706.
8. Abraham J, Mudd JO, Kapur NK, Klein K, Champion HC, Wittstein IS. Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists. J Am Coll Cardiol. 2009;53(15):1320-1325.
9. Wedekind H, Möller K, Scholz KH. Tako-tsubo cardiomyopathy. Incidence in patients with acute coronary syndrome. [in German]. Herz. 2006;31(4):339-346.
10. Khullar M, Datta BN, Wahi PL, Chakravarti RN. Catecholamine-induced experimental cardiomyopathy—a histopathological, histochemical and ultrastructural study. Indian Heart J. 1989;41(5):307-313.
11. Ueyama T, Hano T, Kasamatsu K, Yamamoto K, Tsuruo Y, Nishio I. Estrogen attenuates the emotional stress-induced cardiac responses in the animal model of Tako-tsubo (Ampulla) cardiomyopathy. J Cardiovasc Pharmacol. 2003;42(suppl 1):S117-S119.
12. Sharkey SW, Lesser JR, Zenovich AG, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation. 2005;111(4):472-479.
Takotsubo cardiomyopathy (TCM) is a transient left ventricular (LV) wall motion abnormality often associated with acute medical illnesses, catastrophic life events, and intense physical or emotional stress.1,2 Takotsubo cardiomyopathy also is known as stress-induced transient cardiomyopathy, apical ballooning syndrome, ampulla cardiomyopathy, and broken heart syndrome. The first reported case occurred in 1990 in Japan and accounts for 2% of all suspected acute coronary syndromes. Postmenopausal women seem to be at a higher risk for developing the disease, as about 90% of takotsubo cardiomyopathy occurs in postmenopausal women.3
Diagnosis of TCM is difficult, and there is an ongoing debate about the diagnostic criteria. The Mayo Clinic proposed the following criteria: (1) transient hypokinesis, akinesis, or dyskinesis of the LV mid-segments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often but not always present; (2) absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (3) new electrocardiographic abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin; and (4) absence of pheochromocytoma and myocarditis.4
Depending on the part of the LV involved, TCM can be classified into apical ballooning variant (most common), an inverted or reverse takotsubo variant (basal akinesis with hyper dynamic apex), or a midventricular takotsubo variant.5
Several investigators have proposed the role of catecholamine in the pathogeneses of TCM.6,7 Previous case reports have shown that the clinical circumstances with elevated catecholamine can result in TCM.8,9 The authors recently encountered a case of a patient who developed apical ballooning TCM after an inadvertent injection of a high dose of epinephrine.
Case Report
A 60-year-old man with a history of hypertension, alcohol abuse, tobacco use, non-Hodgkin lymphoma, and recently diagnosed squamous cell carcinoma of the right glossopalatine fossa was admitted to the chemotherapy infusion clinic at the Kansas City VAMC to receive his first dose of cetuximab. Forty-five minutes after starting the test-dose infusion, the patient developed shortness of breath along with hives on his trunk and extremities. His blood pressure was 80/50 mm Hg; heart rate, 100 bpm; 16 breaths per minute respiration rate; and oxygen saturation by pulse oximetry was 90% on ambient air. The patient reported no chest pain, and a cardiac examination was unremarkable without wheezing on lung auscultation.
A clinical diagnosis of acute anaphylaxis reaction was considered; the test dose of cetuximab was discontinued, and the patient was given 50 mg of diphenhydramine, followed by an inadvertent administration of 1 mg of epinephrine intravenously (recommended dose 0.1 mg). After 3 minutes of administration of the medication, the patient’s blood pressure increased to190/110 with a pulse rate of 120 bpm.
An electrocardiogram (EKG) showed ST elevation in the precordial and inferior leads consistent with inferior and anterior myocardial injury (Figure 1). Pertinent laboratory studies revealed normal serum potassium (4.4 mEq/L), elevated serum glucose (219 mg/dL), and elevated troponin-I, (1.180 ng/mL; reference range 0-0.3 ng/mL). An emergent transthoracic echocardiogram showed a LV ejection fraction of 40% with akinesis involving the apical anterior, mid and distal anteroseptal, and anterolateral wall with no significant valvular abnormalities (Figures 2 and 3).
Given these echocardiographic findings, persistent EKG changes, and elevated troponin levels, an emergent coronary angiography along with left ventriculography was performed. The left ventriculogram demonstrated apical ballooning consistent with TCM (Figures 4 and 5). The left epicardial coronary arteries did not reveal any obstructive disease (Figure 6).
The subsequent hospital course was unremarkable, and the patient was discharged on guideline-directed medications for systolic dysfunction (ie, beta blockers and angiotensin-converting-enzyme inhibitors). Serum levels of epinephrine were not checked. A follow-up echocardiogram performed after 8 weeks showed complete recovery of the LV function (Figures 7a and 7b). The temporal sequence of events was highly suggestive of TCM, possibly due to the supratherapeutic dose of epinephrine.
Discussion
The pathogenesis of stress-induced cardiomyopathy is not fully understood. Various hypotheses have been suggested, including catecholamine excess, coronary vasospasm, microvascular dysfunction, and dynamic midcavity or LV outflow tract obstruction.1,10 The hypothesis implicating catecholamine excess in the pathogenesis of TCM is supported by animal studies.7 These studies suggest that catecholamines possibly play a role by “direct toxicity to myocardial cells” as evidenced by histologic findings of myofibrillar degeneration, contraction band necrosis, and leukocyte infiltration in harvested hearts from experimental animals and patients undergoing autopsy.7,11 Similarly, cultured cardiomyocytes exposed to high doses of epinephrine showed apoptic changes. Pretreatment of these cells with α- and β-adrenoreceptor blockers significantly attenuated these changes.7
However, myocardial necrosis alone cannot explain the entire picture, because most patients with TCM regain full recovery of LV function within several days of the event, and the degree of LV dysfunction is inconsistent with the mild elevations in cardiac
The role of estrogen also has been implicated in the pathogenesis of TCM. From a prevalence standpoint, almost 90% of TCM occurs in postmenopausal women.11,12 Estrogen plays a critical role in protecting the myocardium, possibly by down regulating β-adrenergic receptors. Postmenopausal women who do not receive estrogen replacement therapy lose this protection and may be more vulnerable to the catecholamine surge that is associated with stress.11 Overall, the catecholamines play a central role in the pathogenesis. This case suggests that exogenous administration of epinephrine in suprapharmacologic doses can be sufficient to replicate the stressful situation and induce TCM.
Conclusion
The authors’ case report describes the induction of apical ballooning TCM by administration of supratherapeutic doses of epinephrine and supports the role of catecholamines in the pathophysiology of TCM. It is hoped that this report will help clinicians to suspect, recognize, and manage this disease and be aware of possible iatrogenic causes.
