---

CE/CME No: CR-1810

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Distinguish primary tinnitus from secondary tinnitus.
• Understand and implement a full clinical evaluation of tinnitus, including imaging studies when appropriate.
• Discuss expectations regarding treatment options and realistic outcomes of currently recommended therapy.
• Direct patients to specialist care for cognitive behavioral therapy or tinnitus retraining therapy.
• Know when pharmacotherapeutic intervention is indicated.

FACULTY
Wendy Gillian Ross practices urgent care medicine in Lake Grove, New York, and primary care in Patchogue, New York. Randy Danielsen is Professor and Dean, Arizona School of Health Sciences, and Director, Center for the Future of the Health Professions, both at A.T. Still University, in Mesa, Arizona. He is Physician Assistant Editor-in-Chief of Clinician Reviews.

The authors have no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid through September 30, 2019.

Article begins on next page >>

 

Tinnitus can be a debilitating condition that affects quality of life and is often not treated according to guidelines. Cognitive behavioral therapy and tinnitus retraining therapy have been successful in reducing tinnitus bother; pharmacotherapy is not widely accepted as successful, and can, in fact, be deleterious. This article describes pathophysiologic disturbances of hearing and how they relate to chronic subjective tinnitus, discusses the clinical evaluation of tinnitus as a presenting symptom, and reviews current treatments.

Primary chronic subjective tinnitus, often thought of more as a symptom than a diagnosis, affects millions of people worldwide. This troublesome condition has been chronicled as far back as the first century ad, when Celsus gave detailed accounts in his treatise, De Medicina.¹

It is estimated that only 20% of people who experience tinnitus actively seek treatment.² In the United States, 2 to 3 million of the 12 million patients who do request treatment report lasting symptoms that they describe as debilitating.³ For patients who seek help, the treatment recommended by physicians is typically pharmacotherapeutic—which does not follow guidelines.⁴

The aim of this article is to reinforce a greater understanding of the mechanisms of tinnitus and integrate that knowledge into treatment guidelines. The article does not discuss surgical treatment of tinnitus.

DEFINITION AND CLASSIFICATION

A universal standard definition of chronic tinnitus does not exist; Trevis et al define it as a phantom sound that persists for more than three months.⁵ The quality and loudness of tinnitus is variable but is often described as a buzz, hiss, or ringing. Prevalence increases with age, smoking, male gender, and ethnicity, with the non-Latino white population statistically at greater risk.³ Comorbid conditions (eg, diabetes and other autoimmune diseases) are risk factors for tinnitus. A history of exposure to loud sound—occupational, environmental, or recreational—also can predispose a person to tinnitus.³

The American Academy of Otolaryngology–Head and Neck Surgery (AAO–HNS) classifies tinnitus as primary (subjective) or secondary (objective). Primary tinnitus—representing the majority of cases—has no identifiable cause; there may be accompanying sensorineural hearing loss or hyperacusis. Secondary tinnitus can also be associated with sensorineural hearing loss but has an identifiable underlying cause.⁶ The differential diagnosis of tinnitus is listed in the Table.⁷

Tinnitus is further defined by its persistence. Persistent tinnitus is defined as tinnitus lasting more than six months, slightly longer than the duration offered by Trevis et al, who also define tinnitus as bothersome or non-bothersome, depending on its impact on quality of life.^5,6 Causes of reduced quality of life include depression, anxiety, insomnia, and neurocognitive decline—all of which have been associated with chronic subjective tinnitus.⁸

Continue to: Researchers have discovered that...

 

Researchers have discovered that tinnitus is not simply a cochlear phenomenon. The pathology extends well beyond the auditory complex, having a deleterious effect on both the somatosensory and central nervous systems, providing some explanation for the prevalence of anxiety and depression associated with the disorder (see "Pathophysiology of tinnitus").^9-17

Because of the insidious nature of tinnitus and lack of standard measures of severity, true prevalence is difficult to calculate.¹⁸

CLINICAL EVALUATION

Tinnitus can be a presenting complaint or elicited during history-taking. Symptomatic patients should receive full evaluation, including a complete physical exam, medication history, and laboratory workup.

Adverse effect of drugs

Medications that commonly cause tinnitus symptoms are NSAIDs, chemotherapeutic agents, and antibiotics (eg, macrolides and fluoroquinolones). Amiodarone, ACE inhibitors, proton-pump inhibitors, and calcium-channel blockers have also been implicated. Paradoxically, anxiolytics and tricyclic antidepressants, which are sometimes used to treat tinnitus, have been linked to causing the condition.⁷

Laboratory tests and imaging

Testing should include investigation for infectious disease, autoimmune disorders, and vitamin deficiency.⁷ According to the American College of Radiology, imaging is unnecessary in the workup of primary tinnitus. Any suspicion of a vascular cause noted on the physical exam (eg, an associated bruit or venous hum), however, should be explored with imaging. Furthermore, any case of tinnitus that lateralizes also requires additional investigation. Modalities of choice are MRI, CT, and CT angiography.¹⁹

Continue to: Referral for audiology evaluation

 

 

Referral for audiology evaluation

When no underlying pathology can be identified for tinnitus, the patient should be sent for a full audiology evaluation to screen for associated hearing loss. Discussion of audiology screening tests is beyond the scope of this article; however, testing includes otoscopy, audiography, tympanography, otoacoustic emission testing, auditory brainstem-response testing, and vestibular evoked myogenic potential testing.⁷

Probing nonphysical impacts

Quality of life and overall emotional wellness, including cognitive function, should be investigated in patients with tinnitus. Two questionnaires commonly used in the assessment of tinnitus bother are the Tinnitus Handicap Inventory and the Tinnitus Reaction Questionnaire.⁷ In a large, systematic review, Trevis et al report that “64% of studies investigating depression found an increase in depressive symptoms in people with chronic tinnitus compared to hearing control groups, and 62% of studies investigating anxiety reported significantly increased anxiety symptoms.”⁵

MANAGEMENT

Tinnitus management should be viewed two ways: treatment of perceived loudness and treatment of comorbid symptoms relating to tinnitus bother.⁶ In the same meta-analysis, Trevis and colleagues found that patients with tinnitus had higher rates of anxiety, depression, and overall decline in cognitive function, including processing speed, concentration, and sleep disorders.⁵ It is useful to keep this observation in mind when reviewing treatment options for tinnitus.

Five classic pharmacotherapeutic approaches to tinnitus management are

• Anticonvulsants
• Antidepressants
• Anesthetics
• Anxiolytics
• Lidocaine.

Newer medications that show some promise are N-methyl-D-aspartate (NMDA) receptor antagonists, notably neramexane. Alternative pharmaceuticals include vitamin-based treatments, cannabinoids, and herbal compounds.

Continue to: The AAOS-HNS supports...

 

The AAO–HNS supports nonpharmacotherapeutic treatment of tinnitus; its guidelines include a recommendation for cognitive behavioral therapy (CBT) as primary therapy.⁶ In addition, tinnitus-retraining therapy, tinnitus-masking therapy/sound therapy, meditation/mindfulness, and yoga all have been studied for their ability to alleviate tinnitus bother.

Pharmacotherapeutic management

Anticonvulsants have failed to provide strong evidence of usefulness in the treatment of tinnitus and are not supported by the AAO–HNS as such.⁶ This conclusion notwithstanding, the anticonvulsants carbamazepine and gabapentin have historically been two of the more common medications used to treat tinnitus.

Carbamazepine is a glutamate receptor antagonist that suppresses seizure activity. Based on prior research suggesting that spontaneous firing within the auditory complex is similar to seizure activity, Iranian researchers explored the hypothesis that carbamazepine might lessen tinnitus severity. Their study revealed, however, that carbamazepine did not statistically significantly reduce the severity of tinnitus, compared to placebo.²⁰ While carbamazepine may be of limited use in the treatment of subjective tinnitus, recent literature confirms that it is not only useful, but also diagnostic, in typewriter tinnitus (ie, having a staccato quality, like the sound of typewriter keys being depressed). Typewriter tinnitus is a secondary cause of tinnitus related to disruption of the stapes in the middle ear.²¹

Gabapentin works by promoting gamma-aminobutyric acid (GABA) production in the brain. GABA is an inhibitory neurotransmitter, thus slowing down signals between neurons. Following on preliminary research that detected low levels of GABA in the inferior colliculus of rodents with salicylate-induced tinnitus, Aazh and colleagues conducted a double-blind study of gabapentin—and concluded that it yielded no improvement in symptoms, compared to placebo.²²

Valproic acid has not been formally investigated but is commonly incorporated in the treatment of tinnitus.²³ Lamotrigine has provided similarly disappointing results in the treatment of tinnitus.²⁴

Continue to: Antidepressants and anxiolytics

 

Antidepressants and anxiolytics. Based on the results of their early clinical trials, Sullivan and colleagues concluded that tricyclic antidepressants produced significant improvement in tinnitus symptoms, due to the analgesic effects of these drugs. The researchers studied nortriptyline specifically; in severely depressed patients, the drug reduced the loudness of tinnitus and depressive symptoms. In non-depressed subjects, however, nortriptyline was not as efficacious.²⁵

Selective serotonin reuptake inhibitors have not had the same success as nortriptyline. In a study of paroxetine conducted by Oishi and colleagues, there was little evidence that the drug reduced the loudness of tinnitus, although overall, it did reduce tinnitus bother and anxiety.²⁶

Included in the category of anxiolytics, benzodiazepines have long been used to treat severe tinnitus-induced anxiety, with some success. However, as Elgoyhen and Langguth point out, studies of benzodiazepines for tinnitus have been limited in size.²³

The AAO–HNS does not support routine use of antidepressants and anxiolytics for tinnitus bother.⁷

NMDA receptor antagonists. In a recent clinical trial, neramexane was studied for its efficacy in tinnitus. Neramexane acts at the cholinergic nicotinic and NMDA receptors in the efferent auditory system. Its complex reaction is thought to prevent transmission of unwanted sound not only to structures within the auditory system but beyond, to the medial geniculate body and lateral nucleus of the amygdala. The trial has proved some benefit concerning overall perception of tinnitus loudness; a phase 2 trial is being conducted.²⁷

Continue to: Intra-tympanic anesthetics

 

Intra-tympanic anesthetics. Anesthetics, such as lidocaine, have had limited success and results have not been found to be sustained.

Alternative medical managements

Traditional Chinese herbal medications have been used for centuries and are increasingly popular in Western culture. Hilton and colleagues studied Ginkgo biloba, or maidenhair tree, a traditional Chinese herbal supplement available as an extract and as dried leaves. The main action of the extract is vasoregulatory; antiplatelet effects are also seen. Adverse effects include gastrointestinal upset and headache. In a systematic review, Hilton and colleagues concluded that Ginkgo did not reduce overall tinnitus loudness or severity; the review was limited, however, by the fact that only two studies met criteria for inclusion.²⁸

Vitamins, lipoflavinoids, zinc, manganese, and melatonin are all supplements marketed to improve tinnitus symptoms. However, a cross-sectional study confirmed prior research that did not show any benefit from the use of these supplements.²⁹

Cannabinoids are being studied for their proposed antiepileptic effects. There is a popular misconception of Cannabis as a singular chemical when in fact, it is a plant that contains hundreds of chemicals that each act differently on the brain. In a review, Smith and Zheng³⁰ explain that two cannabinoid receptors, CB1 and CB2, are represented, and exert their effects, in different areas of the brain. CB1 receptors block calcium influx in presynaptic terminals, resulting in an inhibitory effect on neurotransmitter release.

CB1 receptors have been found in the dorsal cochlear nuclei, prompting research interest in how cannabinoids affect neurotransmission of unwanted sounds of tinnitus. To date, however, there are conflicting data concerning the benefit of cannabinoids and tinnitus. In fact, Smith and Zheng state that some data suggest that cannabinoids might make tinnitus worse.³⁰

Continue to: Nonpharmacotherapeutic management

 

 

Nonpharmacotherapeutic management

Cognitive behavioral therapy. Conceptualized by Aaron T. Beck in the 1960s, cognitive behavioral therapy (CBT) is the leading recommendation made by the AAO–HNS in its tinnitus treatment guidelines.⁶ Beck’s work centered on the idea that behaviors are modifiable thoughts, through analysis of past experiences and assumptions based on those experiences. By understanding the core belief that a patient attaches to a feeling, Beck hypothesized that behaviors or responses to those feelings could be changed; this is accomplished through discussion to dispel unwarranted fears and by teaching coping mechanisms, such as relaxation. The idea behind CBT in the management of tinnitus is clear: The sound cannot be eliminated, but the patient’s response to the sound can be modified. Ultimately, through this modified response or habituation, the patient can relax and live with the sound.³¹

Since anxiety, depression, and insomnia are common comorbidities of tinnitus, a psychologic approach remains in the forefront of treatment recommendations. Hoare and colleagues reported that in “a meta-analysis of 10 randomized trials evaluating different forms of CBT (by the therapist and over the Internet), CBT improved tinnitus symptoms compared to non-CBT controls.”⁷

Tinnitus retraining therapy (TRT) is another form of habituation therapy, introduced by Jastreboff in the 1990s. His work furthered the idea that tinnitus could be reframed, as it is in CBT. Simply, he proposed that systems outside the auditory complex—namely the autonomic nervous system and the limbic system—respond to the signal produced by damaged hair cells in the cochlear nuclei. TRT retrains connections to block or ignore these signals.¹³ Unlike CBT, the aim of TRT is to eliminate the perception of sound.

By educating patients about the physiologic mechanisms of tinnitus, TRT reduces patient anxiety related to the sound. The process of habituation follows counseling. To accomplish this, the patient wears a sound generator, similar in appearance to hearing aids, using broadband noise. The sound does not mask the tinnitus but closes the gap between silence and the perception of tinnitus. The sound generator is worn for six hours daily for approximately 12 months.

Multiple studies have employed Jastreboff’s original technique, including a clinical trial by Bauer and colleagues. The published outcome of this study confirmed that patients experienced a positive and lasting effect with TRT.³² In addition, a small study of TRT conducted by Barozzi and colleagues, using different colors of sound (ie, how the frequency of a given sound corresponds to the light-wave frequency of a particular color), found statistically significant improvement. Allowing patients to pick a sound that they found more pleasant increased the effectiveness of the treatment.³³ (Patients can learn more about TRT by visiting www.tinnitus-pjj.com, hosted by tinnitus researcher Pawel J. Jastreboff.)

Continue to: Alternative nonmedical therapies...

 

Alternative nonmedical therapies have become popular; they include meditation, yoga, physical therapy, mindfulness, and tinnitus-masking treatment with sound.

Results of a study of yoga and meditation showed that patients felt more relaxed, but that these interventions had no effect on the severity of tinnitus. The principle behind yoga practice, according to Köksoy and colleagues, is that the discipline is thought to affect the limbic system by deactivating the sympathetic response to stimulation from surrounding sounds. In addition, Köksoy states, other researchers have provided evidence that yoga increases circulating levels of antioxidants, which in turn reduce oxidative stress.³⁴

Particularly among members of the millennial generation, mindfulness has become a buzzword. The practice refers to a “method for facing, exploring, and alleviating suffering by relating to present experiences.”³⁵ Roland and colleagues conducted a clinical trial of mindfulness practiced by a cohort of patients with bothersome tinnitus; results were based on scores gleaned from standard rating scales (eg, Global Bothersome Scale, Cognitive and Affective Mindfulness Scale-Revised, Cognitive Failures Questionnaire, Tinnitus Handicap Inventory, and Tinnitus Functional Index). Evaluated before and four weeks after cessation of therapy, subjects reported that tinnitus bother was reduced, but none showed statistically significant improvement in depression, anxiety, or cognitive ability.³⁵

Used for more than 40 years, sound-based therapy has been discussed in conjunction with TRT.³⁶ It is recognized as an approved but optional treatment by the AAO–HNS. In response to a 2010 study by Hobson that used sound-based therapy alone for tinnitus, Tunkel and colleagues cautioned that the modality showed little benefit. The major downside to acoustic therapy, according to the AAO–HNS clinical guidelines, is cost and patients’ excessive expectation of effectiveness.⁶

According to the AAO–HNS, repetitive-transcranial magnetic stimulation is not supported as a valid treatment for tinnitus because it can lead to seizures in patients who are taking medication that lowers the seizure threshold or who have a secondary cause of tinnitus, such as a tumor—therefore creating risk that outweighs any benefit.⁶

Continue to: CONCLUSION

 

CONCLUSION

For a large percentage of the population, chronic subjective tinnitus is a significant variable in the evaluation of quality of life. The condition is not completely understood and often displays features unique to the individual. Much of the initial response to research linking tinnitus with shared pathways typical for chronic pain, anxiety, and depression has resulted in pharmacotherapeutic management that is not always warranted—or successful.

Clinical research into the pathophysiology of tinnitus is providing a better understanding of the neurophysiologic mechanisms that underpin the science of chronic tinnitus. With this information, researchers can one day design medical management that targets specific receptors, resulting in greater management success.

The psychologic impact of tinnitus cannot be underestimated. When almost one-third of patients complain of debilitating symptoms that can also result in neurocognitive decline, tinnitus becomes a condition that cannot be ignored. Guidelines set forth by the AAO–HNS state that CBT and TRT offer some reprieve from symptoms and teach patients habituation without further damage to hearing. The use of broad-based sound generators has been well established as a useful management tool, although it is not curative.

The limitations of some studies that reviewed alternative medicines include small sample size and difficulty comparing research analysis because of disparities in tinnitus rating scales. Also, age bias, comorbid conditions, and study drop-out rates affected overall statistical significance of some studies. Additional, high-quality research is warranted in this area.

Continue to: Prevention of tinnitus...

 

Prevention of tinnitus through education on hearing loss and its causes should be regarded as implicit; occupational noise and recreational use of music devices put people at heightened risk for hearing loss and tinnitus. Information and open discussion that include the discovery of tinnitus symptoms during routine physical examination are recommended.

Last, providers who adhere to recognized guidelines will aid patients in coping with the challenges that tinnitus presents. As research continues to unravel the complex interaction between neurons, medical science is hopeful that curative treatments will become available.

