Osteosarcopenia and Mortality in Older Adults Undergoing Transcatheter Aortic Valve Replacement.

Importance: Osteosarcopenia is an emerging geriatric syndrome characterized by age-related deterioration in muscle and bone. Despite the established relevance of frailty and sarcopenia among older adults undergoing transcatheter aortic valve replacement (TAVR), osteosarcopenia has yet to be investigated in this setting. Objective: To determine the association between osteosarcopenia and adverse outcomes following TAVR. Design, Setting, and Participants: This is a post hoc analysis of the Frailty in Aortic Valve Replacement (FRAILTY-AVR) prospective multicenter cohort study and McGill extension that enrolled patients aged 70 years or older undergoing TAVR from 2012 through 2022. FRAILTY-AVR was conducted at 14 centers in Canada, the United States, and France between 2012 and 2016, and patients at the McGill University-affiliated center in Montreal, Québec, Canada, were enrolled on an ongoing basis up to 2022. Exposure: Osteosarcopenia as measured on computed tomography (CT) scans prior to TAVR. Main Outcomes and Measures: Clinically indicated CT scans acquired prior to TAVR were analyzed to quantify psoas muscle area (PMA) and vertebral bone density (VBD). Osteosarcopenia was defined as a combination of low PMA and low VBD according to published cutoffs. The primary outcome was 1-year all-cause mortality. Secondary outcomes were 30-day mortality, hospital length of stay, disposition, and worsening disability. Multivariable logistic regression was used to adjust for potential confounders. Results: Of the 605 patients (271 [45%] female) in this study, 437 (72%) were octogenarian; the mean (SD) age was 82.6 (6.2) years. Mean (SD) PMA was 22.1 (4.5) cm2 in men and 15.4 (3.5) cm2 in women. Mean (SD) VBD was 104.8 (35.5) Hounsfield units (HU) in men and 98.8 (34.1) HU in women. Ninety-one patients (15%) met the criteria for osteosarcopenia and had higher rates of frailty, fractures, and malnutrition at baseline. One-year mortality was highest in patients with osteosarcopenia (29 patients [32%]) followed by those with low PMA alone (18 patients [14%]), low VBD alone (16 patients [11%]), and normal bone and muscle status (21 patients [9%]) (P < .001). Osteosarcopenia, but not low VBD or PMA alone, was independently associated with 1-year mortality (odds ratio [OR], 3.18; 95% CI, 1.54-6.57) and 1-year worsening disability (OR, 2.11; 95% CI, 1.19-3.74). The association persisted in sensitivity analyses adjusting for the Essential Frailty Toolset, Clinical Frailty Scale, and geriatric conditions such as malnutrition and disability. Conclusions and Relevance: The findings suggest that osteosarcopenia detected using clinical CT scans could be used to identify frail patients with a 3-fold increase in 1-year mortality following TAVR. This opportunistic method for osteosarcopenia assessment could be used to improve risk prediction, support decision-making, and trigger rehabilitation interventions in older adults.

Preauthorization Inconsistencies Prevail in Reduction Mammaplasty.

Background: Despite evidence documenting the physical and psychological benefits of breast reduction, third-party payer approval remains a cumbersome process. The objective of this study was to assess differences in medical necessity criteria for reduction mammaplasty among US insurance carriers while analyzing trends in claim denials and appeals. Methods: The medical necessity criteria for reduction mammaplasty were retrieved from seven large health insurance carriers. Data were extracted from each policy, including claim requirements for approval. Additionally, prospective data on claims and denials submitted from January through August 2022 were collected from The Auctus Group, a medical consulting firm. Results: All the policies have been updated since January 2020. Five of the seven policies specifically listed what documentation was required for preauthorization approval, with five third-party payers requiring photograph documentation. Policies required documentation of one to three symptoms lasting from 6 weeks to 1 year. All companies reported a tissue resection estimate threshold, but cutoffs varied. Of 380 reduction mammaplasties performed, 158 (41.6%) received a denial on initial insurance submission. Considering appeals, a total of 216 denials were reviewed with an average of 1.37 denials per patient. Of the 158 initial denials, 104 (65.8%) of these were from claims that received preauthorization. In 12 cases, third-party payers stated that no prior authorization was necessary yet still denied the claim. Conclusions: Wide variability exists in medical necessity criteria for reduction mammaplasty policies among major insurance carriers. These nuances introduce inefficiencies for practices contributing to high denial and appeal rates while delaying surgical care for patients.

