Migraine is a highly disabling primary headache disorder that affects more than 44 million Americans annually.¹ The disorder causes pain, photophobia, phonophobia, and nausea that can last for hours, even days. Migraine headaches are 2 times more common in women than in men; although migraine is most common in people 30 to 39 years of age, all ages are affected.^2,3 Frequency of migraine headache is variable; chronic migraineurs experience more than 15 headache days a month.

©Cath Riley/Science Source

Recent estimates indicate that the cost of acute and chronic migraine headaches reaches approximately $78 million a year in the United States. ⁴ This high burden of disease has made effective migraine treatment options absolutely essential. Recent advances in our understanding of migraine pathophysiology have led to new therapeutic targets; there are now many novel treatment approaches on the horizon.

In this article, we review the diagnosis and management of migraine in detail. Our emphasis is on evidence-based approaches to acute and prophylactic treatment, including tried-and-true options and newly emerging therapies.

Neuronal dysfunction and a genetic predisposition

Although migraine was once thought to be caused by abnormalities of vasodilation, current research suggests that the disorder has its origins in primary neuronal dysfunction. There appears to be a genetic predisposition toward widespread neuronal hyperexcitability in migraineurs.⁵ In addition, hypothalamic neurons are thought to initiate migraine by responding to changes in brain homeostasis. Increased parasympathetic tone might activate meningeal pain receptors or lower the threshold for transmitting pain signals from the thalamus to the cortex.⁶

Prodromal symptoms and aura appear to originate from multiple areas across the brain, including the hypothalamus, cortex, limbic system, and brainstem. This widespread brain involvement might explain why some headache sufferers concurrently experience a variety of symptoms, including fatigue, depression, muscle pain, and an abnormal sensitivity to light, sound, and smell.^6,7

After taking the initial history (headache onset, location, duration, associated symptoms), focus attention on assessing the risk of intracranial pathology.

Although the exact mechanisms behind each of these symptoms have yet to be defined precisely, waves of neuronal depolarization—known as cortical spreading depression—are suspected to cause migraine aura.^8-10 Cortical spreading depression activates the trigeminal pain pathway and leads to the release of pro-inflammatory markers such as calcitonin gene-related protein (CGRP).⁶ A better understanding of these complex signaling pathways has helped provide potential therapeutic targets for new migraine drugs.

Diagnosis: Close patient inquiry is most helpful

The International Headache Society (IHS) criteria for primary headache disorders serve as the basis for the diagnosis of migraine and its subtypes, which include migraine without aura and migraine with aura. Due to variability of presentation, migraine with aura is further subdivided into migraine with typical aura (with and without headache), migraine with brainstem aura, hemiplegic migraine, and retinal migraine.¹¹

Continue to: How is migraine defined?

How is migraine defined? Simply, migraine is classically defined as a unilateral, pulsating headache of moderate to severe intensity lasting 4 to 72 hours, associated with photophobia and phonophobia or nausea and vomiting, or both.¹¹ Often visual in nature, aura is a set of neurologic symptoms that lasts for minutes and precedes the onset of the headache. The visual aura is often described as a scintillating scotoma that begins near the point of visual fixation and then spreads left or right. Other aura symptoms include tingling or numbness (second most common), speech disturbance (aphasia), motor changes and, in rare cases, a combination of these in succession. By definition, all of these symptoms fully resolve between attacks.¹¹

Validated valuable questionnaires. To help with accurate and timely diagnosis, researchers have developed and validated simplified questionnaires that can be completed independently by patients presenting to primary care (TABLE 1^12,13):

• ID Migraine is a set of 3 questions that scores positive when a patient endorses at least 2 of the 3 symptoms. ¹²
• MS-Q is similar to the ID Migraine but includes 5 items. A score of ≥4 is a positive screen. ¹³

The sensitivity and specificity of MS-Q (0.93 and 0.81, respectively) are slightly higher than those of ID Migraine (0.81 and 0.75).¹³

Remember POUND. This mnemonic device can also be used during history-taking to aid in diagnostic accuracy. Migraine is highly likely (92%) in patients who endorse 4 of the following 5 symptoms and unlikely (17%) in those who endorse ≤2 symptoms¹⁴: Pulsatile quality of headache 4 to 72 hOurs in duration, Unilateral location, Nausea or vomiting, and Disabling intensity.

Differential Dx. Although the differential diagnosis of headache is broad (TABLE 2^14,15), the history alone can often guide clinicians towards the correct assessment. After taking the initial history (headache onset, location, duration, and associated symptoms), focus your attention on assessing the risk of intracranial pathology. This is best accomplished by assessing specific details of the history (TABLE 3¹⁴) and findings on physical examination¹⁵:

• blood pressure measurement (seated, legs uncrossed, feet flat on the floor; having rested for 5 minutes; arm well supported)
• cranial nerve exam
• extremity strength testing
• eye exam (vision, extra-ocular muscles, visual fields, pupillary reactivity, and funduscopic exam)
• gait (tandem walk)
• reflexes.

Continue to: Further testing needed?

Further testing needed? Neuroimaging should be considered only in patients with an abnormal neurologic exam, atypical headache features, or certain risk factors, such as an immune deficiency. There is no role for electroencephalography or other diagnostic testing in migraine.¹⁶

Take a multipronged approach to treatment

As with other complex, chronic conditions, the treatment of migraine should take a multifaceted approach, including management of acute symptoms as well as prevention of future headaches. In 2015, the American Headache Society published a systematic review that specified particular treatment goals for migraine sufferers. ¹⁷ These goals include:

• headache reduction
• headache relief
• decreased disability from headache
• elimination of nausea and vomiting
• elimination of photophobia and phonophobia.

Our review, which follows, of therapeutic options focuses on the management of migraine in adults. Approaches in special populations (older adults, pregnant women, and children) are discussed afterward.

Pharmacotherapy for acute migraine

Acute migraine should be treated with an abortive medication at the onset of headache. The immediate goal is to relieve pain within 2 hours and prevent its recurrence within the subsequent 48 hours (TABLE 4^12,18-20).

Electroencephalography and other diagnostic testing have no role in the workup of migraine.

In the general population, mild, infrequent migraines can be managed with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).²¹

Continue to: For moderate-to-severe migraine...

For moderate-to-severe migraine, triptans, which target serotonin receptors, are the drug of choice for most patients.²¹ Triptans are superior to placebo in achieving a pain-free state at 2 and 24 hours after administration; eletriptan has the most desirable outcome, with 68% of patients pain free at 2 hours and 54% pain free at 24 hours.²² Triptans are available as sublingual tablets and nasal sprays, as well as subcutaneous injections for patients with significant associated nausea and vomiting. Avoid prescribing triptans for patients with known vascular disease (eg, history of stroke, myocardial infarction, peripheral vascular disease, uncontrolled hypertension, or signs and symptoms of these conditions), as well as for patients with severe hepatic impairment.

Treat migraine with a multifaceted approach, including management of acute symptoms and prevention of future headaches.

Importantly, although triptans all have a similar mechanism of action, patients might respond differently to different drugs within the class. If a patient does not get adequate headache relief from an appropriate dosage of a given triptan during a particular migraine episode, a different triptan can be tried during the next migraine.²² Additionally, if a patient experiences an adverse effect from one triptan, this does not necessarily mean that a trial of another triptan at a later time is contraindicated.

For patients who have an incomplete response to migraine treatment or for those with frequent recurrence, the combination formulation of sumatriptan, 85 mg, and naproxen, 500 mg, showed the highest rate of resolution of headache within 2 hours compared with either drug alone.²³ A similar result might be found by combining a triptan known to be effective for a patient and an NSAID other than naproxen. If migraine persists despite initial treatment of an attack, a different class of medication should be tried during the course of that attack to attain relief of symptoms of that migraine.²¹

When a patient is seen in an acute care setting (eg, emergency department, urgent care center) while suffering a migraine, additional treatment options are available. Intravenous (IV) anti-emetics are useful for relieving the pain of migraine and nausea, and can be used in combination with an IV NSAID (eg, ketorolac).²¹ The most effective anti-emetics are dopamine receptor type-2 blockers, including chlorpromazine, droperidol, metoclopramide, and prochlorperazine, which has the highest level of efficacy.²⁴ Note that these medications do present the risk of a dystonic reaction; diphenhydramine is therefore often used in tandem to mitigate such a response.

Looking ahead. Although triptans are the current first-line therapy for acute migraine, their effectiveness is limited. Only 20% of patients report sustained relief of pain in the 2 to 24 hours after treatment, and the response can vary from episode to episode.²⁵

Continue to: With better understading of the pathophysiology of migraine...

With better understanding of the pathophysiology of migraine, a host of novel anti-migraine drugs are on the horizon.

CGRP receptor antagonists. The neuropeptide CGRP, which mediates central and peripheral nervous system pain signaling, has been noted to be elevated during acute migraine attacks²⁶; clinical trials are therefore underway to evaluate the safety and efficacy of CGRP receptor antagonists.¹⁸ These agents appear to be better tolerated than triptans, have fewer vascular and central nervous system adverse effects, and present less of a risk of medication overuse headache.¹⁸ Liver toxicity has been seen with some medications in this class and remains an important concern in their development.¹⁹

Phase 3 clinical trials for 1 drug in this class, ubrogepant, were completed in late 2017; full analysis of the data is not yet available. Primary outcomes being evaluated include relief of pain at 2 hours and relief from the most bothersome symptoms again at 2 hours.²⁷

Selective serotonin-HT_1f receptor agonists, such as lasmiditan, offer another potential approach. Although the exact mechanism of action of these agents is not entirely clear, clinical trials have supported their efficacy and safety.²⁰ Importantly, ongoing trials are specifically targeting patients with known cardiovascular risk factors because they are most likely to benefit from the nonvasoconstrictive mechanism of action.^28,29 Adverse effects reported primarily include dizziness, fatigue, and vertigo.

Strategies for managing recurrent episodic migraine

Because of the risk of medication overuse headache with acute treatment, daily preventive therapy for migraine is indicated for any patient with ³⁰ :

• ≥6 headache days a month
• ≥4 headache days a month with some impairment
• ≥3 headache days a month with severe impairment.

Continue to: Treatment begins by having patients identify...

Treatment begins by having patients identify, and then avoid, migraine triggers (TABLE 5). This can be accomplished by having patients keep a headache diary, in which they can enter notations about personal and environmental situations that precede a headache.

For the individual patient, some triggers are modifiable; others are not. Helping a patient develop strategies for coping with triggers, rather than aiming for complete avoidance, might help her (him) manage those that are inescapable (eg stress, menstruation, etc).³¹ For many patients, however, this is not an adequate intervention and other approaches must be explored. When considering which therapy might be best for a given patient, evaluate her (his) comorbidities and assess that particular treatment for potential secondary benefits and the possibility of adverse effects. Pay attention to the choice of preventive therapy in women who are considering pregnancy because many available treatments are potentially teratogenic.

Oral medications. Oral agents from several classes of drugs can be used for migraine prophylaxis, including anti-epileptics,antidepressants, and antihypertensives (TABLE 6^{20,29,30,32-41}). Selected anti-epileptics (divalproex sodium, sodium valproate, topiramate) and beta-blockers (metoprolol, propranolol, and timolol) have the strongest evidence to support their use.³² Overall, regular use of prophylactic medications can reduce headache frequency by 50% for approximately 40% to 45% of patients who take them.²⁹ However, adherence may be limited by adverse effects or perceived lack of efficacy, thus reducing their potential for benefit.⁴²

OnabotulinumtoxinA. In patients with chronic migraine (≥15 headache days a month for at least 3 months) who have failed oral medications, the American Academy of Neurology (AAN) recommends the use of onabotulinumtoxinA.³⁰ The treatment regimen comprises 31 injections at various sites on the head, neck, and shoulders every 3 months.³³

A 2010 large randomized controlled trial showed a decrease in the frequency of headache days for patients receiving onabotulinumtoxinA compared to placebo after a 24-week treatment period (7.8 fewer headache days a month, compared to 6.4 fewer in the placebo group).³³ A recent systematic review also noted a reduction of 2 headache days a month compared with placebo; the authors cautioned, however, that data with which to evaluate onabotulinumtoxinA in comparison to other prophylactic agents are limited.⁴³

Continue to: In both studies...

In both studies, the risk of adverse drug events due to onabotulinumtoxinA was high and led to a significant rate of discontinuation.^33,43 Despite this, onabotulinumtoxinA remains the only Food and Drug Administration (FDA)–approved treatment for chronic migraine, making it reasonable to consider for appropriate patients.

Acupuncture. A 2016 Cochrane review found benefit for patients using acupuncture compared with sham acupuncture.³⁴ When acupuncture was compared with prophylactic agents such as beta-blockers, calcium-channel blockers, and anti-epileptics, however, there was no significant difference between the procedure and pharmacotherapy. Patients willing and able to try acupuncture might see a reduction in the overall number of headaches. Acupuncture has few adverse effects; however, long-term data are lacking.³⁴

Exercise is not supported by robust data for its role as a prophylactic treatment. It is generally considered safe in most populations, however, and can be pursued with little out-of-pocket cost.³⁵

Cognitive behavioral therapy (CBT). The AAN recommends CBT, relaxation therapy, and biofeedback therapy. Accessibility of these services remains limited for many patients, and cost can be prohibitive.¹⁶

Supplements used to help prevent migraine include the root of Petasites hybridus (butterbur), magnesium, vitamin B2 (riboflavin), Tanacetum parthenium (feverfew), and coenzyme Q10.¹⁶ Although the strength of evidence for these therapies is limited by small trials, their overall risk of adverse effects is low, and they might be easier for patients to obtain than acupuncture or CBT.

Continue to: Butterbur, in particular...

Butterbur, in particular, has been found to be beneficial for migraine prevention in 2 small placebo-controlled trials. In a randomized controlled study of 245 patients P hybridus, (specifically, the German formulation, Petadolex), 75 mg BID, reduced the frequency of migraine attack by 48% at 4 months, compared to placebo (number needed to treat, 5.3).⁴⁴ No difference was found at lower dosages. The most common reported adverse effect was burping.

Regrettably, unpurified butterbur extract contains pyrrolizidine alkaloids, potentially hepatotoxic and carcinogenic compounds. Because of variations in purification in production facilities in the United States, butterbur supplements might not have all of these compounds removed—and so should be used with caution.⁴¹

Magnesium. Studies evaluating the use of magnesium have demonstrated varied results; differences in methods and dosing have limited broad application of findings. As with most supplements considered for prophylactic treatment, magnesium dosing is poorly understood, and bioavailability varies in its different forms. Oral supplementation can be given as magnesium dicitrate, 600 mg/d.⁴⁵

Recently, products containing various combinations of feverfew, coenzyme Q10, riboflavin, magnesium, and other supplements have shown benefit in early clinical trials.^36,37

Neural stimulation. Over the past few years, a variety of transcutaneous nerve stimulator devices have gained FDA approval for use in migraine prophylaxis. The long-term safety and efficacy of these devices is not yet well understood, but they appear to provide headache relief in the short term and decrease the frequency of headache.³⁸ Use of the noninvasive stimulators is limited today by high cost and poor coverage by US health care insurers.

Continue to: Newly available medical therapy

Newly available medical therapy. The FDA recently approved erenumab, a fully human monoclonal antibody for prevention of migraine in adults. This is the first drug in the CGRP antagonist class to be approved for this indication. Trials of this once-monthly, self-injectable drug show promising results for patients whose migraines have been refractory to other therapies.

A recent large trial evaluated 955 adults with migraine, randomizing them to receive erenumab, 70 mg; erenumab, 140 mg; or placebo over 28 weeks.³⁹ The groups receiving erenumab had a nearly 2-fold higher odds of having their migraine reduced by 50%, compared with placebo (number needed to treat with the 140-mg dose, 4.27). Similar numbers of participants from all groups discontinued the study.³⁹ Phase 3 trials that are not yet formally published have produced similarly beneficial results.^40,46 The FDA has listed injection site reaction and constipation as the most reported adverse effects.⁴⁰

Three other anti-CGRP antibodies are likely to be approved in the near future: fremanezumab, galcanezumab, and eptinezumab.

The approach to migraine in special populations

Management of acute and chronic migraine in children, pregnant women, and older adults requires special attention: Treatment approaches are different than they are for adults 19 to 65 years of age.

Pediatric patients. Migraine is the most common acute and recurrent headache syndrome in children. Headaches differ from those of adult migraine as a result of variations in brain maturation, plasticity, and cognitive development.⁴⁷ Migraine attacks are often of shorter duration in children, lasting 1 to 2 hours, but can still be preceded by visual aura.⁴⁸ Just as with adults, imaging, electroencephalography, lumbar puncture, and routine labs should be considered only if a child has an abnormal neurological exam or other concerning features (TABLE 2^14,15).

Continue to: The general approach to migraine treatment...

