Faculty CHAIR David Dodick, MD, FAHS, FRCPC, FACP Professor of - PDF document

12/21/16 Faculty CHAIR David Dodick, MD, FAHS, FRCPC, FACP Professor of Neurology Mayo Clinic Phoenix, AZ FACULTY Deborah I. Friedman, MD, MPH, FAHS Professor, Neurology and Neurotherapeutics and Ophthalmology University of Texas Southwestern Medical Center Dallas, TX Stewart J. Tepper, MD, FAHS Geisel School of Medicine at Dartmouth Professor of Neurology Hanover, NH 1

12/21/16 Activity Description Target Audience This activity is designed for clinicians involved in the care and treatment of patients with migraine pain. Statement of Need Patients with frequent migraines and/or who experience functional disability need preventative migraine treatment. However, studies have shown that of the 38% of patients who stand to benefit from prophylactic therapy, only 3 ‐ 13% of them actually receive it. Calcitonin gene ‐ related peptide (CGRP) monoclonal antibodies are under clinical investigation and constitute a new prophylactic migraine therapy class. Increased physician attention when individualizing treatment plans to maximize therapy efficacy and minimize side effects as well as managing headache triggers and existing comorbidities continue to be vital strategies as new agents emerge and when maximizing patient function. Support This activity is supported by an educational grant from Lilly. For further information concerning Lilly grant funding, visit www.lillygrantoffice.com. Barriers in the Treatment of Chronic Migraine David W. Dodick, M.D. Professor Department of Neurology Mayo Clinic Phoenix, Arizona 2

12/21/16 Migraine 7 th most disabling MOH 20 th most disabling MOH = Migraine overuse headache Lancet 2016; 388: 1545–602 Diagnosis and Management of Migraine (episodic and chronic) in United States Of 775 Only 39% Only 26% patients Only 45% diagnosed by receive meeting EM see an HCP an HCP treatment criteria Of 1254 Only 11% Only 4.5% patients Only 41% diagnosed by receive meeting CM see an HCP an HCP treatment criteria Lipton RB, et al. Headache 2013;51:81-92. Dodick DW, Headache 2016;56:821-834 3

12/21/16 Migraine Still Undertreated! Scale: figure = 1M people 36 M Adults with Migraine¹ 3.7 M Patients Diagnosis of Migraine 2 50% of those 1.8 M 1.9 M diagnosed get Receive Treatment 2 No Prescription prescription treatment Treatment 3 out of 4 Treated Patients Receive Triptans 2 Fewer than 5 in 100 persons with migraine receive prescription treatment. Many diagnosed, yet untreated patients have cardiovascular conditions or risks, or they have stopped treatments due to lack of adequate response 1. www.americanmigrainefoundation.org; 2. IMS Health, PharMetrics Plus, January – December 2013 Cohort Projected to U.S. Insured Patient Population, 2015 Cardiovascular Risk in Migraine Women’s Health Study • A prospective cohort study of 115,541 female nurses aged 25–42 followed from 1989-2011 • Migraine was associated with increased risk of: – Major CVD – Myocardial infarction – Stroke – Angina/coronary revascularisation procedures – Significant increased risk for CVD mortality • Women with migraine should be evaluated for vascular risk CVD=cardiovascular Kurth et al. BMJ disease 2016;353:i2610 4

12/21/16 2600/7800 adverse events attributed to triptans fell under the cardiac category Serious and unexpected Coronary artery spasm (adj ROR 21.6; 16.1–23.9) • Ischemic Arterial dissection (ROR 12.24; 4.42–32.25) cardiovascular Placental infarction (ROR 12.68; 3.23–42.70) events • Aneurysms/dissections • Pregnancy ‐ related vascular events Roberto G, et al . Cephalalgia 2013 • 2H-PF = 18-50% • 24HSPF = 13-33% HR=headache relief PF=pain free SHR=sustained headache relief SPF=sustained pain free Cameron C, et al. Headache 2015 5

12/21/16 Optimal Treatment Strategy of CM associated with medication overuse is not known Studies Evidence Class Early discontinuation 3 III Early discontinuation with preventive 19 III medication Preventive medication 17 II 1.1% 2.1% • Survey of 95 AHS members – I think that a well ‐ designed clinical trial that compares different strategies of treating 9.5% chronic migraine with medication overuse is needed – 92 clinicians – 3 migraine researchers • 88.4% agreed that the most effective tx 87.4% strategy is unknown Strongly agree Somewhat agree Somewhat disagree Disagree Closer Look at Preventive treatment Underutilized, adherence poor 6

12/21/16 Closer look at prevention Chronic Migraine Migraine Su ff erers Prevention Treated Su ff erers Candidates Treated 33% 13% 40% Lipton RB et al. Neurology 2007. Bigal et al. Neurology 2008;71:559 ‐ 66. Adherence to oral migraine preventive medications in patients with chronic migraine Hepp Z., et al. Cephalalgia 2015;35:478-488 7