Clinical characteristics and patient-reported outcomes of chronic and episodic migraine patients at a US tertiary headache center: A retrospective observational study.

OBJECTIVE: To describe differences in clinical and demographic characteristics between patients with episodic migraine (EM) or chronic migraine (CM) and determine the effect of migraine subtype on patient-reported outcome measures (PROM). BACKGROUND: Prior studies have characterized migraine in the general population. While this provides a basis for our understanding of migraine, we have less insight into the characteristics, comorbidities, and outcomes of migraine patients who present to subspecialty headache clinics. These patients represent a subset of the population that bears the greatest burden of migraine disability and are more representative of migraine patients who seek medical care. Valuable insights can be gained from a better understanding of CM and EM in this population. METHODS: We conducted a retrospective observational cohort study of patients with CM or EM seen in the Cleveland Clinic Headache Center between January 2012 and June 2017. Demographics, clinical characteristics, and patient-reported outcome measures (3-Level European Quality of Life 5-Dimension [EQ-5D-3L], Headache Impact Test-6 [HIT-6], Patient Health Questionnaire-9 [PHQ-9]) were compared between groups. RESULTS: Eleven thousand thirty-seven patients who had 29,032 visits were included. More CM patients reported being on disability 517/3652 (14.2%) than EM patients 249/4881 (5.1%) and had significantly worse mean HIT-6 (67.3 ± 7.4 vs. 63.1 ± 7.4, p < 0.001) and median [interquartile range] EQ-5D-3L (0.77 [0.44-0.82] vs. 0.83 [0.77-1.00], p < 0.001), and PHQ-9 (10 [6-16] vs. 5 [2-10], p < 0.001). CONCLUSIONS: There are multiple differences in demographic characteristics and comorbid conditions between patients with CM and EM. After adjustment for these factors, CM patients had higher PHQ-9 scores, lower quality of life scores, greater disability, and greater work restrictions/unemployment.

Burden of migraine with acute medication overuse or psychiatric comorbidities and treatment with CGRP pathway-targeted monoclonal antibodies: A review.

Migraine is a complex and often debilitating neurological disease that affects more than 1 billion people worldwide. It is characterized by moderate-to-intense, throbbing headache attacks that are worsened by activity and is associated with nausea, vomiting, and sensitivity to light and sound. Migraine, ranked the second leading cause of years lived with disability by the World Health Organization, can diminish patients' quality of life and bring significant personal and economic burden. Furthermore, migraine patients with a history of acute medication overuse (AMO) or psychiatric comorbidities, such as depression or anxiety, may experience even greater impairment and burden, and their migraine may be more difficult-to-treat. Appropriate treatment of migraine is essential to reduce this burden and improve patient outcomes, especially for those with AMO or psychiatric comorbidities. There are several available preventive treatment options for migraine, though many of these are not migraine-specific and may have limited efficacy and/or poor tolerability. The calcitonin gene-related peptide pathway plays a key role in the pathophysiology of migraine, and monoclonal antibodies that target the calcitonin gene-related peptide pathway have been developed as specific preventive treatments for migraine. Four of these monoclonal antibodies have been approved for the preventive treatment of migraine after demonstrating favorable safety and efficacy profiles. These treatments offer substantial benefits for migraine patients, including those with AMO or common psychiatric comorbidities, by reducing monthly headache days and migraine days, days of acute medication use, and disability measures, as well as improving quality of life.

Gender Considerations in Rhinoplasty.

SUMMARY: Precise nasofacial analysis ahead of rhinoplasty is imperative. Features common to the White masculine nose are reviewed in a stepwise fashion and contrasted with those of the White feminine nose. A solid understanding of the cisgender male, masculine nose enables the plastic surgeon to determine the changes required for a successful facial feminizing rhinoplasty as a part of facial gender confirmation surgery.