---

CE/CME No: CR-1810

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Distinguish primary tinnitus from secondary tinnitus.
• Understand and implement a full clinical evaluation of tinnitus, including imaging studies when appropriate.
• Discuss expectations regarding treatment options and realistic outcomes of currently recommended therapy.
• Direct patients to specialist care for cognitive behavioral therapy or tinnitus retraining therapy.
• Know when pharmacotherapeutic intervention is indicated.

FACULTY
Wendy Gillian Ross practices urgent care medicine in Lake Grove, New York, and primary care in Patchogue, New York. Randy Danielsen is Professor and Dean, Arizona School of Health Sciences, and Director, Center for the Future of the Health Professions, both at A.T. Still University, in Mesa, Arizona. He is Physician Assistant Editor-in-Chief of Clinician Reviews.

The authors have no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid through September 30, 2019.

Article begins on next page >>

 

Tinnitus can be a debilitating condition that affects quality of life and is often not treated according to guidelines. Cognitive behavioral therapy and tinnitus retraining therapy have been successful in reducing tinnitus bother; pharmacotherapy is not widely accepted as successful, and can, in fact, be deleterious. This article describes pathophysiologic disturbances of hearing and how they relate to chronic subjective tinnitus, discusses the clinical evaluation of tinnitus as a presenting symptom, and reviews current treatments.

Primary chronic subjective tinnitus, often thought of more as a symptom than a diagnosis, affects millions of people worldwide. This troublesome condition has been chronicled as far back as the first century ad, when Celsus gave detailed accounts in his treatise, De Medicina.¹

It is estimated that only 20% of people who experience tinnitus actively seek treatment.² In the United States, 2 to 3 million of the 12 million patients who do request treatment report lasting symptoms that they describe as debilitating.³ For patients who seek help, the treatment recommended by physicians is typically pharmacotherapeutic—which does not follow guidelines.⁴

The aim of this article is to reinforce a greater understanding of the mechanisms of tinnitus and integrate that knowledge into treatment guidelines. The article does not discuss surgical treatment of tinnitus.

DEFINITION AND CLASSIFICATION

A universal standard definition of chronic tinnitus does not exist; Trevis et al define it as a phantom sound that persists for more than three months.⁵ The quality and loudness of tinnitus is variable but is often described as a buzz, hiss, or ringing. Prevalence increases with age, smoking, male gender, and ethnicity, with the non-Latino white population statistically at greater risk.³ Comorbid conditions (eg, diabetes and other autoimmune diseases) are risk factors for tinnitus. A history of exposure to loud sound—occupational, environmental, or recreational—also can predispose a person to tinnitus.³

The American Academy of Otolaryngology–Head and Neck Surgery (AAO–HNS) classifies tinnitus as primary (subjective) or secondary (objective). Primary tinnitus—representing the majority of cases—has no identifiable cause; there may be accompanying sensorineural hearing loss or hyperacusis. Secondary tinnitus can also be associated with sensorineural hearing loss but has an identifiable underlying cause.⁶ The differential diagnosis of tinnitus is listed in the Table.⁷

Tinnitus is further defined by its persistence. Persistent tinnitus is defined as tinnitus lasting more than six months, slightly longer than the duration offered by Trevis et al, who also define tinnitus as bothersome or non-bothersome, depending on its impact on quality of life.^5,6 Causes of reduced quality of life include depression, anxiety, insomnia, and neurocognitive decline—all of which have been associated with chronic subjective tinnitus.⁸

Continue to: Researchers have discovered that...

 

Researchers have discovered that tinnitus is not simply a cochlear phenomenon. The pathology extends well beyond the auditory complex, having a deleterious effect on both the somatosensory and central nervous systems, providing some explanation for the prevalence of anxiety and depression associated with the disorder (see "Pathophysiology of tinnitus").^9-17

Because of the insidious nature of tinnitus and lack of standard measures of severity, true prevalence is difficult to calculate.¹⁸

CLINICAL EVALUATION

Tinnitus can be a presenting complaint or elicited during history-taking. Symptomatic patients should receive full evaluation, including a complete physical exam, medication history, and laboratory workup.

Adverse effect of drugs

Medications that commonly cause tinnitus symptoms are NSAIDs, chemotherapeutic agents, and antibiotics (eg, macrolides and fluoroquinolones). Amiodarone, ACE inhibitors, proton-pump inhibitors, and calcium-channel blockers have also been implicated. Paradoxically, anxiolytics and tricyclic antidepressants, which are sometimes used to treat tinnitus, have been linked to causing the condition.⁷

Laboratory tests and imaging

Testing should include investigation for infectious disease, autoimmune disorders, and vitamin deficiency.⁷ According to the American College of Radiology, imaging is unnecessary in the workup of primary tinnitus. Any suspicion of a vascular cause noted on the physical exam (eg, an associated bruit or venous hum), however, should be explored with imaging. Furthermore, any case of tinnitus that lateralizes also requires additional investigation. Modalities of choice are MRI, CT, and CT angiography.¹⁹

Continue to: Referral for audiology evaluation

 

 

Referral for audiology evaluation

When no underlying pathology can be identified for tinnitus, the patient should be sent for a full audiology evaluation to screen for associated hearing loss. Discussion of audiology screening tests is beyond the scope of this article; however, testing includes otoscopy, audiography, tympanography, otoacoustic emission testing, auditory brainstem-response testing, and vestibular evoked myogenic potential testing.⁷

Probing nonphysical impacts

Quality of life and overall emotional wellness, including cognitive function, should be investigated in patients with tinnitus. Two questionnaires commonly used in the assessment of tinnitus bother are the Tinnitus Handicap Inventory and the Tinnitus Reaction Questionnaire.⁷ In a large, systematic review, Trevis et al report that “64% of studies investigating depression found an increase in depressive symptoms in people with chronic tinnitus compared to hearing control groups, and 62% of studies investigating anxiety reported significantly increased anxiety symptoms.”⁵

MANAGEMENT

Tinnitus management should be viewed two ways: treatment of perceived loudness and treatment of comorbid symptoms relating to tinnitus bother.⁶ In the same meta-analysis, Trevis and colleagues found that patients with tinnitus had higher rates of anxiety, depression, and overall decline in cognitive function, including processing speed, concentration, and sleep disorders.⁵ It is useful to keep this observation in mind when reviewing treatment options for tinnitus.

Five classic pharmacotherapeutic approaches to tinnitus management are

• Anticonvulsants
• Antidepressants
• Anesthetics
• Anxiolytics
• Lidocaine.

Newer medications that show some promise are N-methyl-D-aspartate (NMDA) receptor antagonists, notably neramexane. Alternative pharmaceuticals include vitamin-based treatments, cannabinoids, and herbal compounds.

Continue to: The AAOS-HNS supports...

 

The AAO–HNS supports nonpharmacotherapeutic treatment of tinnitus; its guidelines include a recommendation for cognitive behavioral therapy (CBT) as primary therapy.⁶ In addition, tinnitus-retraining therapy, tinnitus-masking therapy/sound therapy, meditation/mindfulness, and yoga all have been studied for their ability to alleviate tinnitus bother.

Pharmacotherapeutic management

Anticonvulsants have failed to provide strong evidence of usefulness in the treatment of tinnitus and are not supported by the AAO–HNS as such.⁶ This conclusion notwithstanding, the anticonvulsants carbamazepine and gabapentin have historically been two of the more common medications used to treat tinnitus.

Carbamazepine is a glutamate receptor antagonist that suppresses seizure activity. Based on prior research suggesting that spontaneous firing within the auditory complex is similar to seizure activity, Iranian researchers explored the hypothesis that carbamazepine might lessen tinnitus severity. Their study revealed, however, that carbamazepine did not statistically significantly reduce the severity of tinnitus, compared to placebo.²⁰ While carbamazepine may be of limited use in the treatment of subjective tinnitus, recent literature confirms that it is not only useful, but also diagnostic, in typewriter tinnitus (ie, having a staccato quality, like the sound of typewriter keys being depressed). Typewriter tinnitus is a secondary cause of tinnitus related to disruption of the stapes in the middle ear.²¹

Gabapentin works by promoting gamma-aminobutyric acid (GABA) production in the brain. GABA is an inhibitory neurotransmitter, thus slowing down signals between neurons. Following on preliminary research that detected low levels of GABA in the inferior colliculus of rodents with salicylate-induced tinnitus, Aazh and colleagues conducted a double-blind study of gabapentin—and concluded that it yielded no improvement in symptoms, compared to placebo.²²

Valproic acid has not been formally investigated but is commonly incorporated in the treatment of tinnitus.²³ Lamotrigine has provided similarly disappointing results in the treatment of tinnitus.²⁴

Continue to: Antidepressants and anxiolytics

 

Antidepressants and anxiolytics. Based on the results of their early clinical trials, Sullivan and colleagues concluded that tricyclic antidepressants produced significant improvement in tinnitus symptoms, due to the analgesic effects of these drugs. The researchers studied nortriptyline specifically; in severely depressed patients, the drug reduced the loudness of tinnitus and depressive symptoms. In non-depressed subjects, however, nortriptyline was not as efficacious.²⁵

Selective serotonin reuptake inhibitors have not had the same success as nortriptyline. In a study of paroxetine conducted by Oishi and colleagues, there was little evidence that the drug reduced the loudness of tinnitus, although overall, it did reduce tinnitus bother and anxiety.²⁶

Included in the category of anxiolytics, benzodiazepines have long been used to treat severe tinnitus-induced anxiety, with some success. However, as Elgoyhen and Langguth point out, studies of benzodiazepines for tinnitus have been limited in size.²³

The AAO–HNS does not support routine use of antidepressants and anxiolytics for tinnitus bother.⁷

NMDA receptor antagonists. In a recent clinical trial, neramexane was studied for its efficacy in tinnitus. Neramexane acts at the cholinergic nicotinic and NMDA receptors in the efferent auditory system. Its complex reaction is thought to prevent transmission of unwanted sound not only to structures within the auditory system but beyond, to the medial geniculate body and lateral nucleus of the amygdala. The trial has proved some benefit concerning overall perception of tinnitus loudness; a phase 2 trial is being conducted.²⁷

Continue to: Intra-tympanic anesthetics

 

Intra-tympanic anesthetics. Anesthetics, such as lidocaine, have had limited success and results have not been found to be sustained.

Alternative medical managements

Traditional Chinese herbal medications have been used for centuries and are increasingly popular in Western culture. Hilton and colleagues studied Ginkgo biloba, or maidenhair tree, a traditional Chinese herbal supplement available as an extract and as dried leaves. The main action of the extract is vasoregulatory; antiplatelet effects are also seen. Adverse effects include gastrointestinal upset and headache. In a systematic review, Hilton and colleagues concluded that Ginkgo did not reduce overall tinnitus loudness or severity; the review was limited, however, by the fact that only two studies met criteria for inclusion.²⁸

Vitamins, lipoflavinoids, zinc, manganese, and melatonin are all supplements marketed to improve tinnitus symptoms. However, a cross-sectional study confirmed prior research that did not show any benefit from the use of these supplements.²⁹

Cannabinoids are being studied for their proposed antiepileptic effects. There is a popular misconception of Cannabis as a singular chemical when in fact, it is a plant that contains hundreds of chemicals that each act differently on the brain. In a review, Smith and Zheng³⁰ explain that two cannabinoid receptors, CB1 and CB2, are represented, and exert their effects, in different areas of the brain. CB1 receptors block calcium influx in presynaptic terminals, resulting in an inhibitory effect on neurotransmitter release.

CB1 receptors have been found in the dorsal cochlear nuclei, prompting research interest in how cannabinoids affect neurotransmission of unwanted sounds of tinnitus. To date, however, there are conflicting data concerning the benefit of cannabinoids and tinnitus. In fact, Smith and Zheng state that some data suggest that cannabinoids might make tinnitus worse.³⁰

Continue to: Nonpharmacotherapeutic management

 

 

Nonpharmacotherapeutic management

Cognitive behavioral therapy. Conceptualized by Aaron T. Beck in the 1960s, cognitive behavioral therapy (CBT) is the leading recommendation made by the AAO–HNS in its tinnitus treatment guidelines.⁶ Beck’s work centered on the idea that behaviors are modifiable thoughts, through analysis of past experiences and assumptions based on those experiences. By understanding the core belief that a patient attaches to a feeling, Beck hypothesized that behaviors or responses to those feelings could be changed; this is accomplished through discussion to dispel unwarranted fears and by teaching coping mechanisms, such as relaxation. The idea behind CBT in the management of tinnitus is clear: The sound cannot be eliminated, but the patient’s response to the sound can be modified. Ultimately, through this modified response or habituation, the patient can relax and live with the sound.³¹

Since anxiety, depression, and insomnia are common comorbidities of tinnitus, a psychologic approach remains in the forefront of treatment recommendations. Hoare and colleagues reported that in “a meta-analysis of 10 randomized trials evaluating different forms of CBT (by the therapist and over the Internet), CBT improved tinnitus symptoms compared to non-CBT controls.”⁷

Tinnitus retraining therapy (TRT) is another form of habituation therapy, introduced by Jastreboff in the 1990s. His work furthered the idea that tinnitus could be reframed, as it is in CBT. Simply, he proposed that systems outside the auditory complex—namely the autonomic nervous system and the limbic system—respond to the signal produced by damaged hair cells in the cochlear nuclei. TRT retrains connections to block or ignore these signals.¹³ Unlike CBT, the aim of TRT is to eliminate the perception of sound.

By educating patients about the physiologic mechanisms of tinnitus, TRT reduces patient anxiety related to the sound. The process of habituation follows counseling. To accomplish this, the patient wears a sound generator, similar in appearance to hearing aids, using broadband noise. The sound does not mask the tinnitus but closes the gap between silence and the perception of tinnitus. The sound generator is worn for six hours daily for approximately 12 months.

Multiple studies have employed Jastreboff’s original technique, including a clinical trial by Bauer and colleagues. The published outcome of this study confirmed that patients experienced a positive and lasting effect with TRT.³² In addition, a small study of TRT conducted by Barozzi and colleagues, using different colors of sound (ie, how the frequency of a given sound corresponds to the light-wave frequency of a particular color), found statistically significant improvement. Allowing patients to pick a sound that they found more pleasant increased the effectiveness of the treatment.³³ (Patients can learn more about TRT by visiting www.tinnitus-pjj.com, hosted by tinnitus researcher Pawel J. Jastreboff.)

Continue to: Alternative nonmedical therapies...

 

Alternative nonmedical therapies have become popular; they include meditation, yoga, physical therapy, mindfulness, and tinnitus-masking treatment with sound.

Results of a study of yoga and meditation showed that patients felt more relaxed, but that these interventions had no effect on the severity of tinnitus. The principle behind yoga practice, according to Köksoy and colleagues, is that the discipline is thought to affect the limbic system by deactivating the sympathetic response to stimulation from surrounding sounds. In addition, Köksoy states, other researchers have provided evidence that yoga increases circulating levels of antioxidants, which in turn reduce oxidative stress.³⁴

Particularly among members of the millennial generation, mindfulness has become a buzzword. The practice refers to a “method for facing, exploring, and alleviating suffering by relating to present experiences.”³⁵ Roland and colleagues conducted a clinical trial of mindfulness practiced by a cohort of patients with bothersome tinnitus; results were based on scores gleaned from standard rating scales (eg, Global Bothersome Scale, Cognitive and Affective Mindfulness Scale-Revised, Cognitive Failures Questionnaire, Tinnitus Handicap Inventory, and Tinnitus Functional Index). Evaluated before and four weeks after cessation of therapy, subjects reported that tinnitus bother was reduced, but none showed statistically significant improvement in depression, anxiety, or cognitive ability.³⁵

Used for more than 40 years, sound-based therapy has been discussed in conjunction with TRT.³⁶ It is recognized as an approved but optional treatment by the AAO–HNS. In response to a 2010 study by Hobson that used sound-based therapy alone for tinnitus, Tunkel and colleagues cautioned that the modality showed little benefit. The major downside to acoustic therapy, according to the AAO–HNS clinical guidelines, is cost and patients’ excessive expectation of effectiveness.⁶

According to the AAO–HNS, repetitive-transcranial magnetic stimulation is not supported as a valid treatment for tinnitus because it can lead to seizures in patients who are taking medication that lowers the seizure threshold or who have a secondary cause of tinnitus, such as a tumor—therefore creating risk that outweighs any benefit.⁶

Continue to: CONCLUSION

 

CONCLUSION

For a large percentage of the population, chronic subjective tinnitus is a significant variable in the evaluation of quality of life. The condition is not completely understood and often displays features unique to the individual. Much of the initial response to research linking tinnitus with shared pathways typical for chronic pain, anxiety, and depression has resulted in pharmacotherapeutic management that is not always warranted—or successful.

Clinical research into the pathophysiology of tinnitus is providing a better understanding of the neurophysiologic mechanisms that underpin the science of chronic tinnitus. With this information, researchers can one day design medical management that targets specific receptors, resulting in greater management success.

The psychologic impact of tinnitus cannot be underestimated. When almost one-third of patients complain of debilitating symptoms that can also result in neurocognitive decline, tinnitus becomes a condition that cannot be ignored. Guidelines set forth by the AAO–HNS state that CBT and TRT offer some reprieve from symptoms and teach patients habituation without further damage to hearing. The use of broad-based sound generators has been well established as a useful management tool, although it is not curative.

The limitations of some studies that reviewed alternative medicines include small sample size and difficulty comparing research analysis because of disparities in tinnitus rating scales. Also, age bias, comorbid conditions, and study drop-out rates affected overall statistical significance of some studies. Additional, high-quality research is warranted in this area.

Continue to: Prevention of tinnitus...

 

Prevention of tinnitus through education on hearing loss and its causes should be regarded as implicit; occupational noise and recreational use of music devices put people at heightened risk for hearing loss and tinnitus. Information and open discussion that include the discovery of tinnitus symptoms during routine physical examination are recommended.

Last, providers who adhere to recognized guidelines will aid patients in coping with the challenges that tinnitus presents. As research continues to unravel the complex interaction between neurons, medical science is hopeful that curative treatments will become available.