The general approach to migraine treatment in the pediatric population includes education of the child and family about symptom management. Acetaminophen, NSAIDs, and triptans are approved for abortive therapy in children and should be used for acute headache relief in the same way that they are used in adults. Oral rizatriptan, the most well studied triptan in the pediatric population, is approved for use in children as young as 6 years⁴⁹; the pediatric dosage is 5 mg/d for patients weighing 20 to 39 kg and 10 mg/d for patients weighing more than 40 kg (same as the adult dosage).

Don’t prescribe triptans for patients with known vascular disease or severe hepatic impairment.

Oral almotriptan and zolmitriptan are also approved for use in children 12 to 17 years of age. Usual dosages are: almotriptan, 12.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 25 mg/d); and zolmitriptan, 2.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 10 mg/d).⁵⁰

For children who are unable to swallow pills or who are vomiting, a non-oral route of administration is preferable. Rizatriptan is available as an orally disintegrating tablet. Zolmitriptan is available in a nasal spray at a dose of 5 mg for children 12 years and older. Sumatriptan is not approved for use in patients younger than 18 years; however, recent studies have shown that it might have good efficacy and tolerability.⁵⁰

Daily prophylactic treatment for recurrent migraine in the pediatric population is an evolving subject; published guidelines do not exist. It is reasonable to consider treatment using the same guidelines as those in place for adults.⁵¹ Topiramate, 1 to 2 mg/kg/d, is the only therapy approved by the FDA for episodic migraine preventive therapy in adolescents.⁵⁰

If a patient doesn’t get adequate headache relief from an appropriate dosage of a given triptan, try a different triptan during the next migraine.

Notably, a nonpharmacotherapeutic approach may be more effective for pediatric prevention. In 2017, a large double-blind, placebo-controlled trial investigated the use of amitriptyline, topiramate, and placebo for the treatment of recurrent migraine in children 8 to 17 years of age. An interim analysis of the 328 children enrolled found no significant differences in reduction of headache frequency with treatment compared with placebo over a 24-week period; the trial was stopped early due to futility.⁵²

Continue to: The study did show...

The study did show, however, that reducing migraine triggers provided a high level of benefit to study participants. Stress is one of the most common migraine triggers in children; lack of sleep, exposure to a warm climate, and exposure to video games are also notable triggers.⁵³ CBT may augment the efficacy of standard migraine medications in the pediatric population and may help prevent recurrence of episodes.⁵⁴

Pregnancy. The treatment of migraine is different in pregnant women than it is in nonpregnant adults because of a concern over adverse effects on fetal development. For acute headache treatment, first-line therapies include trigger avoidance and acetaminophen, 1000 mg (maximum dosage, 4000 mg/d).⁵⁵ If this is ineffective, a 10-mg dose of metoclopramide, as often as every 6 hours (not an FDA-approved indication), can be considered. During the second trimester, NSAIDs can be considered second-line therapy.

Triptans—specifically, sumatriptan and rizatriptan—can also be considered if first-line therapies fail.⁵⁶ Triptan-exposed pregnant women with migraine have a rate of congenital malformations, spontaneous abortions, and prematurity that is similar to what is seen in pregnant women with migraine who have not been exposed to triptans. However, when triptan-exposed women are compared with healthy, non-migraine-suffering women, the rate of spontaneous abortion appears to be increased in the triptan-exposed population.⁵⁷

Ergotamine is contraindicated during pregnancy because of its potential to induce uterine contractions and vasospasm, which can be detrimental to the fetus.⁵⁶Nonpharmacotherapeutic interventions such as heat, ice, massage, rest, and avoidance of triggers are as successful in the pregnant population as in the nonpregnant population. For migraine prevention, coenzyme Q10, vitamins B2 and B6 (pyridoxine), and oral magnesium can be considered. Feverfew and butterbur should be avoided because of concerns about fetal malformation and preterm labor.⁵⁸

Older adults. Choosing appropriate migraine therapy for older adults requires special consideration because of changes in drug metabolism and risks associated with drug adverse effects. Additionally, few studies of migraine drugs have included large populations of adults older than 65 years; medications should therefore be prescribed cautiously in this population, with particular attention to drug–drug interactions.

Continue to: Just as for younger adults...

Just as for younger adults, mild symptoms can be managed effectively with acetaminophen. NSAIDs may be used as well, but carry increased risks of gastric bleeding and elevation in blood pressure.⁵⁹ The use of triptans is acceptable for the appropriate patient, but should be avoided in patients with known vascular disease.⁶⁰ Antiemetics present an increased risk of extrapyramidal adverse effects in the elderly and should be used with caution at the lowest effective dosage.⁵⁹ Novel mechanisms of action make some of the newer agents potentially safer for use in older adults when treating acute migraine.

Stress is one of the most common migraine triggers in children.

For migraine prevention in older adults, particular attention should be paid to reducing triggers and minimizing polypharmacy.

More and more, successful treatment is within reach

With many clinical trials evaluating novel drugs underway, and additional studies contributing to our understanding of nonpharmacotherapeutic approaches to migraine treatment, improved headache control may become increasingly common over the next few years.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Thomas Jefferson University, 1015 Walnut St, Philadelphia PA 19107; [email protected].

Migraine is a highly disabling primary headache disorder that affects more than 44 million Americans annually.¹ The disorder causes pain, photophobia, phonophobia, and nausea that can last for hours, even days. Migraine headaches are 2 times more common in women than in men; although migraine is most common in people 30 to 39 years of age, all ages are affected.^2,3 Frequency of migraine headache is variable; chronic migraineurs experience more than 15 headache days a month.

©Cath Riley/Science Source

Recent estimates indicate that the cost of acute and chronic migraine headaches reaches approximately $78 million a year in the United States. ⁴ This high burden of disease has made effective migraine treatment options absolutely essential. Recent advances in our understanding of migraine pathophysiology have led to new therapeutic targets; there are now many novel treatment approaches on the horizon.

In this article, we review the diagnosis and management of migraine in detail. Our emphasis is on evidence-based approaches to acute and prophylactic treatment, including tried-and-true options and newly emerging therapies.

Neuronal dysfunction and a genetic predisposition

Although migraine was once thought to be caused by abnormalities of vasodilation, current research suggests that the disorder has its origins in primary neuronal dysfunction. There appears to be a genetic predisposition toward widespread neuronal hyperexcitability in migraineurs.⁵ In addition, hypothalamic neurons are thought to initiate migraine by responding to changes in brain homeostasis. Increased parasympathetic tone might activate meningeal pain receptors or lower the threshold for transmitting pain signals from the thalamus to the cortex.⁶

Prodromal symptoms and aura appear to originate from multiple areas across the brain, including the hypothalamus, cortex, limbic system, and brainstem. This widespread brain involvement might explain why some headache sufferers concurrently experience a variety of symptoms, including fatigue, depression, muscle pain, and an abnormal sensitivity to light, sound, and smell.^6,7

After taking the initial history (headache onset, location, duration, associated symptoms), focus attention on assessing the risk of intracranial pathology.

Although the exact mechanisms behind each of these symptoms have yet to be defined precisely, waves of neuronal depolarization—known as cortical spreading depression—are suspected to cause migraine aura.^8-10 Cortical spreading depression activates the trigeminal pain pathway and leads to the release of pro-inflammatory markers such as calcitonin gene-related protein (CGRP).⁶ A better understanding of these complex signaling pathways has helped provide potential therapeutic targets for new migraine drugs.

Diagnosis: Close patient inquiry is most helpful

The International Headache Society (IHS) criteria for primary headache disorders serve as the basis for the diagnosis of migraine and its subtypes, which include migraine without aura and migraine with aura. Due to variability of presentation, migraine with aura is further subdivided into migraine with typical aura (with and without headache), migraine with brainstem aura, hemiplegic migraine, and retinal migraine.¹¹

Continue to: How is migraine defined?

How is migraine defined? Simply, migraine is classically defined as a unilateral, pulsating headache of moderate to severe intensity lasting 4 to 72 hours, associated with photophobia and phonophobia or nausea and vomiting, or both.¹¹ Often visual in nature, aura is a set of neurologic symptoms that lasts for minutes and precedes the onset of the headache. The visual aura is often described as a scintillating scotoma that begins near the point of visual fixation and then spreads left or right. Other aura symptoms include tingling or numbness (second most common), speech disturbance (aphasia), motor changes and, in rare cases, a combination of these in succession. By definition, all of these symptoms fully resolve between attacks.¹¹

Validated valuable questionnaires. To help with accurate and timely diagnosis, researchers have developed and validated simplified questionnaires that can be completed independently by patients presenting to primary care (TABLE 1^12,13):

• ID Migraine is a set of 3 questions that scores positive when a patient endorses at least 2 of the 3 symptoms. ¹²
• MS-Q is similar to the ID Migraine but includes 5 items. A score of ≥4 is a positive screen. ¹³

The sensitivity and specificity of MS-Q (0.93 and 0.81, respectively) are slightly higher than those of ID Migraine (0.81 and 0.75).¹³

Remember POUND. This mnemonic device can also be used during history-taking to aid in diagnostic accuracy. Migraine is highly likely (92%) in patients who endorse 4 of the following 5 symptoms and unlikely (17%) in those who endorse ≤2 symptoms¹⁴: Pulsatile quality of headache 4 to 72 hOurs in duration, Unilateral location, Nausea or vomiting, and Disabling intensity.

Differential Dx. Although the differential diagnosis of headache is broad (TABLE 2^14,15), the history alone can often guide clinicians towards the correct assessment. After taking the initial history (headache onset, location, duration, and associated symptoms), focus your attention on assessing the risk of intracranial pathology. This is best accomplished by assessing specific details of the history (TABLE 3¹⁴) and findings on physical examination¹⁵:

• blood pressure measurement (seated, legs uncrossed, feet flat on the floor; having rested for 5 minutes; arm well supported)
• cranial nerve exam
• extremity strength testing
• eye exam (vision, extra-ocular muscles, visual fields, pupillary reactivity, and funduscopic exam)
• gait (tandem walk)
• reflexes.

Continue to: Further testing needed?

Further testing needed? Neuroimaging should be considered only in patients with an abnormal neurologic exam, atypical headache features, or certain risk factors, such as an immune deficiency. There is no role for electroencephalography or other diagnostic testing in migraine.¹⁶

Take a multipronged approach to treatment

As with other complex, chronic conditions, the treatment of migraine should take a multifaceted approach, including management of acute symptoms as well as prevention of future headaches. In 2015, the American Headache Society published a systematic review that specified particular treatment goals for migraine sufferers. ¹⁷ These goals include:

• headache reduction
• headache relief
• decreased disability from headache
• elimination of nausea and vomiting
• elimination of photophobia and phonophobia.

Our review, which follows, of therapeutic options focuses on the management of migraine in adults. Approaches in special populations (older adults, pregnant women, and children) are discussed afterward.

Pharmacotherapy for acute migraine

Acute migraine should be treated with an abortive medication at the onset of headache. The immediate goal is to relieve pain within 2 hours and prevent its recurrence within the subsequent 48 hours (TABLE 4^12,18-20).

Electroencephalography and other diagnostic testing have no role in the workup of migraine.

In the general population, mild, infrequent migraines can be managed with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).²¹

Continue to: For moderate-to-severe migraine...

For moderate-to-severe migraine, triptans, which target serotonin receptors, are the drug of choice for most patients.²¹ Triptans are superior to placebo in achieving a pain-free state at 2 and 24 hours after administration; eletriptan has the most desirable outcome, with 68% of patients pain free at 2 hours and 54% pain free at 24 hours.²² Triptans are available as sublingual tablets and nasal sprays, as well as subcutaneous injections for patients with significant associated nausea and vomiting. Avoid prescribing triptans for patients with known vascular disease (eg, history of stroke, myocardial infarction, peripheral vascular disease, uncontrolled hypertension, or signs and symptoms of these conditions), as well as for patients with severe hepatic impairment.

Treat migraine with a multifaceted approach, including management of acute symptoms and prevention of future headaches.

Importantly, although triptans all have a similar mechanism of action, patients might respond differently to different drugs within the class. If a patient does not get adequate headache relief from an appropriate dosage of a given triptan during a particular migraine episode, a different triptan can be tried during the next migraine.²² Additionally, if a patient experiences an adverse effect from one triptan, this does not necessarily mean that a trial of another triptan at a later time is contraindicated.

For patients who have an incomplete response to migraine treatment or for those with frequent recurrence, the combination formulation of sumatriptan, 85 mg, and naproxen, 500 mg, showed the highest rate of resolution of headache within 2 hours compared with either drug alone.²³ A similar result might be found by combining a triptan known to be effective for a patient and an NSAID other than naproxen. If migraine persists despite initial treatment of an attack, a different class of medication should be tried during the course of that attack to attain relief of symptoms of that migraine.²¹

When a patient is seen in an acute care setting (eg, emergency department, urgent care center) while suffering a migraine, additional treatment options are available. Intravenous (IV) anti-emetics are useful for relieving the pain of migraine and nausea, and can be used in combination with an IV NSAID (eg, ketorolac).²¹ The most effective anti-emetics are dopamine receptor type-2 blockers, including chlorpromazine, droperidol, metoclopramide, and prochlorperazine, which has the highest level of efficacy.²⁴ Note that these medications do present the risk of a dystonic reaction; diphenhydramine is therefore often used in tandem to mitigate such a response.

Looking ahead. Although triptans are the current first-line therapy for acute migraine, their effectiveness is limited. Only 20% of patients report sustained relief of pain in the 2 to 24 hours after treatment, and the response can vary from episode to episode.²⁵

Continue to: With better understading of the pathophysiology of migraine...

With better understanding of the pathophysiology of migraine, a host of novel anti-migraine drugs are on the horizon.

CGRP receptor antagonists. The neuropeptide CGRP, which mediates central and peripheral nervous system pain signaling, has been noted to be elevated during acute migraine attacks²⁶; clinical trials are therefore underway to evaluate the safety and efficacy of CGRP receptor antagonists.¹⁸ These agents appear to be better tolerated than triptans, have fewer vascular and central nervous system adverse effects, and present less of a risk of medication overuse headache.¹⁸ Liver toxicity has been seen with some medications in this class and remains an important concern in their development.¹⁹

Phase 3 clinical trials for 1 drug in this class, ubrogepant, were completed in late 2017; full analysis of the data is not yet available. Primary outcomes being evaluated include relief of pain at 2 hours and relief from the most bothersome symptoms again at 2 hours.²⁷

Selective serotonin-HT_1f receptor agonists, such as lasmiditan, offer another potential approach. Although the exact mechanism of action of these agents is not entirely clear, clinical trials have supported their efficacy and safety.²⁰ Importantly, ongoing trials are specifically targeting patients with known cardiovascular risk factors because they are most likely to benefit from the nonvasoconstrictive mechanism of action.^28,29 Adverse effects reported primarily include dizziness, fatigue, and vertigo.

Strategies for managing recurrent episodic migraine

Because of the risk of medication overuse headache with acute treatment, daily preventive therapy for migraine is indicated for any patient with ³⁰ :

• ≥6 headache days a month
• ≥4 headache days a month with some impairment
• ≥3 headache days a month with severe impairment.

Continue to: Treatment begins by having patients identify...

Treatment begins by having patients identify, and then avoid, migraine triggers (TABLE 5). This can be accomplished by having patients keep a headache diary, in which they can enter notations about personal and environmental situations that precede a headache.

For the individual patient, some triggers are modifiable; others are not. Helping a patient develop strategies for coping with triggers, rather than aiming for complete avoidance, might help her (him) manage those that are inescapable (eg stress, menstruation, etc).³¹ For many patients, however, this is not an adequate intervention and other approaches must be explored. When considering which therapy might be best for a given patient, evaluate her (his) comorbidities and assess that particular treatment for potential secondary benefits and the possibility of adverse effects. Pay attention to the choice of preventive therapy in women who are considering pregnancy because many available treatments are potentially teratogenic.

Oral medications. Oral agents from several classes of drugs can be used for migraine prophylaxis, including anti-epileptics,antidepressants, and antihypertensives (TABLE 6^{20,29,30,32-41}). Selected anti-epileptics (divalproex sodium, sodium valproate, topiramate) and beta-blockers (metoprolol, propranolol, and timolol) have the strongest evidence to support their use.³² Overall, regular use of prophylactic medications can reduce headache frequency by 50% for approximately 40% to 45% of patients who take them.²⁹ However, adherence may be limited by adverse effects or perceived lack of efficacy, thus reducing their potential for benefit.⁴²

OnabotulinumtoxinA. In patients with chronic migraine (≥15 headache days a month for at least 3 months) who have failed oral medications, the American Academy of Neurology (AAN) recommends the use of onabotulinumtoxinA.³⁰ The treatment regimen comprises 31 injections at various sites on the head, neck, and shoulders every 3 months.³³

A 2010 large randomized controlled trial showed a decrease in the frequency of headache days for patients receiving onabotulinumtoxinA compared to placebo after a 24-week treatment period (7.8 fewer headache days a month, compared to 6.4 fewer in the placebo group).³³ A recent systematic review also noted a reduction of 2 headache days a month compared with placebo; the authors cautioned, however, that data with which to evaluate onabotulinumtoxinA in comparison to other prophylactic agents are limited.⁴³

Continue to: In both studies...