Facial Expansion: A Blueprint for Coverage.

SUMMARY: The benefits of tissue expansion go unrealized if flap design and coverage concepts do not exist in preoperative thinking. Without proper analysis, the surgeon will likely burden the patient with more expanders than necessary. Tissue coverage needs can be simplified in forms of triangles and rectangles to determine expanded tissue advancement. Single or double back-cuts allow use of all the expanded tissue. Furthermore, early subtotal excisions, especially in children younger than 4 months, can reduce the number of expanders required. With methods presented herein, the face can be resurfaced with better color and less distortion. Eyebrows should be maintained and positioned by keeping the lower frontalis muscles intact. Cheeks can be covered with a large Schrudde design, and color can be improved by using upper neck skin preferentially over lower neck harvest. Laser hair removal allows larger swaths of forehead to be covered by hair-bearing scalp tissue. Prior incisional delay can expedite success with no tissue loss. The results speak for themselves when surfaces are covered with large, expanded flaps that are expeditiously harvested.

Adverse Events Reported with Therapies Targeting the CGRP Pathway During the First 6 Months Post-launch: A Retrospective Analysis Using the FDA Adverse Events Reporting System.

INTRODUCTION: Through 2018, three calcitonin gene-related peptide pathway-targeted monoclonal antibodies (CGRP mAbs) had received US Food and Drug Administration (FDA) approval for migraine prevention: erenumab, fremanezumab, and galcanezumab. METHODS: This retrospective analysis evaluated adverse events (AEs) spontaneously reported to the FDA Adverse Event Reporting System (FAERS) safety surveillance database during the first 6 months post-approval of erenumab (May 2018 to November 2018), fremanezumab (September 2018 to March 2019), and galcanezumab (September 2018 to March 2019). Reporting rates (RR) per 1000 exposed patients were calculated from number of reported events (when product classified as "primary suspect") in each AE category and estimated number of treated patients based on de-identified prescription data (IQVIA database) and were ranked on the basis of frequency for each product. RESULTS: RR per 1000 exposed patients for "migraine" (erenumab, 4.89; fremanezumab, 1.01; galcanezumab, 2.99), "headache" (3.32, 1.27, 3.07), and "drug ineffective" (3.68, 1.14, 1.69) were commonly reported for all three products, as were migraine-associated symptoms ("nausea": 2.94, 0.91, 1.09) and "injection-site" reactions ("pain": 2.94, 0.8, 4.9; "swelling": 0.56, 0.53, 1.25; "pruritus": 0.26, 0.63, 1.14; "erythema": 0.58, 0.71, 1.58). "Constipation" ranked second for erenumab (4.90) but did not make the top ten events for fremanezumab (0.46) or galcanezumab (0.76); cardiovascular events did not rank in the top ten AEs for any product. The frequency of serious outcomes was low, with ≤ 2% of AEs categorized as serious across the CGRP mAbs. CONCLUSION: These results aid in supporting the safety profile of CGRP mAbs in the real-world setting and may provide clinicians and patients with additional insight when considering migraine preventive treatments.

Burden of migraine in Brazil: A cross-sectional real-world study.