---

CE/CME No: CR-1810

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Distinguish primary tinnitus from secondary tinnitus.
• Understand and implement a full clinical evaluation of tinnitus, including imaging studies when appropriate.
• Discuss expectations regarding treatment options and realistic outcomes of currently recommended therapy.
• Direct patients to specialist care for cognitive behavioral therapy or tinnitus retraining therapy.
• Know when pharmacotherapeutic intervention is indicated.

FACULTY
Wendy Gillian Ross practices urgent care medicine in Lake Grove, New York, and primary care in Patchogue, New York. Randy Danielsen is Professor and Dean, Arizona School of Health Sciences, and Director, Center for the Future of the Health Professions, both at A.T. Still University, in Mesa, Arizona. He is Physician Assistant Editor-in-Chief of Clinician Reviews.

The authors have no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid through September 30, 2019.

Article begins on next page >>

 

Tinnitus can be a debilitating condition that affects quality of life and is often not treated according to guidelines. Cognitive behavioral therapy and tinnitus retraining therapy have been successful in reducing tinnitus bother; pharmacotherapy is not widely accepted as successful, and can, in fact, be deleterious. This article describes pathophysiologic disturbances of hearing and how they relate to chronic subjective tinnitus, discusses the clinical evaluation of tinnitus as a presenting symptom, and reviews current treatments.

Primary chronic subjective tinnitus, often thought of more as a symptom than a diagnosis, affects millions of people worldwide. This troublesome condition has been chronicled as far back as the first century ad, when Celsus gave detailed accounts in his treatise, De Medicina.¹

It is estimated that only 20% of people who experience tinnitus actively seek treatment.² In the United States, 2 to 3 million of the 12 million patients who do request treatment report lasting symptoms that they describe as debilitating.³ For patients who seek help, the treatment recommended by physicians is typically pharmacotherapeutic—which does not follow guidelines.⁴

The aim of this article is to reinforce a greater understanding of the mechanisms of tinnitus and integrate that knowledge into treatment guidelines. The article does not discuss surgical treatment of tinnitus.

DEFINITION AND CLASSIFICATION

A universal standard definition of chronic tinnitus does not exist; Trevis et al define it as a phantom sound that persists for more than three months.⁵ The quality and loudness of tinnitus is variable but is often described as a buzz, hiss, or ringing. Prevalence increases with age, smoking, male gender, and ethnicity, with the non-Latino white population statistically at greater risk.³ Comorbid conditions (eg, diabetes and other autoimmune diseases) are risk factors for tinnitus. A history of exposure to loud sound—occupational, environmental, or recreational—also can predispose a person to tinnitus.³

The American Academy of Otolaryngology–Head and Neck Surgery (AAO–HNS) classifies tinnitus as primary (subjective) or secondary (objective). Primary tinnitus—representing the majority of cases—has no identifiable cause; there may be accompanying sensorineural hearing loss or hyperacusis. Secondary tinnitus can also be associated with sensorineural hearing loss but has an identifiable underlying cause.⁶ The differential diagnosis of tinnitus is listed in the Table.⁷

Tinnitus is further defined by its persistence. Persistent tinnitus is defined as tinnitus lasting more than six months, slightly longer than the duration offered by Trevis et al, who also define tinnitus as bothersome or non-bothersome, depending on its impact on quality of life.^5,6 Causes of reduced quality of life include depression, anxiety, insomnia, and neurocognitive decline—all of which have been associated with chronic subjective tinnitus.⁸

Continue to: Researchers have discovered that...

 

Researchers have discovered that tinnitus is not simply a cochlear phenomenon. The pathology extends well beyond the auditory complex, having a deleterious effect on both the somatosensory and central nervous systems, providing some explanation for the prevalence of anxiety and depression associated with the disorder (see "Pathophysiology of tinnitus").^9-17

Because of the insidious nature of tinnitus and lack of standard measures of severity, true prevalence is difficult to calculate.¹⁸

CLINICAL EVALUATION

Tinnitus can be a presenting complaint or elicited during history-taking. Symptomatic patients should receive full evaluation, including a complete physical exam, medication history, and laboratory workup.

Adverse effect of drugs

Medications that commonly cause tinnitus symptoms are NSAIDs, chemotherapeutic agents, and antibiotics (eg, macrolides and fluoroquinolones). Amiodarone, ACE inhibitors, proton-pump inhibitors, and calcium-channel blockers have also been implicated. Paradoxically, anxiolytics and tricyclic antidepressants, which are sometimes used to treat tinnitus, have been linked to causing the condition.⁷

Laboratory tests and imaging

Testing should include investigation for infectious disease, autoimmune disorders, and vitamin deficiency.⁷ According to the American College of Radiology, imaging is unnecessary in the workup of primary tinnitus. Any suspicion of a vascular cause noted on the physical exam (eg, an associated bruit or venous hum), however, should be explored with imaging. Furthermore, any case of tinnitus that lateralizes also requires additional investigation. Modalities of choice are MRI, CT, and CT angiography.¹⁹

Continue to: Referral for audiology evaluation

 

 

Referral for audiology evaluation

When no underlying pathology can be identified for tinnitus, the patient should be sent for a full audiology evaluation to screen for associated hearing loss. Discussion of audiology screening tests is beyond the scope of this article; however, testing includes otoscopy, audiography, tympanography, otoacoustic emission testing, auditory brainstem-response testing, and vestibular evoked myogenic potential testing.⁷

Probing nonphysical impacts

Quality of life and overall emotional wellness, including cognitive function, should be investigated in patients with tinnitus. Two questionnaires commonly used in the assessment of tinnitus bother are the Tinnitus Handicap Inventory and the Tinnitus Reaction Questionnaire.⁷ In a large, systematic review, Trevis et al report that “64% of studies investigating depression found an increase in depressive symptoms in people with chronic tinnitus compared to hearing control groups, and 62% of studies investigating anxiety reported significantly increased anxiety symptoms.”⁵

MANAGEMENT

Tinnitus management should be viewed two ways: treatment of perceived loudness and treatment of comorbid symptoms relating to tinnitus bother.⁶ In the same meta-analysis, Trevis and colleagues found that patients with tinnitus had higher rates of anxiety, depression, and overall decline in cognitive function, including processing speed, concentration, and sleep disorders.⁵ It is useful to keep this observation in mind when reviewing treatment options for tinnitus.

Five classic pharmacotherapeutic approaches to tinnitus management are

• Anticonvulsants
• Antidepressants
• Anesthetics
• Anxiolytics
• Lidocaine.

Newer medications that show some promise are N-methyl-D-aspartate (NMDA) receptor antagonists, notably neramexane. Alternative pharmaceuticals include vitamin-based treatments, cannabinoids, and herbal compounds.

Continue to: The AAOS-HNS supports...

 

The AAO–HNS supports nonpharmacotherapeutic treatment of tinnitus; its guidelines include a recommendation for cognitive behavioral therapy (CBT) as primary therapy.⁶ In addition, tinnitus-retraining therapy, tinnitus-masking therapy/sound therapy, meditation/mindfulness, and yoga all have been studied for their ability to alleviate tinnitus bother.

Pharmacotherapeutic management

Anticonvulsants have failed to provide strong evidence of usefulness in the treatment of tinnitus and are not supported by the AAO–HNS as such.⁶ This conclusion notwithstanding, the anticonvulsants carbamazepine and gabapentin have historically been two of the more common medications used to treat tinnitus.

Carbamazepine is a glutamate receptor antagonist that suppresses seizure activity. Based on prior research suggesting that spontaneous firing within the auditory complex is similar to seizure activity, Iranian researchers explored the hypothesis that carbamazepine might lessen tinnitus severity. Their study revealed, however, that carbamazepine did not statistically significantly reduce the severity of tinnitus, compared to placebo.²⁰ While carbamazepine may be of limited use in the treatment of subjective tinnitus, recent literature confirms that it is not only useful, but also diagnostic, in typewriter tinnitus (ie, having a staccato quality, like the sound of typewriter keys being depressed). Typewriter tinnitus is a secondary cause of tinnitus related to disruption of the stapes in the middle ear.²¹

Gabapentin works by promoting gamma-aminobutyric acid (GABA) production in the brain. GABA is an inhibitory neurotransmitter, thus slowing down signals between neurons. Following on preliminary research that detected low levels of GABA in the inferior colliculus of rodents with salicylate-induced tinnitus, Aazh and colleagues conducted a double-blind study of gabapentin—and concluded that it yielded no improvement in symptoms, compared to placebo.²²

Valproic acid has not been formally investigated but is commonly incorporated in the treatment of tinnitus.²³ Lamotrigine has provided similarly disappointing results in the treatment of tinnitus.²⁴

Continue to: Antidepressants and anxiolytics

 

Antidepressants and anxiolytics. Based on the results of their early clinical trials, Sullivan and colleagues concluded that tricyclic antidepressants produced significant improvement in tinnitus symptoms, due to the analgesic effects of these drugs. The researchers studied nortriptyline specifically; in severely depressed patients, the drug reduced the loudness of tinnitus and depressive symptoms. In non-depressed subjects, however, nortriptyline was not as efficacious.²⁵

Selective serotonin reuptake inhibitors have not had the same success as nortriptyline. In a study of paroxetine conducted by Oishi and colleagues, there was little evidence that the drug reduced the loudness of tinnitus, although overall, it did reduce tinnitus bother and anxiety.²⁶

Included in the category of anxiolytics, benzodiazepines have long been used to treat severe tinnitus-induced anxiety, with some success. However, as Elgoyhen and Langguth point out, studies of benzodiazepines for tinnitus have been limited in size.²³

The AAO–HNS does not support routine use of antidepressants and anxiolytics for tinnitus bother.⁷

NMDA receptor antagonists. In a recent clinical trial, neramexane was studied for its efficacy in tinnitus. Neramexane acts at the cholinergic nicotinic and NMDA receptors in the efferent auditory system. Its complex reaction is thought to prevent transmission of unwanted sound not only to structures within the auditory system but beyond, to the medial geniculate body and lateral nucleus of the amygdala. The trial has proved some benefit concerning overall perception of tinnitus loudness; a phase 2 trial is being conducted.²⁷

Continue to: Intra-tympanic anesthetics

 

Intra-tympanic anesthetics. Anesthetics, such as lidocaine, have had limited success and results have not been found to be sustained.

Alternative medical managements

Traditional Chinese herbal medications have been used for centuries and are increasingly popular in Western culture. Hilton and colleagues studied Ginkgo biloba, or maidenhair tree, a traditional Chinese herbal supplement available as an extract and as dried leaves. The main action of the extract is vasoregulatory; antiplatelet effects are also seen. Adverse effects include gastrointestinal upset and headache. In a systematic review, Hilton and colleagues concluded that Ginkgo did not reduce overall tinnitus loudness or severity; the review was limited, however, by the fact that only two studies met criteria for inclusion.²⁸

Vitamins, lipoflavinoids, zinc, manganese, and melatonin are all supplements marketed to improve tinnitus symptoms. However, a cross-sectional study confirmed prior research that did not show any benefit from the use of these supplements.²⁹

Cannabinoids are being studied for their proposed antiepileptic effects. There is a popular misconception of Cannabis as a singular chemical when in fact, it is a plant that contains hundreds of chemicals that each act differently on the brain. In a review, Smith and Zheng³⁰ explain that two cannabinoid receptors, CB1 and CB2, are represented, and exert their effects, in different areas of the brain. CB1 receptors block calcium influx in presynaptic terminals, resulting in an inhibitory effect on neurotransmitter release.

CB1 receptors have been found in the dorsal cochlear nuclei, prompting research interest in how cannabinoids affect neurotransmission of unwanted sounds of tinnitus. To date, however, there are conflicting data concerning the benefit of cannabinoids and tinnitus. In fact, Smith and Zheng state that some data suggest that cannabinoids might make tinnitus worse.³⁰

Continue to: Nonpharmacotherapeutic management

 

 

Nonpharmacotherapeutic management

Cognitive behavioral therapy. Conceptualized by Aaron T. Beck in the 1960s, cognitive behavioral therapy (CBT) is the leading recommendation made by the AAO–HNS in its tinnitus treatment guidelines.⁶ Beck’s work centered on the idea that behaviors are modifiable thoughts, through analysis of past experiences and assumptions based on those experiences. By understanding the core belief that a patient attaches to a feeling, Beck hypothesized that behaviors or responses to those feelings could be changed; this is accomplished through discussion to dispel unwarranted fears and by teaching coping mechanisms, such as relaxation. The idea behind CBT in the management of tinnitus is clear: The sound cannot be eliminated, but the patient’s response to the sound can be modified. Ultimately, through this modified response or habituation, the patient can relax and live with the sound.³¹

Since anxiety, depression, and insomnia are common comorbidities of tinnitus, a psychologic approach remains in the forefront of treatment recommendations. Hoare and colleagues reported that in “a meta-analysis of 10 randomized trials evaluating different forms of CBT (by the therapist and over the Internet), CBT improved tinnitus symptoms compared to non-CBT controls.”⁷

Tinnitus retraining therapy (TRT) is another form of habituation therapy, introduced by Jastreboff in the 1990s. His work furthered the idea that tinnitus could be reframed, as it is in CBT. Simply, he proposed that systems outside the auditory complex—namely the autonomic nervous system and the limbic system—respond to the signal produced by damaged hair cells in the cochlear nuclei. TRT retrains connections to block or ignore these signals.¹³ Unlike CBT, the aim of TRT is to eliminate the perception of sound.

By educating patients about the physiologic mechanisms of tinnitus, TRT reduces patient anxiety related to the sound. The process of habituation follows counseling. To accomplish this, the patient wears a sound generator, similar in appearance to hearing aids, using broadband noise. The sound does not mask the tinnitus but closes the gap between silence and the perception of tinnitus. The sound generator is worn for six hours daily for approximately 12 months.

Multiple studies have employed Jastreboff’s original technique, including a clinical trial by Bauer and colleagues. The published outcome of this study confirmed that patients experienced a positive and lasting effect with TRT.³² In addition, a small study of TRT conducted by Barozzi and colleagues, using different colors of sound (ie, how the frequency of a given sound corresponds to the light-wave frequency of a particular color), found statistically significant improvement. Allowing patients to pick a sound that they found more pleasant increased the effectiveness of the treatment.³³ (Patients can learn more about TRT by visiting www.tinnitus-pjj.com, hosted by tinnitus researcher Pawel J. Jastreboff.)

Continue to: Alternative nonmedical therapies...

 

Alternative nonmedical therapies have become popular; they include meditation, yoga, physical therapy, mindfulness, and tinnitus-masking treatment with sound.

Results of a study of yoga and meditation showed that patients felt more relaxed, but that these interventions had no effect on the severity of tinnitus. The principle behind yoga practice, according to Köksoy and colleagues, is that the discipline is thought to affect the limbic system by deactivating the sympathetic response to stimulation from surrounding sounds. In addition, Köksoy states, other researchers have provided evidence that yoga increases circulating levels of antioxidants, which in turn reduce oxidative stress.³⁴

Particularly among members of the millennial generation, mindfulness has become a buzzword. The practice refers to a “method for facing, exploring, and alleviating suffering by relating to present experiences.”³⁵ Roland and colleagues conducted a clinical trial of mindfulness practiced by a cohort of patients with bothersome tinnitus; results were based on scores gleaned from standard rating scales (eg, Global Bothersome Scale, Cognitive and Affective Mindfulness Scale-Revised, Cognitive Failures Questionnaire, Tinnitus Handicap Inventory, and Tinnitus Functional Index). Evaluated before and four weeks after cessation of therapy, subjects reported that tinnitus bother was reduced, but none showed statistically significant improvement in depression, anxiety, or cognitive ability.³⁵

Used for more than 40 years, sound-based therapy has been discussed in conjunction with TRT.³⁶ It is recognized as an approved but optional treatment by the AAO–HNS. In response to a 2010 study by Hobson that used sound-based therapy alone for tinnitus, Tunkel and colleagues cautioned that the modality showed little benefit. The major downside to acoustic therapy, according to the AAO–HNS clinical guidelines, is cost and patients’ excessive expectation of effectiveness.⁶

According to the AAO–HNS, repetitive-transcranial magnetic stimulation is not supported as a valid treatment for tinnitus because it can lead to seizures in patients who are taking medication that lowers the seizure threshold or who have a secondary cause of tinnitus, such as a tumor—therefore creating risk that outweighs any benefit.⁶

Continue to: CONCLUSION

 

CONCLUSION

For a large percentage of the population, chronic subjective tinnitus is a significant variable in the evaluation of quality of life. The condition is not completely understood and often displays features unique to the individual. Much of the initial response to research linking tinnitus with shared pathways typical for chronic pain, anxiety, and depression has resulted in pharmacotherapeutic management that is not always warranted—or successful.

Clinical research into the pathophysiology of tinnitus is providing a better understanding of the neurophysiologic mechanisms that underpin the science of chronic tinnitus. With this information, researchers can one day design medical management that targets specific receptors, resulting in greater management success.

The psychologic impact of tinnitus cannot be underestimated. When almost one-third of patients complain of debilitating symptoms that can also result in neurocognitive decline, tinnitus becomes a condition that cannot be ignored. Guidelines set forth by the AAO–HNS state that CBT and TRT offer some reprieve from symptoms and teach patients habituation without further damage to hearing. The use of broad-based sound generators has been well established as a useful management tool, although it is not curative.

The limitations of some studies that reviewed alternative medicines include small sample size and difficulty comparing research analysis because of disparities in tinnitus rating scales. Also, age bias, comorbid conditions, and study drop-out rates affected overall statistical significance of some studies. Additional, high-quality research is warranted in this area.

Continue to: Prevention of tinnitus...

 

Prevention of tinnitus through education on hearing loss and its causes should be regarded as implicit; occupational noise and recreational use of music devices put people at heightened risk for hearing loss and tinnitus. Information and open discussion that include the discovery of tinnitus symptoms during routine physical examination are recommended.

Last, providers who adhere to recognized guidelines will aid patients in coping with the challenges that tinnitus presents. As research continues to unravel the complex interaction between neurons, medical science is hopeful that curative treatments will become available.