Takotsubo cardiomyopathy (TCM) is a transient left ventricular (LV) wall motion abnormality often associated with acute medical illnesses, catastrophic life events, and intense physical or emotional stress.1,2 Takotsubo cardiomyopathy also is known as stress-induced transient cardiomyopathy, apical ballooning syndrome, ampulla cardiomyopathy, and broken heart syndrome. The first reported case occurred in 1990 in Japan and accounts for 2% of all suspected acute coronary syndromes. Postmenopausal women seem to be at a higher risk for developing the disease, as about 90% of takotsubo cardiomyopathy occurs in postmenopausal women.3
Diagnosis of TCM is difficult, and there is an ongoing debate about the diagnostic criteria. The Mayo Clinic proposed the following criteria: (1) transient hypokinesis, akinesis, or dyskinesis of the LV mid-segments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often but not always present; (2) absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (3) new electrocardiographic abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin; and (4) absence of pheochromocytoma and myocarditis.4
Depending on the part of the LV involved, TCM can be classified into apical ballooning variant (most common), an inverted or reverse takotsubo variant (basal akinesis with hyper dynamic apex), or a midventricular takotsubo variant.5
Several investigators have proposed the role of catecholamine in the pathogeneses of TCM.6,7 Previous case reports have shown that the clinical circumstances with elevated catecholamine can result in TCM.8,9 The authors recently encountered a case of a patient who developed apical ballooning TCM after an inadvertent injection of a high dose of epinephrine.
Case Report
A 60-year-old man with a history of hypertension, alcohol abuse, tobacco use, non-Hodgkin lymphoma, and recently diagnosed squamous cell carcinoma of the right glossopalatine fossa was admitted to the chemotherapy infusion clinic at the Kansas City VAMC to receive his first dose of cetuximab. Forty-five minutes after starting the test-dose infusion, the patient developed shortness of breath along with hives on his trunk and extremities. His blood pressure was 80/50 mm Hg; heart rate, 100 bpm; 16 breaths per minute respiration rate; and oxygen saturation by pulse oximetry was 90% on ambient air. The patient reported no chest pain, and a cardiac examination was unremarkable without wheezing on lung auscultation.
A clinical diagnosis of acute anaphylaxis reaction was considered; the test dose of cetuximab was discontinued, and the patient was given 50 mg of diphenhydramine, followed by an inadvertent administration of 1 mg of epinephrine intravenously (recommended dose 0.1 mg). After 3 minutes of administration of the medication, the patient’s blood pressure increased to190/110 with a pulse rate of 120 bpm.
An electrocardiogram (EKG) showed ST elevation in the precordial and inferior leads consistent with inferior and anterior myocardial injury (Figure 1). Pertinent laboratory studies revealed normal serum potassium (4.4 mEq/L), elevated serum glucose (219 mg/dL), and elevated troponin-I, (1.180 ng/mL; reference range 0-0.3 ng/mL). An emergent transthoracic echocardiogram showed a LV ejection fraction of 40% with akinesis involving the apical anterior, mid and distal anteroseptal, and anterolateral wall with no significant valvular abnormalities (Figures 2 and 3).
Given these echocardiographic findings, persistent EKG changes, and elevated troponin levels, an emergent coronary angiography along with left ventriculography was performed. The left ventriculogram demonstrated apical ballooning consistent with TCM (Figures 4 and 5). The left epicardial coronary arteries did not reveal any obstructive disease (Figure 6).
The subsequent hospital course was unremarkable, and the patient was discharged on guideline-directed medications for systolic dysfunction (ie, beta blockers and angiotensin-converting-enzyme inhibitors). Serum levels of epinephrine were not checked. A follow-up echocardiogram performed after 8 weeks showed complete recovery of the LV function (Figures 7a and 7b). The temporal sequence of events was highly suggestive of TCM, possibly due to the supratherapeutic dose of epinephrine.
Discussion
The pathogenesis of stress-induced cardiomyopathy is not fully understood. Various hypotheses have been suggested, including catecholamine excess, coronary vasospasm, microvascular dysfunction, and dynamic midcavity or LV outflow tract obstruction.1,10 The hypothesis implicating catecholamine excess in the pathogenesis of TCM is supported by animal studies.7 These studies suggest that catecholamines possibly play a role by “direct toxicity to myocardial cells” as evidenced by histologic findings of myofibrillar degeneration, contraction band necrosis, and leukocyte infiltration in harvested hearts from experimental animals and patients undergoing autopsy.7,11 Similarly, cultured cardiomyocytes exposed to high doses of epinephrine showed apoptic changes. Pretreatment of these cells with α- and β-adrenoreceptor blockers significantly attenuated these changes.7
However, myocardial necrosis alone cannot explain the entire picture, because most patients with TCM regain full recovery of LV function within several days of the event, and the degree of LV dysfunction is inconsistent with the mild elevations in cardiac
The role of estrogen also has been implicated in the pathogenesis of TCM. From a prevalence standpoint, almost 90% of TCM occurs in postmenopausal women.11,12 Estrogen plays a critical role in protecting the myocardium, possibly by down regulating β-adrenergic receptors. Postmenopausal women who do not receive estrogen replacement therapy lose this protection and may be more vulnerable to the catecholamine surge that is associated with stress.11 Overall, the catecholamines play a central role in the pathogenesis. This case suggests that exogenous administration of epinephrine in suprapharmacologic doses can be sufficient to replicate the stressful situation and induce TCM.
Conclusion
The authors’ case report describes the induction of apical ballooning TCM by administration of supratherapeutic doses of epinephrine and supports the role of catecholamines in the pathophysiology of TCM. It is hoped that this report will help clinicians to suspect, recognize, and manage this disease and be aware of possible iatrogenic causes.
1. Komamura K, Fukui M, Iwasaku T, Hirotani S, Masuyama T. Takotsubo cardiomyopathy: pathophysiology, diagnosis and treatment. World J Cardiol. 2014;6(7):602-609.
2. Wittstein IS, Thiemann DR, Lima JAC, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352(6):539-548.
3. Parodi G, Del Pace S, Carrabba N, et al. Incidence, clinical findings, and outcome of women with left ventricular apical ballooning syndrome. Am J Cardiol. 2007;99(2):182-185.
4. Madhavan M, Prasad A. Proposed Mayo Clinic criteria for the diagnosis of Tako-Tsubo cardiomyopathy and long-term prognosis. Herz. 2010;35(4):240-243.
5. Kawai S, Kitabatake A, Tomoike H; Takotsubo Cardiomyopathy Group. Guidelines for diagnosis of takotsubo (ampulla) cardiomyopathy. Circ J. 2007;71(6):990-992.
6. Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE. Stress (Takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med. 2008;5(1):22-29.
7. Paur H, Wright PT, Sikkel MB, et al. High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation. 2012;126(6):697-706.
8. Abraham J, Mudd JO, Kapur NK, Klein K, Champion HC, Wittstein IS. Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists. J Am Coll Cardiol. 2009;53(15):1320-1325.
9. Wedekind H, Möller K, Scholz KH. Tako-tsubo cardiomyopathy. Incidence in patients with acute coronary syndrome. [in German]. Herz. 2006;31(4):339-346.
10. Khullar M, Datta BN, Wahi PL, Chakravarti RN. Catecholamine-induced experimental cardiomyopathy—a histopathological, histochemical and ultrastructural study. Indian Heart J. 1989;41(5):307-313.
11. Ueyama T, Hano T, Kasamatsu K, Yamamoto K, Tsuruo Y, Nishio I. Estrogen attenuates the emotional stress-induced cardiac responses in the animal model of Tako-tsubo (Ampulla) cardiomyopathy. J Cardiovasc Pharmacol. 2003;42(suppl 1):S117-S119.