OBJECTIVE: To assess the burden and consequences of migraine in Brazil in terms of health-related quality of life (HRQoL), work productivity and daily activities, and healthcare resource utilization (HRU). BACKGROUND: Despite existing data on how migraine affects populations worldwide, there are limited data on the burden of migraine in Latin America. METHODS: This cross-sectional study used patient-reported data from the 2018 Brazil National Health and Wellness Survey. HRQoL scores (EuroQol 5-dimension 5-level [EQ-5D-5L]; 36-item Short Form Health Survey, version 2 [SF-36v2]; and Short Form 6-dimension [SF-6D]), impairments to work productivity and daily activities (Work Productivity and Activity Impairment questionnaire), and all-cause HRU were compared between migraine respondents and matched non-migraine controls. RESULTS: Of the 12,000 total respondents in the survey database, 1643 self-reported a physician diagnosis of migraine and were propensity score matched 1:1 with controls without migraine. HRQoL was lower in patients with migraine versus non-migraine controls, with significantly lower SF-36v2 physical (mean [± SD] 50.3 [7.5] vs. 52.0 [7.6]) and mental component (mean [± SD] 42.9 [10.2] vs. 46.0 [9.9]) summary scores and SF-6D (mean [± SD] 0.7 [0.1] vs. 0.7 [0.1]) and EQ-5D-5L (mean [± SD] 0.7 [0.2] vs. 0.8 [0.2]) utility scores (all p < 0.001). Patients with migraine reported higher levels of work productivity loss (mean [± SD], 40.6% [31.4%] vs. 28.6% [30.9%], including absenteeism 12.8% [19.1%] vs. 8.4% [17.1%] and presenteeism 35.0% [28.7%] vs. 24.8% [28.0%]; all p < 0.001); activity impairment (mean [± SD] 36.0% [28.8%] vs. 25.5% [28.1%]; p < 0.001); and significantly higher HRU in the past 6 months (healthcare provider and emergency department visits [mean [± SD] 7.2 [9.5] vs. 4.5 [6.3] and 1.7 [3.8] vs. 0.9 [2.2]; both p < 0.001] and hospitalizations [mean [± SD] 0.4 [2.7] vs. 0.2 [1.1]; p = 0.002]) than controls. CONCLUSION: Migraine is associated with poorer HRQoL, higher all-cause HRU, and greater activity impairment and work productivity loss versus non-migraine controls in Brazil.

Methamphetamine use and adoption of preventive behaviors early in the COVID-19 pandemic among men who have sex with men in Los Angeles, California.

Background: Methamphetamine (MA) use increased during COVID-19, with men who have sex with men (MSM) exhibiting 3-fold greater use than heterosexual men. Understanding links between reported MA use and COVID-19 prevention behaviors among MSM can inform current transmission risks for HIV, Monkeypox, and other infectious diseases. Methods: This study assesses relationships between self-reported pattern of MA use (past six months; past two weeks) and reported COVID-19 preventive behaviors, adjusting for participant characteristics (HIV serostatus, race/ethnicity, employment and housing stability), in a cohort of ethnically diverse MSM in Los Angeles, California, between April 1 and September 30, 2020. Results: Compared to those who reported no MA use, MSM who reported weekly or more MA use in the past six months were significantly less likely to use COVID-19 protective behaviors of physical distancing (61.8% vs. 81.6%; AOR = 0.39, 95% CI [0.19, 0.81]), of avoiding public transportation (34.5% vs. 60.3%; AOR = 0.42, 95% CI [0.21, 0.83]) and of avoiding traveling overall (32.7% vs. 62.6%; AOR = 0.32, 95% CI [0.16, 0.63]). Parallel findings were observed in analyses of past two-week reported MA use and COVID-19 protective behaviors. Conclusion: Findings highlight ways in which reported MA use frequency links with avoidance of reported preventive behaviors for COVID-19 in urban diverse MSM. Findings also provide evidence to guide public health interventions in future outbreaks of COVID-19 and other infectious diseases among MSM.

Impact of fremanezumab on disability outcomes in patients with episodic and chronic migraine: a pooled analysis of phase 3 studies.