 

The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.

The FDA had placed the hold in April, after an adverse event was observed in a pediatric patient on a phase 1 study. The patient, who had advanced poorly differentiated chordoma, developed secondary T-cell lymphoblastic lymphoma (T-LBL) while taking tazemetostat.

The patient had been on study for approximately 15 months and had achieved a confirmed partial response. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.

“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” Robert Bazemore, president and chief executive officer of Epizyme, said in a webcast on Sept. 24.

Epizyme assessed the risk of secondary malignancies, including T-LBL, as well as the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials. A panel of external scientific and medical experts who reviewed the findings concluded that T-LBL risks appear to be confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.

“The team at Epizyme has worked diligently in collaboration with external experts and the FDA over the past several months,” Mr. Bazemore said.

The company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials. However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies. Mr. Bazemore said Epizyme hopes to submit a New Drug Application for tazemetostat in the treatment of epithelioid sarcoma.

Tazemetostat is under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid-tumor malignancies. The drug is also being studied as part of combination therapy for non–small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).

In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Epizyme is now working to resolve partial clinical holds placed on tazemetostat in France and Germany in order to resume trial enrollment in those countries.

[email protected]

 

The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.

The FDA had placed the hold in April, after an adverse event was observed in a pediatric patient on a phase 1 study. The patient, who had advanced poorly differentiated chordoma, developed secondary T-cell lymphoblastic lymphoma (T-LBL) while taking tazemetostat.

The patient had been on study for approximately 15 months and had achieved a confirmed partial response. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.

“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” Robert Bazemore, president and chief executive officer of Epizyme, said in a webcast on Sept. 24.

Epizyme assessed the risk of secondary malignancies, including T-LBL, as well as the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials. A panel of external scientific and medical experts who reviewed the findings concluded that T-LBL risks appear to be confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.

“The team at Epizyme has worked diligently in collaboration with external experts and the FDA over the past several months,” Mr. Bazemore said.

The company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials. However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies. Mr. Bazemore said Epizyme hopes to submit a New Drug Application for tazemetostat in the treatment of epithelioid sarcoma.

Tazemetostat is under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid-tumor malignancies. The drug is also being studied as part of combination therapy for non–small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).

In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Epizyme is now working to resolve partial clinical holds placed on tazemetostat in France and Germany in order to resume trial enrollment in those countries.

[email protected]

 

The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.

The FDA had placed the hold in April, after an adverse event was observed in a pediatric patient on a phase 1 study. The patient, who had advanced poorly differentiated chordoma, developed secondary T-cell lymphoblastic lymphoma (T-LBL) while taking tazemetostat.

The patient had been on study for approximately 15 months and had achieved a confirmed partial response. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.

“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” Robert Bazemore, president and chief executive officer of Epizyme, said in a webcast on Sept. 24.

Epizyme assessed the risk of secondary malignancies, including T-LBL, as well as the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials. A panel of external scientific and medical experts who reviewed the findings concluded that T-LBL risks appear to be confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.

“The team at Epizyme has worked diligently in collaboration with external experts and the FDA over the past several months,” Mr. Bazemore said.

The company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials. However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies. Mr. Bazemore said Epizyme hopes to submit a New Drug Application for tazemetostat in the treatment of epithelioid sarcoma.

Tazemetostat is under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid-tumor malignancies. The drug is also being studied as part of combination therapy for non–small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).

In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Epizyme is now working to resolve partial clinical holds placed on tazemetostat in France and Germany in order to resume trial enrollment in those countries.

[email protected]

 

Turn on the television, and chances are good that popular dramas (especially hospital-oriented shows) will be showing an episode revolving around a mental health issue.

Bipolar disorder, binge-eating disorder, alcoholism, depression, and others make good fodder for Hollywood script writers. Getting the word out about mental health issues can be beneficial. But these portrayals of mental illness can backfire when the TV episode is sensationalized or the topic is presented inaccurately, writes Jessica Gold, MD, in InStyle magazine.

Issues can be simplified, substance use can be treated trivially, and solutions are miraculously found in the last few minutes of the show, in time for a commercial. Real life is messier.

“Unfortunately mental health story lines are much more likely to be fear-mongering and wildly wrong. As a psychiatrist, this both piques my interest and upends my work-life balance,” Dr. Gold writes. “Whether I’m watching everyone’s favorite medical drama or ‘reality TV,’ it’s impossible not to switch into physician mode, angry on behalf of all of my patients and the many viewers who are being misled.”

Do physicians hear women?

“Rebecca continues to be paranoid.”

That was a note written by someone involved in the medical care of a 30-something woman diagnosed with stage IIB cervical cancer, according to an article in New York magazine.

“There’s a whiff of old ‘female hysteria’ to [the note], with more than a hint of dismissal,” writes the patient’s sister, Kate Beaton. “Becky was scared, and perhaps that was the main takeaway that day. But she was also right.”

The article tells the story of a vibrant woman who, according to her sister, asked her doctors lots of questions, wrote everything down, and faced years of being dismissed when she explained her symptoms. Becky’s sister says she is telling her sister’s story in an effort to make a difference in the lives of other patients.

“[Becky] did not want anyone to go through what she went through, ever again,” Ms. Beaton writes.

Letting children roam free

Children of the 1950s and 1960s can remember tearing out the door after dinner with the parental order to be home before dark. Where we went and what we did was known only to us. Our parents trusted we knew how to look out after ourselves.

In that tradition, as explained by National Public Radio, some parents are actively turning away from the to-the-second scheduling of their children’s lives and Teflon coating them against the perceived danger of everyday life. Instead, they are letting their children be independent. It can be a powerful life benefit for a child. But it can come at a cost to parents. Parents in several states have been arrested for actions that include letting their children walk to school unattended.

“This very pessimistic, fearful way of looking at childhood isn’t based in reality,” says Leonore Skenazy in a story on NPR. “It is something that we have been taught.” Ms. Skenazy is founder of Free Range Kids, a group that promotes childhood independence.

 

Boundaries and remote work

More and more Americans are working from home, according to a 2017 Gallup survey. The survey says that 43% of people worked remotely for part of the time in 2016, compared with 39% in 2012.

But for parents who work remotely, separating their business and family lives is especially challenging, Marie Elizabeth Oliver writes in an article published in The Washington Post.

“Being a parent is isolating, but being a parent and working from home is really isolating,” author Karen Alpert says. “Especially as a mom, there’s so much pressure to do your job as fast and efficiently as possible.”

Experts advise setting boundaries by taking steps such as setting timers and checking in every hour, for example. Or using clothes to make the mental shifts between being on the clock, so to speak, and being in leisure mode.

“It’s not that you have to dress up,” author David Heinemeier Hansson says in the article, describing one of his employees who came up with a system that enabled him to set these boundaries using clothes. “It’s just that he knew, ‘I have my home slippers on right now, so I’m not responding to this email.’ “

Neuroscience as a remedy to heartbreak

The end of a romance can be both frustrating and embarrassing. A person may wallow in the emotional muck for a long time.

Such was the case for Dessa, a well-known rapper, singer, and writer from Minneapolis, who carried the emotional baggage of an ex-boyfriend.

“You’re not only suffering,” she comments in an interview on NPR. “You’re just sort of ridiculous. Discipline and dedication are my strong suits – it really bothered me that, no matter how much effort I tried to expend in trying to solve this problem, I was stuck.”

The stalemate ended when she viewed a TED Talk by Helen Fisher, PhD, a biological anthropologist and visiting research associate at Rutgers University, New Brunswick, N.J. Dr. Fisher used functional MRI to examine some people in the throes of lost love. The examinations revealed revved-up activity of certain parts of their brains.

This prompted the idea that techniques of neurofeedback could be used to wipe the pangs of love from the brain circuitry. It seems to have worked for Dessa, although a placebo effect cannot be ruled out.

“Before [the feedback], I felt that I was really under the thumb of a fixation and a compulsion,” she says. “And now it feels like those feelings have been scaled down.”

 

Turn on the television, and chances are good that popular dramas (especially hospital-oriented shows) will be showing an episode revolving around a mental health issue.

Bipolar disorder, binge-eating disorder, alcoholism, depression, and others make good fodder for Hollywood script writers. Getting the word out about mental health issues can be beneficial. But these portrayals of mental illness can backfire when the TV episode is sensationalized or the topic is presented inaccurately, writes Jessica Gold, MD, in InStyle magazine.

Issues can be simplified, substance use can be treated trivially, and solutions are miraculously found in the last few minutes of the show, in time for a commercial. Real life is messier.

“Unfortunately mental health story lines are much more likely to be fear-mongering and wildly wrong. As a psychiatrist, this both piques my interest and upends my work-life balance,” Dr. Gold writes. “Whether I’m watching everyone’s favorite medical drama or ‘reality TV,’ it’s impossible not to switch into physician mode, angry on behalf of all of my patients and the many viewers who are being misled.”

Do physicians hear women?

“Rebecca continues to be paranoid.”

That was a note written by someone involved in the medical care of a 30-something woman diagnosed with stage IIB cervical cancer, according to an article in New York magazine.

“There’s a whiff of old ‘female hysteria’ to [the note], with more than a hint of dismissal,” writes the patient’s sister, Kate Beaton. “Becky was scared, and perhaps that was the main takeaway that day. But she was also right.”

The article tells the story of a vibrant woman who, according to her sister, asked her doctors lots of questions, wrote everything down, and faced years of being dismissed when she explained her symptoms. Becky’s sister says she is telling her sister’s story in an effort to make a difference in the lives of other patients.

“[Becky] did not want anyone to go through what she went through, ever again,” Ms. Beaton writes.

Letting children roam free

Children of the 1950s and 1960s can remember tearing out the door after dinner with the parental order to be home before dark. Where we went and what we did was known only to us. Our parents trusted we knew how to look out after ourselves.

In that tradition, as explained by National Public Radio, some parents are actively turning away from the to-the-second scheduling of their children’s lives and Teflon coating them against the perceived danger of everyday life. Instead, they are letting their children be independent. It can be a powerful life benefit for a child. But it can come at a cost to parents. Parents in several states have been arrested for actions that include letting their children walk to school unattended.

“This very pessimistic, fearful way of looking at childhood isn’t based in reality,” says Leonore Skenazy in a story on NPR. “It is something that we have been taught.” Ms. Skenazy is founder of Free Range Kids, a group that promotes childhood independence.

 

Boundaries and remote work

More and more Americans are working from home, according to a 2017 Gallup survey. The survey says that 43% of people worked remotely for part of the time in 2016, compared with 39% in 2012.

But for parents who work remotely, separating their business and family lives is especially challenging, Marie Elizabeth Oliver writes in an article published in The Washington Post.

“Being a parent is isolating, but being a parent and working from home is really isolating,” author Karen Alpert says. “Especially as a mom, there’s so much pressure to do your job as fast and efficiently as possible.”

Experts advise setting boundaries by taking steps such as setting timers and checking in every hour, for example. Or using clothes to make the mental shifts between being on the clock, so to speak, and being in leisure mode.

“It’s not that you have to dress up,” author David Heinemeier Hansson says in the article, describing one of his employees who came up with a system that enabled him to set these boundaries using clothes. “It’s just that he knew, ‘I have my home slippers on right now, so I’m not responding to this email.’ “

Neuroscience as a remedy to heartbreak

The end of a romance can be both frustrating and embarrassing. A person may wallow in the emotional muck for a long time.

Such was the case for Dessa, a well-known rapper, singer, and writer from Minneapolis, who carried the emotional baggage of an ex-boyfriend.

“You’re not only suffering,” she comments in an interview on NPR. “You’re just sort of ridiculous. Discipline and dedication are my strong suits – it really bothered me that, no matter how much effort I tried to expend in trying to solve this problem, I was stuck.”

The stalemate ended when she viewed a TED Talk by Helen Fisher, PhD, a biological anthropologist and visiting research associate at Rutgers University, New Brunswick, N.J. Dr. Fisher used functional MRI to examine some people in the throes of lost love. The examinations revealed revved-up activity of certain parts of their brains.

This prompted the idea that techniques of neurofeedback could be used to wipe the pangs of love from the brain circuitry. It seems to have worked for Dessa, although a placebo effect cannot be ruled out.

“Before [the feedback], I felt that I was really under the thumb of a fixation and a compulsion,” she says. “And now it feels like those feelings have been scaled down.”

 

Turn on the television, and chances are good that popular dramas (especially hospital-oriented shows) will be showing an episode revolving around a mental health issue.

Bipolar disorder, binge-eating disorder, alcoholism, depression, and others make good fodder for Hollywood script writers. Getting the word out about mental health issues can be beneficial. But these portrayals of mental illness can backfire when the TV episode is sensationalized or the topic is presented inaccurately, writes Jessica Gold, MD, in InStyle magazine.

Issues can be simplified, substance use can be treated trivially, and solutions are miraculously found in the last few minutes of the show, in time for a commercial. Real life is messier.

“Unfortunately mental health story lines are much more likely to be fear-mongering and wildly wrong. As a psychiatrist, this both piques my interest and upends my work-life balance,” Dr. Gold writes. “Whether I’m watching everyone’s favorite medical drama or ‘reality TV,’ it’s impossible not to switch into physician mode, angry on behalf of all of my patients and the many viewers who are being misled.”

Do physicians hear women?

“Rebecca continues to be paranoid.”

That was a note written by someone involved in the medical care of a 30-something woman diagnosed with stage IIB cervical cancer, according to an article in New York magazine.

“There’s a whiff of old ‘female hysteria’ to [the note], with more than a hint of dismissal,” writes the patient’s sister, Kate Beaton. “Becky was scared, and perhaps that was the main takeaway that day. But she was also right.”

The article tells the story of a vibrant woman who, according to her sister, asked her doctors lots of questions, wrote everything down, and faced years of being dismissed when she explained her symptoms. Becky’s sister says she is telling her sister’s story in an effort to make a difference in the lives of other patients.

“[Becky] did not want anyone to go through what she went through, ever again,” Ms. Beaton writes.

Letting children roam free

Children of the 1950s and 1960s can remember tearing out the door after dinner with the parental order to be home before dark. Where we went and what we did was known only to us. Our parents trusted we knew how to look out after ourselves.

In that tradition, as explained by National Public Radio, some parents are actively turning away from the to-the-second scheduling of their children’s lives and Teflon coating them against the perceived danger of everyday life. Instead, they are letting their children be independent. It can be a powerful life benefit for a child. But it can come at a cost to parents. Parents in several states have been arrested for actions that include letting their children walk to school unattended.

“This very pessimistic, fearful way of looking at childhood isn’t based in reality,” says Leonore Skenazy in a story on NPR. “It is something that we have been taught.” Ms. Skenazy is founder of Free Range Kids, a group that promotes childhood independence.

 

Boundaries and remote work

More and more Americans are working from home, according to a 2017 Gallup survey. The survey says that 43% of people worked remotely for part of the time in 2016, compared with 39% in 2012.

But for parents who work remotely, separating their business and family lives is especially challenging, Marie Elizabeth Oliver writes in an article published in The Washington Post.

“Being a parent is isolating, but being a parent and working from home is really isolating,” author Karen Alpert says. “Especially as a mom, there’s so much pressure to do your job as fast and efficiently as possible.”

Experts advise setting boundaries by taking steps such as setting timers and checking in every hour, for example. Or using clothes to make the mental shifts between being on the clock, so to speak, and being in leisure mode.

“It’s not that you have to dress up,” author David Heinemeier Hansson says in the article, describing one of his employees who came up with a system that enabled him to set these boundaries using clothes. “It’s just that he knew, ‘I have my home slippers on right now, so I’m not responding to this email.’ “

Neuroscience as a remedy to heartbreak

The end of a romance can be both frustrating and embarrassing. A person may wallow in the emotional muck for a long time.

Such was the case for Dessa, a well-known rapper, singer, and writer from Minneapolis, who carried the emotional baggage of an ex-boyfriend.

“You’re not only suffering,” she comments in an interview on NPR. “You’re just sort of ridiculous. Discipline and dedication are my strong suits – it really bothered me that, no matter how much effort I tried to expend in trying to solve this problem, I was stuck.”

The stalemate ended when she viewed a TED Talk by Helen Fisher, PhD, a biological anthropologist and visiting research associate at Rutgers University, New Brunswick, N.J. Dr. Fisher used functional MRI to examine some people in the throes of lost love. The examinations revealed revved-up activity of certain parts of their brains.

This prompted the idea that techniques of neurofeedback could be used to wipe the pangs of love from the brain circuitry. It seems to have worked for Dessa, although a placebo effect cannot be ruled out.

“Before [the feedback], I felt that I was really under the thumb of a fixation and a compulsion,” she says. “And now it feels like those feelings have been scaled down.”

 

MUNICH – Noninvasive assessment of fractional flow reserve (FFR) within coronary arteries using data collected by CT angiography again has been shown to provide important additional diagnostic information that better guides patient management.

Results from two separate studies presented at a session of the annual congress of the European Society of Cardiology documented the added value in calculating FFR within individual coronary arteries using coronary CT angiography (CCTA) data in patients with coronary stenosis of intermediate severity. But results from a third study reported at the session failed to show CCTA-derived FFR (FFR_CT) information was superior to a detailed CCTA study alone for patient assessment.

“The value of FFR_CT is to reduce the number of patients who go to the cath lab. For patients with a stenosis of 60% that is not likely to have functional significance we can avoid catheterization and treat the patient medically. FFR_CT is a valuable technology, but my concern is that currently it costs about $1,400 for this test,” commented Todd C. Villines, MD, a cardiologist at Georgetown University in Washington who was a discussant for the study. “Given the cost, we need to better define the patients on whom we use FFR_CT and integrate it into clinical decision making,” Dr. Villines said in an interview.

Perhaps the best demonstration of the potential role for FFR_CT came from a single-center study at Aarhus (Denmark) University with 3,674 patients with stable chest pain who underwent CCTA as their initial assessment for suspected coronary artery disease between May 2014 and December 2016. More than two-thirds of these patients had coronary stenoses of less than 30% and had no further assessment or treatment, and 11% had at least one coronary stenosis of at least 70% on CCTA and then had follow-up testing by either conventional angiography or myocardial perfusion imaging. The report at the congress focused on the 697 patients with an inconclusive result based on CCTA alone and at least one stenosis of 30%-69% who underwent FFR_CT analysis, and focused specifically on 677 patients with a useful FFR_CT result.

