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Original Investigation |

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

Josep Rodés-Cabau, MD1; Eric Horlick, MD2; Reda Ibrahim, MD3; Asim N. Cheema, MD4; Marino Labinaz, MD5; Najaf Nadeem, MD6; Mark Osten, MD2; Mélanie Côté, MSc1; Josep Ramon Marsal, MSc7; Donald Rivest, MD8; Alier Marrero, MD9; Christine Houde, MD10
[+] Author Affiliations
1Department of Cardiology, Quebec Heart and Lung Institute, Quebec City, Quebec, Canada
2Department of Cardiology, Toronto General Hospital, Toronto, Ontario, Canada
3Department of Cardiology, Montreal Heart Institute, Montreal, Quebec, Canada
4Department of Cardiology, St. Michael’s Hospital, Toronto, Ontario, Canada
5Department of Cardiology, Ottawa Heart Institute, Ottawa, Ontario, Canada
6Department of Cardiology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
7Epidemiology Unit of the Cardiology Department, Vall d'Hebron Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain
8Department of Neurology, Hôtel Dieu de Lévis, Quebec City, Quebec, Canada
9Department of Neurology, Centre Hospitalier Universitaire Georges. L Dumont, Moncton, New Brunswick, Canada
10Department of Pediatric Cardiology, Centre Hospitalier Universitaire de Québec, Quebec City, Quebec, Canada
JAMA. 2015;314(20):2147-2154. doi:10.1001/jama.2015.13919.
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Published online

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

Figures in this Article

The occurrence of new-onset migraine attacks has been reported in approximately 15% of patients following transcatheter atrial septal defect (ASD) closure, with the majority of initial episodes occurring within the days to weeks following the procedure.110

Antithrombotic therapy following transcatheter ASD closure remains empirical, with aspirin for 6 months being commonly prescribed. Preliminary observational retrospective studies have suggested an association with lower incidence and severity of migraine headaches following ASD closure when ticlopidine or clopidogrel is added to aspirin treatment.710 Subsequently there has been a widespread use of dual antiplatelet therapy following ASD closure, although no randomized data have confirmed such observations. The objective of this study was to assess the effect of clopidogrel on preventing the occurrence and reducing the number of new-onset migraine headache episodes following transcatheter ASD closure in patients with no history of migraine headaches.

Study Design and Patients

This was a randomized, double-blind clinical trial. CANOA (Clopidogrel for the Prevention of New-Onset Migraine Headache Following Transcatheter Closure of Atrial Septal Defects) was conducted in 6 centers in Canada, and it was approved by Health Canada and the local ethics committee of each participating center. All patients provided written informed consent for trial participation (trial protocol reported in Supplement 1).

The study included patients aged 18 years and older with a clinical indication for transcatheter ASD closure. Within the 60 days prior to undergoing the procedure, each patient completed a structured migraine headache questionnaire (eAppendix 1 in Supplement 1), which was subsequently evaluated by a neurologist to determine whether a history of migraine headaches was present. Patients with a history of migraine headaches, based on the International Headache Society criteria,11 were excluded. Other exclusion criteria were allergy or intolerance to any of the antithrombotic drugs used in the study (aspirin, clopidogrel), need for anticoagulation therapy, previous stroke, pregnancy or breastfeeding, not using an effective method of birth control in premenopausal women, use of ASD closure devices other than the Amplatzer Septal Occluder device (St Jude Medical), unsuccessful ASD closure (defined as no device implanted at the time of the procedure), and failure to provide informed consent.

The transcatheter ASD closure procedure has been described in detail in prior studies.12 The procedure was performed though transfemoral venous approach under guidance of echocardiography (transesophageal or intracardiac). Following the measurement of the ASD size by echocardiography, a further assessment of the ASD size was performed by inflation of a sizing balloon within the ASD defect, which determined the size of the ASD closure device. Device implantation was performed using current techniques. The procedures were performed while the patient was under full anticoagulation receiving intravenous heparin. Transthoracic echocardiography was performed at hospital discharge and at 3 months following the procedure.

Patients were randomized (1:1) before the ASD closure procedure to receive either aspirin (80 mg/d) plus placebo (the placebo group) or aspirin (80 mg/d) plus clopidogrel (75 mg/d) (the clopidogrel group). Random block sizes were used to conceal treatment allocation from the patients, and randomization was stratified by clinical center. The treatment was initiated (without loading dose) within 24 hours prior to ASD closure and continued for 3 months thereafter. A headache diary was given to each patient at the time of randomization. Patients were asked to indicate, on a daily basis, the occurrence of headache episodes and describe the characteristics, duration, severity, and medication used for headache relief. The occurrence of headache episodes was also assessed at 1- and 3-month follow-up using a structured migraine headache questionnaire, which included the Migraine Disability Assessment (MIDAS) questionnaire (grade I [score of 0-5] indicates little or no disability, grade II [score, 6-10] mild disability, grade III [score, 11-20] moderate disability, and grade IV [score ≥21] severe disability). The questionnaires were provided by the study coordinator of each participating center. All questionnaires and headache diaries were evaluated by 2 neurologists blinded to procedural details and treatment allocation. If headache episodes occurred, the diagnosis of migraine attacks was established according to the International Headache Society criteria.11 Also, migraine attacks were further classified as with or without aura.