BACKGROUND: Migraine is the second leading cause of disability worldwide. Although many preventive treatments reduce migraine frequency and severity, it is unclear whether these treatments reduce migraine-related disability in a clinically meaningful way. This pooled analysis evaluated the ability of fremanezumab to reduce migraine-related disability, based on responses and shifts in severity in patient-reported disability outcomes. METHODS: This pooled analysis included 3 double-blind phase 3 trials (HALO EM, HALO CM, FOCUS) in which patients with episodic or chronic migraine were randomly assigned 1:1:1 to quarterly or monthly fremanezumab or matched placebo for 12 weeks. Migraine-related disability was assessed using the 6-item Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) questionnaires. A clinically meaningful improvement in disability was defined per American Headache Society guidelines: for HIT-6, a ≥ 5-point reduction; for MIDAS, a ≥ 5-point reduction when baseline score was 11 to 20 or ≥ 30% reduction when baseline score was > 20. Proportions of patients who demonstrated shifts in severity for each outcome were also evaluated. RESULTS: For patients with baseline MIDAS scores of 11 to 20 (n = 234), significantly higher proportions achieved 5-point reductions from baseline in MIDAS scores with fremanezumab (quarterly, 71%; monthly, 70%) compared with placebo (49%; both P ≤ 0.01). For patients with baseline MIDAS scores of > 20 (n = 1266), proportions achieving ≥30% reduction from baseline in MIDAS scores were also significantly higher with fremanezumab (quarterly, 69%; monthly, 79%) compared with placebo (58%; both P < 0.001). For HIT-6 scores, proportions of patients achieving 5-point reductions from baseline were significantly higher with fremanezumab (quarterly, 53%; monthly, 55%) compared with placebo (39%; both P < 0.0001). Proportions of patients with shifts of 1 to 3 grades down in MIDAS or HIT-6 disability severity were significantly greater with quarterly and monthly fremanezumab compared with placebo (all P < 0.0001). CONCLUSION: Fremanezumab demonstrated clinically meaningful improvements in disability severity in this pooled analysis. TRIAL REGISTRATIONS: HALO CM, NCT02621931 ; HALO EM, NCT02629861 ; FOCUS, NCT03308968 .

Reducing the Burden of Migraine: Safety and Efficacy of CGRP Pathway-Targeted Preventive Treatments.

Migraine is a highly disabling and often chronic neurological disease that affects more than one billion people globally. Preventive migraine treatment is recommended for individuals who have frequent and/or disabling attacks; however, many of the medications used for migraine prevention (e.g., antiepileptics, antidepressants, antihypertensives) were not specifically developed for migraine, and often have limited efficacy or poor tolerability. Four monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, which is believed to play a crucial role in the pathophysiology of migraine, have been approved by the US Food and Drug Administration for the preventive treatment of migraine in adults. All four migraine-specific treatments have demonstrated efficacy based on reductions in monthly days with migraine for patients with both episodic and chronic migraine, including those with comorbidities. They have also demonstrated favorable safety and tolerability profiles. Based on these accounts, CGRP pathway-targeted monoclonal antibodies have the potential to revolutionize preventive treatment for patients with migraine.

Subcutaneous Lateral Temporal Lift.

Over the past decades, the understanding of the nuances of forehead anatomy and facial aging has grown immensely. Safe and reliable options for forehead rejuvenation followed. Although noninvasive techniques are an important adjunct in forehead rejuvenation, the mainstay of treatment of the eyebrow is operative intervention. The senior author's technique has developed over many years, first focusing on the open coronal and anterior hairline approach to the forehead lift, then the endoscopic brow lift, and most recently, the lateral subcutaneous temporal lift. This technique allows for reliable and safe elevation of the lateral brow with minimal complications.

A real-world study of acute and preventive medication use, adherence, and persistence in patients prescribed fremanezumab in the United States.