Of these patients_, 410 (61% of this subgroup) had no coronary lesion that created a FFR_CT of 0.8 or less. All received treatment with optimal medical therapy only, and after a median follow-up had a 3.9% incidence of the primary endpoint, the combined rate of all-cause death, nonfatal MI, hospitalization for unstable angina, or unplanned revascularization. This 3.9% rate was not significantly different from the 2.8% rate seen during follow-up of the patients with no coronary stenosis of 30% or greater.

The remaining 267 patients (39% of the subgroup) with a FFR_CT that showed 80% or less flow reserve either received optimal medical therapy (112 patients, 42% of this group) or angiography by coronary catheterization (155 patients, 58% of this group).

Mitchel L. Zoler/MDedge News

During follow-up, the combined endpoint occurred in 6.6% of patients treated with invasive angiography and possibly a catheter-based intervention. That result was not statistically different from the patients without more severe stenoses, and in 9.4% of patients treated with optimal medical therapy was a statistically significant worse outcome than in the patients with less consequential coronary stenoses. Further analysis showed that the better outcomes in patients with meaningful stenoses treated with catheterization occurred because this strategy substantially reduced the rate of nonfatal MIs and unplanned revascularizations, reported Bjarne L. Nørgaard, MD, an Aarhus cardiologist. Major limitations of the study were that it ran at only a single center and had a relatively short follow-up, he noted. Concurrently with the congress report, an article with the results appeared online (J Am Coll Cardiol. 2018 Aug 25. doi: 10.1016/j.jacc.2018.07.043).

The second report used data collected from 5,083 patients entered into a multinational registry, ADVANCE, with symptoms suggestive of coronary artery disease and results from CCTA that suggested coronary stenosis. The collaborating researchers then used the CCTA results to generate a FFR analysis for 4,893 (96%) of the patients, and the analysis was usable for 4,737 of them. The FFR_CT results led to reclassification of the management strategy for 67% of the patients, the primary endpoint for this analysis, reported Timothy A. Fairbairn, MD, a cardiologist at the Liverpool (England) Heart and Chest Hospital.

Mitchel L. Zoler/MDedge News

The results also showed that stratifying patients by their FFR_CT results significantly reduced the percentage of patients referred for invasive coronary angiography who had nonobstructive coronary disease. The results showed that 19% of patients with a FFR of at least 0.81 underwent invasive angiography, and 44% of those had nonobstructive disease. In contrast, among patients with a FFR of 0.8 or less, 56% underwent invasive angiography, which failed to find obstructive disease in just 14%, reported Dr. Fairbairn. In addition, none of the 1,592 patients with a FFR_CT of at least 0.81 had a death or MI during 90 day follow-up, while among the 3,145 patients with a FFR_CT of 0.8 or less, the 90-day death or MI rate was 0.3%, a statistically significant difference that calculated to a nearly 15-fold higher hazard ratio.

One limitation of this study was the relatively brief, 90-day follow-up, but it is the first real-world, multicenter assessment of the utility and safety of FFR_CT.

These findings highlight what a “disruptive technology” FFR_CT represents, commented Dr. Villines. He also noted that the reclassifications triggered by the FFR_CT analysis led to fewer patients undergoing invasive angiography, a good outcome from a cost-effectiveness perspective.

Concurrently with Dr. Fairbairn’s report the results from ADVANCE also appeared in an article published online (Euro Heart J. 2018 Aug 25. doi: 10.1093/eurheartj/ehy530).

A third FFR_CT study reported at the session, the Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia (CREDENCE) study, enrolled 612 patients with suspected coronary artery disease who had been referred for and underwent invasive coronary angiography with FFR evaluation at 13 international centers, including several in the United States. All 612 patients also had assessment by CCTA and FFR_CT, and also some type of functional myocardial perfusion assessment using positron emission tomography, single-photon emission CT, or coronary MR.

Mitchel L. Zoler/MDedge News

The results showed that coronary evaluation by CCTA performed significantly better than functional testing. A receiver operator characteristic curve analysis showed an area under the curve of 0.83 for CCTA in the validation phase of the analysis, compared with 0.68 for myocardial perfusion assessment, showing significantly better diagnostic performance of CCTA, reported Wijnand J. Stuijfzand, MD, a cardiologist at Cornell University in New York. In this analysis, five key variables improved the diagnostic performance of the CCTA analysis: stenosis severity, the number of coronary lesions producing at least 30% stenosis, noncalcified plaque volume, the presence of high-risk plaque, and lumen volume. In this analysis, adding FFR_CT information to a CCTA assessment that already included these five key elements did not further improve diagnostic performance, Dr. Stuijfzand said.

The Aarhus University study received no commercial funding. Dr. Nørgaard has received research funding from Edwards; Siemens; and HeartFlow, the company that markets FFR analysis for coronary CT angiography data. The ADVANCE registry was sponsored by HeartFlow. Dr. Fairbairn has been a speaker for Heartflow. Dr. Stuijfzand and Dr. Villines had no relevant disclosures.

[email protected]

 

MUNICH – Noninvasive assessment of fractional flow reserve (FFR) within coronary arteries using data collected by CT angiography again has been shown to provide important additional diagnostic information that better guides patient management.

Results from two separate studies presented at a session of the annual congress of the European Society of Cardiology documented the added value in calculating FFR within individual coronary arteries using coronary CT angiography (CCTA) data in patients with coronary stenosis of intermediate severity. But results from a third study reported at the session failed to show CCTA-derived FFR (FFR_CT) information was superior to a detailed CCTA study alone for patient assessment.

“The value of FFR_CT is to reduce the number of patients who go to the cath lab. For patients with a stenosis of 60% that is not likely to have functional significance we can avoid catheterization and treat the patient medically. FFR_CT is a valuable technology, but my concern is that currently it costs about $1,400 for this test,” commented Todd C. Villines, MD, a cardiologist at Georgetown University in Washington who was a discussant for the study. “Given the cost, we need to better define the patients on whom we use FFR_CT and integrate it into clinical decision making,” Dr. Villines said in an interview.

Perhaps the best demonstration of the potential role for FFR_CT came from a single-center study at Aarhus (Denmark) University with 3,674 patients with stable chest pain who underwent CCTA as their initial assessment for suspected coronary artery disease between May 2014 and December 2016. More than two-thirds of these patients had coronary stenoses of less than 30% and had no further assessment or treatment, and 11% had at least one coronary stenosis of at least 70% on CCTA and then had follow-up testing by either conventional angiography or myocardial perfusion imaging. The report at the congress focused on the 697 patients with an inconclusive result based on CCTA alone and at least one stenosis of 30%-69% who underwent FFR_CT analysis, and focused specifically on 677 patients with a useful FFR_CT result.

Of these patients_, 410 (61% of this subgroup) had no coronary lesion that created a FFR_CT of 0.8 or less. All received treatment with optimal medical therapy only, and after a median follow-up had a 3.9% incidence of the primary endpoint, the combined rate of all-cause death, nonfatal MI, hospitalization for unstable angina, or unplanned revascularization. This 3.9% rate was not significantly different from the 2.8% rate seen during follow-up of the patients with no coronary stenosis of 30% or greater.

The remaining 267 patients (39% of the subgroup) with a FFR_CT that showed 80% or less flow reserve either received optimal medical therapy (112 patients, 42% of this group) or angiography by coronary catheterization (155 patients, 58% of this group).

Mitchel L. Zoler/MDedge News

During follow-up, the combined endpoint occurred in 6.6% of patients treated with invasive angiography and possibly a catheter-based intervention. That result was not statistically different from the patients without more severe stenoses, and in 9.4% of patients treated with optimal medical therapy was a statistically significant worse outcome than in the patients with less consequential coronary stenoses. Further analysis showed that the better outcomes in patients with meaningful stenoses treated with catheterization occurred because this strategy substantially reduced the rate of nonfatal MIs and unplanned revascularizations, reported Bjarne L. Nørgaard, MD, an Aarhus cardiologist. Major limitations of the study were that it ran at only a single center and had a relatively short follow-up, he noted. Concurrently with the congress report, an article with the results appeared online (J Am Coll Cardiol. 2018 Aug 25. doi: 10.1016/j.jacc.2018.07.043).

The second report used data collected from 5,083 patients entered into a multinational registry, ADVANCE, with symptoms suggestive of coronary artery disease and results from CCTA that suggested coronary stenosis. The collaborating researchers then used the CCTA results to generate a FFR analysis for 4,893 (96%) of the patients, and the analysis was usable for 4,737 of them. The FFR_CT results led to reclassification of the management strategy for 67% of the patients, the primary endpoint for this analysis, reported Timothy A. Fairbairn, MD, a cardiologist at the Liverpool (England) Heart and Chest Hospital.

Mitchel L. Zoler/MDedge News

The results also showed that stratifying patients by their FFR_CT results significantly reduced the percentage of patients referred for invasive coronary angiography who had nonobstructive coronary disease. The results showed that 19% of patients with a FFR of at least 0.81 underwent invasive angiography, and 44% of those had nonobstructive disease. In contrast, among patients with a FFR of 0.8 or less, 56% underwent invasive angiography, which failed to find obstructive disease in just 14%, reported Dr. Fairbairn. In addition, none of the 1,592 patients with a FFR_CT of at least 0.81 had a death or MI during 90 day follow-up, while among the 3,145 patients with a FFR_CT of 0.8 or less, the 90-day death or MI rate was 0.3%, a statistically significant difference that calculated to a nearly 15-fold higher hazard ratio.

One limitation of this study was the relatively brief, 90-day follow-up, but it is the first real-world, multicenter assessment of the utility and safety of FFR_CT.

These findings highlight what a “disruptive technology” FFR_CT represents, commented Dr. Villines. He also noted that the reclassifications triggered by the FFR_CT analysis led to fewer patients undergoing invasive angiography, a good outcome from a cost-effectiveness perspective.

Concurrently with Dr. Fairbairn’s report the results from ADVANCE also appeared in an article published online (Euro Heart J. 2018 Aug 25. doi: 10.1093/eurheartj/ehy530).

A third FFR_CT study reported at the session, the Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia (CREDENCE) study, enrolled 612 patients with suspected coronary artery disease who had been referred for and underwent invasive coronary angiography with FFR evaluation at 13 international centers, including several in the United States. All 612 patients also had assessment by CCTA and FFR_CT, and also some type of functional myocardial perfusion assessment using positron emission tomography, single-photon emission CT, or coronary MR.

Mitchel L. Zoler/MDedge News

The results showed that coronary evaluation by CCTA performed significantly better than functional testing. A receiver operator characteristic curve analysis showed an area under the curve of 0.83 for CCTA in the validation phase of the analysis, compared with 0.68 for myocardial perfusion assessment, showing significantly better diagnostic performance of CCTA, reported Wijnand J. Stuijfzand, MD, a cardiologist at Cornell University in New York. In this analysis, five key variables improved the diagnostic performance of the CCTA analysis: stenosis severity, the number of coronary lesions producing at least 30% stenosis, noncalcified plaque volume, the presence of high-risk plaque, and lumen volume. In this analysis, adding FFR_CT information to a CCTA assessment that already included these five key elements did not further improve diagnostic performance, Dr. Stuijfzand said.

The Aarhus University study received no commercial funding. Dr. Nørgaard has received research funding from Edwards; Siemens; and HeartFlow, the company that markets FFR analysis for coronary CT angiography data. The ADVANCE registry was sponsored by HeartFlow. Dr. Fairbairn has been a speaker for Heartflow. Dr. Stuijfzand and Dr. Villines had no relevant disclosures.

[email protected]

 

MUNICH – Noninvasive assessment of fractional flow reserve (FFR) within coronary arteries using data collected by CT angiography again has been shown to provide important additional diagnostic information that better guides patient management.

Results from two separate studies presented at a session of the annual congress of the European Society of Cardiology documented the added value in calculating FFR within individual coronary arteries using coronary CT angiography (CCTA) data in patients with coronary stenosis of intermediate severity. But results from a third study reported at the session failed to show CCTA-derived FFR (FFR_CT) information was superior to a detailed CCTA study alone for patient assessment.

“The value of FFR_CT is to reduce the number of patients who go to the cath lab. For patients with a stenosis of 60% that is not likely to have functional significance we can avoid catheterization and treat the patient medically. FFR_CT is a valuable technology, but my concern is that currently it costs about $1,400 for this test,” commented Todd C. Villines, MD, a cardiologist at Georgetown University in Washington who was a discussant for the study. “Given the cost, we need to better define the patients on whom we use FFR_CT and integrate it into clinical decision making,” Dr. Villines said in an interview.

Perhaps the best demonstration of the potential role for FFR_CT came from a single-center study at Aarhus (Denmark) University with 3,674 patients with stable chest pain who underwent CCTA as their initial assessment for suspected coronary artery disease between May 2014 and December 2016. More than two-thirds of these patients had coronary stenoses of less than 30% and had no further assessment or treatment, and 11% had at least one coronary stenosis of at least 70% on CCTA and then had follow-up testing by either conventional angiography or myocardial perfusion imaging. The report at the congress focused on the 697 patients with an inconclusive result based on CCTA alone and at least one stenosis of 30%-69% who underwent FFR_CT analysis, and focused specifically on 677 patients with a useful FFR_CT result.

Of these patients_, 410 (61% of this subgroup) had no coronary lesion that created a FFR_CT of 0.8 or less. All received treatment with optimal medical therapy only, and after a median follow-up had a 3.9% incidence of the primary endpoint, the combined rate of all-cause death, nonfatal MI, hospitalization for unstable angina, or unplanned revascularization. This 3.9% rate was not significantly different from the 2.8% rate seen during follow-up of the patients with no coronary stenosis of 30% or greater.

The remaining 267 patients (39% of the subgroup) with a FFR_CT that showed 80% or less flow reserve either received optimal medical therapy (112 patients, 42% of this group) or angiography by coronary catheterization (155 patients, 58% of this group).

Mitchel L. Zoler/MDedge News

During follow-up, the combined endpoint occurred in 6.6% of patients treated with invasive angiography and possibly a catheter-based intervention. That result was not statistically different from the patients without more severe stenoses, and in 9.4% of patients treated with optimal medical therapy was a statistically significant worse outcome than in the patients with less consequential coronary stenoses. Further analysis showed that the better outcomes in patients with meaningful stenoses treated with catheterization occurred because this strategy substantially reduced the rate of nonfatal MIs and unplanned revascularizations, reported Bjarne L. Nørgaard, MD, an Aarhus cardiologist. Major limitations of the study were that it ran at only a single center and had a relatively short follow-up, he noted. Concurrently with the congress report, an article with the results appeared online (J Am Coll Cardiol. 2018 Aug 25. doi: 10.1016/j.jacc.2018.07.043).

The second report used data collected from 5,083 patients entered into a multinational registry, ADVANCE, with symptoms suggestive of coronary artery disease and results from CCTA that suggested coronary stenosis. The collaborating researchers then used the CCTA results to generate a FFR analysis for 4,893 (96%) of the patients, and the analysis was usable for 4,737 of them. The FFR_CT results led to reclassification of the management strategy for 67% of the patients, the primary endpoint for this analysis, reported Timothy A. Fairbairn, MD, a cardiologist at the Liverpool (England) Heart and Chest Hospital.

Mitchel L. Zoler/MDedge News

The results also showed that stratifying patients by their FFR_CT results significantly reduced the percentage of patients referred for invasive coronary angiography who had nonobstructive coronary disease. The results showed that 19% of patients with a FFR of at least 0.81 underwent invasive angiography, and 44% of those had nonobstructive disease. In contrast, among patients with a FFR of 0.8 or less, 56% underwent invasive angiography, which failed to find obstructive disease in just 14%, reported Dr. Fairbairn. In addition, none of the 1,592 patients with a FFR_CT of at least 0.81 had a death or MI during 90 day follow-up, while among the 3,145 patients with a FFR_CT of 0.8 or less, the 90-day death or MI rate was 0.3%, a statistically significant difference that calculated to a nearly 15-fold higher hazard ratio.

One limitation of this study was the relatively brief, 90-day follow-up, but it is the first real-world, multicenter assessment of the utility and safety of FFR_CT.

These findings highlight what a “disruptive technology” FFR_CT represents, commented Dr. Villines. He also noted that the reclassifications triggered by the FFR_CT analysis led to fewer patients undergoing invasive angiography, a good outcome from a cost-effectiveness perspective.

Concurrently with Dr. Fairbairn’s report the results from ADVANCE also appeared in an article published online (Euro Heart J. 2018 Aug 25. doi: 10.1093/eurheartj/ehy530).

A third FFR_CT study reported at the session, the Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia (CREDENCE) study, enrolled 612 patients with suspected coronary artery disease who had been referred for and underwent invasive coronary angiography with FFR evaluation at 13 international centers, including several in the United States. All 612 patients also had assessment by CCTA and FFR_CT, and also some type of functional myocardial perfusion assessment using positron emission tomography, single-photon emission CT, or coronary MR.

Mitchel L. Zoler/MDedge News

The results showed that coronary evaluation by CCTA performed significantly better than functional testing. A receiver operator characteristic curve analysis showed an area under the curve of 0.83 for CCTA in the validation phase of the analysis, compared with 0.68 for myocardial perfusion assessment, showing significantly better diagnostic performance of CCTA, reported Wijnand J. Stuijfzand, MD, a cardiologist at Cornell University in New York. In this analysis, five key variables improved the diagnostic performance of the CCTA analysis: stenosis severity, the number of coronary lesions producing at least 30% stenosis, noncalcified plaque volume, the presence of high-risk plaque, and lumen volume. In this analysis, adding FFR_CT information to a CCTA assessment that already included these five key elements did not further improve diagnostic performance, Dr. Stuijfzand said.