12. Sharkey SW, Lesser JR, Zenovich AG, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation. 2005;111(4):472-479.
1. Komamura K, Fukui M, Iwasaku T, Hirotani S, Masuyama T. Takotsubo cardiomyopathy: pathophysiology, diagnosis and treatment. World J Cardiol. 2014;6(7):602-609.
2. Wittstein IS, Thiemann DR, Lima JAC, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352(6):539-548.
3. Parodi G, Del Pace S, Carrabba N, et al. Incidence, clinical findings, and outcome of women with left ventricular apical ballooning syndrome. Am J Cardiol. 2007;99(2):182-185.
4. Madhavan M, Prasad A. Proposed Mayo Clinic criteria for the diagnosis of Tako-Tsubo cardiomyopathy and long-term prognosis. Herz. 2010;35(4):240-243.
5. Kawai S, Kitabatake A, Tomoike H; Takotsubo Cardiomyopathy Group. Guidelines for diagnosis of takotsubo (ampulla) cardiomyopathy. Circ J. 2007;71(6):990-992.
6. Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE. Stress (Takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med. 2008;5(1):22-29.
7. Paur H, Wright PT, Sikkel MB, et al. High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation. 2012;126(6):697-706.
8. Abraham J, Mudd JO, Kapur NK, Klein K, Champion HC, Wittstein IS. Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists. J Am Coll Cardiol. 2009;53(15):1320-1325.
9. Wedekind H, Möller K, Scholz KH. Tako-tsubo cardiomyopathy. Incidence in patients with acute coronary syndrome. [in German]. Herz. 2006;31(4):339-346.
10. Khullar M, Datta BN, Wahi PL, Chakravarti RN. Catecholamine-induced experimental cardiomyopathy—a histopathological, histochemical and ultrastructural study. Indian Heart J. 1989;41(5):307-313.
11. Ueyama T, Hano T, Kasamatsu K, Yamamoto K, Tsuruo Y, Nishio I. Estrogen attenuates the emotional stress-induced cardiac responses in the animal model of Tako-tsubo (Ampulla) cardiomyopathy. J Cardiovasc Pharmacol. 2003;42(suppl 1):S117-S119.
12. Sharkey SW, Lesser JR, Zenovich AG, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation. 2005;111(4):472-479.
Proteins may be therapeutic targets for AML subtype
Image by Eric Smith
Preclinical research suggests a pair of histone-modifying proteins may be promising therapeutic targets for NPM1-mutated acute myeloid leukemia (AML).
Investigators found that these proteins—MLL and DOT1L—play key roles in NPM1-mutated AML.
Pharmacologic inhibition of either protein alone produced anti-leukemic activity in vitro and in vivo, but inhibiting both proteins together had a more profound effect.
Michael Kühn, MD, of the Mainz University Medical Center in Mainz, Germany, and his colleagues reported these findings in Cancer Discovery.
The investigators noted that nearly all NPM1-mutated AMLs are characterized by aberrant HOX expression, and FLT3 is concomitantly mutated in roughly 60% of these cases. However, it hasn’t been clear how mutant NPM1 cells maintain aberrant gene expression.
With this study, Dr Kühn and his colleagues showed that MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1-mutated AML.
The investigators were able to demonstrate that survival of NPM1-mutated AML cells depends on these 2 proteins. And NPM1-mutated AML is “exceptionally dependent” on the menin binding site in MLL1.
The team tested MI-503, a menin–MLL1 inhibitor, and the DOT1L inhibitor EPZ4777 in human and murine models of NPM1-mutated AML.
Each of the drugs reduced the activity of HOX genes in NPM1-mutated AML cells, but combining the drugs resulted in near-complete inactivation of HOX genes.
When given alone, EPZ4777 and MI-503 each reduced the proliferation and colony-forming potential of NPM1-mutated AML cells in vitro. And each of the drugs prolonged survival in mouse models of NPM1-mutated AML.
However, EPZ4777 and MI-503 given in combination significantly delayed the onset of leukemia and significantly prolonged survival when compared to either drug given alone.
The investigators said this suggests that inhibiting both DOT1L and menin–MLL1 affects leukemia-initiating cells, and this approach represents the first molecularly targeted treatment of NPM1-mutated AML that works by reversing a key mechanism of leukemogenesis.
They added that this research paves the way for trials assessing EPZ4777 and MI-503 in patients with NPM1-mutated AML. 
Image by Eric Smith
Preclinical research suggests a pair of histone-modifying proteins may be promising therapeutic targets for NPM1-mutated acute myeloid leukemia (AML).
Investigators found that these proteins—MLL and DOT1L—play key roles in NPM1-mutated AML.
Pharmacologic inhibition of either protein alone produced anti-leukemic activity in vitro and in vivo, but inhibiting both proteins together had a more profound effect.
Michael Kühn, MD, of the Mainz University Medical Center in Mainz, Germany, and his colleagues reported these findings in Cancer Discovery.
The investigators noted that nearly all NPM1-mutated AMLs are characterized by aberrant HOX expression, and FLT3 is concomitantly mutated in roughly 60% of these cases. However, it hasn’t been clear how mutant NPM1 cells maintain aberrant gene expression.
With this study, Dr Kühn and his colleagues showed that MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1-mutated AML.
The investigators were able to demonstrate that survival of NPM1-mutated AML cells depends on these 2 proteins. And NPM1-mutated AML is “exceptionally dependent” on the menin binding site in MLL1.
The team tested MI-503, a menin–MLL1 inhibitor, and the DOT1L inhibitor EPZ4777 in human and murine models of NPM1-mutated AML.
Each of the drugs reduced the activity of HOX genes in NPM1-mutated AML cells, but combining the drugs resulted in near-complete inactivation of HOX genes.
When given alone, EPZ4777 and MI-503 each reduced the proliferation and colony-forming potential of NPM1-mutated AML cells in vitro. And each of the drugs prolonged survival in mouse models of NPM1-mutated AML.
However, EPZ4777 and MI-503 given in combination significantly delayed the onset of leukemia and significantly prolonged survival when compared to either drug given alone.
The investigators said this suggests that inhibiting both DOT1L and menin–MLL1 affects leukemia-initiating cells, and this approach represents the first molecularly targeted treatment of NPM1-mutated AML that works by reversing a key mechanism of leukemogenesis.
They added that this research paves the way for trials assessing EPZ4777 and MI-503 in patients with NPM1-mutated AML.
Image by Eric Smith
Preclinical research suggests a pair of histone-modifying proteins may be promising therapeutic targets for NPM1-mutated acute myeloid leukemia (AML).
Investigators found that these proteins—MLL and DOT1L—play key roles in NPM1-mutated AML.
Pharmacologic inhibition of either protein alone produced anti-leukemic activity in vitro and in vivo, but inhibiting both proteins together had a more profound effect.
Michael Kühn, MD, of the Mainz University Medical Center in Mainz, Germany, and his colleagues reported these findings in Cancer Discovery.
The investigators noted that nearly all NPM1-mutated AMLs are characterized by aberrant HOX expression, and FLT3 is concomitantly mutated in roughly 60% of these cases. However, it hasn’t been clear how mutant NPM1 cells maintain aberrant gene expression.