BACKGROUND: Following approval of fremanezumab for the prevention of migraine in adults, health care decision makers are interested in understanding real-world clinical characteristics and treatment patterns among patients initiating fremanezumab therapy. METHODS: Data were obtained for this retrospective (pre-post) study from the Veradigm Health Insights database. The study period was January 1, 2014, to June 30, 2019. Patients were included if they were aged ≥ 18 years; had ≥ 1 migraine diagnosis during the study period; and had a medication record for fremanezumab on or after diagnosis during the identification period (September 1, 2018-December 31, 2018). Treatment patterns, including adherence, persistence, and utilization of acute and preventive migraine medication prescriptions, were evaluated. RESULTS: Of 987 patients initiating fremanezumab during the study period, 738 (74.8%) were adherent to fremanezumab by proportion of days covered (PDC; ≥ 80%) and 780 (79.0%) were adherent by medication possession ratio (MPR; ≥ 80%). A total of 746 (75.6%) patients were persistent for ≥ 6 months. Quarterly fremanezumab (n = 186) was associated with higher rates of adherence versus monthly fremanezumab (n = 801) by PDC (quarterly, 91.3%; monthly, 84.9%; P < 0.001) and MPR (quarterly, 92.2%; monthly, 87.9%; P = 0.006) and higher persistence at ≥ 6 months (quarterly, 82.8%; monthly, 73.9%; P = 0.011). After fremanezumab initiation, patients who were persistent for ≥ 6 months experienced significant reductions from baseline in the mean monthly number of acute and preventive migraine medication prescriptions (P < 0.001). Subgroup analyses in patients with comorbid depression and anxiety showed meaningful real-world benefits based on significant reductions in the number of patients who were prescribed antidepressants (baseline, 68.6%; follow-up, 56.4%; P = 0.0025) and anxiolytic medications (baseline, 55.0%; follow-up, 47.2%; P = 0.037), respectively. In a subgroup of patients with comorbid hypertension at baseline, fremanezumab treatment resulted in nonsignificant reductions in blood pressure. CONCLUSIONS: Overall, adherence and persistence to fremanezumab in this real-world study was high in patients with migraine, with higher rates observed for quarterly fremanezumab. Patients who were persistent for ≥ 6 months experienced significant reductions in acute and preventive migraine medication use, while a subgroup of migraine patients with comorbid depression and anxiety at baseline showed significant reductions in antidepressant and anxiolytic medication use.

Real-world effectiveness after initiating fremanezumab treatment in US patients with episodic and chronic migraine or difficult-to-treat migraine.

BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody (mAb; IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), is approved for the preventive treatment of migraine in adults. The efficacy and safety of fremanezumab for migraine prevention have been demonstrated in randomized, double-blind, placebo-controlled trials. Real-world effectiveness data are needed to complement clinical trial data. This study assessed the effectiveness of fremanezumab across different subgroups of adult patients with episodic migraine (EM), chronic migraine (CM), or difficult-to-treat (DTT) migraine in real-world clinical settings. METHODS: This retrospective, panel-based online chart review used electronic case report forms. Patient inclusion criteria were a physician diagnosis of EM or CM; age ≥ 18 years at the time of first fremanezumab initiation; ≥ 1 dose of fremanezumab treatment; ≥ 1 follow-up visit since first initiation; and ≥ 2 measurements of monthly migraine days (MMD; with 1 within a month before or at first initiation and ≥ 1 after first initiation). Changes in MMD and monthly headache days were assessed during the follow-up period. These endpoints were evaluated in subgroups of patients by migraine type (EM/CM) and in subgroups with DTT migraine (diagnosis of medication overuse [MO], major depressive disorder [MDD], generalized anxiety disorder [GAD], or prior exposure to a different CGRP pathway-targeted mAb [CGRP mAb]). RESULTS: Data were collected from 421 clinicians and 1003 patients. Mean (percent) reductions from baseline in MMD at Month 6 were - 7.7 (77.0%) in EM patients, - 10.1 (68.7%) in CM patients, - 10.8 (80.6%) in the MO subgroup, - 9.9 (68.3%) in the MDD subgroup, - 9.5 (66.4%) in the GAD subgroup, and - 9.0 (68.7%) in the prior CGRP mAb exposure subgroup. Improvements in MDD or GAD severity were reported by 45.5% and 45.8% of patients with comorbid MDD or GAD, respectively. CONCLUSIONS: In this real-world study, fremanezumab demonstrated effectiveness for migraine regardless of migraine type or the presence of factors contributing to DTT migraine (MO, GAD, MDD, or prior exposure to a different CGRP mAb).

Real-world effectiveness of fremanezumab in migraine patients initiating treatment in the United States: results from a retrospective chart study.