In both studies, the risk of adverse drug events due to onabotulinumtoxinA was high and led to a significant rate of discontinuation.^33,43 Despite this, onabotulinumtoxinA remains the only Food and Drug Administration (FDA)–approved treatment for chronic migraine, making it reasonable to consider for appropriate patients.

Acupuncture. A 2016 Cochrane review found benefit for patients using acupuncture compared with sham acupuncture.³⁴ When acupuncture was compared with prophylactic agents such as beta-blockers, calcium-channel blockers, and anti-epileptics, however, there was no significant difference between the procedure and pharmacotherapy. Patients willing and able to try acupuncture might see a reduction in the overall number of headaches. Acupuncture has few adverse effects; however, long-term data are lacking.³⁴

Exercise is not supported by robust data for its role as a prophylactic treatment. It is generally considered safe in most populations, however, and can be pursued with little out-of-pocket cost.³⁵

Cognitive behavioral therapy (CBT). The AAN recommends CBT, relaxation therapy, and biofeedback therapy. Accessibility of these services remains limited for many patients, and cost can be prohibitive.¹⁶

Supplements used to help prevent migraine include the root of Petasites hybridus (butterbur), magnesium, vitamin B2 (riboflavin), Tanacetum parthenium (feverfew), and coenzyme Q10.¹⁶ Although the strength of evidence for these therapies is limited by small trials, their overall risk of adverse effects is low, and they might be easier for patients to obtain than acupuncture or CBT.

Continue to: Butterbur, in particular...

Butterbur, in particular, has been found to be beneficial for migraine prevention in 2 small placebo-controlled trials. In a randomized controlled study of 245 patients P hybridus, (specifically, the German formulation, Petadolex), 75 mg BID, reduced the frequency of migraine attack by 48% at 4 months, compared to placebo (number needed to treat, 5.3).⁴⁴ No difference was found at lower dosages. The most common reported adverse effect was burping.

Regrettably, unpurified butterbur extract contains pyrrolizidine alkaloids, potentially hepatotoxic and carcinogenic compounds. Because of variations in purification in production facilities in the United States, butterbur supplements might not have all of these compounds removed—and so should be used with caution.⁴¹

Magnesium. Studies evaluating the use of magnesium have demonstrated varied results; differences in methods and dosing have limited broad application of findings. As with most supplements considered for prophylactic treatment, magnesium dosing is poorly understood, and bioavailability varies in its different forms. Oral supplementation can be given as magnesium dicitrate, 600 mg/d.⁴⁵

Recently, products containing various combinations of feverfew, coenzyme Q10, riboflavin, magnesium, and other supplements have shown benefit in early clinical trials.^36,37

Neural stimulation. Over the past few years, a variety of transcutaneous nerve stimulator devices have gained FDA approval for use in migraine prophylaxis. The long-term safety and efficacy of these devices is not yet well understood, but they appear to provide headache relief in the short term and decrease the frequency of headache.³⁸ Use of the noninvasive stimulators is limited today by high cost and poor coverage by US health care insurers.

Continue to: Newly available medical therapy

Newly available medical therapy. The FDA recently approved erenumab, a fully human monoclonal antibody for prevention of migraine in adults. This is the first drug in the CGRP antagonist class to be approved for this indication. Trials of this once-monthly, self-injectable drug show promising results for patients whose migraines have been refractory to other therapies.

A recent large trial evaluated 955 adults with migraine, randomizing them to receive erenumab, 70 mg; erenumab, 140 mg; or placebo over 28 weeks.³⁹ The groups receiving erenumab had a nearly 2-fold higher odds of having their migraine reduced by 50%, compared with placebo (number needed to treat with the 140-mg dose, 4.27). Similar numbers of participants from all groups discontinued the study.³⁹ Phase 3 trials that are not yet formally published have produced similarly beneficial results.^40,46 The FDA has listed injection site reaction and constipation as the most reported adverse effects.⁴⁰

Three other anti-CGRP antibodies are likely to be approved in the near future: fremanezumab, galcanezumab, and eptinezumab.

The approach to migraine in special populations

Management of acute and chronic migraine in children, pregnant women, and older adults requires special attention: Treatment approaches are different than they are for adults 19 to 65 years of age.

Pediatric patients. Migraine is the most common acute and recurrent headache syndrome in children. Headaches differ from those of adult migraine as a result of variations in brain maturation, plasticity, and cognitive development.⁴⁷ Migraine attacks are often of shorter duration in children, lasting 1 to 2 hours, but can still be preceded by visual aura.⁴⁸ Just as with adults, imaging, electroencephalography, lumbar puncture, and routine labs should be considered only if a child has an abnormal neurological exam or other concerning features (TABLE 2^14,15).

Continue to: The general approach to migraine treatment...

The general approach to migraine treatment in the pediatric population includes education of the child and family about symptom management. Acetaminophen, NSAIDs, and triptans are approved for abortive therapy in children and should be used for acute headache relief in the same way that they are used in adults. Oral rizatriptan, the most well studied triptan in the pediatric population, is approved for use in children as young as 6 years⁴⁹; the pediatric dosage is 5 mg/d for patients weighing 20 to 39 kg and 10 mg/d for patients weighing more than 40 kg (same as the adult dosage).

Don’t prescribe triptans for patients with known vascular disease or severe hepatic impairment.

Oral almotriptan and zolmitriptan are also approved for use in children 12 to 17 years of age. Usual dosages are: almotriptan, 12.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 25 mg/d); and zolmitriptan, 2.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 10 mg/d).⁵⁰

For children who are unable to swallow pills or who are vomiting, a non-oral route of administration is preferable. Rizatriptan is available as an orally disintegrating tablet. Zolmitriptan is available in a nasal spray at a dose of 5 mg for children 12 years and older. Sumatriptan is not approved for use in patients younger than 18 years; however, recent studies have shown that it might have good efficacy and tolerability.⁵⁰

Daily prophylactic treatment for recurrent migraine in the pediatric population is an evolving subject; published guidelines do not exist. It is reasonable to consider treatment using the same guidelines as those in place for adults.⁵¹ Topiramate, 1 to 2 mg/kg/d, is the only therapy approved by the FDA for episodic migraine preventive therapy in adolescents.⁵⁰

If a patient doesn’t get adequate headache relief from an appropriate dosage of a given triptan, try a different triptan during the next migraine.

Notably, a nonpharmacotherapeutic approach may be more effective for pediatric prevention. In 2017, a large double-blind, placebo-controlled trial investigated the use of amitriptyline, topiramate, and placebo for the treatment of recurrent migraine in children 8 to 17 years of age. An interim analysis of the 328 children enrolled found no significant differences in reduction of headache frequency with treatment compared with placebo over a 24-week period; the trial was stopped early due to futility.⁵²

Continue to: The study did show...

The study did show, however, that reducing migraine triggers provided a high level of benefit to study participants. Stress is one of the most common migraine triggers in children; lack of sleep, exposure to a warm climate, and exposure to video games are also notable triggers.⁵³ CBT may augment the efficacy of standard migraine medications in the pediatric population and may help prevent recurrence of episodes.⁵⁴

Pregnancy. The treatment of migraine is different in pregnant women than it is in nonpregnant adults because of a concern over adverse effects on fetal development. For acute headache treatment, first-line therapies include trigger avoidance and acetaminophen, 1000 mg (maximum dosage, 4000 mg/d).⁵⁵ If this is ineffective, a 10-mg dose of metoclopramide, as often as every 6 hours (not an FDA-approved indication), can be considered. During the second trimester, NSAIDs can be considered second-line therapy.

Triptans—specifically, sumatriptan and rizatriptan—can also be considered if first-line therapies fail.⁵⁶ Triptan-exposed pregnant women with migraine have a rate of congenital malformations, spontaneous abortions, and prematurity that is similar to what is seen in pregnant women with migraine who have not been exposed to triptans. However, when triptan-exposed women are compared with healthy, non-migraine-suffering women, the rate of spontaneous abortion appears to be increased in the triptan-exposed population.⁵⁷

Ergotamine is contraindicated during pregnancy because of its potential to induce uterine contractions and vasospasm, which can be detrimental to the fetus.⁵⁶Nonpharmacotherapeutic interventions such as heat, ice, massage, rest, and avoidance of triggers are as successful in the pregnant population as in the nonpregnant population. For migraine prevention, coenzyme Q10, vitamins B2 and B6 (pyridoxine), and oral magnesium can be considered. Feverfew and butterbur should be avoided because of concerns about fetal malformation and preterm labor.⁵⁸

Older adults. Choosing appropriate migraine therapy for older adults requires special consideration because of changes in drug metabolism and risks associated with drug adverse effects. Additionally, few studies of migraine drugs have included large populations of adults older than 65 years; medications should therefore be prescribed cautiously in this population, with particular attention to drug–drug interactions.

Continue to: Just as for younger adults...

Just as for younger adults, mild symptoms can be managed effectively with acetaminophen. NSAIDs may be used as well, but carry increased risks of gastric bleeding and elevation in blood pressure.⁵⁹ The use of triptans is acceptable for the appropriate patient, but should be avoided in patients with known vascular disease.⁶⁰ Antiemetics present an increased risk of extrapyramidal adverse effects in the elderly and should be used with caution at the lowest effective dosage.⁵⁹ Novel mechanisms of action make some of the newer agents potentially safer for use in older adults when treating acute migraine.

Stress is one of the most common migraine triggers in children.

For migraine prevention in older adults, particular attention should be paid to reducing triggers and minimizing polypharmacy.

More and more, successful treatment is within reach

With many clinical trials evaluating novel drugs underway, and additional studies contributing to our understanding of nonpharmacotherapeutic approaches to migraine treatment, improved headache control may become increasingly common over the next few years.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Thomas Jefferson University, 1015 Walnut St, Philadelphia PA 19107; [email protected].

Migraine is a highly disabling primary headache disorder that affects more than 44 million Americans annually.¹ The disorder causes pain, photophobia, phonophobia, and nausea that can last for hours, even days. Migraine headaches are 2 times more common in women than in men; although migraine is most common in people 30 to 39 years of age, all ages are affected.^2,3 Frequency of migraine headache is variable; chronic migraineurs experience more than 15 headache days a month.

©Cath Riley/Science Source

Recent estimates indicate that the cost of acute and chronic migraine headaches reaches approximately $78 million a year in the United States. ⁴ This high burden of disease has made effective migraine treatment options absolutely essential. Recent advances in our understanding of migraine pathophysiology have led to new therapeutic targets; there are now many novel treatment approaches on the horizon.

In this article, we review the diagnosis and management of migraine in detail. Our emphasis is on evidence-based approaches to acute and prophylactic treatment, including tried-and-true options and newly emerging therapies.

Neuronal dysfunction and a genetic predisposition

Although migraine was once thought to be caused by abnormalities of vasodilation, current research suggests that the disorder has its origins in primary neuronal dysfunction. There appears to be a genetic predisposition toward widespread neuronal hyperexcitability in migraineurs.⁵ In addition, hypothalamic neurons are thought to initiate migraine by responding to changes in brain homeostasis. Increased parasympathetic tone might activate meningeal pain receptors or lower the threshold for transmitting pain signals from the thalamus to the cortex.⁶

Prodromal symptoms and aura appear to originate from multiple areas across the brain, including the hypothalamus, cortex, limbic system, and brainstem. This widespread brain involvement might explain why some headache sufferers concurrently experience a variety of symptoms, including fatigue, depression, muscle pain, and an abnormal sensitivity to light, sound, and smell.^6,7

After taking the initial history (headache onset, location, duration, associated symptoms), focus attention on assessing the risk of intracranial pathology.

Although the exact mechanisms behind each of these symptoms have yet to be defined precisely, waves of neuronal depolarization—known as cortical spreading depression—are suspected to cause migraine aura.^8-10 Cortical spreading depression activates the trigeminal pain pathway and leads to the release of pro-inflammatory markers such as calcitonin gene-related protein (CGRP).⁶ A better understanding of these complex signaling pathways has helped provide potential therapeutic targets for new migraine drugs.

Diagnosis: Close patient inquiry is most helpful

The International Headache Society (IHS) criteria for primary headache disorders serve as the basis for the diagnosis of migraine and its subtypes, which include migraine without aura and migraine with aura. Due to variability of presentation, migraine with aura is further subdivided into migraine with typical aura (with and without headache), migraine with brainstem aura, hemiplegic migraine, and retinal migraine.¹¹

Continue to: How is migraine defined?

How is migraine defined? Simply, migraine is classically defined as a unilateral, pulsating headache of moderate to severe intensity lasting 4 to 72 hours, associated with photophobia and phonophobia or nausea and vomiting, or both.¹¹ Often visual in nature, aura is a set of neurologic symptoms that lasts for minutes and precedes the onset of the headache. The visual aura is often described as a scintillating scotoma that begins near the point of visual fixation and then spreads left or right. Other aura symptoms include tingling or numbness (second most common), speech disturbance (aphasia), motor changes and, in rare cases, a combination of these in succession. By definition, all of these symptoms fully resolve between attacks.¹¹

Validated valuable questionnaires. To help with accurate and timely diagnosis, researchers have developed and validated simplified questionnaires that can be completed independently by patients presenting to primary care (TABLE 1^12,13):

• ID Migraine is a set of 3 questions that scores positive when a patient endorses at least 2 of the 3 symptoms. ¹²
• MS-Q is similar to the ID Migraine but includes 5 items. A score of ≥4 is a positive screen. ¹³

The sensitivity and specificity of MS-Q (0.93 and 0.81, respectively) are slightly higher than those of ID Migraine (0.81 and 0.75).¹³

Remember POUND. This mnemonic device can also be used during history-taking to aid in diagnostic accuracy. Migraine is highly likely (92%) in patients who endorse 4 of the following 5 symptoms and unlikely (17%) in those who endorse ≤2 symptoms¹⁴: Pulsatile quality of headache 4 to 72 hOurs in duration, Unilateral location, Nausea or vomiting, and Disabling intensity.

Differential Dx. Although the differential diagnosis of headache is broad (TABLE 2^14,15), the history alone can often guide clinicians towards the correct assessment. After taking the initial history (headache onset, location, duration, and associated symptoms), focus your attention on assessing the risk of intracranial pathology. This is best accomplished by assessing specific details of the history (TABLE 3¹⁴) and findings on physical examination¹⁵:

• blood pressure measurement (seated, legs uncrossed, feet flat on the floor; having rested for 5 minutes; arm well supported)
• cranial nerve exam
• extremity strength testing
• eye exam (vision, extra-ocular muscles, visual fields, pupillary reactivity, and funduscopic exam)
• gait (tandem walk)
• reflexes.

Continue to: Further testing needed?

Further testing needed? Neuroimaging should be considered only in patients with an abnormal neurologic exam, atypical headache features, or certain risk factors, such as an immune deficiency. There is no role for electroencephalography or other diagnostic testing in migraine.¹⁶

Take a multipronged approach to treatment

As with other complex, chronic conditions, the treatment of migraine should take a multifaceted approach, including management of acute symptoms as well as prevention of future headaches. In 2015, the American Headache Society published a systematic review that specified particular treatment goals for migraine sufferers. ¹⁷ These goals include:

• headache reduction
• headache relief
• decreased disability from headache
• elimination of nausea and vomiting
• elimination of photophobia and phonophobia.

Our review, which follows, of therapeutic options focuses on the management of migraine in adults. Approaches in special populations (older adults, pregnant women, and children) are discussed afterward.

Pharmacotherapy for acute migraine

Acute migraine should be treated with an abortive medication at the onset of headache. The immediate goal is to relieve pain within 2 hours and prevent its recurrence within the subsequent 48 hours (TABLE 4^12,18-20).

Electroencephalography and other diagnostic testing have no role in the workup of migraine.

In the general population, mild, infrequent migraines can be managed with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).²¹

Continue to: For moderate-to-severe migraine...

For moderate-to-severe migraine, triptans, which target serotonin receptors, are the drug of choice for most patients.²¹ Triptans are superior to placebo in achieving a pain-free state at 2 and 24 hours after administration; eletriptan has the most desirable outcome, with 68% of patients pain free at 2 hours and 54% pain free at 24 hours.²² Triptans are available as sublingual tablets and nasal sprays, as well as subcutaneous injections for patients with significant associated nausea and vomiting. Avoid prescribing triptans for patients with known vascular disease (eg, history of stroke, myocardial infarction, peripheral vascular disease, uncontrolled hypertension, or signs and symptoms of these conditions), as well as for patients with severe hepatic impairment.

Treat migraine with a multifaceted approach, including management of acute symptoms and prevention of future headaches.

Importantly, although triptans all have a similar mechanism of action, patients might respond differently to different drugs within the class. If a patient does not get adequate headache relief from an appropriate dosage of a given triptan during a particular migraine episode, a different triptan can be tried during the next migraine.²² Additionally, if a patient experiences an adverse effect from one triptan, this does not necessarily mean that a trial of another triptan at a later time is contraindicated.

