Effect of Clopidogrel and Aspirin vs Aspirin Alone on Migraine Headaches After Transcatheter Atrial Septal Defect Closure: The CANOA Randomized Clinical Trial.

IMPORTANCE: The occurrence of new-onset migraine attacks is a complication of transcatheter atrial septal defect (ASD) closure. It has been suggested that clopidogrel may reduce migraine attacks after ASD closure. OBJECTIVE: To assess the efficacy of clopidogrel, used in addition to taking aspirin, for the prevention of migraine attacks following ASD closure. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind clinical trial performed in 6 university hospitals in Canada. Participants were 171 patients with an indication for ASD closure and no history of migraine. INTERVENTIONS: Patients were randomized (1:1) to receive dual antiplatelet therapy (aspirin + clopidogrel [the clopidogrel group], n = 84) vs single antiplatelet therapy (aspirin + placebo [the placebo group], n = 87) for 3 months following transcatheter ASD closure. The first patient was enrolled in December 2008, and the last follow-up was completed in February 2015. MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was the monthly number of migraine days within the 3 months following ASD closure in the entire study population. The incidence and severity of new-onset migraine attacks, as evaluated by the Migraine Disability Assessment questionnaire, were prespecified secondary end points. A zero-inflated Poisson regression model was used for data analysis. RESULTS: The mean (SD) age of the participants was 49 (15) years and 62% (106) were women. Patients in the clopidogrel group had a reduced mean (SD) number of monthly migraine days within the 3 months following the procedure (0.4 [95% CI, 0.07 to 0.69] days) vs the placebo group (1.4 [95% CI, 0.54 to 2.26] days; difference, -1.02 days [95% CI, -1.94 to -0.10 days]; incident risk ratio [IRR], 0.61 [95% CI, 0.41 to 0.91]; P = .04) and a lower incidence of migraine attacks following ASD closure (9.5% for the clopidogrel group vs 21.8% for the placebo group; difference, -12.3% [95% CI, -23% to -1.6%]; odds ratio [OR], 0.38 [95% CI, 0.15 to 0.89]; P = .03). Among patients with migraines, those in the clopidogrel group had less-severe migraine attacks (zero patients with moderately or severely disabling migraine attacks vs 37% [7 patients] in the placebo group; difference, -36.8% [95% CI, -58.5% to -15.2%]; P = .046). There were no between-group differences in the rate of patients with at least 1 adverse event (16.7% [14 patients] in the clopidogrel group vs 21.8% [19 patients] in the placebo group; difference, -5.2% [95% CI, -17% to 6.6%]; P = .44). CONCLUSIONS AND RELEVANCE: Among patients who underwent transcatheter ASD closure, the use of clopidogrel and aspirin, compared with aspirin alone, resulted in a lower monthly frequency of migraine attacks over 3 months. Further studies are needed to assess generalizability and durability of this effect. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00799045.

Effect of Clopidogrel and Aspirin vs Aspirin Alone on Migraine Headaches After Transcatheter Atrial Septal Defect Closure: One-Year Results of the CANOA Randomized Clinical Trial.

Importance: Adding clopidogrel to aspirin for 3 months after transcatheter atrial septal defect (ASD) closure results in a lower incidence of new-onset migraine attacks. However, the outcomes at 6- to 12-month follow-up (after clopidogrel cessation at 3 months) remain largely unknown. Objective: To assess the incidence of migraine attacks at 6- and 12-month follow-up after transcatheter ASD closure. Design, Setting, and Participants: This prespecified analysis of a randomized, double-blind clinical trial included patients with no prior history of migraine undergoing ASD closure from 6 university hospitals in Canada from December 2008 to November 2014. Patients were followed up at 3, 6, and 12 months, and a migraine headache questionnaire was administered at each time. Analysis began June 2019. Interventions: Patients were randomized (1:1) to receive dual antiplatelet therapy (aspirin plus clopidogrel; n = 84) vs single antiplatelet therapy (aspirin plus placebo; n = 87) for 3 months following transcatheter ASD closure. After 3 months, only single antiplatelet therapy (aspirin) was pursued. Main Outcomes and Measures: Incidence and severity of migraine attacks at 6- and 12-month follow-up. Results: The mean (SD) age of the study population was 38 (12) years, with 106 women (62%). A total of 27 patients (15.8%) had new-onset migraine attacks within the 3 months following ASD closure (8 of 84 [9.5%] vs 19 of 87 [21.8%] in the initial clopidogrel and placebo groups, respectively; P = .03). After cessation of clopidogrel and aspirin monotherapy, the percentage of patients with migraine attacks decreased over time, with 8 (4.7%) and 4 patients (2.3%) continuing to have migraine attacks at 6 and 12 months, respectively (vs 3 months: P < .001). The severity of migraine attacks progressively decreased over time; no moderate or severe attacks occurred at 6 and 12 months (vs 3 months: P < .001). There were no differences between groups in the rate of migraine attacks at 6 months (initial clopidogrel group: 2 of 84 [2.4%]; initial placebo group: 6 of 87 [6.9%]; P = .28) and 12 months (initial clopidogrel group: 3 of 84 [3.6%]; initial placebo group: 1 of 87 [1.1%]; P = .36) after ASD closure. Only 2 patients (1.2%; 1 patient per group) presented with new-onset migraine attacks after 3 months. Conclusions and Relevance: New-onset migraine attacks after ASD closure improved or resolved spontaneously within 6 to 12 months in most patients. No significant rebound effect was observed after clopidogrel cessation at 3 months. These results demonstrate a low rate of migraine events beyond 3 months following transcatheter ASD closure and support the early discontinuation of clopidogrel therapy if administered. Trial Registration: ClinicalTrials.gov Identifier: NCT00799045.