The Aarhus University study received no commercial funding. Dr. Nørgaard has received research funding from Edwards; Siemens; and HeartFlow, the company that markets FFR analysis for coronary CT angiography data. The ADVANCE registry was sponsored by HeartFlow. Dr. Fairbairn has been a speaker for Heartflow. Dr. Stuijfzand and Dr. Villines had no relevant disclosures.

[email protected]

 

Researchers found a lower rate of pediatric fever after applying a standard definition of fever across three different clinical trials of pediatric patients receiving influenza vaccinations, according to research published in the Pediatric Infectious Disease Journal.

Yangna/Thinkstock

Investigators in future studies must adopt a standardized definition of pediatric fever after an influenza vaccination. “Our study demonstrates the variability in results which occur due to minor differences in the definition of fever, methods of analysis and reporting of results,” Jean Li-Kim-Moy, MBBS, of the University of Sydney, and colleagues wrote.

Dr. Li-Kim-Moy and colleagues analyzed pediatric datasets from three different clinical trials using trivalent influenza vaccine (TIV); the primary trial included 3,317 children aged 6-35 months who were randomized to receive Fluarix at 0.25 mL or 0.5 mL, or receive 0.25 mL of Fluzone. The other two trials studied children receiving TIV between 6 months–17 years and 3-17 years. The researchers also performed a multivariable regression analysis to determine the relationship between immunogenicity, antipyretic use, and postvaccination fever.

The primary study initially reported the fever rate 0 days–3 days after vaccination was between 6% and 7%. After reporting the rate of fever separately for each dose and changing the criteria to “defining fever as greater than or equal to 38.0°C by any route of measurement” for the primary study, the researchers found a rate of any-cause fever was 3%-4% for the first dose and 4%-5% for the second dose. The rate of vaccine-related fever in the primary study was 3% for the first dose and 3%-4% for the second dose, with researchers noting vaccine-related fever occurred significantly earlier compared with any-cause fever (mean 1 days vs. 2 days after vaccination; P equals .04).

Impact of fever, antipyretics

The researchers also performed a pooled immunogenicity analysis of 5,902 children from all three trials and found a strong association between fever after vaccination and increased geometric mean titer (GMT) ratios (1.21-1.39; P less than or equal to .01) and an association between antipyretic use and reduced GMT ratios (0.80-0.87; P less than .0006).

“Our pooled analysis of the three trials demonstrated highly significant associations, for all strains, between postvaccination fever and up to 39% higher GMT; this may suggest a close role between fever and the body’s immunologic response to the influenza antigens within the vaccine. Similarly, strong evidence of associations in the opposite direction was found between postvaccination antipyretic use (days 0-3), adjusting for all other factors including fever, and decreased immunogenicity against all vaccine strains in children,” Dr. Li-Kim-Moy and colleagues said.

Antipyretic use was common in the primary study, occurring in one in six of the children, they said. These findings of “significant associations between fever and increased vaccine immunogenicity, and between antipyretic use and reduced immunogenicity in children after influenza vaccination” suggest the need for further study, especially because parents often give antipyretics if their children are febrile after vaccinations.

“There is uncertainty whether our findings, and those of others, on immunogenicity translate into clinically significant effects,” they wrote. “However, the fact that influenza vaccine, unlike many routine childhood vaccines, is only moderately protective may mean that modest reductions in antibody response are more likely to correlate to less protection.”

 

Dr. Wood reported receiving a fellowship from the National Health and Medical Research Council (NHMRC) and being an investigator for GlaxoSmithKline trials. Dr. Booy reported being an advisor for influenza vaccine manufacturing, an advisory board member, on the speaker’s bureau, and a researcher of vaccines for several manufacturers. The other authors reported no relevant conflicts of interest.

SOURCE: Li-Kim-Moy J et al. Pediatr Infect Dis J. 2018 Oct;37(10):971-5.

 

Researchers found a lower rate of pediatric fever after applying a standard definition of fever across three different clinical trials of pediatric patients receiving influenza vaccinations, according to research published in the Pediatric Infectious Disease Journal.

Yangna/Thinkstock

Investigators in future studies must adopt a standardized definition of pediatric fever after an influenza vaccination. “Our study demonstrates the variability in results which occur due to minor differences in the definition of fever, methods of analysis and reporting of results,” Jean Li-Kim-Moy, MBBS, of the University of Sydney, and colleagues wrote.

Dr. Li-Kim-Moy and colleagues analyzed pediatric datasets from three different clinical trials using trivalent influenza vaccine (TIV); the primary trial included 3,317 children aged 6-35 months who were randomized to receive Fluarix at 0.25 mL or 0.5 mL, or receive 0.25 mL of Fluzone. The other two trials studied children receiving TIV between 6 months–17 years and 3-17 years. The researchers also performed a multivariable regression analysis to determine the relationship between immunogenicity, antipyretic use, and postvaccination fever.

The primary study initially reported the fever rate 0 days–3 days after vaccination was between 6% and 7%. After reporting the rate of fever separately for each dose and changing the criteria to “defining fever as greater than or equal to 38.0°C by any route of measurement” for the primary study, the researchers found a rate of any-cause fever was 3%-4% for the first dose and 4%-5% for the second dose. The rate of vaccine-related fever in the primary study was 3% for the first dose and 3%-4% for the second dose, with researchers noting vaccine-related fever occurred significantly earlier compared with any-cause fever (mean 1 days vs. 2 days after vaccination; P equals .04).

Impact of fever, antipyretics

The researchers also performed a pooled immunogenicity analysis of 5,902 children from all three trials and found a strong association between fever after vaccination and increased geometric mean titer (GMT) ratios (1.21-1.39; P less than or equal to .01) and an association between antipyretic use and reduced GMT ratios (0.80-0.87; P less than .0006).

“Our pooled analysis of the three trials demonstrated highly significant associations, for all strains, between postvaccination fever and up to 39% higher GMT; this may suggest a close role between fever and the body’s immunologic response to the influenza antigens within the vaccine. Similarly, strong evidence of associations in the opposite direction was found between postvaccination antipyretic use (days 0-3), adjusting for all other factors including fever, and decreased immunogenicity against all vaccine strains in children,” Dr. Li-Kim-Moy and colleagues said.

Antipyretic use was common in the primary study, occurring in one in six of the children, they said. These findings of “significant associations between fever and increased vaccine immunogenicity, and between antipyretic use and reduced immunogenicity in children after influenza vaccination” suggest the need for further study, especially because parents often give antipyretics if their children are febrile after vaccinations.

“There is uncertainty whether our findings, and those of others, on immunogenicity translate into clinically significant effects,” they wrote. “However, the fact that influenza vaccine, unlike many routine childhood vaccines, is only moderately protective may mean that modest reductions in antibody response are more likely to correlate to less protection.”

 

Dr. Wood reported receiving a fellowship from the National Health and Medical Research Council (NHMRC) and being an investigator for GlaxoSmithKline trials. Dr. Booy reported being an advisor for influenza vaccine manufacturing, an advisory board member, on the speaker’s bureau, and a researcher of vaccines for several manufacturers. The other authors reported no relevant conflicts of interest.

SOURCE: Li-Kim-Moy J et al. Pediatr Infect Dis J. 2018 Oct;37(10):971-5.

 

Researchers found a lower rate of pediatric fever after applying a standard definition of fever across three different clinical trials of pediatric patients receiving influenza vaccinations, according to research published in the Pediatric Infectious Disease Journal.

Yangna/Thinkstock

Investigators in future studies must adopt a standardized definition of pediatric fever after an influenza vaccination. “Our study demonstrates the variability in results which occur due to minor differences in the definition of fever, methods of analysis and reporting of results,” Jean Li-Kim-Moy, MBBS, of the University of Sydney, and colleagues wrote.

Dr. Li-Kim-Moy and colleagues analyzed pediatric datasets from three different clinical trials using trivalent influenza vaccine (TIV); the primary trial included 3,317 children aged 6-35 months who were randomized to receive Fluarix at 0.25 mL or 0.5 mL, or receive 0.25 mL of Fluzone. The other two trials studied children receiving TIV between 6 months–17 years and 3-17 years. The researchers also performed a multivariable regression analysis to determine the relationship between immunogenicity, antipyretic use, and postvaccination fever.

The primary study initially reported the fever rate 0 days–3 days after vaccination was between 6% and 7%. After reporting the rate of fever separately for each dose and changing the criteria to “defining fever as greater than or equal to 38.0°C by any route of measurement” for the primary study, the researchers found a rate of any-cause fever was 3%-4% for the first dose and 4%-5% for the second dose. The rate of vaccine-related fever in the primary study was 3% for the first dose and 3%-4% for the second dose, with researchers noting vaccine-related fever occurred significantly earlier compared with any-cause fever (mean 1 days vs. 2 days after vaccination; P equals .04).

Impact of fever, antipyretics

The researchers also performed a pooled immunogenicity analysis of 5,902 children from all three trials and found a strong association between fever after vaccination and increased geometric mean titer (GMT) ratios (1.21-1.39; P less than or equal to .01) and an association between antipyretic use and reduced GMT ratios (0.80-0.87; P less than .0006).

“Our pooled analysis of the three trials demonstrated highly significant associations, for all strains, between postvaccination fever and up to 39% higher GMT; this may suggest a close role between fever and the body’s immunologic response to the influenza antigens within the vaccine. Similarly, strong evidence of associations in the opposite direction was found between postvaccination antipyretic use (days 0-3), adjusting for all other factors including fever, and decreased immunogenicity against all vaccine strains in children,” Dr. Li-Kim-Moy and colleagues said.

Antipyretic use was common in the primary study, occurring in one in six of the children, they said. These findings of “significant associations between fever and increased vaccine immunogenicity, and between antipyretic use and reduced immunogenicity in children after influenza vaccination” suggest the need for further study, especially because parents often give antipyretics if their children are febrile after vaccinations.

“There is uncertainty whether our findings, and those of others, on immunogenicity translate into clinically significant effects,” they wrote. “However, the fact that influenza vaccine, unlike many routine childhood vaccines, is only moderately protective may mean that modest reductions in antibody response are more likely to correlate to less protection.”

 

Dr. Wood reported receiving a fellowship from the National Health and Medical Research Council (NHMRC) and being an investigator for GlaxoSmithKline trials. Dr. Booy reported being an advisor for influenza vaccine manufacturing, an advisory board member, on the speaker’s bureau, and a researcher of vaccines for several manufacturers. The other authors reported no relevant conflicts of interest.

SOURCE: Li-Kim-Moy J et al. Pediatr Infect Dis J. 2018 Oct;37(10):971-5.

 

SAN ANTONIO – A definitive laparotomy isn’t much more clinically costly than a damage-control procedure, but it can cost fewer resources: fewer days in intensive care, fewer days on a ventilator, and a shorter overall length of stay.

Among damage-control abdominal trauma cases that could have been closed, definitive laparotomy (DEF) was associated with a 56% probability of major abdominal complications – very close to the probability associated with damage-control closure, John Harvin, MD, said at the annual meeting of the American Association for the Surgery of Trauma.

Definitive closure was also associated with about a 72% chance of more ventilator- and hospital-free days and a 77% chance of more ICU-free days than damage-control closure, said Dr. Harvin of the University of Texas, Austin.

“Our analysis tells us that there’s a minimal chance of reducing complications with a definitive laparotomy, compared to leaving them open, but this also comes with more than a 70% chance of having a shorter hospital staying and getting off the ventilator faster.”

The data from a 2-year quality review process reaffirms what trauma surgeons have been seeing, and reporting, since damage-control closure became more popular in the past decade, said Peter Rhee, MD, commenting on the study.

Michele Sullivan/MDedge News

“There are three congregations in this faith of damage-control laparotomy,” said Dr. Rhee, a surgeon in Atlanta, Ga. “The first believes it should be the default for all these types of operations and that being preemptive is better than anything. The second believes that it doesn’t hurt the patient too much, and that it can be done when absolutely needed to save a life. The third belief is that there’s minimal data to support it, that it should rarely be used, and that it’s always costly. We all know that the pendulum of damage-control laparotomy is finally swinging back to the center.”

The study arose from an effort at the Red Duke Trauma Institute, Austin, Tex., to reduce its rate of damage-control laparotomy (DCL). Surgeons examined all emergent trauma laparotomies conducted from 2013 to 2015. They discussed each case and compared morbidity and mortality rates to a published control group. This work was published last year in the Journal of the American College of Surgeons.

By adopting this review procedure, the hospital was able to decrease its 39% DCL rate to 23% over 2 years (an absolute reduction of 68 cases) without any change in infection rates, fascial dehiscence, unplanned reoperation, or mortality. The improvements continued, Dr. Harvin noted, with a farther 17% reduction in DCL after the project concluded.

Dr. Harvin’s analysis looked at 44 of these procedures which, according to the adjudication panel, could have been managed by DEF. Each was matched to a DEF case, and the outcomes were calculated with a Bayesian statistical model.

The primary outcome was major abdominal complication, a composite measure of fascial dehiscence, organ or space surgical-site infection, reopening of fascia, and enteric suture line failure. Secondary outcomes were days off the ventilator and out of the ICU and hospital.

Of the 872 patients in the study, most (639; 73%) were managed by DEF; the rest (209; 24%) were managed by DCL. Of these, the panel agreed that 44 (22%) could have been safely closed at the time of surgery and survived at least 5 days. The propensity-matching scheme comprised 39 of these cases matched with 39 DEF cases.

Most were male (74%); the mean age was 38 years. Penetrating injuries were most common (54%). The abdominal Abbreviated Injury Score was 3. The mean Injury Severity Score was 22 in the DEF cases and 25 in the DCL cases, but this was not a significant difference. There were no differences in blood pressure at presentation or at the end of the surgery, no differences in blood transfusion needs, and no differences in body temperature.

A major abdominal complication occurred in 31% of the DEF cases and 21% of the DCL cases, a relative risk of 0.99. This amounted to a 56% posterior probability of a complication associated with DEF.

Comparing DCL cases with DEF cases, the mean number of hospital-free days was 15 vs.13; ICU-free days, 26 vs. 21; and ventilator-free days, 29 vs. 26. These differences amount to a 72% chance that DEL would result in more hospital-free days and more ventilator-free days, and a 77% chance that DEL would result in more ICU-free days.

The numbers underscore the need to rethink DCL for abdominal trauma, Dr. Rhee said.

“I too once believed in this procedure and used to do it all the time. After 2 decades, we now know that it contributed to the frozen bellies, abdominal wound hernias, fascial dehiscence, missed complications, and to the never-ending enteroatmospheric fistulas. If we want to reduce fistulas, we must first reduce damage-control laparotomy. Nurses will love you for not creating the narcotic-addicted, total parenteral nutrition–dependent patient with a fragrant open belly and a fistula.”

Neither Dr. Harvin nor Dr Rhee had any relevant financial disclosures.

[email protected]

SOURCE: Harvin L et al. AAST 2018, Oral paper 12.

 

SAN ANTONIO – A definitive laparotomy isn’t much more clinically costly than a damage-control procedure, but it can cost fewer resources: fewer days in intensive care, fewer days on a ventilator, and a shorter overall length of stay.

Among damage-control abdominal trauma cases that could have been closed, definitive laparotomy (DEF) was associated with a 56% probability of major abdominal complications – very close to the probability associated with damage-control closure, John Harvin, MD, said at the annual meeting of the American Association for the Surgery of Trauma.

Definitive closure was also associated with about a 72% chance of more ventilator- and hospital-free days and a 77% chance of more ICU-free days than damage-control closure, said Dr. Harvin of the University of Texas, Austin.

“Our analysis tells us that there’s a minimal chance of reducing complications with a definitive laparotomy, compared to leaving them open, but this also comes with more than a 70% chance of having a shorter hospital staying and getting off the ventilator faster.”

The data from a 2-year quality review process reaffirms what trauma surgeons have been seeing, and reporting, since damage-control closure became more popular in the past decade, said Peter Rhee, MD, commenting on the study.

Michele Sullivan/MDedge News

“There are three congregations in this faith of damage-control laparotomy,” said Dr. Rhee, a surgeon in Atlanta, Ga. “The first believes it should be the default for all these types of operations and that being preemptive is better than anything. The second believes that it doesn’t hurt the patient too much, and that it can be done when absolutely needed to save a life. The third belief is that there’s minimal data to support it, that it should rarely be used, and that it’s always costly. We all know that the pendulum of damage-control laparotomy is finally swinging back to the center.”

The study arose from an effort at the Red Duke Trauma Institute, Austin, Tex., to reduce its rate of damage-control laparotomy (DCL). Surgeons examined all emergent trauma laparotomies conducted from 2013 to 2015. They discussed each case and compared morbidity and mortality rates to a published control group. This work was published last year in the Journal of the American College of Surgeons.

By adopting this review procedure, the hospital was able to decrease its 39% DCL rate to 23% over 2 years (an absolute reduction of 68 cases) without any change in infection rates, fascial dehiscence, unplanned reoperation, or mortality. The improvements continued, Dr. Harvin noted, with a farther 17% reduction in DCL after the project concluded.

Dr. Harvin’s analysis looked at 44 of these procedures which, according to the adjudication panel, could have been managed by DEF. Each was matched to a DEF case, and the outcomes were calculated with a Bayesian statistical model.

The primary outcome was major abdominal complication, a composite measure of fascial dehiscence, organ or space surgical-site infection, reopening of fascia, and enteric suture line failure. Secondary outcomes were days off the ventilator and out of the ICU and hospital.

Of the 872 patients in the study, most (639; 73%) were managed by DEF; the rest (209; 24%) were managed by DCL. Of these, the panel agreed that 44 (22%) could have been safely closed at the time of surgery and survived at least 5 days. The propensity-matching scheme comprised 39 of these cases matched with 39 DEF cases.

Most were male (74%); the mean age was 38 years. Penetrating injuries were most common (54%). The abdominal Abbreviated Injury Score was 3. The mean Injury Severity Score was 22 in the DEF cases and 25 in the DCL cases, but this was not a significant difference. There were no differences in blood pressure at presentation or at the end of the surgery, no differences in blood transfusion needs, and no differences in body temperature.

A major abdominal complication occurred in 31% of the DEF cases and 21% of the DCL cases, a relative risk of 0.99. This amounted to a 56% posterior probability of a complication associated with DEF.