For patients who have an incomplete response to migraine treatment or for those with frequent recurrence, the combination formulation of sumatriptan, 85 mg, and naproxen, 500 mg, showed the highest rate of resolution of headache within 2 hours compared with either drug alone.²³ A similar result might be found by combining a triptan known to be effective for a patient and an NSAID other than naproxen. If migraine persists despite initial treatment of an attack, a different class of medication should be tried during the course of that attack to attain relief of symptoms of that migraine.²¹

When a patient is seen in an acute care setting (eg, emergency department, urgent care center) while suffering a migraine, additional treatment options are available. Intravenous (IV) anti-emetics are useful for relieving the pain of migraine and nausea, and can be used in combination with an IV NSAID (eg, ketorolac).²¹ The most effective anti-emetics are dopamine receptor type-2 blockers, including chlorpromazine, droperidol, metoclopramide, and prochlorperazine, which has the highest level of efficacy.²⁴ Note that these medications do present the risk of a dystonic reaction; diphenhydramine is therefore often used in tandem to mitigate such a response.

Looking ahead. Although triptans are the current first-line therapy for acute migraine, their effectiveness is limited. Only 20% of patients report sustained relief of pain in the 2 to 24 hours after treatment, and the response can vary from episode to episode.²⁵

Continue to: With better understading of the pathophysiology of migraine...

With better understanding of the pathophysiology of migraine, a host of novel anti-migraine drugs are on the horizon.

CGRP receptor antagonists. The neuropeptide CGRP, which mediates central and peripheral nervous system pain signaling, has been noted to be elevated during acute migraine attacks²⁶; clinical trials are therefore underway to evaluate the safety and efficacy of CGRP receptor antagonists.¹⁸ These agents appear to be better tolerated than triptans, have fewer vascular and central nervous system adverse effects, and present less of a risk of medication overuse headache.¹⁸ Liver toxicity has been seen with some medications in this class and remains an important concern in their development.¹⁹

Phase 3 clinical trials for 1 drug in this class, ubrogepant, were completed in late 2017; full analysis of the data is not yet available. Primary outcomes being evaluated include relief of pain at 2 hours and relief from the most bothersome symptoms again at 2 hours.²⁷

Selective serotonin-HT_1f receptor agonists, such as lasmiditan, offer another potential approach. Although the exact mechanism of action of these agents is not entirely clear, clinical trials have supported their efficacy and safety.²⁰ Importantly, ongoing trials are specifically targeting patients with known cardiovascular risk factors because they are most likely to benefit from the nonvasoconstrictive mechanism of action.^28,29 Adverse effects reported primarily include dizziness, fatigue, and vertigo.

Strategies for managing recurrent episodic migraine

Because of the risk of medication overuse headache with acute treatment, daily preventive therapy for migraine is indicated for any patient with ³⁰ :

• ≥6 headache days a month
• ≥4 headache days a month with some impairment
• ≥3 headache days a month with severe impairment.

Continue to: Treatment begins by having patients identify...

Treatment begins by having patients identify, and then avoid, migraine triggers (TABLE 5). This can be accomplished by having patients keep a headache diary, in which they can enter notations about personal and environmental situations that precede a headache.

For the individual patient, some triggers are modifiable; others are not. Helping a patient develop strategies for coping with triggers, rather than aiming for complete avoidance, might help her (him) manage those that are inescapable (eg stress, menstruation, etc).³¹ For many patients, however, this is not an adequate intervention and other approaches must be explored. When considering which therapy might be best for a given patient, evaluate her (his) comorbidities and assess that particular treatment for potential secondary benefits and the possibility of adverse effects. Pay attention to the choice of preventive therapy in women who are considering pregnancy because many available treatments are potentially teratogenic.

Oral medications. Oral agents from several classes of drugs can be used for migraine prophylaxis, including anti-epileptics,antidepressants, and antihypertensives (TABLE 6^{20,29,30,32-41}). Selected anti-epileptics (divalproex sodium, sodium valproate, topiramate) and beta-blockers (metoprolol, propranolol, and timolol) have the strongest evidence to support their use.³² Overall, regular use of prophylactic medications can reduce headache frequency by 50% for approximately 40% to 45% of patients who take them.²⁹ However, adherence may be limited by adverse effects or perceived lack of efficacy, thus reducing their potential for benefit.⁴²

OnabotulinumtoxinA. In patients with chronic migraine (≥15 headache days a month for at least 3 months) who have failed oral medications, the American Academy of Neurology (AAN) recommends the use of onabotulinumtoxinA.³⁰ The treatment regimen comprises 31 injections at various sites on the head, neck, and shoulders every 3 months.³³

A 2010 large randomized controlled trial showed a decrease in the frequency of headache days for patients receiving onabotulinumtoxinA compared to placebo after a 24-week treatment period (7.8 fewer headache days a month, compared to 6.4 fewer in the placebo group).³³ A recent systematic review also noted a reduction of 2 headache days a month compared with placebo; the authors cautioned, however, that data with which to evaluate onabotulinumtoxinA in comparison to other prophylactic agents are limited.⁴³

Continue to: In both studies...

In both studies, the risk of adverse drug events due to onabotulinumtoxinA was high and led to a significant rate of discontinuation.^33,43 Despite this, onabotulinumtoxinA remains the only Food and Drug Administration (FDA)–approved treatment for chronic migraine, making it reasonable to consider for appropriate patients.

Acupuncture. A 2016 Cochrane review found benefit for patients using acupuncture compared with sham acupuncture.³⁴ When acupuncture was compared with prophylactic agents such as beta-blockers, calcium-channel blockers, and anti-epileptics, however, there was no significant difference between the procedure and pharmacotherapy. Patients willing and able to try acupuncture might see a reduction in the overall number of headaches. Acupuncture has few adverse effects; however, long-term data are lacking.³⁴

Exercise is not supported by robust data for its role as a prophylactic treatment. It is generally considered safe in most populations, however, and can be pursued with little out-of-pocket cost.³⁵

Cognitive behavioral therapy (CBT). The AAN recommends CBT, relaxation therapy, and biofeedback therapy. Accessibility of these services remains limited for many patients, and cost can be prohibitive.¹⁶

Supplements used to help prevent migraine include the root of Petasites hybridus (butterbur), magnesium, vitamin B2 (riboflavin), Tanacetum parthenium (feverfew), and coenzyme Q10.¹⁶ Although the strength of evidence for these therapies is limited by small trials, their overall risk of adverse effects is low, and they might be easier for patients to obtain than acupuncture or CBT.

Continue to: Butterbur, in particular...

Butterbur, in particular, has been found to be beneficial for migraine prevention in 2 small placebo-controlled trials. In a randomized controlled study of 245 patients P hybridus, (specifically, the German formulation, Petadolex), 75 mg BID, reduced the frequency of migraine attack by 48% at 4 months, compared to placebo (number needed to treat, 5.3).⁴⁴ No difference was found at lower dosages. The most common reported adverse effect was burping.

Regrettably, unpurified butterbur extract contains pyrrolizidine alkaloids, potentially hepatotoxic and carcinogenic compounds. Because of variations in purification in production facilities in the United States, butterbur supplements might not have all of these compounds removed—and so should be used with caution.⁴¹

Magnesium. Studies evaluating the use of magnesium have demonstrated varied results; differences in methods and dosing have limited broad application of findings. As with most supplements considered for prophylactic treatment, magnesium dosing is poorly understood, and bioavailability varies in its different forms. Oral supplementation can be given as magnesium dicitrate, 600 mg/d.⁴⁵

Recently, products containing various combinations of feverfew, coenzyme Q10, riboflavin, magnesium, and other supplements have shown benefit in early clinical trials.^36,37

Neural stimulation. Over the past few years, a variety of transcutaneous nerve stimulator devices have gained FDA approval for use in migraine prophylaxis. The long-term safety and efficacy of these devices is not yet well understood, but they appear to provide headache relief in the short term and decrease the frequency of headache.³⁸ Use of the noninvasive stimulators is limited today by high cost and poor coverage by US health care insurers.

Continue to: Newly available medical therapy

Newly available medical therapy. The FDA recently approved erenumab, a fully human monoclonal antibody for prevention of migraine in adults. This is the first drug in the CGRP antagonist class to be approved for this indication. Trials of this once-monthly, self-injectable drug show promising results for patients whose migraines have been refractory to other therapies.

A recent large trial evaluated 955 adults with migraine, randomizing them to receive erenumab, 70 mg; erenumab, 140 mg; or placebo over 28 weeks.³⁹ The groups receiving erenumab had a nearly 2-fold higher odds of having their migraine reduced by 50%, compared with placebo (number needed to treat with the 140-mg dose, 4.27). Similar numbers of participants from all groups discontinued the study.³⁹ Phase 3 trials that are not yet formally published have produced similarly beneficial results.^40,46 The FDA has listed injection site reaction and constipation as the most reported adverse effects.⁴⁰

Three other anti-CGRP antibodies are likely to be approved in the near future: fremanezumab, galcanezumab, and eptinezumab.

The approach to migraine in special populations

Management of acute and chronic migraine in children, pregnant women, and older adults requires special attention: Treatment approaches are different than they are for adults 19 to 65 years of age.

Pediatric patients. Migraine is the most common acute and recurrent headache syndrome in children. Headaches differ from those of adult migraine as a result of variations in brain maturation, plasticity, and cognitive development.⁴⁷ Migraine attacks are often of shorter duration in children, lasting 1 to 2 hours, but can still be preceded by visual aura.⁴⁸ Just as with adults, imaging, electroencephalography, lumbar puncture, and routine labs should be considered only if a child has an abnormal neurological exam or other concerning features (TABLE 2^14,15).

Continue to: The general approach to migraine treatment...

The general approach to migraine treatment in the pediatric population includes education of the child and family about symptom management. Acetaminophen, NSAIDs, and triptans are approved for abortive therapy in children and should be used for acute headache relief in the same way that they are used in adults. Oral rizatriptan, the most well studied triptan in the pediatric population, is approved for use in children as young as 6 years⁴⁹; the pediatric dosage is 5 mg/d for patients weighing 20 to 39 kg and 10 mg/d for patients weighing more than 40 kg (same as the adult dosage).

Don’t prescribe triptans for patients with known vascular disease or severe hepatic impairment.

Oral almotriptan and zolmitriptan are also approved for use in children 12 to 17 years of age. Usual dosages are: almotriptan, 12.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 25 mg/d); and zolmitriptan, 2.5 mg at onset, can repeat in 2 hours as needed (maximum dosage, 10 mg/d).⁵⁰

For children who are unable to swallow pills or who are vomiting, a non-oral route of administration is preferable. Rizatriptan is available as an orally disintegrating tablet. Zolmitriptan is available in a nasal spray at a dose of 5 mg for children 12 years and older. Sumatriptan is not approved for use in patients younger than 18 years; however, recent studies have shown that it might have good efficacy and tolerability.⁵⁰

Daily prophylactic treatment for recurrent migraine in the pediatric population is an evolving subject; published guidelines do not exist. It is reasonable to consider treatment using the same guidelines as those in place for adults.⁵¹ Topiramate, 1 to 2 mg/kg/d, is the only therapy approved by the FDA for episodic migraine preventive therapy in adolescents.⁵⁰

If a patient doesn’t get adequate headache relief from an appropriate dosage of a given triptan, try a different triptan during the next migraine.

Notably, a nonpharmacotherapeutic approach may be more effective for pediatric prevention. In 2017, a large double-blind, placebo-controlled trial investigated the use of amitriptyline, topiramate, and placebo for the treatment of recurrent migraine in children 8 to 17 years of age. An interim analysis of the 328 children enrolled found no significant differences in reduction of headache frequency with treatment compared with placebo over a 24-week period; the trial was stopped early due to futility.⁵²

Continue to: The study did show...

The study did show, however, that reducing migraine triggers provided a high level of benefit to study participants. Stress is one of the most common migraine triggers in children; lack of sleep, exposure to a warm climate, and exposure to video games are also notable triggers.⁵³ CBT may augment the efficacy of standard migraine medications in the pediatric population and may help prevent recurrence of episodes.⁵⁴

Pregnancy. The treatment of migraine is different in pregnant women than it is in nonpregnant adults because of a concern over adverse effects on fetal development. For acute headache treatment, first-line therapies include trigger avoidance and acetaminophen, 1000 mg (maximum dosage, 4000 mg/d).⁵⁵ If this is ineffective, a 10-mg dose of metoclopramide, as often as every 6 hours (not an FDA-approved indication), can be considered. During the second trimester, NSAIDs can be considered second-line therapy.

Triptans—specifically, sumatriptan and rizatriptan—can also be considered if first-line therapies fail.⁵⁶ Triptan-exposed pregnant women with migraine have a rate of congenital malformations, spontaneous abortions, and prematurity that is similar to what is seen in pregnant women with migraine who have not been exposed to triptans. However, when triptan-exposed women are compared with healthy, non-migraine-suffering women, the rate of spontaneous abortion appears to be increased in the triptan-exposed population.⁵⁷

Ergotamine is contraindicated during pregnancy because of its potential to induce uterine contractions and vasospasm, which can be detrimental to the fetus.⁵⁶Nonpharmacotherapeutic interventions such as heat, ice, massage, rest, and avoidance of triggers are as successful in the pregnant population as in the nonpregnant population. For migraine prevention, coenzyme Q10, vitamins B2 and B6 (pyridoxine), and oral magnesium can be considered. Feverfew and butterbur should be avoided because of concerns about fetal malformation and preterm labor.⁵⁸

Older adults. Choosing appropriate migraine therapy for older adults requires special consideration because of changes in drug metabolism and risks associated with drug adverse effects. Additionally, few studies of migraine drugs have included large populations of adults older than 65 years; medications should therefore be prescribed cautiously in this population, with particular attention to drug–drug interactions.

Continue to: Just as for younger adults...

Just as for younger adults, mild symptoms can be managed effectively with acetaminophen. NSAIDs may be used as well, but carry increased risks of gastric bleeding and elevation in blood pressure.⁵⁹ The use of triptans is acceptable for the appropriate patient, but should be avoided in patients with known vascular disease.⁶⁰ Antiemetics present an increased risk of extrapyramidal adverse effects in the elderly and should be used with caution at the lowest effective dosage.⁵⁹ Novel mechanisms of action make some of the newer agents potentially safer for use in older adults when treating acute migraine.

Stress is one of the most common migraine triggers in children.

For migraine prevention in older adults, particular attention should be paid to reducing triggers and minimizing polypharmacy.

More and more, successful treatment is within reach

With many clinical trials evaluating novel drugs underway, and additional studies contributing to our understanding of nonpharmacotherapeutic approaches to migraine treatment, improved headache control may become increasingly common over the next few years.

CORRESPONDENCE
Kathryn McGrath, MD, Department of Family and Community Medicine, Thomas Jefferson University, 1015 Walnut St, Philadelphia PA 19107; [email protected].

A small subpopulation of quiescent hematopoietic stem cells (HSCs) that restores the HSC pool and supports hematopoietic regeneration after chemotherapy has been identified, researchers reported.

These “reserve” HSCs were resistant to chemotherapy, whereas “primed” HSCs were sensitive to DNA damage from chemotherapy, the researchers said.

Both reserve and active stem cells were maintained in the bone marrow by specific niches, researchers demonstrated in experiments described in detail in Cell Reports.

Of note, primitive reserve HSCs were maintained in a bone marrow region that enriches N-cadherin expressing (N-cad+) bone and marrow stromal progenitor cells. According to investigators, those N-cad+ cells protected primitive reserve HSCs from chemotherapy-related stress, which survived to support hematopoietic regeneration after myeloablation.

These findings advance understanding of HSC biology, and could open new avenues for treating blood diseases and autoimmune disorders.

“In effect, we showed that hematopoietic stem cells have functionally distinct subpopulations: one that acts under normal conditions, and the other that acts under times of stress,” study senior author Linheng Li, PhD, a researcher at Stowers Institute for Medical Research in Kansas City, Mo., said in a statement.

Hematopoietic stem cells are heterogeneous, with some maintained in an active state, and others in a quiescent state that is related to their self-renewal capacity and linked to low metabolic activity, sometimes called HSC dormancy or hibernation, Dr. Li and his coinvestigators explained in their report.

However, despite their quiescence, the majority of those HSCs will not survive chemotherapeutic stress, they added.

A small subpopulation of cells termed reserve HSCs can survive stress related to 5-fluorouracil chemotherapy in mice and following transplantation, Dr. Li and his colleagues demonstrated in experiments described in the paper. By contrast, a much larger population of quiescent cells, primed HSCs, were chemotherapy sensitive.

“Most likely, primed HSCs reflect a transitional state between [reserve HSCs] and proliferating [short-term HSCs],” Dr. Li and his colleagues said in their report.

In one key experiment, Dr. Li and his coinvestigators used a cell surface marker to isolate reserve HSCs and primed HSCs, which were transplanted into mice. Following engraftment, the mice were treated with 5-fluorouracil. They found that reserve HSCs, reflected by their derived blood cells, were unaffected by treatment, whereas derivatives of primed HSCs declined.