With this study, Dr Kühn and his colleagues showed that MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1-mutated AML.
The investigators were able to demonstrate that survival of NPM1-mutated AML cells depends on these 2 proteins. And NPM1-mutated AML is “exceptionally dependent” on the menin binding site in MLL1.
The team tested MI-503, a menin–MLL1 inhibitor, and the DOT1L inhibitor EPZ4777 in human and murine models of NPM1-mutated AML.
Each of the drugs reduced the activity of HOX genes in NPM1-mutated AML cells, but combining the drugs resulted in near-complete inactivation of HOX genes.
When given alone, EPZ4777 and MI-503 each reduced the proliferation and colony-forming potential of NPM1-mutated AML cells in vitro. And each of the drugs prolonged survival in mouse models of NPM1-mutated AML.
However, EPZ4777 and MI-503 given in combination significantly delayed the onset of leukemia and significantly prolonged survival when compared to either drug given alone.
The investigators said this suggests that inhibiting both DOT1L and menin–MLL1 affects leukemia-initiating cells, and this approach represents the first molecularly targeted treatment of NPM1-mutated AML that works by reversing a key mechanism of leukemogenesis.
They added that this research paves the way for trials assessing EPZ4777 and MI-503 in patients with NPM1-mutated AML.
Heart failure in Primary Care
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The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
NOACs show benefit in calciphylaxis
VIENNA – The novel oral anticoagulants may provide effective adjunctive therapy in patients with calciphylaxis, Brian J. King, MD, said at the annual congress of the European Academy of Dermatology and Venereology.
He presented a retrospective case series of 16 patients with a confirmed diagnosis of calciphylaxis who were treated with NOACs at the Mayo Clinic in Rochester, Minn., where he is a dermatology resident. The results were impressive, particularly given that the estimated 1-year survival following diagnosis of calciphylaxis is only 45%.
At a mean followup of 418 days, 9 of 16 patients were still alive. More remarkably, five of those nine experienced complete resolution of their clinical lesions and remained alive at a mean followup of 775 days.
Calciphylaxis is a cutaneous manifestation of arteriolar thrombosis. It is classically associated with end-stage renal disease, hyperparathyroidism, a variety of hypercoagulable states, diabetes, and/or obesity. Fifteen of the 16 patients in the Mayo series were women. Fourteen patients had proximal involvement. The lesions occurred most often in fatty tissue on the hips, abdomen, thighs, breasts, and buttocks.
“It’s important to know that this is a deep, incredibly painful process and should not be confused with superficial crusted ulcerations,” Dr. King said.
A variety of treatments have been utilized for calciphylaxis, including sodium thiosulfate, debridement, advanced wound care, hyperbaric oxygen, and parathyroidectomy. But they are often ineffective.
Why not simply use warfarin instead of a costlier NOAC in addressing the problem? Because warfarin has actually been implicated as a cause of the vascular calcification that leads to thrombosis of dermal and pannicular arterioles. Indeed, 12 of the 16 patients in this series were on warfarin at the time of diagnosis of calciphylaxis, either for deep venous thrombosis, pulmonary embolism, or stroke prevention in atrial fibrillation. All were transitioned to a NOAC.
One group of Belgian investigators has provided evidence that strongly suggests the mechanism by which warfarin causes vascular calcification is via inhibition of vitamin K-dependent activation of matrix GLA 1, an enzyme which prevents calcification of vascular endothelial cells (BMC Nephrol. 2014 Sep 4;15:145).
“It is possible and even likely that the vessel calcification we see in patients on warfarin predisposes to thrombosis,” according to Dr. King.
The pathologic diagnostic criteria for calciphylaxis utilized at the Mayo Clinic require skin biopsy evidence of medial calcification and intimal fibroplasia of pannicular arterioles with cutaneous necrosis. Extravascular calcium deposition or thrombosis of pannicular or dermal arterioles is also typically present.
The major clinical criteria are necrotic cutaneous ulcers over indurated plaques, or indurated plaques without ulceration in adipose-rich tissue. The minor criteria are livedo racemosa, hemorrhagic bullae, or hemorrhagic plaques.
Asked if the NOACs can be used interchangeably for treatment of calciphylaxis, Dr. King said the direct factor Xa inhibitor apixaban is the NOAC of choice for this condition at the Mayo Clinic because unlike rivaroxaban (Xarelto) it doesn’t require dosing adjustment in the setting of renal impairment, which is extremely common in patients with calciphylaxis. The direct thrombin inhibitor dabigatran (Pradaxa) is contraindicated in chronic renal failure. Edoxaban (Savaysa) is not on the Mayo Clinic’s formulary, but it is contraindicated in patients with a creatinine clearance of 95 mL/min or more.
Dr. King said he and his coinvestigators recognize that a retrospective case series such as this must be considered hypothesis-generating and nondefinitive. They have already begun a larger prospective comparative outcomes study.
Dr. King reported having no financial conflicts of interest.
VIENNA – The novel oral anticoagulants may provide effective adjunctive therapy in patients with calciphylaxis, Brian J. King, MD, said at the annual congress of the European Academy of Dermatology and Venereology.
He presented a retrospective case series of 16 patients with a confirmed diagnosis of calciphylaxis who were treated with NOACs at the Mayo Clinic in Rochester, Minn., where he is a dermatology resident. The results were impressive, particularly given that the estimated 1-year survival following diagnosis of calciphylaxis is only 45%.
At a mean followup of 418 days, 9 of 16 patients were still alive. More remarkably, five of those nine experienced complete resolution of their clinical lesions and remained alive at a mean followup of 775 days.
Calciphylaxis is a cutaneous manifestation of arteriolar thrombosis. It is classically associated with end-stage renal disease, hyperparathyroidism, a variety of hypercoagulable states, diabetes, and/or obesity. Fifteen of the 16 patients in the Mayo series were women. Fourteen patients had proximal involvement. The lesions occurred most often in fatty tissue on the hips, abdomen, thighs, breasts, and buttocks.
“It’s important to know that this is a deep, incredibly painful process and should not be confused with superficial crusted ulcerations,” Dr. King said.
A variety of treatments have been utilized for calciphylaxis, including sodium thiosulfate, debridement, advanced wound care, hyperbaric oxygen, and parathyroidectomy. But they are often ineffective.
Why not simply use warfarin instead of a costlier NOAC in addressing the problem? Because warfarin has actually been implicated as a cause of the vascular calcification that leads to thrombosis of dermal and pannicular arterioles. Indeed, 12 of the 16 patients in this series were on warfarin at the time of diagnosis of calciphylaxis, either for deep venous thrombosis, pulmonary embolism, or stroke prevention in atrial fibrillation. All were transitioned to a NOAC.
One group of Belgian investigators has provided evidence that strongly suggests the mechanism by which warfarin causes vascular calcification is via inhibition of vitamin K-dependent activation of matrix GLA 1, an enzyme which prevents calcification of vascular endothelial cells (BMC Nephrol. 2014 Sep 4;15:145).
“It is possible and even likely that the vessel calcification we see in patients on warfarin predisposes to thrombosis,” according to Dr. King.