Comparing DCL cases with DEF cases, the mean number of hospital-free days was 15 vs.13; ICU-free days, 26 vs. 21; and ventilator-free days, 29 vs. 26. These differences amount to a 72% chance that DEL would result in more hospital-free days and more ventilator-free days, and a 77% chance that DEL would result in more ICU-free days.

The numbers underscore the need to rethink DCL for abdominal trauma, Dr. Rhee said.

“I too once believed in this procedure and used to do it all the time. After 2 decades, we now know that it contributed to the frozen bellies, abdominal wound hernias, fascial dehiscence, missed complications, and to the never-ending enteroatmospheric fistulas. If we want to reduce fistulas, we must first reduce damage-control laparotomy. Nurses will love you for not creating the narcotic-addicted, total parenteral nutrition–dependent patient with a fragrant open belly and a fistula.”

Neither Dr. Harvin nor Dr Rhee had any relevant financial disclosures.

[email protected]

SOURCE: Harvin L et al. AAST 2018, Oral paper 12.

 

SAN ANTONIO – A definitive laparotomy isn’t much more clinically costly than a damage-control procedure, but it can cost fewer resources: fewer days in intensive care, fewer days on a ventilator, and a shorter overall length of stay.

Among damage-control abdominal trauma cases that could have been closed, definitive laparotomy (DEF) was associated with a 56% probability of major abdominal complications – very close to the probability associated with damage-control closure, John Harvin, MD, said at the annual meeting of the American Association for the Surgery of Trauma.

Definitive closure was also associated with about a 72% chance of more ventilator- and hospital-free days and a 77% chance of more ICU-free days than damage-control closure, said Dr. Harvin of the University of Texas, Austin.

“Our analysis tells us that there’s a minimal chance of reducing complications with a definitive laparotomy, compared to leaving them open, but this also comes with more than a 70% chance of having a shorter hospital staying and getting off the ventilator faster.”

The data from a 2-year quality review process reaffirms what trauma surgeons have been seeing, and reporting, since damage-control closure became more popular in the past decade, said Peter Rhee, MD, commenting on the study.

Michele Sullivan/MDedge News

“There are three congregations in this faith of damage-control laparotomy,” said Dr. Rhee, a surgeon in Atlanta, Ga. “The first believes it should be the default for all these types of operations and that being preemptive is better than anything. The second believes that it doesn’t hurt the patient too much, and that it can be done when absolutely needed to save a life. The third belief is that there’s minimal data to support it, that it should rarely be used, and that it’s always costly. We all know that the pendulum of damage-control laparotomy is finally swinging back to the center.”

The study arose from an effort at the Red Duke Trauma Institute, Austin, Tex., to reduce its rate of damage-control laparotomy (DCL). Surgeons examined all emergent trauma laparotomies conducted from 2013 to 2015. They discussed each case and compared morbidity and mortality rates to a published control group. This work was published last year in the Journal of the American College of Surgeons.

By adopting this review procedure, the hospital was able to decrease its 39% DCL rate to 23% over 2 years (an absolute reduction of 68 cases) without any change in infection rates, fascial dehiscence, unplanned reoperation, or mortality. The improvements continued, Dr. Harvin noted, with a farther 17% reduction in DCL after the project concluded.

Dr. Harvin’s analysis looked at 44 of these procedures which, according to the adjudication panel, could have been managed by DEF. Each was matched to a DEF case, and the outcomes were calculated with a Bayesian statistical model.

The primary outcome was major abdominal complication, a composite measure of fascial dehiscence, organ or space surgical-site infection, reopening of fascia, and enteric suture line failure. Secondary outcomes were days off the ventilator and out of the ICU and hospital.

Of the 872 patients in the study, most (639; 73%) were managed by DEF; the rest (209; 24%) were managed by DCL. Of these, the panel agreed that 44 (22%) could have been safely closed at the time of surgery and survived at least 5 days. The propensity-matching scheme comprised 39 of these cases matched with 39 DEF cases.

Most were male (74%); the mean age was 38 years. Penetrating injuries were most common (54%). The abdominal Abbreviated Injury Score was 3. The mean Injury Severity Score was 22 in the DEF cases and 25 in the DCL cases, but this was not a significant difference. There were no differences in blood pressure at presentation or at the end of the surgery, no differences in blood transfusion needs, and no differences in body temperature.

A major abdominal complication occurred in 31% of the DEF cases and 21% of the DCL cases, a relative risk of 0.99. This amounted to a 56% posterior probability of a complication associated with DEF.

Comparing DCL cases with DEF cases, the mean number of hospital-free days was 15 vs.13; ICU-free days, 26 vs. 21; and ventilator-free days, 29 vs. 26. These differences amount to a 72% chance that DEL would result in more hospital-free days and more ventilator-free days, and a 77% chance that DEL would result in more ICU-free days.

The numbers underscore the need to rethink DCL for abdominal trauma, Dr. Rhee said.

“I too once believed in this procedure and used to do it all the time. After 2 decades, we now know that it contributed to the frozen bellies, abdominal wound hernias, fascial dehiscence, missed complications, and to the never-ending enteroatmospheric fistulas. If we want to reduce fistulas, we must first reduce damage-control laparotomy. Nurses will love you for not creating the narcotic-addicted, total parenteral nutrition–dependent patient with a fragrant open belly and a fistula.”

Neither Dr. Harvin nor Dr Rhee had any relevant financial disclosures.

[email protected]

SOURCE: Harvin L et al. AAST 2018, Oral paper 12.

 

MUNICH – A comprehensive home telemonitoring program paid off big for selected patients with heart failure in a large, German nationwide masked randomization trial.

Bruce Jancin/MDedge News

In the 1,538-patient Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial, participants randomized to the noninvasive home monitoring program had a 30% reduction in all-cause mortality during 12-13 months of prospective follow-up, compared with control subjects randomized to guideline-directed usual care. They also experienced an average of 6 fewer days of unplanned cardiovascular hospitalizations, Friedrich Koehler, MD, reported at the annual congress of the European Society of Cardiology.

Previous studies of home telemonitoring in heart failure patients have yielded mixed results. Dr. Koehler cited two explanations why TIM-HF2 was unreservedly positive while some other studies failed to demonstrate significant benefit.

First, TIM-HF2 didn’t rely on passive monitoring of the patients’ daily electronically submitted home data. Instead, the data went straight to a central telemonitoring center staffed 24/7 by physicians and nurses with heart failure expertise. There, the information was immediately analyzed using proprietary telemedical analytic software known as the Fontane system. The software employs individually tailored, self-adapting algorithms in order to alert staff when trouble is brewing.

But the telemonitoring intervention doesn’t merely detect early clinical deterioration. It’s also a vehicle for ongoing patient education, outpatient adjustment of drugs, management of major comorbid conditions, and hospital admissions as needed. The patient’s local primary care physician was also plugged into the remote monitoring system and kept abreast of the patient’s condition.

Second, TIM-HF2 focused on a carefully selected subgroup of heart failure patients whom prior studies suggested were particularly likely to benefit from home telemedical management. All participants were NYHA class II or III with a left ventricular ejection fraction of 45% or less, a hospitalization for heart failure within 12 months prior to randomization, and free of moderate or severe depression as evidenced by a baseline Patient Health Questionnaire-9 score of 9 or less, explained Dr. Koehler, head of the center for cardiovascular telemedicine at Charite University in Berlin.

Why exclude patients with depression?

“In this concept, with wholistic remote patient management, we need an active patient who is able to measure every day, who is able to communicate with the telemedical center, and who is able to communicate in this network created between the telemedical center and local caregivers. If someone is really depressed, unable to act, lying in bed saying it makes no sense to take drugs or do anything, then we cannot help. That is for us, I think, the most important thing. We’ve seen it now in two trials,” according to the cardiologist.

The all-cause mortality rate was 7.86 per 100 person-years in the home-telemonitoring group versus 11.34 in usual-care controls. Patients in the active intervention arm lost a mean of 17.8 days per year because of unplanned cardiovascular hospital admissions, compared with 24.2 days per year in controls.

Importantly, outcomes were equally good in the remote patient-management group regardless of whether patients were among the 40% of participants living in urban Germany or the 60% in rural areas. Thus, the telemonitoring intervention eliminated the geographic disparity in health care outcomes which is a prominent issue in Germany, as well as the United States.

A formal cost-benefit analysis of the TIM-HF2 results is in the works, Dr. Koehler said.

Simultaneous with his presentation in Munich, the TIM-HF2 study was published online in the Lancet.

In an accompanying editorial, two prominent heart failure experts – John F.G. Cleland, MD, of the University of Glasgow and Robin A. Clark, MD, of Flinders University in Adelaide – hailed TIM-HF2 as a major advance and indicated in sharp terms that it’s time for guideline writers to sit up and take notice.

“Despite much clinical skepticism and feeble support from most guidelines, in our view the growing weight of evidence suggests that home telemonitoring does reduce mortality for patients with heart failure, and this effect might be substantial. These and other trials also show that the emphasis placed on hospital admission for heart failure might be misplaced, at least from a patient’s perspective, because the proportion of days lost due to hospital admission is small, compared with those lost to death,” the physicians wrote in the editorial.

They also noted that, even though the between-group difference in the number of days during which patients were hospitalized for cardiovascular causes was relatively small, it’s clear that home telemonitoring triggered some potentially life-saving hospitalizations. “Home telemonitoring puts the patient back in the center of health care, ensuring that they know what the health professional is trying to achieve and that they agree with those aims. Ultimately, patients and their families are a large and relatively untapped health care resource,” they wrote.

The TIM-HF 2 trial was funded by the German Federal Ministry of Education and Research. Dr. Koehler reported receiving speaking and/or consultant fees from Novartis, Abbott, and Medtronic.

[email protected]

SOURCE: Koehler F et al. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.

 

MUNICH – A comprehensive home telemonitoring program paid off big for selected patients with heart failure in a large, German nationwide masked randomization trial.

Bruce Jancin/MDedge News

In the 1,538-patient Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial, participants randomized to the noninvasive home monitoring program had a 30% reduction in all-cause mortality during 12-13 months of prospective follow-up, compared with control subjects randomized to guideline-directed usual care. They also experienced an average of 6 fewer days of unplanned cardiovascular hospitalizations, Friedrich Koehler, MD, reported at the annual congress of the European Society of Cardiology.

Previous studies of home telemonitoring in heart failure patients have yielded mixed results. Dr. Koehler cited two explanations why TIM-HF2 was unreservedly positive while some other studies failed to demonstrate significant benefit.

First, TIM-HF2 didn’t rely on passive monitoring of the patients’ daily electronically submitted home data. Instead, the data went straight to a central telemonitoring center staffed 24/7 by physicians and nurses with heart failure expertise. There, the information was immediately analyzed using proprietary telemedical analytic software known as the Fontane system. The software employs individually tailored, self-adapting algorithms in order to alert staff when trouble is brewing.

But the telemonitoring intervention doesn’t merely detect early clinical deterioration. It’s also a vehicle for ongoing patient education, outpatient adjustment of drugs, management of major comorbid conditions, and hospital admissions as needed. The patient’s local primary care physician was also plugged into the remote monitoring system and kept abreast of the patient’s condition.

Second, TIM-HF2 focused on a carefully selected subgroup of heart failure patients whom prior studies suggested were particularly likely to benefit from home telemedical management. All participants were NYHA class II or III with a left ventricular ejection fraction of 45% or less, a hospitalization for heart failure within 12 months prior to randomization, and free of moderate or severe depression as evidenced by a baseline Patient Health Questionnaire-9 score of 9 or less, explained Dr. Koehler, head of the center for cardiovascular telemedicine at Charite University in Berlin.

Why exclude patients with depression?

“In this concept, with wholistic remote patient management, we need an active patient who is able to measure every day, who is able to communicate with the telemedical center, and who is able to communicate in this network created between the telemedical center and local caregivers. If someone is really depressed, unable to act, lying in bed saying it makes no sense to take drugs or do anything, then we cannot help. That is for us, I think, the most important thing. We’ve seen it now in two trials,” according to the cardiologist.

The all-cause mortality rate was 7.86 per 100 person-years in the home-telemonitoring group versus 11.34 in usual-care controls. Patients in the active intervention arm lost a mean of 17.8 days per year because of unplanned cardiovascular hospital admissions, compared with 24.2 days per year in controls.

Importantly, outcomes were equally good in the remote patient-management group regardless of whether patients were among the 40% of participants living in urban Germany or the 60% in rural areas. Thus, the telemonitoring intervention eliminated the geographic disparity in health care outcomes which is a prominent issue in Germany, as well as the United States.

A formal cost-benefit analysis of the TIM-HF2 results is in the works, Dr. Koehler said.

Simultaneous with his presentation in Munich, the TIM-HF2 study was published online in the Lancet.

In an accompanying editorial, two prominent heart failure experts – John F.G. Cleland, MD, of the University of Glasgow and Robin A. Clark, MD, of Flinders University in Adelaide – hailed TIM-HF2 as a major advance and indicated in sharp terms that it’s time for guideline writers to sit up and take notice.

“Despite much clinical skepticism and feeble support from most guidelines, in our view the growing weight of evidence suggests that home telemonitoring does reduce mortality for patients with heart failure, and this effect might be substantial. These and other trials also show that the emphasis placed on hospital admission for heart failure might be misplaced, at least from a patient’s perspective, because the proportion of days lost due to hospital admission is small, compared with those lost to death,” the physicians wrote in the editorial.

They also noted that, even though the between-group difference in the number of days during which patients were hospitalized for cardiovascular causes was relatively small, it’s clear that home telemonitoring triggered some potentially life-saving hospitalizations. “Home telemonitoring puts the patient back in the center of health care, ensuring that they know what the health professional is trying to achieve and that they agree with those aims. Ultimately, patients and their families are a large and relatively untapped health care resource,” they wrote.

The TIM-HF 2 trial was funded by the German Federal Ministry of Education and Research. Dr. Koehler reported receiving speaking and/or consultant fees from Novartis, Abbott, and Medtronic.

[email protected]

SOURCE: Koehler F et al. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.

 

MUNICH – A comprehensive home telemonitoring program paid off big for selected patients with heart failure in a large, German nationwide masked randomization trial.

Bruce Jancin/MDedge News

In the 1,538-patient Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial, participants randomized to the noninvasive home monitoring program had a 30% reduction in all-cause mortality during 12-13 months of prospective follow-up, compared with control subjects randomized to guideline-directed usual care. They also experienced an average of 6 fewer days of unplanned cardiovascular hospitalizations, Friedrich Koehler, MD, reported at the annual congress of the European Society of Cardiology.

Previous studies of home telemonitoring in heart failure patients have yielded mixed results. Dr. Koehler cited two explanations why TIM-HF2 was unreservedly positive while some other studies failed to demonstrate significant benefit.

First, TIM-HF2 didn’t rely on passive monitoring of the patients’ daily electronically submitted home data. Instead, the data went straight to a central telemonitoring center staffed 24/7 by physicians and nurses with heart failure expertise. There, the information was immediately analyzed using proprietary telemedical analytic software known as the Fontane system. The software employs individually tailored, self-adapting algorithms in order to alert staff when trouble is brewing.

But the telemonitoring intervention doesn’t merely detect early clinical deterioration. It’s also a vehicle for ongoing patient education, outpatient adjustment of drugs, management of major comorbid conditions, and hospital admissions as needed. The patient’s local primary care physician was also plugged into the remote monitoring system and kept abreast of the patient’s condition.

Second, TIM-HF2 focused on a carefully selected subgroup of heart failure patients whom prior studies suggested were particularly likely to benefit from home telemedical management. All participants were NYHA class II or III with a left ventricular ejection fraction of 45% or less, a hospitalization for heart failure within 12 months prior to randomization, and free of moderate or severe depression as evidenced by a baseline Patient Health Questionnaire-9 score of 9 or less, explained Dr. Koehler, head of the center for cardiovascular telemedicine at Charite University in Berlin.

Why exclude patients with depression?

“In this concept, with wholistic remote patient management, we need an active patient who is able to measure every day, who is able to communicate with the telemedical center, and who is able to communicate in this network created between the telemedical center and local caregivers. If someone is really depressed, unable to act, lying in bed saying it makes no sense to take drugs or do anything, then we cannot help. That is for us, I think, the most important thing. We’ve seen it now in two trials,” according to the cardiologist.

The all-cause mortality rate was 7.86 per 100 person-years in the home-telemonitoring group versus 11.34 in usual-care controls. Patients in the active intervention arm lost a mean of 17.8 days per year because of unplanned cardiovascular hospital admissions, compared with 24.2 days per year in controls.

Importantly, outcomes were equally good in the remote patient-management group regardless of whether patients were among the 40% of participants living in urban Germany or the 60% in rural areas. Thus, the telemonitoring intervention eliminated the geographic disparity in health care outcomes which is a prominent issue in Germany, as well as the United States.

A formal cost-benefit analysis of the TIM-HF2 results is in the works, Dr. Koehler said.

Simultaneous with his presentation in Munich, the TIM-HF2 study was published online in the Lancet.

In an accompanying editorial, two prominent heart failure experts – John F.G. Cleland, MD, of the University of Glasgow and Robin A. Clark, MD, of Flinders University in Adelaide – hailed TIM-HF2 as a major advance and indicated in sharp terms that it’s time for guideline writers to sit up and take notice.

“Despite much clinical skepticism and feeble support from most guidelines, in our view the growing weight of evidence suggests that home telemonitoring does reduce mortality for patients with heart failure, and this effect might be substantial. These and other trials also show that the emphasis placed on hospital admission for heart failure might be misplaced, at least from a patient’s perspective, because the proportion of days lost due to hospital admission is small, compared with those lost to death,” the physicians wrote in the editorial.

They also noted that, even though the between-group difference in the number of days during which patients were hospitalized for cardiovascular causes was relatively small, it’s clear that home telemonitoring triggered some potentially life-saving hospitalizations. “Home telemonitoring puts the patient back in the center of health care, ensuring that they know what the health professional is trying to achieve and that they agree with those aims. Ultimately, patients and their families are a large and relatively untapped health care resource,” they wrote.