In another experiment, the researchers labeled HSCs with fluorescent tags to identify their location in the bone marrow. They found reserve cells concentrated in a specific bone marrow niche adjacent to N-cad+ cells.

The N-cad+ cells were bone and marrow stromal progenitor cells (BMSPCs), giving rise to osteoblasts, adipocytes, and chondrocytes, according to investigators.

Ablating the N-cad+ niche cells impaired reserve HSC maintenance in both homeostasis and regeneration, investigators added.

The work was supported by the Stowers Institute for Medical Research, the National Cancer Institute, and other grant support. The researchers reported that they had no competing interests related to the study.

SOURCE: Zhao M et al. Cell Rep. 2019 Jan 15;26(3):652-69.e6.

A small subpopulation of quiescent hematopoietic stem cells (HSCs) that restores the HSC pool and supports hematopoietic regeneration after chemotherapy has been identified, researchers reported.

These “reserve” HSCs were resistant to chemotherapy, whereas “primed” HSCs were sensitive to DNA damage from chemotherapy, the researchers said.

Both reserve and active stem cells were maintained in the bone marrow by specific niches, researchers demonstrated in experiments described in detail in Cell Reports.

Of note, primitive reserve HSCs were maintained in a bone marrow region that enriches N-cadherin expressing (N-cad+) bone and marrow stromal progenitor cells. According to investigators, those N-cad+ cells protected primitive reserve HSCs from chemotherapy-related stress, which survived to support hematopoietic regeneration after myeloablation.

These findings advance understanding of HSC biology, and could open new avenues for treating blood diseases and autoimmune disorders.

“In effect, we showed that hematopoietic stem cells have functionally distinct subpopulations: one that acts under normal conditions, and the other that acts under times of stress,” study senior author Linheng Li, PhD, a researcher at Stowers Institute for Medical Research in Kansas City, Mo., said in a statement.

Hematopoietic stem cells are heterogeneous, with some maintained in an active state, and others in a quiescent state that is related to their self-renewal capacity and linked to low metabolic activity, sometimes called HSC dormancy or hibernation, Dr. Li and his coinvestigators explained in their report.

However, despite their quiescence, the majority of those HSCs will not survive chemotherapeutic stress, they added.

A small subpopulation of cells termed reserve HSCs can survive stress related to 5-fluorouracil chemotherapy in mice and following transplantation, Dr. Li and his colleagues demonstrated in experiments described in the paper. By contrast, a much larger population of quiescent cells, primed HSCs, were chemotherapy sensitive.

“Most likely, primed HSCs reflect a transitional state between [reserve HSCs] and proliferating [short-term HSCs],” Dr. Li and his colleagues said in their report.

In one key experiment, Dr. Li and his coinvestigators used a cell surface marker to isolate reserve HSCs and primed HSCs, which were transplanted into mice. Following engraftment, the mice were treated with 5-fluorouracil. They found that reserve HSCs, reflected by their derived blood cells, were unaffected by treatment, whereas derivatives of primed HSCs declined.

In another experiment, the researchers labeled HSCs with fluorescent tags to identify their location in the bone marrow. They found reserve cells concentrated in a specific bone marrow niche adjacent to N-cad+ cells.

The N-cad+ cells were bone and marrow stromal progenitor cells (BMSPCs), giving rise to osteoblasts, adipocytes, and chondrocytes, according to investigators.

Ablating the N-cad+ niche cells impaired reserve HSC maintenance in both homeostasis and regeneration, investigators added.

The work was supported by the Stowers Institute for Medical Research, the National Cancer Institute, and other grant support. The researchers reported that they had no competing interests related to the study.

SOURCE: Zhao M et al. Cell Rep. 2019 Jan 15;26(3):652-69.e6.

A small subpopulation of quiescent hematopoietic stem cells (HSCs) that restores the HSC pool and supports hematopoietic regeneration after chemotherapy has been identified, researchers reported.

These “reserve” HSCs were resistant to chemotherapy, whereas “primed” HSCs were sensitive to DNA damage from chemotherapy, the researchers said.

Both reserve and active stem cells were maintained in the bone marrow by specific niches, researchers demonstrated in experiments described in detail in Cell Reports.

Of note, primitive reserve HSCs were maintained in a bone marrow region that enriches N-cadherin expressing (N-cad+) bone and marrow stromal progenitor cells. According to investigators, those N-cad+ cells protected primitive reserve HSCs from chemotherapy-related stress, which survived to support hematopoietic regeneration after myeloablation.

These findings advance understanding of HSC biology, and could open new avenues for treating blood diseases and autoimmune disorders.

“In effect, we showed that hematopoietic stem cells have functionally distinct subpopulations: one that acts under normal conditions, and the other that acts under times of stress,” study senior author Linheng Li, PhD, a researcher at Stowers Institute for Medical Research in Kansas City, Mo., said in a statement.

Hematopoietic stem cells are heterogeneous, with some maintained in an active state, and others in a quiescent state that is related to their self-renewal capacity and linked to low metabolic activity, sometimes called HSC dormancy or hibernation, Dr. Li and his coinvestigators explained in their report.

However, despite their quiescence, the majority of those HSCs will not survive chemotherapeutic stress, they added.

A small subpopulation of cells termed reserve HSCs can survive stress related to 5-fluorouracil chemotherapy in mice and following transplantation, Dr. Li and his colleagues demonstrated in experiments described in the paper. By contrast, a much larger population of quiescent cells, primed HSCs, were chemotherapy sensitive.

“Most likely, primed HSCs reflect a transitional state between [reserve HSCs] and proliferating [short-term HSCs],” Dr. Li and his colleagues said in their report.

In one key experiment, Dr. Li and his coinvestigators used a cell surface marker to isolate reserve HSCs and primed HSCs, which were transplanted into mice. Following engraftment, the mice were treated with 5-fluorouracil. They found that reserve HSCs, reflected by their derived blood cells, were unaffected by treatment, whereas derivatives of primed HSCs declined.

In another experiment, the researchers labeled HSCs with fluorescent tags to identify their location in the bone marrow. They found reserve cells concentrated in a specific bone marrow niche adjacent to N-cad+ cells.

The N-cad+ cells were bone and marrow stromal progenitor cells (BMSPCs), giving rise to osteoblasts, adipocytes, and chondrocytes, according to investigators.

Ablating the N-cad+ niche cells impaired reserve HSC maintenance in both homeostasis and regeneration, investigators added.

The work was supported by the Stowers Institute for Medical Research, the National Cancer Institute, and other grant support. The researchers reported that they had no competing interests related to the study.

SOURCE: Zhao M et al. Cell Rep. 2019 Jan 15;26(3):652-69.e6.

CHICAGO – Inhibition of PCSK9 puts only a modest dent in markedly elevated lipoprotein (a) levels and doesn’t attenuate the associated arterial wall inflammation, according to the results of the ANITSCHKOW study, Erik S. Stroes, MD, PhD, reported at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

“The reality is that for now we don’t have any drugs to significantly lower elevated Lp(a),” he said. “We can identify patients with elevated Lp(a), but we don’t have a clue how to treat them.”

Elevated Lp(a) is a highly prevalent lipid abnormality. It induces arterial wall inflammation, a known predictor of future cardiovascular events. The monoclonal antibodies that inhibit PCSK9 (proprotein convertase subtilisin/kexin type 9) dramatically reduce LDL cholesterol and also reduce arterial wall inflammation. In the published studies, PCSK9 inhibitors also reduced Lp(a) by an average of 27%; however, most participants in those studies had isolated high LDL with a normal or slightly elevated Lp(a).

ANITSCHKOW was the first double-blind, randomized, placebo-controlled study to look at the effects of a PCSK9 inhibitor – in this case, evolocumab (Repatha) – in patients with severe elevations in both LDL and Lp(a). The results proved disappointing yet informative, according to Dr. Stroes, professor of internal medicine and a vascular medicine specialist at the University of Amsterdam.

The 16-week, 14-site trial included 128 Dutch, American, and Canadian patients with a mean baseline LDL of 146 mg/dL and a median Lp(a) of 202 nmol/L who were randomized to monthly subcutanous injections of evolocumab at 420 mg or placebo. All participants had evidence of significant arterial wall inflammation at baseline as measured by PET-CT. Of the subjects, 54% were on statin therapy.

Evolucumab achieved a placebo-subtracted 61% reduction in LDL to 60 mg/dL but a mere 14% reduction in Lp(a) to 188 nmol/L, still far in excess of the 50 nmol/L cutoff defining elevated Lp(a).

The primary endpoint was change in arterial wall inflammation from baseline to week 16 as measured using PET-CT. Based upon the results of other studies showing a 3.3% drop in arterial wall inflammation for every 10% reduction in LDL, Dr. Stroes and his coinvestigators expected to see a 20% decrease in arterial wall inflammation in the evolocumab group. Instead, they found a mere 8.4% reduction, which wasn’t significantly different than in placebo-treated controls. And there was no difference in arterial wall inflammation between the group on concomitant statin therapy and those who weren’t.

The implication is that the residual Lp(a) elevation despite PCSK9 inhibitor therapy might explain the discrepancy, compared with previous studies in which LDL lowering did reduce arterial wall inflammation, according to Dr. Stroes.

“Persistent arterial wall inflammation on PET-CT after evolocumab, potentially related to persistent Lp(a) elevation, implies the need for additional therapies to decrease the proinflammatory state in Lp(a) elevation,” he observed.

Lp(a) in the spotlight

An elevated Lp(a) of 50 nmol/L or more is present in 20% of the general population, according to a Danish study. More than 70% of a person’s Lp(a) level is genetically driven. And a genetically driven elevated Lp(a) has been shown to be associated with a twofold to fourfold increased risk of cardiovascular events.

Moreover, other investigators have shown that a severely elevated Lp(a) (greater than 180 nmol/L) poses a cardiovascular risk comparable with that of heterozygous familial hypercholesterolemia and is present in 1 in 100 individuals.

“We spend a lot of time on familial hypercholesterolemia, and we should. But mind you, this severe Lp(a) elevation is more frequent than heterozygous FH,” Dr. Stroes said.

Session cochair Robert H. Eckel, MD, asked the audience for a show of hands by those who regularly measure Lp(a) in their patients. Very few hands were raised.

“I measure Lp(a) frequently, and I think it’s a very important risk factor,” declared Dr. Eckel, professor of medicine and director of the lipid clinic at University of Colorado Hospital, Aurora.

The ANITSCHKOW study was sponsored by Amgen. Dr. Stroes reported receiving institutional research grants from and serving as a paid speaker for Amgen, Merck, Novartis, and Regeneron.

[email protected]

CHICAGO – Inhibition of PCSK9 puts only a modest dent in markedly elevated lipoprotein (a) levels and doesn’t attenuate the associated arterial wall inflammation, according to the results of the ANITSCHKOW study, Erik S. Stroes, MD, PhD, reported at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

“The reality is that for now we don’t have any drugs to significantly lower elevated Lp(a),” he said. “We can identify patients with elevated Lp(a), but we don’t have a clue how to treat them.”

Elevated Lp(a) is a highly prevalent lipid abnormality. It induces arterial wall inflammation, a known predictor of future cardiovascular events. The monoclonal antibodies that inhibit PCSK9 (proprotein convertase subtilisin/kexin type 9) dramatically reduce LDL cholesterol and also reduce arterial wall inflammation. In the published studies, PCSK9 inhibitors also reduced Lp(a) by an average of 27%; however, most participants in those studies had isolated high LDL with a normal or slightly elevated Lp(a).

ANITSCHKOW was the first double-blind, randomized, placebo-controlled study to look at the effects of a PCSK9 inhibitor – in this case, evolocumab (Repatha) – in patients with severe elevations in both LDL and Lp(a). The results proved disappointing yet informative, according to Dr. Stroes, professor of internal medicine and a vascular medicine specialist at the University of Amsterdam.

The 16-week, 14-site trial included 128 Dutch, American, and Canadian patients with a mean baseline LDL of 146 mg/dL and a median Lp(a) of 202 nmol/L who were randomized to monthly subcutanous injections of evolocumab at 420 mg or placebo. All participants had evidence of significant arterial wall inflammation at baseline as measured by PET-CT. Of the subjects, 54% were on statin therapy.

Evolucumab achieved a placebo-subtracted 61% reduction in LDL to 60 mg/dL but a mere 14% reduction in Lp(a) to 188 nmol/L, still far in excess of the 50 nmol/L cutoff defining elevated Lp(a).

The primary endpoint was change in arterial wall inflammation from baseline to week 16 as measured using PET-CT. Based upon the results of other studies showing a 3.3% drop in arterial wall inflammation for every 10% reduction in LDL, Dr. Stroes and his coinvestigators expected to see a 20% decrease in arterial wall inflammation in the evolocumab group. Instead, they found a mere 8.4% reduction, which wasn’t significantly different than in placebo-treated controls. And there was no difference in arterial wall inflammation between the group on concomitant statin therapy and those who weren’t.

The implication is that the residual Lp(a) elevation despite PCSK9 inhibitor therapy might explain the discrepancy, compared with previous studies in which LDL lowering did reduce arterial wall inflammation, according to Dr. Stroes.

“Persistent arterial wall inflammation on PET-CT after evolocumab, potentially related to persistent Lp(a) elevation, implies the need for additional therapies to decrease the proinflammatory state in Lp(a) elevation,” he observed.

Lp(a) in the spotlight

An elevated Lp(a) of 50 nmol/L or more is present in 20% of the general population, according to a Danish study. More than 70% of a person’s Lp(a) level is genetically driven. And a genetically driven elevated Lp(a) has been shown to be associated with a twofold to fourfold increased risk of cardiovascular events.

Moreover, other investigators have shown that a severely elevated Lp(a) (greater than 180 nmol/L) poses a cardiovascular risk comparable with that of heterozygous familial hypercholesterolemia and is present in 1 in 100 individuals.

“We spend a lot of time on familial hypercholesterolemia, and we should. But mind you, this severe Lp(a) elevation is more frequent than heterozygous FH,” Dr. Stroes said.

Session cochair Robert H. Eckel, MD, asked the audience for a show of hands by those who regularly measure Lp(a) in their patients. Very few hands were raised.

“I measure Lp(a) frequently, and I think it’s a very important risk factor,” declared Dr. Eckel, professor of medicine and director of the lipid clinic at University of Colorado Hospital, Aurora.

The ANITSCHKOW study was sponsored by Amgen. Dr. Stroes reported receiving institutional research grants from and serving as a paid speaker for Amgen, Merck, Novartis, and Regeneron.

[email protected]

CHICAGO – Inhibition of PCSK9 puts only a modest dent in markedly elevated lipoprotein (a) levels and doesn’t attenuate the associated arterial wall inflammation, according to the results of the ANITSCHKOW study, Erik S. Stroes, MD, PhD, reported at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

“The reality is that for now we don’t have any drugs to significantly lower elevated Lp(a),” he said. “We can identify patients with elevated Lp(a), but we don’t have a clue how to treat them.”

Elevated Lp(a) is a highly prevalent lipid abnormality. It induces arterial wall inflammation, a known predictor of future cardiovascular events. The monoclonal antibodies that inhibit PCSK9 (proprotein convertase subtilisin/kexin type 9) dramatically reduce LDL cholesterol and also reduce arterial wall inflammation. In the published studies, PCSK9 inhibitors also reduced Lp(a) by an average of 27%; however, most participants in those studies had isolated high LDL with a normal or slightly elevated Lp(a).

ANITSCHKOW was the first double-blind, randomized, placebo-controlled study to look at the effects of a PCSK9 inhibitor – in this case, evolocumab (Repatha) – in patients with severe elevations in both LDL and Lp(a). The results proved disappointing yet informative, according to Dr. Stroes, professor of internal medicine and a vascular medicine specialist at the University of Amsterdam.

The 16-week, 14-site trial included 128 Dutch, American, and Canadian patients with a mean baseline LDL of 146 mg/dL and a median Lp(a) of 202 nmol/L who were randomized to monthly subcutanous injections of evolocumab at 420 mg or placebo. All participants had evidence of significant arterial wall inflammation at baseline as measured by PET-CT. Of the subjects, 54% were on statin therapy.

Evolucumab achieved a placebo-subtracted 61% reduction in LDL to 60 mg/dL but a mere 14% reduction in Lp(a) to 188 nmol/L, still far in excess of the 50 nmol/L cutoff defining elevated Lp(a).

The primary endpoint was change in arterial wall inflammation from baseline to week 16 as measured using PET-CT. Based upon the results of other studies showing a 3.3% drop in arterial wall inflammation for every 10% reduction in LDL, Dr. Stroes and his coinvestigators expected to see a 20% decrease in arterial wall inflammation in the evolocumab group. Instead, they found a mere 8.4% reduction, which wasn’t significantly different than in placebo-treated controls. And there was no difference in arterial wall inflammation between the group on concomitant statin therapy and those who weren’t.