The pathologic diagnostic criteria for calciphylaxis utilized at the Mayo Clinic require skin biopsy evidence of medial calcification and intimal fibroplasia of pannicular arterioles with cutaneous necrosis. Extravascular calcium deposition or thrombosis of pannicular or dermal arterioles is also typically present.
The major clinical criteria are necrotic cutaneous ulcers over indurated plaques, or indurated plaques without ulceration in adipose-rich tissue. The minor criteria are livedo racemosa, hemorrhagic bullae, or hemorrhagic plaques.
Asked if the NOACs can be used interchangeably for treatment of calciphylaxis, Dr. King said the direct factor Xa inhibitor apixaban is the NOAC of choice for this condition at the Mayo Clinic because unlike rivaroxaban (Xarelto) it doesn’t require dosing adjustment in the setting of renal impairment, which is extremely common in patients with calciphylaxis. The direct thrombin inhibitor dabigatran (Pradaxa) is contraindicated in chronic renal failure. Edoxaban (Savaysa) is not on the Mayo Clinic’s formulary, but it is contraindicated in patients with a creatinine clearance of 95 mL/min or more.
Dr. King said he and his coinvestigators recognize that a retrospective case series such as this must be considered hypothesis-generating and nondefinitive. They have already begun a larger prospective comparative outcomes study.
Dr. King reported having no financial conflicts of interest.
VIENNA – The novel oral anticoagulants may provide effective adjunctive therapy in patients with calciphylaxis, Brian J. King, MD, said at the annual congress of the European Academy of Dermatology and Venereology.
He presented a retrospective case series of 16 patients with a confirmed diagnosis of calciphylaxis who were treated with NOACs at the Mayo Clinic in Rochester, Minn., where he is a dermatology resident. The results were impressive, particularly given that the estimated 1-year survival following diagnosis of calciphylaxis is only 45%.
At a mean followup of 418 days, 9 of 16 patients were still alive. More remarkably, five of those nine experienced complete resolution of their clinical lesions and remained alive at a mean followup of 775 days.
Calciphylaxis is a cutaneous manifestation of arteriolar thrombosis. It is classically associated with end-stage renal disease, hyperparathyroidism, a variety of hypercoagulable states, diabetes, and/or obesity. Fifteen of the 16 patients in the Mayo series were women. Fourteen patients had proximal involvement. The lesions occurred most often in fatty tissue on the hips, abdomen, thighs, breasts, and buttocks.
“It’s important to know that this is a deep, incredibly painful process and should not be confused with superficial crusted ulcerations,” Dr. King said.
A variety of treatments have been utilized for calciphylaxis, including sodium thiosulfate, debridement, advanced wound care, hyperbaric oxygen, and parathyroidectomy. But they are often ineffective.
Why not simply use warfarin instead of a costlier NOAC in addressing the problem? Because warfarin has actually been implicated as a cause of the vascular calcification that leads to thrombosis of dermal and pannicular arterioles. Indeed, 12 of the 16 patients in this series were on warfarin at the time of diagnosis of calciphylaxis, either for deep venous thrombosis, pulmonary embolism, or stroke prevention in atrial fibrillation. All were transitioned to a NOAC.
One group of Belgian investigators has provided evidence that strongly suggests the mechanism by which warfarin causes vascular calcification is via inhibition of vitamin K-dependent activation of matrix GLA 1, an enzyme which prevents calcification of vascular endothelial cells (BMC Nephrol. 2014 Sep 4;15:145).
“It is possible and even likely that the vessel calcification we see in patients on warfarin predisposes to thrombosis,” according to Dr. King.
The pathologic diagnostic criteria for calciphylaxis utilized at the Mayo Clinic require skin biopsy evidence of medial calcification and intimal fibroplasia of pannicular arterioles with cutaneous necrosis. Extravascular calcium deposition or thrombosis of pannicular or dermal arterioles is also typically present.
The major clinical criteria are necrotic cutaneous ulcers over indurated plaques, or indurated plaques without ulceration in adipose-rich tissue. The minor criteria are livedo racemosa, hemorrhagic bullae, or hemorrhagic plaques.
Asked if the NOACs can be used interchangeably for treatment of calciphylaxis, Dr. King said the direct factor Xa inhibitor apixaban is the NOAC of choice for this condition at the Mayo Clinic because unlike rivaroxaban (Xarelto) it doesn’t require dosing adjustment in the setting of renal impairment, which is extremely common in patients with calciphylaxis. The direct thrombin inhibitor dabigatran (Pradaxa) is contraindicated in chronic renal failure. Edoxaban (Savaysa) is not on the Mayo Clinic’s formulary, but it is contraindicated in patients with a creatinine clearance of 95 mL/min or more.
Dr. King said he and his coinvestigators recognize that a retrospective case series such as this must be considered hypothesis-generating and nondefinitive. They have already begun a larger prospective comparative outcomes study.
Dr. King reported having no financial conflicts of interest.
AT THE EADV CONGRESS
Key clinical point:
Major finding: Nine of 16 patients with calciphylaxis who were placed on adjunctive therapy with a novel oral anticoagulant responded with significant improvement in their cutaneous disease, four experienced disease stabilization, and three had progressive disease.
Data source: This was a retrospective case study of 16 patients with biopsy-confirmed calciphylaxis.
Disclosures: The study presenter reported having no financial conflicts of interest.
Atopic dermatitis prevention strategies under study
VIENNA – Diverse strategies aimed at preventing childhood atopic dermatitis (AD) now under study include installation of home water softeners, daily use of emollients starting at birth, and maternal consumption of probiotics beginning late in pregnancy, Carsten Flohr, PhD, said at a joint program of the International Eczema Council and the International Psoriasis Council held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.
To date there is no effective method for preventing AD. Preventive strategies are needed sorely because the prevalence of pediatric AD worldwide is expected to increase substantially. It appears to have stabilized at roughly 20% in many affluent countries, but the global burden of the disease will climb as low-income countries – where AD is historically uncommon – become more developed and urbanized. This trend has been well documented via the International Study of Asthma and Allergies in Childhood (ISAAC), which in several phases has studied nearly 2 million children in more than 100 countries, noted Dr. Flohr of St. John’s Institute of Dermatology at King’s College London.
Dr. Flohr and coinvestigators in the Enquiring About Tolerance (EAT) study recently documented a significant association between water hardness and the risk of infant-onset AD. The investigators took advantage of the considerable variation in the amount of bedrock limestone across England, which enabled them to study the relationship between domestic water calcium carbonate concentrations and the presence of AD in 1,303 babies at 3 monthd of age drawn from the general population across the country. Filaggrin skin barrier gene mutation status was determined in all infants.
Infants whose water supply contained a calcium carbonate level above the median value were at an adjusted 46% greater risk of having visible AD at age 3 months than those whose household water calcium carbonate level was below the median. The AD risk rose by 1% for each 1 mg/L increase in calcium carbonate concentration above the median. This increased risk was confined to infants with a filaggrin skin barrier gene mutation; hard water didn’t increase early AD risk in children with the normal, wild-type version of the filaggrin gene (J Allergy Clin Immunol. 2016 Aug;138[2]:509-16).
As a result of these findings, a UK prevention trial is underway in which home water softeners are provided to families at high risk of having a baby with AD in water districts with high calcium carbonate concentrations. An earlier UK study found that installation of home water softeners didn’t reduce AD severity in children with established disease (PLoS Med. 2011 Feb 15;8[2]:e1000395), but disease prevention may be another story.