Efficacy Outcomes

The primary efficacy outcome was the monthly number of new-onset migraine attacks within the 3 months following ASD closure in the entire study population. Secondary efficacy end points were the incidence of new-onset migraine attacks, total number of migraine attacks during the first month and 3-month period following ASD closure (the entire population and patients with migraine attacks only), monthly number of new-onset migraine attacks within 3 months following ASD closure in patients with migraine attacks only, severity of migraine attacks as evaluated by the MIDAS questionnaire at 3-month follow-up, and time to first migraine episode. Secondary safety end points included the incidence of adverse events (recorded at 1- and 3-month follow-up) including death, transient ischemic attack, stroke, bleeding complications, and adverse drug reactions.

There were no changes to methods or trial outcomes after the trial commenced.

Statistical Analyses

Based on previous studies,3,4,9 we anticipated an incidence of 15% of new-onset migraine attacks following ASD closure, with a median (interquartile range [IQR]) number of 5 (IQR, 1-23) migraine days per month within the 3 months following the procedure among patients with migraine attacks. The addition of clopidogrel therapy was expected to reduce the incidence and number of migraine headaches by at least 50%.3,7 Considering that a substantial number of patients were not expected to have migraine attacks following ASD closure, the mean number of migraine days per month by patient (including those who did not have migraine attacks) was modeled by a mixture of zero-truncated Poisson distribution and zero-constant distribution, which was calculated with a logistic model (SAS Proc Genmod program).13 The power of the test was computed for several sample sizes by Monte Carlo simulations, and a total number of 70 patients per group were estimated to provide 80% power to detect differences between groups. To account for a potential dropout rate of approximately 10%, the sample size was increased to 160 patients.

Qualitative variables were expressed as percentages and quantitative variables as mean (SD) or median (IQR). Qualitative variables were compared using the χ2 or Fisher exact test. Comparison of numerical baseline and procedural variables and migraine variables (number of migraine days) within the group of patients with new-onset migraine attacks was performed using the t test or Mann-Whitney rank-sum test depending on variable distribution. Comparison of the mean number of monthly migraine days and total number of migraine days at 1- and 3-month follow-up in the entire study population (with and without migraines) were performed using the zero-inflated Poisson (ZIP) regression model. ZIP models provide the methodology to explain the excess zeros by modeling the data as a mixture of 2 separate distributions: first, a Poisson distribution to model the counts among the patients who had at least 1 migraine attack; and second, a logistic regression to model the occurrence (or not) of new-onset migraine episodes. The effects estimated are incident risk ratios (IRRs) for the Poisson distribution, which can be interpreted as the ratio of expected mean number of migraine days per month during the 3 months compared between the placebo and clopidogrel groups and the odds ratio (OR) for the logistic model. Additionally, the effect of the treatment on the new-onset migraine attacks was estimated using logistic regression. For the other 2 secondary end points (total migraine days at the first month and at 3 months), a ZIP model was also used.

Excluding the patients nonadherent to allocated treatment, the efficacy analyses were repeated. Differences were considered statistically significant at P values of less than .05 (2-tailed). No type-I error from multiple comparisons of secondary outcomes was addressed in the analyses and the results from these analyses should be interpreted as exploratory. The data were analyzed using SAS version 9.1.3 and RStudio version 0.98.953.

The flow of patient participation through the trial is shown in Figure 1. Patients were enrolled from December 2008 to November 2014, and the last patient follow-up was completed in February 2015. A total of 291 patients diagnosed with an ASD for whom transcatheter ASD closure was planned were screened. Of these, 71 patients (24%) were excluded because of a history of migraine attacks and were included in a prospective migraine registry. Additionally, 49 patients were excluded at the time of the procedure because device implantation was not attempted (n = 17), was unsuccessful (n = 19), or because the patient declined to continue in the study after ASD closure (n = 13). The final study population consisted of 171 patients: 87 in the placebo group, and 84 patients in the clopidogrel group. A total of 155 patients (91%) were adherent with the treatment during the study period (>80% of tablets taken as scheduled during the study period, as determined by tablet count). The treatment was temporarily or definitely stopped by the investigator due to adverse events in 9 patients and by the patients (for unknown reasons) in 7 patients.