The implication is that the residual Lp(a) elevation despite PCSK9 inhibitor therapy might explain the discrepancy, compared with previous studies in which LDL lowering did reduce arterial wall inflammation, according to Dr. Stroes.

“Persistent arterial wall inflammation on PET-CT after evolocumab, potentially related to persistent Lp(a) elevation, implies the need for additional therapies to decrease the proinflammatory state in Lp(a) elevation,” he observed.

Lp(a) in the spotlight

An elevated Lp(a) of 50 nmol/L or more is present in 20% of the general population, according to a Danish study. More than 70% of a person’s Lp(a) level is genetically driven. And a genetically driven elevated Lp(a) has been shown to be associated with a twofold to fourfold increased risk of cardiovascular events.

Moreover, other investigators have shown that a severely elevated Lp(a) (greater than 180 nmol/L) poses a cardiovascular risk comparable with that of heterozygous familial hypercholesterolemia and is present in 1 in 100 individuals.

“We spend a lot of time on familial hypercholesterolemia, and we should. But mind you, this severe Lp(a) elevation is more frequent than heterozygous FH,” Dr. Stroes said.

Session cochair Robert H. Eckel, MD, asked the audience for a show of hands by those who regularly measure Lp(a) in their patients. Very few hands were raised.

“I measure Lp(a) frequently, and I think it’s a very important risk factor,” declared Dr. Eckel, professor of medicine and director of the lipid clinic at University of Colorado Hospital, Aurora.

The ANITSCHKOW study was sponsored by Amgen. Dr. Stroes reported receiving institutional research grants from and serving as a paid speaker for Amgen, Merck, Novartis, and Regeneron.

[email protected]

After dropping for two consecutive weeks, U.S. influenza activity rose during the week ending Jan. 19, 2019, according to the Centers for Disease Control and Prevention.

The proportion of outpatient visits for influenza-like illness (ILI) was 3.3% for the most recent measurement period, the CDC’s influenza division reported Jan 25. The previous 2-week decline had seen ILI visits dip down to 3.1% for the week ending Jan. 12 after hitting a season high of 4%.

To go along with the national increase in visits, more states reported high levels of flu activity. For the week ending Jan. 19, seven states were at level 10 on the CDC’s 1-10 scale, compared with four the previous week, and there were 18 states in the high range (levels 8-10), compared with 9 the week before, the CDC said.

Three flu-related pediatric deaths were reported in the week ending Jan. 19, although all three occurred during earlier weeks. The total number of pediatric deaths for the 2018-2019 season is now up to 22. Deaths among all ages, which are reported a week later, totaled 118 for the week ending Jan. 12, with 63% of reporting complete. There were 144 deaths during the week ending Jan. 5, with reporting 86% complete. During the second full week of 2018, in the middle of the very severe 2017-2018 season, there were 1,537 flu-related deaths, CDC data show.

[email protected]

After dropping for two consecutive weeks, U.S. influenza activity rose during the week ending Jan. 19, 2019, according to the Centers for Disease Control and Prevention.

The proportion of outpatient visits for influenza-like illness (ILI) was 3.3% for the most recent measurement period, the CDC’s influenza division reported Jan 25. The previous 2-week decline had seen ILI visits dip down to 3.1% for the week ending Jan. 12 after hitting a season high of 4%.

To go along with the national increase in visits, more states reported high levels of flu activity. For the week ending Jan. 19, seven states were at level 10 on the CDC’s 1-10 scale, compared with four the previous week, and there were 18 states in the high range (levels 8-10), compared with 9 the week before, the CDC said.

Three flu-related pediatric deaths were reported in the week ending Jan. 19, although all three occurred during earlier weeks. The total number of pediatric deaths for the 2018-2019 season is now up to 22. Deaths among all ages, which are reported a week later, totaled 118 for the week ending Jan. 12, with 63% of reporting complete. There were 144 deaths during the week ending Jan. 5, with reporting 86% complete. During the second full week of 2018, in the middle of the very severe 2017-2018 season, there were 1,537 flu-related deaths, CDC data show.

[email protected]

After dropping for two consecutive weeks, U.S. influenza activity rose during the week ending Jan. 19, 2019, according to the Centers for Disease Control and Prevention.

The proportion of outpatient visits for influenza-like illness (ILI) was 3.3% for the most recent measurement period, the CDC’s influenza division reported Jan 25. The previous 2-week decline had seen ILI visits dip down to 3.1% for the week ending Jan. 12 after hitting a season high of 4%.

To go along with the national increase in visits, more states reported high levels of flu activity. For the week ending Jan. 19, seven states were at level 10 on the CDC’s 1-10 scale, compared with four the previous week, and there were 18 states in the high range (levels 8-10), compared with 9 the week before, the CDC said.

Three flu-related pediatric deaths were reported in the week ending Jan. 19, although all three occurred during earlier weeks. The total number of pediatric deaths for the 2018-2019 season is now up to 22. Deaths among all ages, which are reported a week later, totaled 118 for the week ending Jan. 12, with 63% of reporting complete. There were 144 deaths during the week ending Jan. 5, with reporting 86% complete. During the second full week of 2018, in the middle of the very severe 2017-2018 season, there were 1,537 flu-related deaths, CDC data show.

[email protected]

Women with rheumatoid arthritis who undergo assisted reproduction treatment have a decreased likelihood of live births versus women without rheumatoid arthritis, according to authors of a recent Denmark-wide cohort study.

The problem might be caused by an impaired chance of embryo implantation, authors of the study reported in the Annals of the Rheumatic Diseases.

Corticosteroids prescribed before embryo transfer might have improved the likelihood of live birth in these women with rheumatoid arthritis, according to the investigators, led by Professor Bente Mertz Nørgård of the center for clinical epidemiology at the Odense (Denmark) University Hospital.

However, findings with regard to that potential effect of corticosteroids were “not unambiguous,” said Prof. Nørgård and her coauthors said in their report.

The cohort study, based on Danish registry data from 1994-2017, included 1,149 embryo transfers in women and rheumatoid arthritis with 198,941 embryo transfers in women without rheumatoid arthritis.

Live births per embryo transfer were less likely in women with rheumatoid arthritis versus those they were in women with no rheumatoid arthritis, with an adjusted odds ratio of 0.78 (95% confidence interval, 0.65-0.92), according to investigators.

Chances of biochemical and clinical pregnancies were also lower in women with rheumatoid arthritis, with odds ratios of 0.81 (95% CI, 0.68-0.95) and 0.82 (95% CI, 0.59-1.15), respectively, the investigators found in an analysis of secondary outcomes in the study.

Corticosteroids prescribed before embryo transfer increased odds of live birth, with an adjusted odds ratio of 1.32 (95% CI, 0.85-2.05), though the underlying reason why corticosteroids were prescribed could not be established in this data set, investigators cautioned.

“The impact of corticosteroid prior to embryo transfer, found in our study, could be due to a suppression of ‘abnormalities in the immune system’ in women with RA, but we have to underline that this is speculative,” Prof. Nørgård and her colleagues said in a discussion of their results.

Future investigations are needed to clarify the role of corticosteroids in women with rheumatoid arthritis undergoing assisted reproduction treatment, they added.

Support for the study came from the Research Foundation of the Region of Southern Denmark and the Free Research Foundation at Odense University Hospital. Dr. Nørgård and her coauthors said they had no competing interests related to the research.

SOURCE: Nørgård BM et al. Ann Rheum Dis. 2019 Jan 12. doi: 10.1136/annrheumdis-2018-214619.

Women with rheumatoid arthritis who undergo assisted reproduction treatment have a decreased likelihood of live births versus women without rheumatoid arthritis, according to authors of a recent Denmark-wide cohort study.

The problem might be caused by an impaired chance of embryo implantation, authors of the study reported in the Annals of the Rheumatic Diseases.

Corticosteroids prescribed before embryo transfer might have improved the likelihood of live birth in these women with rheumatoid arthritis, according to the investigators, led by Professor Bente Mertz Nørgård of the center for clinical epidemiology at the Odense (Denmark) University Hospital.

However, findings with regard to that potential effect of corticosteroids were “not unambiguous,” said Prof. Nørgård and her coauthors said in their report.

The cohort study, based on Danish registry data from 1994-2017, included 1,149 embryo transfers in women and rheumatoid arthritis with 198,941 embryo transfers in women without rheumatoid arthritis.

Live births per embryo transfer were less likely in women with rheumatoid arthritis versus those they were in women with no rheumatoid arthritis, with an adjusted odds ratio of 0.78 (95% confidence interval, 0.65-0.92), according to investigators.

Chances of biochemical and clinical pregnancies were also lower in women with rheumatoid arthritis, with odds ratios of 0.81 (95% CI, 0.68-0.95) and 0.82 (95% CI, 0.59-1.15), respectively, the investigators found in an analysis of secondary outcomes in the study.

Corticosteroids prescribed before embryo transfer increased odds of live birth, with an adjusted odds ratio of 1.32 (95% CI, 0.85-2.05), though the underlying reason why corticosteroids were prescribed could not be established in this data set, investigators cautioned.

“The impact of corticosteroid prior to embryo transfer, found in our study, could be due to a suppression of ‘abnormalities in the immune system’ in women with RA, but we have to underline that this is speculative,” Prof. Nørgård and her colleagues said in a discussion of their results.

Future investigations are needed to clarify the role of corticosteroids in women with rheumatoid arthritis undergoing assisted reproduction treatment, they added.

Support for the study came from the Research Foundation of the Region of Southern Denmark and the Free Research Foundation at Odense University Hospital. Dr. Nørgård and her coauthors said they had no competing interests related to the research.

SOURCE: Nørgård BM et al. Ann Rheum Dis. 2019 Jan 12. doi: 10.1136/annrheumdis-2018-214619.

Women with rheumatoid arthritis who undergo assisted reproduction treatment have a decreased likelihood of live births versus women without rheumatoid arthritis, according to authors of a recent Denmark-wide cohort study.

The problem might be caused by an impaired chance of embryo implantation, authors of the study reported in the Annals of the Rheumatic Diseases.

Corticosteroids prescribed before embryo transfer might have improved the likelihood of live birth in these women with rheumatoid arthritis, according to the investigators, led by Professor Bente Mertz Nørgård of the center for clinical epidemiology at the Odense (Denmark) University Hospital.

However, findings with regard to that potential effect of corticosteroids were “not unambiguous,” said Prof. Nørgård and her coauthors said in their report.

The cohort study, based on Danish registry data from 1994-2017, included 1,149 embryo transfers in women and rheumatoid arthritis with 198,941 embryo transfers in women without rheumatoid arthritis.

Live births per embryo transfer were less likely in women with rheumatoid arthritis versus those they were in women with no rheumatoid arthritis, with an adjusted odds ratio of 0.78 (95% confidence interval, 0.65-0.92), according to investigators.

Chances of biochemical and clinical pregnancies were also lower in women with rheumatoid arthritis, with odds ratios of 0.81 (95% CI, 0.68-0.95) and 0.82 (95% CI, 0.59-1.15), respectively, the investigators found in an analysis of secondary outcomes in the study.

Corticosteroids prescribed before embryo transfer increased odds of live birth, with an adjusted odds ratio of 1.32 (95% CI, 0.85-2.05), though the underlying reason why corticosteroids were prescribed could not be established in this data set, investigators cautioned.

“The impact of corticosteroid prior to embryo transfer, found in our study, could be due to a suppression of ‘abnormalities in the immune system’ in women with RA, but we have to underline that this is speculative,” Prof. Nørgård and her colleagues said in a discussion of their results.

Future investigations are needed to clarify the role of corticosteroids in women with rheumatoid arthritis undergoing assisted reproduction treatment, they added.

Support for the study came from the Research Foundation of the Region of Southern Denmark and the Free Research Foundation at Odense University Hospital. Dr. Nørgård and her coauthors said they had no competing interests related to the research.

SOURCE: Nørgård BM et al. Ann Rheum Dis. 2019 Jan 12. doi: 10.1136/annrheumdis-2018-214619.

Patients with self-reported mild bleeding symptoms may have impaired clot lysis, according to investigators. This finding is remarkable because it contrasts with known bleeding disorders, such as hemophilia, which are associated with enhanced clot lysis, reported lead author Minka J.A. Vries, MD, of the Cardiovascular Research Institute Maastricht (CARIM) at Maastricht (the Netherlands) University and her colleagues.

Svisio/Thinkstock

The observational study, which included 335 patients undergoing elective surgery at Maastricht University Medical Center, was conducted to better understand lysis capacity, which is challenging to assess in a clinical setting. Although the Euglobulin Lysis Time (ELT) is often used in the clinic, it cannot determine the influence of hemostatic proteins or formation of a fibrin clot under physiological conditions.

“In the more recently developed lysis assays,” the investigators wrote in Thrombosis Research, “the turbidity lysis assay and the tissue plasminogen activator–rotational thromboelastometry (tPA-ROTEM) [assay], all plasma proteins are present and fibrin is formed under more physiological conditions for the measurement of fibrinolysis.” These two tests were used in the present study.

Of the 335 adult patients, 240 had self-reported mild bleeding symptoms, and 95 did not. Patients with bleeding disorders, thrombocytopenia, or anemia were excluded, as were pregnant women and those taking blood thinners or NSAIDs. Along with assessing time parameters of fibrinolysis, clot-associated proteins were measured for possible imbalances.

“We hypothesized that clot lysis capacity is enhanced in patients with mild bleeding symptoms,” the investigators wrote, based on other bleeding disorders. Surprisingly, the results told a different story.

After adjusting for sex, BMI, and age, patients with bleeding symptoms had lower tPA-ROTEM lysis speed (beta −0.35; P = .007) and longer tPA-ROTEM lysis time (beta 0.29; P = .022) than did patients without bleeding symptoms. The investigators found that tPA-ROTEM measurements depended on factor II, factor XII, alpha2-antiplasmin, plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor–1 (PAI-1) level. In contrast, turbidity lysis assay measurements were not significantly different between groups. This latter assay was influenced by alpha2-antiplasmin, TAFI, and PAI-1.

“We did not find evidence for systemic hyperfibrinolytic capacity in patients reporting mild bleeding symptoms in comparison to patients not reporting bleeding symptoms,” the investigators concluded. “tPA-ROTEM even suggested a slower clot lysis in these patients. Though this may appear counterintuitive, our results are in line with two papers assessing systemic clot lysis in mild bleeders.”

While this phenomenon gains supporting evidence, it remains poorly understood.

“We have no good explanation for these findings,” the investigators noted.

This study was funded by the Sint Annadal Foundation Maastricht, Maastricht University Medical Centre, CTMM INCOAG Maastricht, Cardiovascular Research Institute Maastricht, and the British Heart Foundation. No conflicts of interest were reported.

SOURCE: Vries MJA et al. Thromb Res. 2018 Dec 4. doi: 10.1016/j.thromres.2018.12.004.

Patients with self-reported mild bleeding symptoms may have impaired clot lysis, according to investigators. This finding is remarkable because it contrasts with known bleeding disorders, such as hemophilia, which are associated with enhanced clot lysis, reported lead author Minka J.A. Vries, MD, of the Cardiovascular Research Institute Maastricht (CARIM) at Maastricht (the Netherlands) University and her colleagues.

Svisio/Thinkstock

The observational study, which included 335 patients undergoing elective surgery at Maastricht University Medical Center, was conducted to better understand lysis capacity, which is challenging to assess in a clinical setting. Although the Euglobulin Lysis Time (ELT) is often used in the clinic, it cannot determine the influence of hemostatic proteins or formation of a fibrin clot under physiological conditions.

“In the more recently developed lysis assays,” the investigators wrote in Thrombosis Research, “the turbidity lysis assay and the tissue plasminogen activator–rotational thromboelastometry (tPA-ROTEM) [assay], all plasma proteins are present and fibrin is formed under more physiological conditions for the measurement of fibrinolysis.” These two tests were used in the present study.

Of the 335 adult patients, 240 had self-reported mild bleeding symptoms, and 95 did not. Patients with bleeding disorders, thrombocytopenia, or anemia were excluded, as were pregnant women and those taking blood thinners or NSAIDs. Along with assessing time parameters of fibrinolysis, clot-associated proteins were measured for possible imbalances.

“We hypothesized that clot lysis capacity is enhanced in patients with mild bleeding symptoms,” the investigators wrote, based on other bleeding disorders. Surprisingly, the results told a different story.

After adjusting for sex, BMI, and age, patients with bleeding symptoms had lower tPA-ROTEM lysis speed (beta −0.35; P = .007) and longer tPA-ROTEM lysis time (beta 0.29; P = .022) than did patients without bleeding symptoms. The investigators found that tPA-ROTEM measurements depended on factor II, factor XII, alpha2-antiplasmin, plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor–1 (PAI-1) level. In contrast, turbidity lysis assay measurements were not significantly different between groups. This latter assay was influenced by alpha2-antiplasmin, TAFI, and PAI-1.