The role of the gut microbiota in development of childhood AD is an active area of investigation. Dr. Flohr said “there is a signal” that maternal intake of probiotics including lactobacilli and bifidobacteria in the third trimester and postnatally may reduce a child’s risk of developing AD by encouraging establishment of a more diverse gut microflora. He cited a meta-analysis of 14 published studies of probiotics which provided evidence of a 21% reduction in the incidence of AD in young children (Epidemiology 2012 May;23[3]:402-14). The studies have methodologic shortcomings, so multiple research groups are continuing to pursue the signal of an AD preventive effect.
Dr. Flor reported having no financial conflicts of interest regarding his presentation.
VIENNA – Diverse strategies aimed at preventing childhood atopic dermatitis (AD) now under study include installation of home water softeners, daily use of emollients starting at birth, and maternal consumption of probiotics beginning late in pregnancy, Carsten Flohr, PhD, said at a joint program of the International Eczema Council and the International Psoriasis Council held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.
To date there is no effective method for preventing AD. Preventive strategies are needed sorely because the prevalence of pediatric AD worldwide is expected to increase substantially. It appears to have stabilized at roughly 20% in many affluent countries, but the global burden of the disease will climb as low-income countries – where AD is historically uncommon – become more developed and urbanized. This trend has been well documented via the International Study of Asthma and Allergies in Childhood (ISAAC), which in several phases has studied nearly 2 million children in more than 100 countries, noted Dr. Flohr of St. John’s Institute of Dermatology at King’s College London.
Dr. Flohr and coinvestigators in the Enquiring About Tolerance (EAT) study recently documented a significant association between water hardness and the risk of infant-onset AD. The investigators took advantage of the considerable variation in the amount of bedrock limestone across England, which enabled them to study the relationship between domestic water calcium carbonate concentrations and the presence of AD in 1,303 babies at 3 monthd of age drawn from the general population across the country. Filaggrin skin barrier gene mutation status was determined in all infants.
Infants whose water supply contained a calcium carbonate level above the median value were at an adjusted 46% greater risk of having visible AD at age 3 months than those whose household water calcium carbonate level was below the median. The AD risk rose by 1% for each 1 mg/L increase in calcium carbonate concentration above the median. This increased risk was confined to infants with a filaggrin skin barrier gene mutation; hard water didn’t increase early AD risk in children with the normal, wild-type version of the filaggrin gene (J Allergy Clin Immunol. 2016 Aug;138[2]:509-16).
As a result of these findings, a UK prevention trial is underway in which home water softeners are provided to families at high risk of having a baby with AD in water districts with high calcium carbonate concentrations. An earlier UK study found that installation of home water softeners didn’t reduce AD severity in children with established disease (PLoS Med. 2011 Feb 15;8[2]:e1000395), but disease prevention may be another story.
The role of the gut microbiota in development of childhood AD is an active area of investigation. Dr. Flohr said “there is a signal” that maternal intake of probiotics including lactobacilli and bifidobacteria in the third trimester and postnatally may reduce a child’s risk of developing AD by encouraging establishment of a more diverse gut microflora. He cited a meta-analysis of 14 published studies of probiotics which provided evidence of a 21% reduction in the incidence of AD in young children (Epidemiology 2012 May;23[3]:402-14). The studies have methodologic shortcomings, so multiple research groups are continuing to pursue the signal of an AD preventive effect.
Dr. Flor reported having no financial conflicts of interest regarding his presentation.
VIENNA – Diverse strategies aimed at preventing childhood atopic dermatitis (AD) now under study include installation of home water softeners, daily use of emollients starting at birth, and maternal consumption of probiotics beginning late in pregnancy, Carsten Flohr, PhD, said at a joint program of the International Eczema Council and the International Psoriasis Council held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.
To date there is no effective method for preventing AD. Preventive strategies are needed sorely because the prevalence of pediatric AD worldwide is expected to increase substantially. It appears to have stabilized at roughly 20% in many affluent countries, but the global burden of the disease will climb as low-income countries – where AD is historically uncommon – become more developed and urbanized. This trend has been well documented via the International Study of Asthma and Allergies in Childhood (ISAAC), which in several phases has studied nearly 2 million children in more than 100 countries, noted Dr. Flohr of St. John’s Institute of Dermatology at King’s College London.
Dr. Flohr and coinvestigators in the Enquiring About Tolerance (EAT) study recently documented a significant association between water hardness and the risk of infant-onset AD. The investigators took advantage of the considerable variation in the amount of bedrock limestone across England, which enabled them to study the relationship between domestic water calcium carbonate concentrations and the presence of AD in 1,303 babies at 3 monthd of age drawn from the general population across the country. Filaggrin skin barrier gene mutation status was determined in all infants.
Infants whose water supply contained a calcium carbonate level above the median value were at an adjusted 46% greater risk of having visible AD at age 3 months than those whose household water calcium carbonate level was below the median. The AD risk rose by 1% for each 1 mg/L increase in calcium carbonate concentration above the median. This increased risk was confined to infants with a filaggrin skin barrier gene mutation; hard water didn’t increase early AD risk in children with the normal, wild-type version of the filaggrin gene (J Allergy Clin Immunol. 2016 Aug;138[2]:509-16).
As a result of these findings, a UK prevention trial is underway in which home water softeners are provided to families at high risk of having a baby with AD in water districts with high calcium carbonate concentrations. An earlier UK study found that installation of home water softeners didn’t reduce AD severity in children with established disease (PLoS Med. 2011 Feb 15;8[2]:e1000395), but disease prevention may be another story.
The role of the gut microbiota in development of childhood AD is an active area of investigation. Dr. Flohr said “there is a signal” that maternal intake of probiotics including lactobacilli and bifidobacteria in the third trimester and postnatally may reduce a child’s risk of developing AD by encouraging establishment of a more diverse gut microflora. He cited a meta-analysis of 14 published studies of probiotics which provided evidence of a 21% reduction in the incidence of AD in young children (Epidemiology 2012 May;23[3]:402-14). The studies have methodologic shortcomings, so multiple research groups are continuing to pursue the signal of an AD preventive effect.
Dr. Flor reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE EADV CONGRESS
Palliative care boosts heart failure patient outcomes
ORLANDO – Systematic introduction of palliative care interventions for patients with advanced heart failure improved patients’ quality of life and spurred their development of advanced-care preferences in a pair of independently performed, controlled, pilot studies.
But, despite demonstrating the ability of palliative-care interventions to help heart failure patients during their final months of life, the findings raised questions about the generalizability and reproducibility of palliative-care interventions that may depend on the skills and experience of the individual specialists who deliver the palliative care.
“Palliative care for patients with cardiovascular disease is in desperate need of good-quality evidence,” commented Larry A, Allen, MD, a heart failure cardiologist at the University of Colorado in Aurora and designated discussant for one of the two studies presented at the meeting. “We need large, randomized trials with clinical outcomes to look at patient outcomes from palliative-care interventions.”
The patients average 71 years old, about half were women, and about 40% were African Americans. They had been diagnosed with heart failure for an average of more than 5 years, all had advanced heart failure, about 60% spent at least half of their time awake immobilized in a bed or chair, and they had average NT-proBNP blood levels of greater than 10,000 pg/mL.
