Original research J Investig Med: first published as 10.1136/jim-2020-001342 on 26 August 2020. Downloaded from Clopidogrel can be an effective complementary prophylactic for drug- refractory migraine with patent foramen ovale Yichen Guo , Yujie Shi, Dan Zhu, Rui Liu, Yi Qi , Guogang Luo Department of Neurology, ABSTRACT The First Affiliated Hospital The present study aims to determine the potential Significance of this study of Xi’an Jiaotong University, Xi’an, Shaanxi, China prophylactic effect of clopidogrel for migraine with patent foramen ovale (PFO) in patients who What is already known about this subject? ► The incidence of patent foramen ovale Correspondence to are poor responders to two or more common Professor Guogang Luo, preventive medications. Migraineurs underwent (PFO) is higher in patients with migraine Department of Neurology, contrast- enhanced transcranial doppler examination than in those without migraine; migraine The First Affiliated Hospital to confirm the presence of PFO and determine the is alleviated after PFO closure; clopidogrel of Xi’an Jiaotong University, right-to- left shunt degree. Clopidogrel 75 mg/day could improve new- onset migraine after Xi’an, Shaanxi 710061, device implantation. China; lguogang@ 163. com was added to the existing prophylactic regimen for 3 months and 6 months. The presence of PFO What are the new findings? Accepted 28 July 2020 was found in 56.8% (151/266) of all patients with ► PFO was closely correlated with migraine, Published Online First migraine and 70.2% (59/84) of migraine with aura 26 August 2020 especially in migraine with aura(MHA); a (MHA), and among MHA a large shunt was observed large right- to- left shunt is very common in in 36 patients. Twenty- six patients with drug- patients with MHA; clopidogrel could play refractory migraine took clopidogrel 75 mg/day for 3 an additional prophylactic role for migraine months. Compared with those at baseline, headache with PFO in patients with poor response to frequencies and attack durations were significantly routine prophylactics. lower (6.17±3.93/month (M) vs 3.28±2.67/M, p=0.003; 13.62±13.98/hour (H) vs 7.36±7.33/H, How might these results change the focus p=0.0049, respectively); visual analog scale scores of research or clinical practice? and migraine disability assessment scores were also ► For the patients with PFO whom traditional obviously decreased (6.32±1.97 vs 4.71±1.20, drug therapy has not worked, compared p<0.001; 22.14±7.13 vs 16.00±5.92, p=0.001, with invasive surgical closure, we can http://jim.bmj.com/ respectively). These improvements were maintained firstly try to use clopidogrel to maximize for 6 months in 12 patients. We concluded that improvement in patients with headache PFO was closely correlated with migraine, especially symptoms. in MHA. Clopidogrel could act as an effective complementary prophylactic for migraine with PFO in patients with poor response to routine prophylactics. clopidogrel inhibits platelet aggregation and on September 28, 2021 by guest. Protected copyright. modulates the release of vasoactive substances,8 which could improve new- onset migraine after 9 INTRODUCTION device implantation. Therefore, some scholars Many studies have shown that the incidence of believe that clopidogrel administered early in patent foramen ovale (PFO) is higher in patients the postoperative period plays a greater role in with migraine than in those without migraine, decreasing the number of migraine events than 10 ranging from 15% to 90%, and is significantly mechanical closure. higher in migraine with aura (MHA), with a We therefore conducted this study to evaluate prevalence of 16% to 90%.1 2 Conversely, the the rate of PFO in patients with migraine and to prevalence of migraine with PFO is also higher determine the effect of clopidogrel on patients than that in normal controls, ranging from with drug- refractory migraine and PFO. approximately 16% to 64%.2 Platelet aggrega- © American Federation for tion and paradoxical embolization might link PATIENTS AND METHODS 3 Medical Research 2020. cardiac right-to- left shunts (RLS) to migraine. This was a single- center non- randomized open- Re- use permitted under Many observational trials have suggested label trial. From January 2015 to March 2017, CC BY- NC. No commercial that migraine is alleviated after PFO closure,4 5 the study was conducted in the headache clinic re-use . Published by BMJ. but the results of three prospective, random- of the neurology department at the First Affili- To cite: Guo Y, Shi Y, ized controlled trials—the MIST, PRIMA, ated Hospital, Xi’an Jiao Tong University. The Zhu D, et al. J Investig Med and PREMIUM studies—did not report this inclusion criteria for patients were as follows: 2020;68:1250–1255. result.2 6 7 Some articles have shown that (1) patients with migraine diagnosed according 1250 Guo Y, et al. J Investig Med 2020;68:1250–1255. doi:10.1136/jim-2020-001342 Original