“We did not find evidence for systemic hyperfibrinolytic capacity in patients reporting mild bleeding symptoms in comparison to patients not reporting bleeding symptoms,” the investigators concluded. “tPA-ROTEM even suggested a slower clot lysis in these patients. Though this may appear counterintuitive, our results are in line with two papers assessing systemic clot lysis in mild bleeders.”

While this phenomenon gains supporting evidence, it remains poorly understood.

“We have no good explanation for these findings,” the investigators noted.

This study was funded by the Sint Annadal Foundation Maastricht, Maastricht University Medical Centre, CTMM INCOAG Maastricht, Cardiovascular Research Institute Maastricht, and the British Heart Foundation. No conflicts of interest were reported.

SOURCE: Vries MJA et al. Thromb Res. 2018 Dec 4. doi: 10.1016/j.thromres.2018.12.004.

Patients with self-reported mild bleeding symptoms may have impaired clot lysis, according to investigators. This finding is remarkable because it contrasts with known bleeding disorders, such as hemophilia, which are associated with enhanced clot lysis, reported lead author Minka J.A. Vries, MD, of the Cardiovascular Research Institute Maastricht (CARIM) at Maastricht (the Netherlands) University and her colleagues.

Svisio/Thinkstock

The observational study, which included 335 patients undergoing elective surgery at Maastricht University Medical Center, was conducted to better understand lysis capacity, which is challenging to assess in a clinical setting. Although the Euglobulin Lysis Time (ELT) is often used in the clinic, it cannot determine the influence of hemostatic proteins or formation of a fibrin clot under physiological conditions.

“In the more recently developed lysis assays,” the investigators wrote in Thrombosis Research, “the turbidity lysis assay and the tissue plasminogen activator–rotational thromboelastometry (tPA-ROTEM) [assay], all plasma proteins are present and fibrin is formed under more physiological conditions for the measurement of fibrinolysis.” These two tests were used in the present study.

Of the 335 adult patients, 240 had self-reported mild bleeding symptoms, and 95 did not. Patients with bleeding disorders, thrombocytopenia, or anemia were excluded, as were pregnant women and those taking blood thinners or NSAIDs. Along with assessing time parameters of fibrinolysis, clot-associated proteins were measured for possible imbalances.

“We hypothesized that clot lysis capacity is enhanced in patients with mild bleeding symptoms,” the investigators wrote, based on other bleeding disorders. Surprisingly, the results told a different story.

After adjusting for sex, BMI, and age, patients with bleeding symptoms had lower tPA-ROTEM lysis speed (beta −0.35; P = .007) and longer tPA-ROTEM lysis time (beta 0.29; P = .022) than did patients without bleeding symptoms. The investigators found that tPA-ROTEM measurements depended on factor II, factor XII, alpha2-antiplasmin, plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor–1 (PAI-1) level. In contrast, turbidity lysis assay measurements were not significantly different between groups. This latter assay was influenced by alpha2-antiplasmin, TAFI, and PAI-1.

“We did not find evidence for systemic hyperfibrinolytic capacity in patients reporting mild bleeding symptoms in comparison to patients not reporting bleeding symptoms,” the investigators concluded. “tPA-ROTEM even suggested a slower clot lysis in these patients. Though this may appear counterintuitive, our results are in line with two papers assessing systemic clot lysis in mild bleeders.”

While this phenomenon gains supporting evidence, it remains poorly understood.

“We have no good explanation for these findings,” the investigators noted.

This study was funded by the Sint Annadal Foundation Maastricht, Maastricht University Medical Centre, CTMM INCOAG Maastricht, Cardiovascular Research Institute Maastricht, and the British Heart Foundation. No conflicts of interest were reported.

SOURCE: Vries MJA et al. Thromb Res. 2018 Dec 4. doi: 10.1016/j.thromres.2018.12.004.

Transitioning toward retirement or looking for postgrad training opportunities? Or maybe you need some advice on good “power meals” to have during your busy days? These are only a few of the many threads attracting comments on SVSConnect, your online community. Members can discuss, collaborate, network and even share documents with one another. Log in with your SVS credentials and add your thoughts. If you’re not signed up, do so today.

Transitioning toward retirement or looking for postgrad training opportunities? Or maybe you need some advice on good “power meals” to have during your busy days? These are only a few of the many threads attracting comments on SVSConnect, your online community. Members can discuss, collaborate, network and even share documents with one another. Log in with your SVS credentials and add your thoughts. If you’re not signed up, do so today.

Transitioning toward retirement or looking for postgrad training opportunities? Or maybe you need some advice on good “power meals” to have during your busy days? These are only a few of the many threads attracting comments on SVSConnect, your online community. Members can discuss, collaborate, network and even share documents with one another. Log in with your SVS credentials and add your thoughts. If you’re not signed up, do so today.

CORONADO, CALIF. – Eosinophilic chronic rhinosinusitis with nasal polyposis decreases quality of life improvement after sinus surgery in patients with concurrent asthma, results from a retrospective study demonstrated.

They also have significantly higher Lund-Kennedy endoscopy and Lund-McKay CT scores, compared with control groups.

“Patients with concurrent asthma and chronic sinusitis require more aggressive management than nonasthmatics,” one of the study authors, Aykut A. Unsal, DO, said in an interview in advance of the Triological Society’s Combined Sections Meeting. “Additionally, the degree of improvement of not only their sinusitis but possibly their asthma following medical/surgical treatment will also be limited if that patient also suffers from nasal polyps and/or eosinophilia. These patients will ultimately become more difficult to manage.”

In order to examine the relationship of eosinophilia and nasal polyps on quality of life (QOL) in patients with asthma who have chronic rhinosinusitis (CRS) who were treated with surgery, Dr. Unsal and his associates reviewed the records of 457 patients with a diagnosis of CRS who underwent sinus surgery in the department of otolaryngology at the Medical College of Georgia, Augusta. The researchers subdivided patients based on the presence or absence of an asthma diagnosis and further subdivided them based on tissue eosinophilia and nasal polyposis. Next, they compared the Sinonasal Outcome Test (SNOT-22), Lund-Kennedy endoscopy scores, and Lund-McKay CT scores preoperatively and postoperatively at 6 months – 1 year and at 2, 3, 4, and 5 years. They performed a T-test analysis to determine statistical significance.

Of the 457 patients included in the analysis, 92 had asthma and eosinophilic CRS with nasal polyps (eCRScNP), 20 had asthma and eosinophilic CRS without nasal polyps (eCRSsNP), 8 had asthma and noneosinophilic CRS with nasal polyps (neCRScNP), and 16 had asthma and noneosinophilic CRS without nasal polyps (neCRSsNP). The researchers observed that patients in the eCRScNP group showed no difference in QOL preoperatively, but their QOL declined significantly at the 1- and 2-year analysis (P less than .03). No significant QOL improvement appeared in the eCRSsNP group until 4 years (P less than .008), and there was no significant QOL difference among the neCRS groups regardless of nasal polyposis. A statistical difference in endoscopy scores was seen among patients in the preoperative neCRScNP group (P less than .001) and in the eCRScNP group from preoperatively until 5 years postoperatively (P less than .03). Finally, statistical significance appeared in preoperative CT scores analysis among patients in the eCRScNP group (P less than .001).

Dragana991/Getty Images

[email protected]

CORONADO, CALIF. – Eosinophilic chronic rhinosinusitis with nasal polyposis decreases quality of life improvement after sinus surgery in patients with concurrent asthma, results from a retrospective study demonstrated.

They also have significantly higher Lund-Kennedy endoscopy and Lund-McKay CT scores, compared with control groups.

“Patients with concurrent asthma and chronic sinusitis require more aggressive management than nonasthmatics,” one of the study authors, Aykut A. Unsal, DO, said in an interview in advance of the Triological Society’s Combined Sections Meeting. “Additionally, the degree of improvement of not only their sinusitis but possibly their asthma following medical/surgical treatment will also be limited if that patient also suffers from nasal polyps and/or eosinophilia. These patients will ultimately become more difficult to manage.”

In order to examine the relationship of eosinophilia and nasal polyps on quality of life (QOL) in patients with asthma who have chronic rhinosinusitis (CRS) who were treated with surgery, Dr. Unsal and his associates reviewed the records of 457 patients with a diagnosis of CRS who underwent sinus surgery in the department of otolaryngology at the Medical College of Georgia, Augusta. The researchers subdivided patients based on the presence or absence of an asthma diagnosis and further subdivided them based on tissue eosinophilia and nasal polyposis. Next, they compared the Sinonasal Outcome Test (SNOT-22), Lund-Kennedy endoscopy scores, and Lund-McKay CT scores preoperatively and postoperatively at 6 months – 1 year and at 2, 3, 4, and 5 years. They performed a T-test analysis to determine statistical significance.

Of the 457 patients included in the analysis, 92 had asthma and eosinophilic CRS with nasal polyps (eCRScNP), 20 had asthma and eosinophilic CRS without nasal polyps (eCRSsNP), 8 had asthma and noneosinophilic CRS with nasal polyps (neCRScNP), and 16 had asthma and noneosinophilic CRS without nasal polyps (neCRSsNP). The researchers observed that patients in the eCRScNP group showed no difference in QOL preoperatively, but their QOL declined significantly at the 1- and 2-year analysis (P less than .03). No significant QOL improvement appeared in the eCRSsNP group until 4 years (P less than .008), and there was no significant QOL difference among the neCRS groups regardless of nasal polyposis. A statistical difference in endoscopy scores was seen among patients in the preoperative neCRScNP group (P less than .001) and in the eCRScNP group from preoperatively until 5 years postoperatively (P less than .03). Finally, statistical significance appeared in preoperative CT scores analysis among patients in the eCRScNP group (P less than .001).

Dragana991/Getty Images

[email protected]

CORONADO, CALIF. – Eosinophilic chronic rhinosinusitis with nasal polyposis decreases quality of life improvement after sinus surgery in patients with concurrent asthma, results from a retrospective study demonstrated.

They also have significantly higher Lund-Kennedy endoscopy and Lund-McKay CT scores, compared with control groups.

“Patients with concurrent asthma and chronic sinusitis require more aggressive management than nonasthmatics,” one of the study authors, Aykut A. Unsal, DO, said in an interview in advance of the Triological Society’s Combined Sections Meeting. “Additionally, the degree of improvement of not only their sinusitis but possibly their asthma following medical/surgical treatment will also be limited if that patient also suffers from nasal polyps and/or eosinophilia. These patients will ultimately become more difficult to manage.”

In order to examine the relationship of eosinophilia and nasal polyps on quality of life (QOL) in patients with asthma who have chronic rhinosinusitis (CRS) who were treated with surgery, Dr. Unsal and his associates reviewed the records of 457 patients with a diagnosis of CRS who underwent sinus surgery in the department of otolaryngology at the Medical College of Georgia, Augusta. The researchers subdivided patients based on the presence or absence of an asthma diagnosis and further subdivided them based on tissue eosinophilia and nasal polyposis. Next, they compared the Sinonasal Outcome Test (SNOT-22), Lund-Kennedy endoscopy scores, and Lund-McKay CT scores preoperatively and postoperatively at 6 months – 1 year and at 2, 3, 4, and 5 years. They performed a T-test analysis to determine statistical significance.

Of the 457 patients included in the analysis, 92 had asthma and eosinophilic CRS with nasal polyps (eCRScNP), 20 had asthma and eosinophilic CRS without nasal polyps (eCRSsNP), 8 had asthma and noneosinophilic CRS with nasal polyps (neCRScNP), and 16 had asthma and noneosinophilic CRS without nasal polyps (neCRSsNP). The researchers observed that patients in the eCRScNP group showed no difference in QOL preoperatively, but their QOL declined significantly at the 1- and 2-year analysis (P less than .03). No significant QOL improvement appeared in the eCRSsNP group until 4 years (P less than .008), and there was no significant QOL difference among the neCRS groups regardless of nasal polyposis. A statistical difference in endoscopy scores was seen among patients in the preoperative neCRScNP group (P less than .001) and in the eCRScNP group from preoperatively until 5 years postoperatively (P less than .03). Finally, statistical significance appeared in preoperative CT scores analysis among patients in the eCRScNP group (P less than .001).

Dragana991/Getty Images

[email protected]

BROOKLYN, N.Y. – There are studies demonstrating depression is more likely to resolve if depressed parents are also treated dating back more than 10 years, but new evidence suggests this effect may extend to children as young as 3 years of age, according to an update on current strategies for early intervention presented at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Of multiple triggers that can be caught and treated early to prevent children from progressing to chronic depression, addressing parental depression is an important target, according to Karen Dineen Wagner, MD, Director of the Division of Child and Adolescent Psychiatry at the University of Texas Medical Branch in Galveston.

In an overview of strategies for intervening early in children who have or are at risk for depression, Dr. Wagner looked at several targets. The purpose of recognizing and addressing such targets as parental depression is to get children well faster and avoid disease chronicity.

“If we want to intervene and potentially prevent the occurrence of depression, we need to look at disorders or triggers that may precede the depression and that, had they been treated, might have eliminated the stressors that tip the child into depression,” Dr. Wagner said.

Parental depression was just one of these factors, but along with others, such as child abuse of any kind and bullying, each poses a threat for chronic mood disorders, according to Dr. Wagner.

In the case of parental depression, Dr. Wagner cited numerous studies demonstrating a close correlation between remission in the parent and remission in the child. These trajectories interact, so children are less likely to get well if an affected parent does not get well.

“Make sure you consider depression in the parent when you are doing an evaluation, and it is not just depression in the parent who is there. Ask about the other partner who is not there,” Dr. Wagner advised. Parents reluctant to address their own depression should be informed that the mental health of their child is at risk.

The most recent evidence to show benefit from treating both child and parent was drawn from a controlled study that enrolled young children (Luby JL et al. Am J Psychiatry. 2018 Jun 20. doi: 10.1176/appi.ajp.2018.18030321).

In this study, 229 parent-child dyads were randomized to receive parent-child psychotherapy for early childhood depression or to a wait-list. The age range for the children was 3-6.2 years. The therapy was specifically designed to improve the parents’ ability to help young children cope with their feelings.

The parent-child interaction therapy “focused on emotional development which was designed to train parents to work with the child on developing emotional competence in which the child understands their emotions, understands how events affect how they are feeling, and controls emotional reactivity,” Dr. Wagner explained.

For the primary outcome of depression at the end of 18 weeks, the rates were significantly lower in those who participated in the interaction therapy than they were in those on the wait-list. Measures of parent depression and stress were also lower in the therapy group.

Currently, the U. S. Preventive Task Force recommends screening all children at age 12 for depression with the adolescent version of the Patient Health Questionnaire (PHQ-A), according to Dr. Wagner. Given the rising prevalence of depression in adolescents, which climbed 46% from 2005 (8.7%) to 2015 (12.7%) according to a published national survey, this screening is prudent, Dr. Wagner indicated. However, she further suggested that it is reasonable to screen children with risk factors, such as learning disorders or anxiety disorders, even earlier.

The reason is that there are effective therapies. Early treatment may prevent chronic and more severe forms of depression, according to Dr. Wagner. She suggested that there is a growing emphasis on not just treating depression at its early stages but also in recognizing the child at risk, identifying subsyndromal symptoms leading toward depression, and preventing children from ever reaching diagnostic criteria.

Indeed, an initiative for better and earlier detection and treatment of depression in children was begun by the AACAP when Dr. Wagner served recently as its president. Several parts of that program have now been launched. Dr. Wagner encouraged those with an interest to visit the AACAP website, where more information about this initiative can be accessed.

Dr. Wagner reported no potential conflicts of interest.

BROOKLYN, N.Y. – There are studies demonstrating depression is more likely to resolve if depressed parents are also treated dating back more than 10 years, but new evidence suggests this effect may extend to children as young as 3 years of age, according to an update on current strategies for early intervention presented at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Of multiple triggers that can be caught and treated early to prevent children from progressing to chronic depression, addressing parental depression is an important target, according to Karen Dineen Wagner, MD, Director of the Division of Child and Adolescent Psychiatry at the University of Texas Medical Branch in Galveston.

In an overview of strategies for intervening early in children who have or are at risk for depression, Dr. Wagner looked at several targets. The purpose of recognizing and addressing such targets as parental depression is to get children well faster and avoid disease chronicity.

“If we want to intervene and potentially prevent the occurrence of depression, we need to look at disorders or triggers that may precede the depression and that, had they been treated, might have eliminated the stressors that tip the child into depression,” Dr. Wagner said.

Parental depression was just one of these factors, but along with others, such as child abuse of any kind and bullying, each poses a threat for chronic mood disorders, according to Dr. Wagner.

In the case of parental depression, Dr. Wagner cited numerous studies demonstrating a close correlation between remission in the parent and remission in the child. These trajectories interact, so children are less likely to get well if an affected parent does not get well.

“Make sure you consider depression in the parent when you are doing an evaluation, and it is not just depression in the parent who is there. Ask about the other partner who is not there,” Dr. Wagner advised. Parents reluctant to address their own depression should be informed that the mental health of their child is at risk.

The most recent evidence to show benefit from treating both child and parent was drawn from a controlled study that enrolled young children (Luby JL et al. Am J Psychiatry. 2018 Jun 20. doi: 10.1176/appi.ajp.2018.18030321).