After 24 weeks of intervention, the palliative-care program produced both statistically significant and clinically meaningful improvements in two different measures of health-related quality of life, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Functional Assessment of Chronic Illness Therapy – Palliative Care (FACIT-PAL). The KCCQ showed the palliative care intervention linked with an average rise of more than 9 points compared with patients in the control arm after adjustment for age and sex, a statistically significant increase on a scale where a 5-point rise is considered clinically meaningful. The FACIT-PAL showed an average, adjusted 11-point rise linked with the intervention, a statistically significant increase on a scale where an increase of at least 10 is judged clinically meaningful, reported Dr. Rogers, a heart failure cardiologist and professor of medicine at Duke University.
The palliative-care intervention also led to significant improvements in measures of spirituality, depression, and anxiety, but intervention had no impact on mortality.
“I like these endpoints and the idea that we can make quality-of-life better. These are very sick patients, with a predicted 6-month mortality of 50%. Patients reach a time when they don’t want to live longer but want better life quality for the days they still have,” he said in an interview.
The second report came from a single-center pilot study of 50 patients enrolled when they were hospitalized for acute decompensated heart failure and had at least one addition risk factor for poor prognosis such as age of at least 81 years, renal dysfunction, or a prior heart failure hospitalization within the past year. Patients randomized to the intervention arm underwent a structured evaluation based on the Serious Illness Conversation Guide and performed by a social worker experienced in palliative care and embedded in the heart failure clinical team. The primary endpoint of the SWAP-HF (Social Worker–Aided Palliative Care Intervention in High Risk Patients with Heart Failure) study was clinical-level documentation of advanced-care preferences by 6 months after the program began.
“Although more comprehensive, multidisciplinary palliative care interventions may also be effective, the focused approach [used in this study] may represent a cost-effective and scalable method for shepherding limited specialty resources to enhance the delivery of patient-centered care,” Dr. Desai said. In other words, a program with a social worker costs less than a two-person staff with a palliative-care physician and nurse practitioner.
Despite its relative simplicity, the SWAP-HF intervention had some unique aspects that make it generalizability uncertain, commented Dr. Allen. The embedding of a social worker on the heart failure team placed a professional with a “good understanding of social context” right on the scene with everyone else delivering care to the heart failure patient, a good strategy for minimizing fragmentation, he said. In addition, the place where the study was done, Brigham and Women’s Hospital, “is not your average hospital,” he noted,
In addition, the timing of the intervention studied during hospitalization may be problematic. Clinicians need to “be careful about patients making long-term decisions” about their care while they are hospitalized, a time when patients can be “ill, confused, and scared.” He cited recent findings from a study of hospital-based palliative-care interventions for family members of patients with chronic critical illness that did not reduce anxiety or depression symptoms among the treated family members and may have increased symptoms of posttraumatic stress disorder (JAMA. 2016 July 5;374[1]:51-62).
[email protected]
On Twitter @mitchelzoler
It’s very exciting to have these two studies presented at the Heart Failure Society of America’s annual meeting. Palliative-care research now receives funding from the National Institutes of Health, but consistently and successfully integrating palliative care into heart failure management still has a long way to go. In 2004, my colleagues and I published a set of consensus recommendations on how to apply palliative care methods to patients with advanced heart failure and what research needs existed for the field (J Card Fail. 2004 June;10[3]:200-9). Today, 12 years later, many of those research needs remain inadequately addressed.
Sarah J. Goodlin, MD , is chief of geriatrics at the Portland (Ore.) VA Medical Center. She had no disclosures. She made these comments as the designated discussant for Dr. Rogers’ report.
It’s very exciting to have these two studies presented at the Heart Failure Society of America’s annual meeting. Palliative-care research now receives funding from the National Institutes of Health, but consistently and successfully integrating palliative care into heart failure management still has a long way to go. In 2004, my colleagues and I published a set of consensus recommendations on how to apply palliative care methods to patients with advanced heart failure and what research needs existed for the field (J Card Fail. 2004 June;10[3]:200-9). Today, 12 years later, many of those research needs remain inadequately addressed.
Sarah J. Goodlin, MD , is chief of geriatrics at the Portland (Ore.) VA Medical Center. She had no disclosures. She made these comments as the designated discussant for Dr. Rogers’ report.
It’s very exciting to have these two studies presented at the Heart Failure Society of America’s annual meeting. Palliative-care research now receives funding from the National Institutes of Health, but consistently and successfully integrating palliative care into heart failure management still has a long way to go. In 2004, my colleagues and I published a set of consensus recommendations on how to apply palliative care methods to patients with advanced heart failure and what research needs existed for the field (J Card Fail. 2004 June;10[3]:200-9). Today, 12 years later, many of those research needs remain inadequately addressed.
Sarah J. Goodlin, MD , is chief of geriatrics at the Portland (Ore.) VA Medical Center. She had no disclosures. She made these comments as the designated discussant for Dr. Rogers’ report.
ORLANDO – Systematic introduction of palliative care interventions for patients with advanced heart failure improved patients’ quality of life and spurred their development of advanced-care preferences in a pair of independently performed, controlled, pilot studies.
But, despite demonstrating the ability of palliative-care interventions to help heart failure patients during their final months of life, the findings raised questions about the generalizability and reproducibility of palliative-care interventions that may depend on the skills and experience of the individual specialists who deliver the palliative care.
“Palliative care for patients with cardiovascular disease is in desperate need of good-quality evidence,” commented Larry A, Allen, MD, a heart failure cardiologist at the University of Colorado in Aurora and designated discussant for one of the two studies presented at the meeting. “We need large, randomized trials with clinical outcomes to look at patient outcomes from palliative-care interventions.”
The patients average 71 years old, about half were women, and about 40% were African Americans. They had been diagnosed with heart failure for an average of more than 5 years, all had advanced heart failure, about 60% spent at least half of their time awake immobilized in a bed or chair, and they had average NT-proBNP blood levels of greater than 10,000 pg/mL.
After 24 weeks of intervention, the palliative-care program produced both statistically significant and clinically meaningful improvements in two different measures of health-related quality of life, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Functional Assessment of Chronic Illness Therapy – Palliative Care (FACIT-PAL). The KCCQ showed the palliative care intervention linked with an average rise of more than 9 points compared with patients in the control arm after adjustment for age and sex, a statistically significant increase on a scale where a 5-point rise is considered clinically meaningful. The FACIT-PAL showed an average, adjusted 11-point rise linked with the intervention, a statistically significant increase on a scale where an increase of at least 10 is judged clinically meaningful, reported Dr. Rogers, a heart failure cardiologist and professor of medicine at Duke University.
The palliative-care intervention also led to significant improvements in measures of spirituality, depression, and anxiety, but intervention had no impact on mortality.
“I like these endpoints and the idea that we can make quality-of-life better. These are very sick patients, with a predicted 6-month mortality of 50%. Patients reach a time when they don’t want to live longer but want better life quality for the days they still have,” he said in an interview.