BACKGROUND: The efficacy and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP) and is approved for the preventive treatment of migraine in adults, have been demonstrated in randomized, double-blind, placebo-controlled trials. Real-world data can further support those clinical trial data and demonstrate the full clinical benefits of fremanezumab. This chart review assessed the effectiveness of fremanezumab for improving clinical outcomes in adult patients with migraine treated according to real-world clinical practice. METHODS: This retrospective, panel-based, online physician chart review study used electronic case report forms with US physicians. Patient inclusion criteria were a physician diagnosis of migraine, fremanezumab treatment initiation at ≥ 18 years of age after US Food and Drug Administration approval, ≥ 1 dose of fremanezumab treatment, and ≥ 2 assessments of monthly migraine days (MMD; 1 within 30 days before treatment initiation and ≥ 1 after initiation). Changes from baseline in MMD, monthly headache days (MHD), and Migraine Disability Assessment (MIDAS) and 6-item Headache Impact Test (HIT-6) scores were assessed over 6 months. These endpoints were evaluated in the overall population and subgroups divided by dosing schedule and number of prior migraine preventive treatment failures. RESULTS: This study included data from 421 clinicians and 1003 patients. Mean age at fremanezumab initiation was 39.7 years, and most patients were female (75.8%). In the overall population, mean baseline MMD and MHD were 12.7 and 14.0, respectively. Mean (percent) reductions from baseline in MMD and MHD, respectively, were - 4.6 (36.2%) and - 4.7 (33.6%) at Month 1, - 6.7 (52.8%) and - 6.8 (48.6%) at Month 3, and - 9.2 (72.4%) and - 9.8 (70.0%) at Month 6. Mean (percent) reductions from baseline in MIDAS and HIT-6 scores also increased over the 6-month study period, from - 6.2 (21.6%) and - 8.4 (14.0%) at Month 1 to - 18.1 (63.1%) and - 16.2 (27.0%) at Month 6, respectively. Improvements in these outcomes over 6 months were observed across all evaluated subgroups. CONCLUSIONS: This real-world study demonstrated effectiveness of fremanezumab treatment for up to 6 months, irrespective of dosing regimen or number of prior migraine preventive treatment failures, reflecting ongoing, clinically meaningful improvements in patient outcomes.

Safety and tolerability of fremanezumab in patients with episodic and chronic migraine: a pooled analysis of phase 3 studies.

BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, has demonstrated efficacy for preventive treatment of episodic and chronic migraine. Since calcitonin gene-related peptide is expressed within the cardio- and cerebrovascular system and may have cardioprotective effects, it is critical to understand the cardio- and cerebrovascular safety of fremanezumab. METHODS: This was a pooled analysis of three randomized, double-blind, placebo-controlled, phase 3, 12-week trials in which patients with episodic migraine or chronic migraine received quarterly fremanezumab, monthly fremanezumab, or placebo. Incidences of overall and serious adverse events were analyzed. Cardio- and cerebrovascular adverse events (CVAEs) were analyzed in subgroups stratified by cardio- and cerebrovascular medical history, cardiovascular risk factors (CVRFs), and use of cardio- and cerebrovascular medications or triptans. RESULTS: Two thousand, eight hundred and forty-two patients were included in the study. Overall (58-65%) and serious adverse events (<1-2%) occurred in similar proportions across fremanezumab and placebo groups. CVAEs were infrequent, regardless of cardio- and cerebrovascular medical history (2-6%). CVAEs occurred in low, similar proportions of patients with CVRFs and those using cardio- and cerebrovascular medications or triptans. No cardio- and cerebrovascular signals were identified. CONCLUSION: Fremanezumab demonstrated a favorable overall and cardio- and cerebrovascular safety profile in more than 2800 patients with episodic migraine or chronic migraine, regardless of cardio- and cerebrovascular medical history, CVRFs, or medication use.Trial Registrations: NCT02629861 (HALO EM, https://clinicaltrials.gov/ct2/show/NCT02629861), NCT02621931 (HALO CM, https://clinicaltrials.gov/ct2/show/NCT02621931), NCT03308968 (FOCUS, https://clinicaltrials.gov/ct2/ show/NCT03308968).

Efficacy and quality-of-life improvements with fremanezumab treatment in patients with difficult-to-treat migraine with associated neurological dysfunction.