Atherosclerotic burden findings in young cryptogenic stroke patients with and without a patent foramen ovale.

BACKGROUND AND PURPOSE: To further determine the mechanisms of cryptogenic stroke or transient ischemic attack in young patients, we evaluated indices of atherosclerosis in patients

Incidence, timing, and predictive factors of new-onset migraine headache attack after transcatheter closure of atrial septal defect or patent foramen ovale.

The objectives of this study were to evaluate the incidence, predictive factors, and duration of migraine headache attack (MHA) after transcatheter atrial septal defect (ASD) or patent foramen ovale (PFO) closure. A total of 260 consecutive patients who underwent ASD or PFO closure in our center answered a structured headache questionnaire focused in 3 period times, including (1) at baseline (just before closure), (2) within the 3 months after ASD-PFO closure, and (3) at the last (median 27 months, range 6 to 80 months) follow-up. All questionnaires were evaluated by a neurologist who established the diagnosis of MHA with or without aura, according to International Headache Society criteria. The Amplatzer ASD or PFO device was used in 95% of the patients, and aspirin, for at least 6 months, was the antithrombotic treatment in 91% of the cases. A total of 185 patients (71%) had no history of MHA before ASD-PFO closure, and these constituted the study population (mean age 39 +/- 21 years). MHA occurred in 13 patients (7%) after ASD-PFO closure, with aura in 9 of them. MHA appeared after a median of 10 days (range 0.3 to 30 days) after the procedure and were still present at the last follow-up (23 +/- 17 months) in 9 patients (69%). The median number of MHA within the 3 months after the procedure was 4 per month (interquartile range 1 to 23), and decreased to 1 per month (interquartile range 0.3 to 1) at the latest follow-up (p = 0.03). Compared with the patients who did not develop MHA, patients with MHA after ASD-PFO closure were younger (26 +/- 16 vs 39 +/- 21 years; p = 0.02) and were more likely to have undergone ASD closure (100% vs 58%; p = 0.001). In the multivariate analysis, ASD closure was the only predictor of MHA occurrence after the procedure (odds ratio 7.7; 95% confidence interval 1.5 to 22; p = 0.01). In conclusion, MHA, mostly with aura, occurred in 7% of patients after transcatheter ASD-PFO closure and persisted in most of them after a mean follow-up of 2 years. ASD closure was the only independent predictor of MHA occurrence after the procedure. These results suggest that mechanisms other than device composition are involved in the occurrence of MHA in these cases.

Enhanced thrombogenesis but not platelet activation is associated with transcatheter closure of patent foramen ovale in patients with cryptogenic stroke.

BACKGROUND AND PURPOSE: No studies have yet determined whether antiplatelet or anticoagulant therapy is the more appropriate treatment after transcatheter closure of patent foramen ovale (PFO) in patients with cryptogenic stroke. The objective of this study was to prospectively evaluate the presence, degree, and timing of activation of the platelet and coagulation systems after transcatheter closure of PFO in patients with cryptogenic stroke. METHODS: Twenty-four consecutive patients (mean age, 44+/-10 years; 11 men) with previous cryptogenic stroke who had undergone successful transcatheter closure of PFO were included in the study. Prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin III (TAT) were used as markers of coagulation activation, and soluble P-selectin and soluble CD40 ligand were used as markers of platelet activation. Measurements of all hemostatic markers were taken at baseline just before the procedure and at 7, 30, and 90 days after device implantation. RESULTS: F1+2 and TAT levels increased from 0.41+/-0.16 nmol/L and 2.34+/-1.81 ng/mL, respectively, at baseline to a maximal value of 0.61+/-0.16 nmol/L and 4.34+/-1.83 ng/mL, respectively, at 7 days, gradually returning to baseline levels at 90 days (P<0.001 for both markers). F1+2 and TAT levels at 7 days after PFO closure were higher than those obtained in a group of 25 healthy controls (P<0.001 for both markers). Levels of soluble P-selectin and soluble CD40 ligand did not change at any time after PFO closure. CONCLUSIONS: Transcatheter closure of PFO is associated with significant activation of the coagulation system, with no increase in platelet activation markers. These findings raise the question of whether optimal antithrombotic treatment after PFO closure should be short-term anticoagulant rather than antiplatelet therapy.

Acute porphyria presenting as epilepsia partialis continua.

PURPOSE: The porphyrias are a defect in the biosynthesis of heme which can be associated with different neurological symptoms during acute attacks such as peripheral neuropathy, mental disturbance and seizures. So far, there have only been a few case reports of status epilepticus, none of which were of epilepsia partialis continua (EPC). We present here two cases of hereditary coproporphyria (HCP) manifesting EPC as part of the clinical presentation. METHOD: The patients' medical charts, EEG and imaging studies were carefully reviewed. RESULTS: Case 1 is a 49-year-old male who first presented a tonic-clonic seizure. Case 2 is a 30-year-old male who came to the emergency room for a convulsive status epilepticus. Both evolved to EPC over the next days. EPC persisted despite several antiepileptic drug trials. Diagnosis of HCP was confirmed by a high level of urine, fecal and serum porphyrins in both cases and by genetic testing in one. Over the last 3 years, the first patient has continued to present non-disabling EPC and has had four tonic-clonic seizures associated with alcohol consumption. The second patient died from brain edema one month and half after admission. CONCLUSION: Acute porphyrias should be included in the differential diagnosis of new onset status epilepticus, including EPC. Their recognition is important as it modifies significantly patient management, since many anticonvulsants are porphyrogenic.