The second report came from a single-center pilot study of 50 patients enrolled when they were hospitalized for acute decompensated heart failure and had at least one addition risk factor for poor prognosis such as age of at least 81 years, renal dysfunction, or a prior heart failure hospitalization within the past year. Patients randomized to the intervention arm underwent a structured evaluation based on the Serious Illness Conversation Guide and performed by a social worker experienced in palliative care and embedded in the heart failure clinical team. The primary endpoint of the SWAP-HF (Social Worker–Aided Palliative Care Intervention in High Risk Patients with Heart Failure) study was clinical-level documentation of advanced-care preferences by 6 months after the program began.
“Although more comprehensive, multidisciplinary palliative care interventions may also be effective, the focused approach [used in this study] may represent a cost-effective and scalable method for shepherding limited specialty resources to enhance the delivery of patient-centered care,” Dr. Desai said. In other words, a program with a social worker costs less than a two-person staff with a palliative-care physician and nurse practitioner.
Despite its relative simplicity, the SWAP-HF intervention had some unique aspects that make it generalizability uncertain, commented Dr. Allen. The embedding of a social worker on the heart failure team placed a professional with a “good understanding of social context” right on the scene with everyone else delivering care to the heart failure patient, a good strategy for minimizing fragmentation, he said. In addition, the place where the study was done, Brigham and Women’s Hospital, “is not your average hospital,” he noted,
In addition, the timing of the intervention studied during hospitalization may be problematic. Clinicians need to “be careful about patients making long-term decisions” about their care while they are hospitalized, a time when patients can be “ill, confused, and scared.” He cited recent findings from a study of hospital-based palliative-care interventions for family members of patients with chronic critical illness that did not reduce anxiety or depression symptoms among the treated family members and may have increased symptoms of posttraumatic stress disorder (JAMA. 2016 July 5;374[1]:51-62).
[email protected]
On Twitter @mitchelzoler
ORLANDO – Systematic introduction of palliative care interventions for patients with advanced heart failure improved patients’ quality of life and spurred their development of advanced-care preferences in a pair of independently performed, controlled, pilot studies.
But, despite demonstrating the ability of palliative-care interventions to help heart failure patients during their final months of life, the findings raised questions about the generalizability and reproducibility of palliative-care interventions that may depend on the skills and experience of the individual specialists who deliver the palliative care.
“Palliative care for patients with cardiovascular disease is in desperate need of good-quality evidence,” commented Larry A, Allen, MD, a heart failure cardiologist at the University of Colorado in Aurora and designated discussant for one of the two studies presented at the meeting. “We need large, randomized trials with clinical outcomes to look at patient outcomes from palliative-care interventions.”
The patients average 71 years old, about half were women, and about 40% were African Americans. They had been diagnosed with heart failure for an average of more than 5 years, all had advanced heart failure, about 60% spent at least half of their time awake immobilized in a bed or chair, and they had average NT-proBNP blood levels of greater than 10,000 pg/mL.
After 24 weeks of intervention, the palliative-care program produced both statistically significant and clinically meaningful improvements in two different measures of health-related quality of life, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Functional Assessment of Chronic Illness Therapy – Palliative Care (FACIT-PAL). The KCCQ showed the palliative care intervention linked with an average rise of more than 9 points compared with patients in the control arm after adjustment for age and sex, a statistically significant increase on a scale where a 5-point rise is considered clinically meaningful. The FACIT-PAL showed an average, adjusted 11-point rise linked with the intervention, a statistically significant increase on a scale where an increase of at least 10 is judged clinically meaningful, reported Dr. Rogers, a heart failure cardiologist and professor of medicine at Duke University.
The palliative-care intervention also led to significant improvements in measures of spirituality, depression, and anxiety, but intervention had no impact on mortality.
“I like these endpoints and the idea that we can make quality-of-life better. These are very sick patients, with a predicted 6-month mortality of 50%. Patients reach a time when they don’t want to live longer but want better life quality for the days they still have,” he said in an interview.
The second report came from a single-center pilot study of 50 patients enrolled when they were hospitalized for acute decompensated heart failure and had at least one addition risk factor for poor prognosis such as age of at least 81 years, renal dysfunction, or a prior heart failure hospitalization within the past year. Patients randomized to the intervention arm underwent a structured evaluation based on the Serious Illness Conversation Guide and performed by a social worker experienced in palliative care and embedded in the heart failure clinical team. The primary endpoint of the SWAP-HF (Social Worker–Aided Palliative Care Intervention in High Risk Patients with Heart Failure) study was clinical-level documentation of advanced-care preferences by 6 months after the program began.
“Although more comprehensive, multidisciplinary palliative care interventions may also be effective, the focused approach [used in this study] may represent a cost-effective and scalable method for shepherding limited specialty resources to enhance the delivery of patient-centered care,” Dr. Desai said. In other words, a program with a social worker costs less than a two-person staff with a palliative-care physician and nurse practitioner.
Despite its relative simplicity, the SWAP-HF intervention had some unique aspects that make it generalizability uncertain, commented Dr. Allen. The embedding of a social worker on the heart failure team placed a professional with a “good understanding of social context” right on the scene with everyone else delivering care to the heart failure patient, a good strategy for minimizing fragmentation, he said. In addition, the place where the study was done, Brigham and Women’s Hospital, “is not your average hospital,” he noted,
In addition, the timing of the intervention studied during hospitalization may be problematic. Clinicians need to “be careful about patients making long-term decisions” about their care while they are hospitalized, a time when patients can be “ill, confused, and scared.” He cited recent findings from a study of hospital-based palliative-care interventions for family members of patients with chronic critical illness that did not reduce anxiety or depression symptoms among the treated family members and may have increased symptoms of posttraumatic stress disorder (JAMA. 2016 July 5;374[1]:51-62).
[email protected]
On Twitter @mitchelzoler
AT THE HFSA ANNUAL SCIENTIFIC MEETING
Key clinical point:
Major finding: Palliative care measures boosted patients’ Kansas City Cardiomyopathy Questionnaire score by an average of 9 points over that of controls.
Data source: PAL-HF, a single-center study with 150 randomized patients with heart failure and SWAP-HF, a single-center study with 50 randomized patients.
Disclosures: Dr. Rogers, Dr. Allen, and Dr. Desai had no relevant disclosures.
Help Improve Quality at Your Institution with SHM
October 16–22 is the National Association for Healthcare Quality’s “Healthcare Quality Week,” and SHM’s Center for Hospital Innovation & Improvement provides a variety of resources, tools, and programs to help address quality and patient safety issues at your institution. Find out how SHM can help you improve patient safety and outcomes through our Center for Hospital Innovation & Improvement at www.hospialmedicine.org/QI.
October 16–22 is the National Association for Healthcare Quality’s “Healthcare Quality Week,” and SHM’s Center for Hospital Innovation & Improvement provides a variety of resources, tools, and programs to help address quality and patient safety issues at your institution. Find out how SHM can help you improve patient safety and outcomes through our Center for Hospital Innovation & Improvement at www.hospialmedicine.org/QI.
October 16–22 is the National Association for Healthcare Quality’s “Healthcare Quality Week,” and SHM’s Center for Hospital Innovation & Improvement provides a variety of resources, tools, and programs to help address quality and patient safety issues at your institution. Find out how SHM can help you improve patient safety and outcomes through our Center for Hospital Innovation & Improvement at www.hospialmedicine.org/QI.