12/21/16 86% discontinue at 12 months 4 0 % 3 6 % Persistent At 6 M o n t h s Persistent at 1 2 M o n t h s 3 5 % Proportionof Patients 3 3 % 3 2 % 3 1 % 2 9 % 2 9 % 3 0 % 2 8 % 2 6 % 2 4 % 2 4 % 2 5 % 2 3 % Persistent 2 1 % 2 1 % 2 0 % 1 9 % 1 9 % 2 0 % 1 8 % 1 7 % 1 7 % 1 6 % 1 6 % 1 4 % 1 4 % 1 5 % 1 3 % 1 2 % 1 1 % 1 0 % 1 0 % 1 0 % 1 0 % 8 % 5 % 0 % N=9,632 Nortriptyline Fluoxetine Paroxetine Venlafaxine Propranolol Metoprolol Gabapentin Divalproex Sertraline Nadolol Atenolol Amitriptyline Citalopram N=110 Topiramate N=195 Total N=622 N=1,150 N=421 N=292 N=190 N=395 N=2,604 N=277 N=699 N=860 N=1,164 N=653 Antidepressants Beta Blockers Anticonvulsants All Cla sse s Hepp Z., et al. Cephalalgia 2015;35:478-488 An even higher percentage discontinue drugs after switching 3 rd Prophylactic 1 st Prophylactic 2 nd Prophylactic Switch 27% Discontinue90% Persist14% Switch 23% Discontinue87% Start a Prophylactic N=9,632 Reinitiate 32% Discontinue100% Discontinue86% Reinitiate 43% Discontinue92% Untreated34% Hepp Z., et al. Cephalalgia 2015;35:478-488 18 8

12/21/16 Summary Enormous disability associated with migraine, chronic migraine and medication overuse headache EM and CM are poorly recognized and under ‐ treated in clinical practice There remains a large unmet acute treatment need with drugs that are more effective, lack safety concerns, and do not induce MOH Prophylactic therapies for migraine are under ‐ utilized and lack the efficacy and tolerability to enable patients to persist Curren Curr ent and and Em Emer ergin ging Ther Therapies apies Stewart J Tepper, MD, FAHS Professor of Neurology Geisel School of Medicine at Dartmouth Hanover, New Hampshire 9

12/21/16 Episodic Migraine (EM) Prophylaxis: Anti ‐ Epilepsy Drugs • Topiramate • FDA ‐ approved for migraine prevention with Level A/Class 1 evidence and 2 large RCTs (studied up to 200 mg/day) • Commonly reported side effects: paresthesia, weight loss, cognitive dysfunction, mood change, kidney stones • Contraindicated in pregnancy due to teratogenicity • Multiple mechanisms include anti ‐ glutamate effects and inhibition of cortical spreading depression (CSD) • Also 2 RCTS showing effectiveness in prevention of Chronic Migraine (not FDA approved for this) • Divalproex sodium, sodium valproate • Level A/class I evidence • 500 ‐ 1000 mg/day, significant reduction in 4 ‐ week migraine headache rate as compared with PBO • AEs: weight gain, alopecia, nausea, tremor, hepatotoxicity, polycystic ovaries • Contraindicated in pregnancy due to teratogenicity • Gabapentin • Level U evidence • Cochrane meta ‐ analysis found ineffective in migraine prophylaxis Silberstein SD, et al . Neurology . 2012;78:1337-1345. Linde M, et al. Cochrane Database Syst Rev . 2013;(6):CD010609. doi: 10.1002/14651858.CD010609. Episodic Migraine Prophylaxis: Anti ‐ hypertensives • Beta Blockers • Level A evidence: propranolol, timolol (both FDA approved), also metoprolol • Level B evidence: atenolol, nadolol • Contraindicated in patients with asthma, COPD, emphysema, pre ‐ existing bradycardia, partial AV block, hypotension, and hypoglycemia associated with diabetes treatment • Beta blockers inhibit CSD and central neuronal hyperexcitability • The ARB candesartan now has Level A evidence and is equal to (directly compared) propranolol Silberstein SD, et al. Neurology . 2012;78:1337-1345. Barbanti P, et al. Neurol Sci. 2011;32(suppl1):S111-115. Stovner E, et al. Cephalalgia. 2014;34:523-532. 10

12/21/16 Onabotulinumtoxin A for Prevention of Chronic Migraine (CM): Pooled Analysis of the PREEMPT Trials • Design • Two trials that were double ‐ blind, randomized, 24 ‐ week, placebo ‐ controlled identically designed trials of Chronic Migraine (CM) patients • Followed by a 32 ‐ week open label trial • Primary endpoint • Onabot (155 ‐ 195U) injections q 12 weeks for 2 cycles (n=688), placebo n= 3,696 • At week 24, there was a significant decrease in frequency of headache days for the experimental ( ‐ 8.4 days, onabot) vs the pbo group ( ‐ 6.6 days, P<.001) • Few treatment AEs • Only 3.8% of onabot pts discontinued due to AEs (vs 1.2% of pbo patients) Dodick DW, et al. Headache. 2010;50:921-936. AAN Practice Guidelines for OnabotulinumtoxinA • Class A evidence: Safe and effective for reducing the number of headache days in CM (2 Class I studies) • Probably effective for improving QOL (1 Class I study) • Insufficient evidence to compare onabot with oral topiramate (no direct comparison) • Ineffective for EM and not recommended • Probably ineffective for treating CTTH Simpson DM et al. Neurology 2016;86:1818 ‐ 26 11