The TIM-HF 2 trial was funded by the German Federal Ministry of Education and Research. Dr. Koehler reported receiving speaking and/or consultant fees from Novartis, Abbott, and Medtronic.

[email protected]

SOURCE: Koehler F et al. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.

 

SAN DIEGO – Pulmonary artery denervation is efficacious for treating combined pre- and postcapillary pulmonary hypertension attributable to left heart failure, based on results of the Chinese PADN-5 trial reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

Susan London/MDedge News

This ablative treatment has been studied among patients with pulmonary hypertension attributable to other etiologies, but not in randomized fashion among this population, noted lead investigator Shao-Liang Chen, MD, of Nanjing (China) First Hospital, Nanjing Medical University. The treatment is an attractive one, as medications recommended for pulmonary arterial hypertension are not recommended for joint pre- and postcapillary pulmonary hypertension (group II pulmonary hypertension).

In PADN-5, 98 patients were randomized to pulmonary artery denervation or to sham denervation plus open-label sildenafil (Viagra), which at the time of trial initiation was thought to be safe and potentially beneficial.

The trial’s main outcome, 6-minute walk distance at 6 months, improved in both groups, according to data reported at the meeting and simultaneously published in JACC Cardiovascular Interventions. But the improvement was about four times greater in the pulmonary artery denervation group. Secondary efficacy outcomes also favored that group, and the rate of fatal pulmonary embolism did not differ for the two groups.

“The PADN-5 trial demonstrates the benefits of pulmonary artery denervation for patients with combined pre- and postcapillary pulmonary hypertension. Patients with preserved and with reduced ejection fraction equally benefited,” summarized Dr. Chen, who pioneered this procedure about 7 years ago. “There was no sign of any harm of sildenafil in patients with combined pre- and postcapillary pulmonary hypertension.”
 

Trial critique

“This is a very difficult study to conduct, being able to recruit patients and actually have these procedures done,” commented press conference moderator Ori Ben-Yehuda, MD, professor of clinical medicine and director, coronary care unit, UC San Diego Medical Center.

At the same time, he expressed some reservations about the trial. “Sildenafil in the control group might actually be expected to ... decrease your effect size. Also, particularly in men, perhaps even in women, it might unblind them to which group they are in and undermine your sham design,” he noted. In addition, some hemodynamic changes after pulmonary artery denervation – a decrease in wedge pressure and an increase in ejection fraction – were puzzling.

“We need a lot more data here. There are some issues with this trial in terms of design, and we haven’t even gotten into the issue of whether there were core labs, whether the echoes, the hemodynamics, were read blindly,” Dr. Ben-Yehuda maintained. “This issue of secondary or group II pulmonary hypertension due to left heart failure is one that has been very frustrating in terms of actual PA-specific therapies. So this is an important step further, but it needs confirmation in truly sham-controlled trials that have no potential for unblinding.”

The catheter used in PADN-5 is available in China but has not received clearance in the United States, he pointed out. “There are alternative or competing technologies, one using ultrasound, for example, that has a very similar approach. … We’ll have to see how it ends up [performing].”
 

 

Trial details

Patients in the PADN-5 pulmonary artery denervation group underwent ablation only in the periconjunctional area between the distal main trunk and the left ostial branch with a multifunction catheter having premounted electrodes. Those in the control group underwent a sham procedure, with catheter positioning at the target sites and connection to a generator but no ablation, and were given open-label sildenafil. All additionally received standard heart failure medical therapy. (No sildenafil placebo was used in the denervation group.)

Trial results reported at the meeting, which is sponsored by the Cardiovascular Research Foundation, showed that most echocardiographic and hemodynamic measures improved more in the pulmonary artery denervation group.

The greater improvement in 6-minute walk test with denervation versus sham sildenafil at 6 months was evident in a variety of measures: absolute median distance walked (432.5 m vs. 358 m) and mean distance walked (434.6 m vs. 359.4 m), and absolute increase (80 m vs. 17.5 m) and relative increase (21.4% vs. 4.9%) The difference was significant for all measures at P less than .001.

The denervation group had a comparatively greater reduction of pulmonary vascular resistance (29.8% vs. 3.4%; P less than .001) and were less likely to experience clinical worsening (16.7% vs. 40.0%; P = .014).

There was a single fatal pulmonary embolism in each treatment group. Of the seven total deaths, two occurred in the denervation group (one attributable to pump failure, one a sudden death) and five occurred in the sham sildenafil group (all but one attributable to pump failure).

Dr. Chen disclosed that he had no relevant conflicts of interest. The trial was sponsored by Nanjing First Hospital, Nanjing Medical University.

SOURCE: Chen S-J et al. TCT 2018. JACC Cardiovasc Interv. 2018 Sep 23.

 

SAN DIEGO – Pulmonary artery denervation is efficacious for treating combined pre- and postcapillary pulmonary hypertension attributable to left heart failure, based on results of the Chinese PADN-5 trial reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

Susan London/MDedge News

This ablative treatment has been studied among patients with pulmonary hypertension attributable to other etiologies, but not in randomized fashion among this population, noted lead investigator Shao-Liang Chen, MD, of Nanjing (China) First Hospital, Nanjing Medical University. The treatment is an attractive one, as medications recommended for pulmonary arterial hypertension are not recommended for joint pre- and postcapillary pulmonary hypertension (group II pulmonary hypertension).

In PADN-5, 98 patients were randomized to pulmonary artery denervation or to sham denervation plus open-label sildenafil (Viagra), which at the time of trial initiation was thought to be safe and potentially beneficial.

The trial’s main outcome, 6-minute walk distance at 6 months, improved in both groups, according to data reported at the meeting and simultaneously published in JACC Cardiovascular Interventions. But the improvement was about four times greater in the pulmonary artery denervation group. Secondary efficacy outcomes also favored that group, and the rate of fatal pulmonary embolism did not differ for the two groups.

“The PADN-5 trial demonstrates the benefits of pulmonary artery denervation for patients with combined pre- and postcapillary pulmonary hypertension. Patients with preserved and with reduced ejection fraction equally benefited,” summarized Dr. Chen, who pioneered this procedure about 7 years ago. “There was no sign of any harm of sildenafil in patients with combined pre- and postcapillary pulmonary hypertension.”
 

Trial critique

“This is a very difficult study to conduct, being able to recruit patients and actually have these procedures done,” commented press conference moderator Ori Ben-Yehuda, MD, professor of clinical medicine and director, coronary care unit, UC San Diego Medical Center.

At the same time, he expressed some reservations about the trial. “Sildenafil in the control group might actually be expected to ... decrease your effect size. Also, particularly in men, perhaps even in women, it might unblind them to which group they are in and undermine your sham design,” he noted. In addition, some hemodynamic changes after pulmonary artery denervation – a decrease in wedge pressure and an increase in ejection fraction – were puzzling.

“We need a lot more data here. There are some issues with this trial in terms of design, and we haven’t even gotten into the issue of whether there were core labs, whether the echoes, the hemodynamics, were read blindly,” Dr. Ben-Yehuda maintained. “This issue of secondary or group II pulmonary hypertension due to left heart failure is one that has been very frustrating in terms of actual PA-specific therapies. So this is an important step further, but it needs confirmation in truly sham-controlled trials that have no potential for unblinding.”

The catheter used in PADN-5 is available in China but has not received clearance in the United States, he pointed out. “There are alternative or competing technologies, one using ultrasound, for example, that has a very similar approach. … We’ll have to see how it ends up [performing].”
 

 

Trial details

Patients in the PADN-5 pulmonary artery denervation group underwent ablation only in the periconjunctional area between the distal main trunk and the left ostial branch with a multifunction catheter having premounted electrodes. Those in the control group underwent a sham procedure, with catheter positioning at the target sites and connection to a generator but no ablation, and were given open-label sildenafil. All additionally received standard heart failure medical therapy. (No sildenafil placebo was used in the denervation group.)

Trial results reported at the meeting, which is sponsored by the Cardiovascular Research Foundation, showed that most echocardiographic and hemodynamic measures improved more in the pulmonary artery denervation group.

The greater improvement in 6-minute walk test with denervation versus sham sildenafil at 6 months was evident in a variety of measures: absolute median distance walked (432.5 m vs. 358 m) and mean distance walked (434.6 m vs. 359.4 m), and absolute increase (80 m vs. 17.5 m) and relative increase (21.4% vs. 4.9%) The difference was significant for all measures at P less than .001.

The denervation group had a comparatively greater reduction of pulmonary vascular resistance (29.8% vs. 3.4%; P less than .001) and were less likely to experience clinical worsening (16.7% vs. 40.0%; P = .014).

There was a single fatal pulmonary embolism in each treatment group. Of the seven total deaths, two occurred in the denervation group (one attributable to pump failure, one a sudden death) and five occurred in the sham sildenafil group (all but one attributable to pump failure).

Dr. Chen disclosed that he had no relevant conflicts of interest. The trial was sponsored by Nanjing First Hospital, Nanjing Medical University.

SOURCE: Chen S-J et al. TCT 2018. JACC Cardiovasc Interv. 2018 Sep 23.

 

SAN DIEGO – Pulmonary artery denervation is efficacious for treating combined pre- and postcapillary pulmonary hypertension attributable to left heart failure, based on results of the Chinese PADN-5 trial reported at the Transcatheter Cardiovascular Therapeutics annual meeting.

Susan London/MDedge News

This ablative treatment has been studied among patients with pulmonary hypertension attributable to other etiologies, but not in randomized fashion among this population, noted lead investigator Shao-Liang Chen, MD, of Nanjing (China) First Hospital, Nanjing Medical University. The treatment is an attractive one, as medications recommended for pulmonary arterial hypertension are not recommended for joint pre- and postcapillary pulmonary hypertension (group II pulmonary hypertension).

In PADN-5, 98 patients were randomized to pulmonary artery denervation or to sham denervation plus open-label sildenafil (Viagra), which at the time of trial initiation was thought to be safe and potentially beneficial.

The trial’s main outcome, 6-minute walk distance at 6 months, improved in both groups, according to data reported at the meeting and simultaneously published in JACC Cardiovascular Interventions. But the improvement was about four times greater in the pulmonary artery denervation group. Secondary efficacy outcomes also favored that group, and the rate of fatal pulmonary embolism did not differ for the two groups.

“The PADN-5 trial demonstrates the benefits of pulmonary artery denervation for patients with combined pre- and postcapillary pulmonary hypertension. Patients with preserved and with reduced ejection fraction equally benefited,” summarized Dr. Chen, who pioneered this procedure about 7 years ago. “There was no sign of any harm of sildenafil in patients with combined pre- and postcapillary pulmonary hypertension.”
 

Trial critique

“This is a very difficult study to conduct, being able to recruit patients and actually have these procedures done,” commented press conference moderator Ori Ben-Yehuda, MD, professor of clinical medicine and director, coronary care unit, UC San Diego Medical Center.

At the same time, he expressed some reservations about the trial. “Sildenafil in the control group might actually be expected to ... decrease your effect size. Also, particularly in men, perhaps even in women, it might unblind them to which group they are in and undermine your sham design,” he noted. In addition, some hemodynamic changes after pulmonary artery denervation – a decrease in wedge pressure and an increase in ejection fraction – were puzzling.

“We need a lot more data here. There are some issues with this trial in terms of design, and we haven’t even gotten into the issue of whether there were core labs, whether the echoes, the hemodynamics, were read blindly,” Dr. Ben-Yehuda maintained. “This issue of secondary or group II pulmonary hypertension due to left heart failure is one that has been very frustrating in terms of actual PA-specific therapies. So this is an important step further, but it needs confirmation in truly sham-controlled trials that have no potential for unblinding.”

The catheter used in PADN-5 is available in China but has not received clearance in the United States, he pointed out. “There are alternative or competing technologies, one using ultrasound, for example, that has a very similar approach. … We’ll have to see how it ends up [performing].”
 

 

Trial details

Patients in the PADN-5 pulmonary artery denervation group underwent ablation only in the periconjunctional area between the distal main trunk and the left ostial branch with a multifunction catheter having premounted electrodes. Those in the control group underwent a sham procedure, with catheter positioning at the target sites and connection to a generator but no ablation, and were given open-label sildenafil. All additionally received standard heart failure medical therapy. (No sildenafil placebo was used in the denervation group.)

Trial results reported at the meeting, which is sponsored by the Cardiovascular Research Foundation, showed that most echocardiographic and hemodynamic measures improved more in the pulmonary artery denervation group.

The greater improvement in 6-minute walk test with denervation versus sham sildenafil at 6 months was evident in a variety of measures: absolute median distance walked (432.5 m vs. 358 m) and mean distance walked (434.6 m vs. 359.4 m), and absolute increase (80 m vs. 17.5 m) and relative increase (21.4% vs. 4.9%) The difference was significant for all measures at P less than .001.

The denervation group had a comparatively greater reduction of pulmonary vascular resistance (29.8% vs. 3.4%; P less than .001) and were less likely to experience clinical worsening (16.7% vs. 40.0%; P = .014).

There was a single fatal pulmonary embolism in each treatment group. Of the seven total deaths, two occurred in the denervation group (one attributable to pump failure, one a sudden death) and five occurred in the sham sildenafil group (all but one attributable to pump failure).

Dr. Chen disclosed that he had no relevant conflicts of interest. The trial was sponsored by Nanjing First Hospital, Nanjing Medical University.

SOURCE: Chen S-J et al. TCT 2018. JACC Cardiovasc Interv. 2018 Sep 23.

 

The U.S. Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, the agency announced in a press release.

The monoclonal antibody drug – a checkpoint inhibitor that blocks the PD-1 pathway – is the first treatment to be approved specifically for advanced cutaneous squamous cell carcinoma in patients who are not candidates for curative surgery or curative radiation.

The approval was granted based on data from two open-label clinical trials involving a total of 108 patients: the phase 2 EMPOWER-CSCC-1 trial (NCT02760498) and two expansion cohorts from an open-label, nonrandomized phase 1 trial.

These trials, which included 75 patients with metastatic disease and 33 with locally advanced disease, found an overall response rate of 47.2%, and most of those patients still showed ongoing responses at the time of data analysis. Among patients with metastatic disease, 5% had a complete response, according to a press release from the manufacturer, Sanofi.

This is the sixth FDA approval for a checkpoint inhibitor targeting the PD-1/PD-L1 pathway. The drug was evaluated under the FDA’s Priority Review program for drugs that represent significant improvements in the safety or effectiveness of treatments for serious conditions. Manufacturer Sanofi was granted Breakthrough Therapy designation for cemiplimab in 2017 for advanced cutaneous squamous cell carcinoma, and the drug is also being reviewed by the European Medicines Agency.

Cemiplimab is administered as a 350-mg intravenous therapy every 3 weeks – costing $9,100 per treatment – until the disease progresses or patients experience unacceptable toxicity, according to the manufacturer. The most common side effects include fatigue, rash and diarrhea, but more serious adverse events can include immune-mediated reactions such as pneumonitis, colitis, hepatitis, endocrinopathies, and skin and kidney problems.

 

The U.S. Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, the agency announced in a press release.

The monoclonal antibody drug – a checkpoint inhibitor that blocks the PD-1 pathway – is the first treatment to be approved specifically for advanced cutaneous squamous cell carcinoma in patients who are not candidates for curative surgery or curative radiation.

The approval was granted based on data from two open-label clinical trials involving a total of 108 patients: the phase 2 EMPOWER-CSCC-1 trial (NCT02760498) and two expansion cohorts from an open-label, nonrandomized phase 1 trial.

These trials, which included 75 patients with metastatic disease and 33 with locally advanced disease, found an overall response rate of 47.2%, and most of those patients still showed ongoing responses at the time of data analysis. Among patients with metastatic disease, 5% had a complete response, according to a press release from the manufacturer, Sanofi.

This is the sixth FDA approval for a checkpoint inhibitor targeting the PD-1/PD-L1 pathway. The drug was evaluated under the FDA’s Priority Review program for drugs that represent significant improvements in the safety or effectiveness of treatments for serious conditions. Manufacturer Sanofi was granted Breakthrough Therapy designation for cemiplimab in 2017 for advanced cutaneous squamous cell carcinoma, and the drug is also being reviewed by the European Medicines Agency.

Cemiplimab is administered as a 350-mg intravenous therapy every 3 weeks – costing $9,100 per treatment – until the disease progresses or patients experience unacceptable toxicity, according to the manufacturer. The most common side effects include fatigue, rash and diarrhea, but more serious adverse events can include immune-mediated reactions such as pneumonitis, colitis, hepatitis, endocrinopathies, and skin and kidney problems.

 

The U.S. Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma, the agency announced in a press release.

The monoclonal antibody drug – a checkpoint inhibitor that blocks the PD-1 pathway – is the first treatment to be approved specifically for advanced cutaneous squamous cell carcinoma in patients who are not candidates for curative surgery or curative radiation.

The approval was granted based on data from two open-label clinical trials involving a total of 108 patients: the phase 2 EMPOWER-CSCC-1 trial (NCT02760498) and two expansion cohorts from an open-label, nonrandomized phase 1 trial.

These trials, which included 75 patients with metastatic disease and 33 with locally advanced disease, found an overall response rate of 47.2%, and most of those patients still showed ongoing responses at the time of data analysis. Among patients with metastatic disease, 5% had a complete response, according to a press release from the manufacturer, Sanofi.

This is the sixth FDA approval for a checkpoint inhibitor targeting the PD-1/PD-L1 pathway. The drug was evaluated under the FDA’s Priority Review program for drugs that represent significant improvements in the safety or effectiveness of treatments for serious conditions. Manufacturer Sanofi was granted Breakthrough Therapy designation for cemiplimab in 2017 for advanced cutaneous squamous cell carcinoma, and the drug is also being reviewed by the European Medicines Agency.

Cemiplimab is administered as a 350-mg intravenous therapy every 3 weeks – costing $9,100 per treatment – until the disease progresses or patients experience unacceptable toxicity, according to the manufacturer. The most common side effects include fatigue, rash and diarrhea, but more serious adverse events can include immune-mediated reactions such as pneumonitis, colitis, hepatitis, endocrinopathies, and skin and kidney problems.