BACKGROUND AND PURPOSE: Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin-gene-related peptide, has demonstrated efficacy as a preventive treatment for adults with episodic migraine or chronic migraine and inadequate response to two to four prior preventive treatment classes in the phase 3b FOCUS study. In this post hoc analysis, efficacy and effects on quality-of-life outcomes for fremanezumab were evaluated in subgroups of patients with and without aura or similar neurological symptoms, here referred to as migraine with or without associated neurological dysfunction. METHODS: In the FOCUS study, 838 patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab or matched placebo for 12 weeks of double-blind treatment. For this post hoc analysis, subgroups of patients with migraine with and without associated neurological dysfunction at baseline were identified based on patient response to questions about symptoms. RESULTS: In patients with migraine with associated neurological dysfunction at baseline, fremanezumab significantly reduced monthly average days with neurological symptoms (quarterly, -1.7 days; monthly, -1.8 days) compared to placebo (-0.5 days; both p ≤ 0.01). In comparison with placebo, both dosing regimens of fremanezumab yielded greater reductions in monthly migraine days over 12 weeks (p < 0.0001) and improvements in Headache Impact Test 6 and Migraine-Specific Quality of Life scores over the last 4 weeks (p < 0.05), regardless of neurological dysfunction at baseline. CONCLUSIONS: Fremanezumab reduced days with neurological symptoms, effectively prevented migraine, and improved quality of life in patients with migraine with associated neurological dysfunction, including those with previous inadequate response to two to four migraine preventive medication classes.

Impact of age and sex on the efficacy of fremanezumab in patients with difficult-to-treat migraine: results of the randomized, placebo-controlled, phase 3b FOCUS study.

BACKGROUND: Migraine prevalence is age and sex dependent, predominating in women in early and middle adulthood; however, migraine also represents a substantial burden for men and adults of all ages. Thus, understanding this burden and the efficacy of migraine preventive medications in both sexes and across age groups is critical. The randomized, placebo-controlled, double-blind, phase 3b FOCUS study demonstrated the safety and efficacy of fremanezumab, a fully humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide as a migraine preventive treatment for individuals with migraine and prior inadequate response to 2 to 4 migraine preventive medication classes. Here, we assessed the efficacy of fremanezumab in participants from FOCUS subgrouped by age (18-45 years and > 45 years) and sex. METHODS: In the FOCUS study, eligible participants were randomized (1:1:1) to 12 weeks of double-blind treatment with quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. In this post hoc analysis, we evaluated changes from baseline in monthly migraine days (primary endpoint of FOCUS) and other secondary and exploratory efficacy outcomes in prespecified age (18-45 and > 45 years) and sex subgroups. RESULTS: The modified intention-to-treat population (received ≥ 1 dose of study drug and had ≥ 10 days of postbaseline efficacy assessments for the primary endpoint) totaled 837 participants (18-45 years, n = 373; > 45 years, n = 464; male, n = 138; female, n = 699). Consistent reductions in monthly average number of migraine days during 12 weeks were observed, regardless of age (18-45 years: quarterly fremanezumab, - 4.1 days; monthly fremanezumab, - 4.7 days; placebo, - 0.9 days; P < 0.001; > 45 years: quarterly fremanezumab, - 3.6 days; monthly fremanezumab, - 3.7 days; placebo, - 0.3 days; P < 0.001) and sex (male: quarterly fremanezumab, - 4.1 days; monthly fremanezumab, - 4.6 days; placebo, - 0.3 days; P < 0.001; female: quarterly fremanezumab, - 3.6 days; monthly fremanezumab, - 3.9 days; placebo, - 0.6 days; P < 0.001). Fremanezumab also reduced monthly headache days of at least moderate severity, monthly days of acute medication use, and improved Migraine Disability Assessment scores across subgroups. CONCLUSIONS: These results demonstrate the efficacy of fremanezumab in patients with difficult-to-treat migraine for reducing migraine and headache days, acute medication use, and disability, regardless of age or sex. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03308968 (FOCUS), registered October 13, 2017.