In this study, 229 parent-child dyads were randomized to receive parent-child psychotherapy for early childhood depression or to a wait-list. The age range for the children was 3-6.2 years. The therapy was specifically designed to improve the parents’ ability to help young children cope with their feelings.

The parent-child interaction therapy “focused on emotional development which was designed to train parents to work with the child on developing emotional competence in which the child understands their emotions, understands how events affect how they are feeling, and controls emotional reactivity,” Dr. Wagner explained.

For the primary outcome of depression at the end of 18 weeks, the rates were significantly lower in those who participated in the interaction therapy than they were in those on the wait-list. Measures of parent depression and stress were also lower in the therapy group.

Currently, the U. S. Preventive Task Force recommends screening all children at age 12 for depression with the adolescent version of the Patient Health Questionnaire (PHQ-A), according to Dr. Wagner. Given the rising prevalence of depression in adolescents, which climbed 46% from 2005 (8.7%) to 2015 (12.7%) according to a published national survey, this screening is prudent, Dr. Wagner indicated. However, she further suggested that it is reasonable to screen children with risk factors, such as learning disorders or anxiety disorders, even earlier.

The reason is that there are effective therapies. Early treatment may prevent chronic and more severe forms of depression, according to Dr. Wagner. She suggested that there is a growing emphasis on not just treating depression at its early stages but also in recognizing the child at risk, identifying subsyndromal symptoms leading toward depression, and preventing children from ever reaching diagnostic criteria.

Indeed, an initiative for better and earlier detection and treatment of depression in children was begun by the AACAP when Dr. Wagner served recently as its president. Several parts of that program have now been launched. Dr. Wagner encouraged those with an interest to visit the AACAP website, where more information about this initiative can be accessed.

Dr. Wagner reported no potential conflicts of interest.

BROOKLYN, N.Y. – There are studies demonstrating depression is more likely to resolve if depressed parents are also treated dating back more than 10 years, but new evidence suggests this effect may extend to children as young as 3 years of age, according to an update on current strategies for early intervention presented at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Of multiple triggers that can be caught and treated early to prevent children from progressing to chronic depression, addressing parental depression is an important target, according to Karen Dineen Wagner, MD, Director of the Division of Child and Adolescent Psychiatry at the University of Texas Medical Branch in Galveston.

In an overview of strategies for intervening early in children who have or are at risk for depression, Dr. Wagner looked at several targets. The purpose of recognizing and addressing such targets as parental depression is to get children well faster and avoid disease chronicity.

“If we want to intervene and potentially prevent the occurrence of depression, we need to look at disorders or triggers that may precede the depression and that, had they been treated, might have eliminated the stressors that tip the child into depression,” Dr. Wagner said.

Parental depression was just one of these factors, but along with others, such as child abuse of any kind and bullying, each poses a threat for chronic mood disorders, according to Dr. Wagner.

In the case of parental depression, Dr. Wagner cited numerous studies demonstrating a close correlation between remission in the parent and remission in the child. These trajectories interact, so children are less likely to get well if an affected parent does not get well.

“Make sure you consider depression in the parent when you are doing an evaluation, and it is not just depression in the parent who is there. Ask about the other partner who is not there,” Dr. Wagner advised. Parents reluctant to address their own depression should be informed that the mental health of their child is at risk.

The most recent evidence to show benefit from treating both child and parent was drawn from a controlled study that enrolled young children (Luby JL et al. Am J Psychiatry. 2018 Jun 20. doi: 10.1176/appi.ajp.2018.18030321).

In this study, 229 parent-child dyads were randomized to receive parent-child psychotherapy for early childhood depression or to a wait-list. The age range for the children was 3-6.2 years. The therapy was specifically designed to improve the parents’ ability to help young children cope with their feelings.

The parent-child interaction therapy “focused on emotional development which was designed to train parents to work with the child on developing emotional competence in which the child understands their emotions, understands how events affect how they are feeling, and controls emotional reactivity,” Dr. Wagner explained.

For the primary outcome of depression at the end of 18 weeks, the rates were significantly lower in those who participated in the interaction therapy than they were in those on the wait-list. Measures of parent depression and stress were also lower in the therapy group.

Currently, the U. S. Preventive Task Force recommends screening all children at age 12 for depression with the adolescent version of the Patient Health Questionnaire (PHQ-A), according to Dr. Wagner. Given the rising prevalence of depression in adolescents, which climbed 46% from 2005 (8.7%) to 2015 (12.7%) according to a published national survey, this screening is prudent, Dr. Wagner indicated. However, she further suggested that it is reasonable to screen children with risk factors, such as learning disorders or anxiety disorders, even earlier.

The reason is that there are effective therapies. Early treatment may prevent chronic and more severe forms of depression, according to Dr. Wagner. She suggested that there is a growing emphasis on not just treating depression at its early stages but also in recognizing the child at risk, identifying subsyndromal symptoms leading toward depression, and preventing children from ever reaching diagnostic criteria.

Indeed, an initiative for better and earlier detection and treatment of depression in children was begun by the AACAP when Dr. Wagner served recently as its president. Several parts of that program have now been launched. Dr. Wagner encouraged those with an interest to visit the AACAP website, where more information about this initiative can be accessed.

Dr. Wagner reported no potential conflicts of interest.

BOSTON – Sixty-three patients with atrial fibrillation (AF) and a history of intracranial hemorrhage have safely received a Watchman device for left atrial appendage (LAA) closure followed by 6 months of treatment with an individualized drug regimen to prevent thrombus formation at three U.S. centers. The 6-month outcomes of these patients were as good as the outcomes of 95 similar patients who did not have a history of intracranial hemorrhage, Moussa C. Mansour, MD, said at the annual International AF Symposium.

Mitchel L. Zoler/MDedge News

“Individualized, postprocedural antithrombotic management ranging from dual antiplatelet therapy to oral anticoagulation plus aspirin can be used short term,” said Dr. Mansour, director of the atrial AF program at Massachusetts General Hospital. He and his associates devised this approach “out of necessity,” he said. The findings “show that you can get these patients through the initial postprocedural period” by individualizing their antiplatelet or anticoagulant treatment.

Not many U.S. operators are currently placing LAA closure devices in patients with a history of intracranial hemorrhage (ICH). “No one knows what to do with them. There is no standard approach; it’s an evolving field,” he said in an interview.

Dr. Mansour reviewed his group’s experience at Massachusetts General with LAA closure using the Watchman device combined with the experience of teams at the Texas Cardiac Arrhythmia Institute in Austin and the HCA Midwest Health in Overland Park, Kan. This included 63 AF patients with an ICH history and 95 similar AF patients with no hemorrhagic history. Nearly half of the patients with a prior ICH also had a history of at least one ischemic stroke or transient ischemic attack, compared with just over a third of the patients without a prior ICH. The two groups had nearly identical CHA2DS2-VASc scores, 4.9 and 4.7, and also very similar HAS-BLED scores.

The patients with a prior ICH included 57% with a prior intracerebral hemorrhage, 29% with a prior subdural hemorrhage, 10% with a subarachnoid hemorrhage, and the remainder unspecified.

Thirty-two of the 63 patients with an ICH history received postprocedural anticoagulation with a direct-acting oral anticoagulant, 18 received warfarin, and 13 received dual antiplatelet therapy but no anticoagulant. Among the 45 patients treated with an oral anticoagulant, 27 also received aspirin. Among the 95 patients reviewed without an ICH history, 93 received an oral anticoagulant, and 2 received dual antiplatelet therapy.

During 180 days of follow-up, the combined incidence of death, stroke, or a major bleed was about 5% among the patients with an ICH history and about 10% among those without this history, a difference that was not statistically significant, Dr. Mansour said.

At Massachusetts General, the decision on how to treat AF patients with an ICH history after they undergo LAA closure is made by a multidisciplinary team of clinicians from the arrhythmia, neurology, radiology, anesthesia, and cardiovascular surgery services. A key factor when determining the drug regimen these patients will receive is the location and size of the ICH when imaged with CT or MRI, Dr. Mansour said. The team also assessed the current likelihood that the patient will bleed. “One size does not fit all” patients, he explained.

A randomized trial, ASAP-TOO (Assessment of the Watchman Device in Patients Unsuitable for Oral Anticoagulation) is now in progress and was designed to compare the safety and efficacy of LAA closure using Watchman with medical management in 888 patients deemed ineligible for anticoagulation, but enrollment into the trial has been slow. As of early 2019, the study’s organizers posted an estimated completion date of late 2023. Until that study finishes, the field will have no definitive data on how to manage these patients, Dr. Mansour said. He noted that a handful of other reports have presented evidence for the safety of LAA closure in these patients, including a review from the Cleveland Clinic on 38 AF patients who received the Watchman device after an ICH (Heart Rhythm. 2018 Dec 2. doi: 10.1016/j.hrthm.2018.11.022); a review of the Amplatzer Cardiac Plug registry, which included 198 patients with an ICH history (Int J Cardiol. 2017 June 1;236[1]:232-6); and a single-center review of 46 French patients who underwent LAA closure after intracerebral hemorrhage (J Stroke Cerebrovasc Dis. 2017 March;26[3]:545-51).

[email protected]

BOSTON – Sixty-three patients with atrial fibrillation (AF) and a history of intracranial hemorrhage have safely received a Watchman device for left atrial appendage (LAA) closure followed by 6 months of treatment with an individualized drug regimen to prevent thrombus formation at three U.S. centers. The 6-month outcomes of these patients were as good as the outcomes of 95 similar patients who did not have a history of intracranial hemorrhage, Moussa C. Mansour, MD, said at the annual International AF Symposium.

Mitchel L. Zoler/MDedge News

“Individualized, postprocedural antithrombotic management ranging from dual antiplatelet therapy to oral anticoagulation plus aspirin can be used short term,” said Dr. Mansour, director of the atrial AF program at Massachusetts General Hospital. He and his associates devised this approach “out of necessity,” he said. The findings “show that you can get these patients through the initial postprocedural period” by individualizing their antiplatelet or anticoagulant treatment.

Not many U.S. operators are currently placing LAA closure devices in patients with a history of intracranial hemorrhage (ICH). “No one knows what to do with them. There is no standard approach; it’s an evolving field,” he said in an interview.

Dr. Mansour reviewed his group’s experience at Massachusetts General with LAA closure using the Watchman device combined with the experience of teams at the Texas Cardiac Arrhythmia Institute in Austin and the HCA Midwest Health in Overland Park, Kan. This included 63 AF patients with an ICH history and 95 similar AF patients with no hemorrhagic history. Nearly half of the patients with a prior ICH also had a history of at least one ischemic stroke or transient ischemic attack, compared with just over a third of the patients without a prior ICH. The two groups had nearly identical CHA2DS2-VASc scores, 4.9 and 4.7, and also very similar HAS-BLED scores.

The patients with a prior ICH included 57% with a prior intracerebral hemorrhage, 29% with a prior subdural hemorrhage, 10% with a subarachnoid hemorrhage, and the remainder unspecified.

Thirty-two of the 63 patients with an ICH history received postprocedural anticoagulation with a direct-acting oral anticoagulant, 18 received warfarin, and 13 received dual antiplatelet therapy but no anticoagulant. Among the 45 patients treated with an oral anticoagulant, 27 also received aspirin. Among the 95 patients reviewed without an ICH history, 93 received an oral anticoagulant, and 2 received dual antiplatelet therapy.

During 180 days of follow-up, the combined incidence of death, stroke, or a major bleed was about 5% among the patients with an ICH history and about 10% among those without this history, a difference that was not statistically significant, Dr. Mansour said.

At Massachusetts General, the decision on how to treat AF patients with an ICH history after they undergo LAA closure is made by a multidisciplinary team of clinicians from the arrhythmia, neurology, radiology, anesthesia, and cardiovascular surgery services. A key factor when determining the drug regimen these patients will receive is the location and size of the ICH when imaged with CT or MRI, Dr. Mansour said. The team also assessed the current likelihood that the patient will bleed. “One size does not fit all” patients, he explained.

A randomized trial, ASAP-TOO (Assessment of the Watchman Device in Patients Unsuitable for Oral Anticoagulation) is now in progress and was designed to compare the safety and efficacy of LAA closure using Watchman with medical management in 888 patients deemed ineligible for anticoagulation, but enrollment into the trial has been slow. As of early 2019, the study’s organizers posted an estimated completion date of late 2023. Until that study finishes, the field will have no definitive data on how to manage these patients, Dr. Mansour said. He noted that a handful of other reports have presented evidence for the safety of LAA closure in these patients, including a review from the Cleveland Clinic on 38 AF patients who received the Watchman device after an ICH (Heart Rhythm. 2018 Dec 2. doi: 10.1016/j.hrthm.2018.11.022); a review of the Amplatzer Cardiac Plug registry, which included 198 patients with an ICH history (Int J Cardiol. 2017 June 1;236[1]:232-6); and a single-center review of 46 French patients who underwent LAA closure after intracerebral hemorrhage (J Stroke Cerebrovasc Dis. 2017 March;26[3]:545-51).

[email protected]

BOSTON – Sixty-three patients with atrial fibrillation (AF) and a history of intracranial hemorrhage have safely received a Watchman device for left atrial appendage (LAA) closure followed by 6 months of treatment with an individualized drug regimen to prevent thrombus formation at three U.S. centers. The 6-month outcomes of these patients were as good as the outcomes of 95 similar patients who did not have a history of intracranial hemorrhage, Moussa C. Mansour, MD, said at the annual International AF Symposium.

Mitchel L. Zoler/MDedge News

“Individualized, postprocedural antithrombotic management ranging from dual antiplatelet therapy to oral anticoagulation plus aspirin can be used short term,” said Dr. Mansour, director of the atrial AF program at Massachusetts General Hospital. He and his associates devised this approach “out of necessity,” he said. The findings “show that you can get these patients through the initial postprocedural period” by individualizing their antiplatelet or anticoagulant treatment.

Not many U.S. operators are currently placing LAA closure devices in patients with a history of intracranial hemorrhage (ICH). “No one knows what to do with them. There is no standard approach; it’s an evolving field,” he said in an interview.

Dr. Mansour reviewed his group’s experience at Massachusetts General with LAA closure using the Watchman device combined with the experience of teams at the Texas Cardiac Arrhythmia Institute in Austin and the HCA Midwest Health in Overland Park, Kan. This included 63 AF patients with an ICH history and 95 similar AF patients with no hemorrhagic history. Nearly half of the patients with a prior ICH also had a history of at least one ischemic stroke or transient ischemic attack, compared with just over a third of the patients without a prior ICH. The two groups had nearly identical CHA2DS2-VASc scores, 4.9 and 4.7, and also very similar HAS-BLED scores.

The patients with a prior ICH included 57% with a prior intracerebral hemorrhage, 29% with a prior subdural hemorrhage, 10% with a subarachnoid hemorrhage, and the remainder unspecified.

Thirty-two of the 63 patients with an ICH history received postprocedural anticoagulation with a direct-acting oral anticoagulant, 18 received warfarin, and 13 received dual antiplatelet therapy but no anticoagulant. Among the 45 patients treated with an oral anticoagulant, 27 also received aspirin. Among the 95 patients reviewed without an ICH history, 93 received an oral anticoagulant, and 2 received dual antiplatelet therapy.

During 180 days of follow-up, the combined incidence of death, stroke, or a major bleed was about 5% among the patients with an ICH history and about 10% among those without this history, a difference that was not statistically significant, Dr. Mansour said.

At Massachusetts General, the decision on how to treat AF patients with an ICH history after they undergo LAA closure is made by a multidisciplinary team of clinicians from the arrhythmia, neurology, radiology, anesthesia, and cardiovascular surgery services. A key factor when determining the drug regimen these patients will receive is the location and size of the ICH when imaged with CT or MRI, Dr. Mansour said. The team also assessed the current likelihood that the patient will bleed. “One size does not fit all” patients, he explained.

A randomized trial, ASAP-TOO (Assessment of the Watchman Device in Patients Unsuitable for Oral Anticoagulation) is now in progress and was designed to compare the safety and efficacy of LAA closure using Watchman with medical management in 888 patients deemed ineligible for anticoagulation, but enrollment into the trial has been slow. As of early 2019, the study’s organizers posted an estimated completion date of late 2023. Until that study finishes, the field will have no definitive data on how to manage these patients, Dr. Mansour said. He noted that a handful of other reports have presented evidence for the safety of LAA closure in these patients, including a review from the Cleveland Clinic on 38 AF patients who received the Watchman device after an ICH (Heart Rhythm. 2018 Dec 2. doi: 10.1016/j.hrthm.2018.11.022); a review of the Amplatzer Cardiac Plug registry, which included 198 patients with an ICH history (Int J Cardiol. 2017 June 1;236[1]:232-6); and a single-center review of 46 French patients who underwent LAA closure after intracerebral hemorrhage (J Stroke Cerebrovasc Dis. 2017 March;26[3]:545-51).

[email protected]