research J Investig Med: first published as 10.1136/jim-2020-001342 on 26 August 2020. Downloaded from to the diagnostic criteria of both episodic migraine (EM) of the possible preventive effects and potential side effects and chronic migraine (CM) in the 2013 International Clas- of clopidogrel, and they provided signed informed consent. sification of Headache Disorders third edition (ICHD, beta Clopidogrel 75 mg/day was added to the existing prophy- version)11 and aged 18–65 years, that CM defined as ≥15 lactic migraine regimen for at least 3 months. Ibuprofen was headache days/month averaged over the past 3 months used as an acute pain reliever for unbearable headache for not and aged 18–65 years; (2) patients with no positive signs more than 2 days during the experimental period. All base- of neurological disorders and negative results on head CT line information, including headache frequency, headache or MRI; (3) patients with normal ECG, routine hematuria, duration, Migraine Disability Assessment (MIDAS) score, and coagulation tests results; (4) patients with no history and headache severity, was registered in detail. Headache of medication overuse or drug allergy. The exclusion severity was evaluated with the visual analog scale (VAS). criteria were as follows: (1) patients with other types of After 3 months and 6 months, all of the enrolled patients primary headache; (2) patients with secondary headache; were re-interviewed in the headache clinic; the above indica- (3) patients with histories of hypertension, heart disease, tors were measured based on the patients’ headache diaries. diabetes, or other chronic diseases; (4) patients with soma- The trial diagram is shown in figure 1. tization disorders or mental disorders; (5) patients with a history of chest or head trauma; (6) pregnant or lactating women. All of the subjects underwent contrast-enhanced STATISTICAL ANALYSIS transcranial doppler (cTCD) imaging to determine PFO Categorical variables are expressed as frequencies and and the size of the shunt. RLS was classified according to percentages, and continuous variables are expressed as microbubble (MB) numbers: (1) 0 MBs (negative result); means±SDs. All data were tested for normality. The t-test (2) mild: 1–10 MBs; (3) moderate: 10<MBs≤25; (4) large: and Wilcoxon’s test were used to analyze differences >25 MBs.12 between baseline data and that measured 3 or 6 months Then, we selected drug- refractory migraineurs from after clopidogrel treatment. One- way ANOVA or non- patients with PFO. Drug- refractory migraine was defined parametric tests were used to compare the differences as ≥2 headache attacks/month while on at least two classes among the data at baseline, 3 months and 6 months, and of prophylactics,6 including β-blockers, anticonvulsants, Bonferroni’s multiple comparison test was used for post calcium channel blockers, tricyclics, and serotonin antago- hoc tests. The p-value <0.05 was considered an acceptable nists, for at least 3 months. All of the patients were told statistically significant cut-off value. http://jim.bmj.com/ on September 28, 2021 by guest. Protected copyright. Figure 1 Trials diagram. cTCD, contrast- enhanced transcranial Doppler; ICHD-3, International Classification of Headache Disorders 3rd edition; PFO, patent foramen ovale. Guo Y, et al. J Investig Med 2020;68:1250–1255. doi:10.1136/jim-2020-001342 1251 Original research J Investig Med: first published as 10.1136/jim-2020-001342 on 26 August 2020. Downloaded from Table 1 Demographic characteristics of this study population Table 2 Demographic characteristics of the patients with drug- Migraine with Migraine without refractory migraine with patent foramen ovale aura aura Migraine Migraine (n=84) (n=182) (n=266) Patient symptom RLS Prior medications used Sex F (%) 56/84 (66.7) 113/182 (62.1) 169/266 (63.5) 1 MHA Large Valproate, sumatripan Age 32.45±10.75 35.84±13.37 34.77±12.68 2 MoA Moderate Flunarizine, gabapentin Mean±SD (years) 3 CM Large Propranolol, amitriptyline, Attack frequency (/ 3.37±1.24 2.58±0.76 3.02±1.14 naproxen month) 4 MHA Mild Flunarizine, gabapentin Headache duration 8.46±8.75 6.38±10.39 7.29±9.10 5 MoA Moderate Propranolol, amitriptyline, of each onset (/h) topiramate, magnesium VAS scores 4.28±1.47 3.23±0.89 3.70±1.26 6 MoA Mild Sumatripan, propranolol MIDAS scores 10.56±3.78 12.29±4.65 10.93±2.49 7 MHA Large Flunarizine, lamotrigine PFO+ (%) 59/84 (70.2) 92/182 (50.5) 151/266 (56.8) 8 MHA Large Flunarizine, topiramate Large RLS 36 29 65 9 MHA Large Metoprolol, valproate MIDAS, migraine disability assessment; PFO, patent foramen ovale; RLS, right- 10 MoA Mild Flunarizine, amitriptyline, to- left shunt; VAS, visual analog scale. ibuprofen 11 MoA Moderate Flunarizine, propranolol 12 CM Large Divitamins, flunarizine, herb RESULTS 13 MoA Mild Propranolol, topiramate The demographic characteristics of each group are presented 14 MoA Mild Topiramate, flunarizine in table 1.