Place holder to copy figure label and caption
Figure 1.
Flowchart of the CANOA Study Population

ASD indicates atrial septal defect.

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The baseline and procedural characteristics of the study population, according to treatment allocation, are reported in Table 1. The mean (SD) age of the study population was 49 (15) years, and 106 (62%) patients were women. The mean size of the ASD was 16.3 (5.5) mm, as measured by transesophageal echocardiography, and 20.9 (5.7) mm by balloon measurement. The median device size was 22 (IQR, 18-26) mm. There were no significant between-group differences regarding baseline and procedural characteristics.

Table Graphic Jump LocationTable 1.  Baseline and Procedural Characteristics of the Study Population

A total of 27 patients (15.8%) had the diagnosis of new-onset migraine attacks within the 3 months following the procedure (14 [52%] of them with aura). In these patients, the median number of total migraine days was 12 (IQR, 6-20), and the median monthly number of migraine days was 4 (IQR, 2-7). The primary and secondary efficacy end points for the entire study population are shown in Table 2. The mean (95% CI) number of monthly migraine days (primary outcome) was lower in the clopidogrel group (0.4 [95% CI, 0.07 to 0.69] days) than in the placebo group (1.4 [95% CI, 0.54 to 2.26] days; difference, −1.02 days [95% CI, −1.94 to −0.10]; IRR, 0.61 [95% CI, 0.41 to 0.91]; P = .04). The incidence of new-onset migraine attacks was lower in the clopidogrel group (9.5% [8] of patients) than in the placebo group (21.8% [19] of patients; difference, −12.3% [95% CI, −23% to −1.6%]; OR, 0.38 [95% CI, 0.15 to 0.89]; P = .03. The secondary efficacy end points for the group of patients with migraine attacks following ASD closure (n = 27) are shown in Table 3. In the presence of migraine attacks following ASD closure, the addition of clopidogrel was associated with a reduced migraine severity (as evaluated by the MIDAS questionnaire [zero patients in the clopidogrel group had moderate or severe disabling migraine attacks vs 36.8% {7 patients} in the placebo group; difference, −36.8% {95% CI, −58.5% to −15.2%}]; P = .046). There were no between-group differences regarding the type of migraine (aura vs no aura), migraine duration, or time to first migraine episode. Figure 2 shows the timing of the first and subsequent migraine attacks during the 3 months following ASD closure according to treatment allocation. In the clopidogrel group, 6 patients (75%) received paracetamol during the migraine episodes. In the aspirin group, 16 patients (84%) received analgesic therapy during the migraine attacks, distributed as follows: acetaminophen/paracetamol (10 patients), ibuprofen (4 patients), ibuprofen + acetaminophen/paracetamol (1 patient), and apotramadol + acetaminophen/paracetamol (1 patient). One patient in the placebo group received preventive medication (amitripyline) during the study period. A total of 77 patients had nonmigraine headaches within the 3 months following the transcatheter ASD closure procedure, 41 patients (49%) in the aspirin + clopidogrel group, and 36 patients (41%) in the aspirin group, P = .36.

Table Graphic Jump LocationTable 2.  Occurrence and Number of New-Onset Migraine Attacks Within the 3 Months Following ASD Closure
Table Graphic Jump LocationTable 3.  Migraine Characteristics in Patients With Migraine Headaches
Place holder to copy figure label and caption
Figure 2.
Timing of the First and Subsequent Migraine Attacks During the 3 Months Following ASD Closure

The first vertical column of data markers on the left indicates day 1. Day 0 was the day of ASD closure.

Graphic Jump Location

The main outcomes, excluding the nonadherent patients (ie, <80% of treatment tablets taken as scheduled during the study period, n = 16), are shown in eTables 1 and 2 in Supplement 2. A total of 155 patients were adherent with the treatment during the study period (76 in the clopidogrel group, 79 in the placebo group). The mean (SD) number of migraine days per month within the 3 months following ASD closure was lower in the clopidogrel group (0.4 [1.4] days) than in the placebo group (1.6 [4.3] days; difference, −1.2 days [95% CI, −2.2 to −0.19]; IRR, 0.58 [95% CI, 0.38 to 0.90]; P = .02). Also, the incidence of migraine attacks was lower in the clopidogrel group (9.2% [7] of patients) than in the aspirin group (24.1% [19] of patients; difference, −14.8% [95% CI, −26.3% to −3.4%]; OR, 0.32 [95% CI, 0.13 to 0.81]; P = .02).

The occurrence and type of adverse events during the trial, according to treatment allocation, are shown in Table 4. There were no deaths or stroke events during the entire study period. One patient in the placebo group experienced a transient ischmic attack. There were no between-group differences in the occurrence of bleeding complications (no major bleeding events; and for minor bleeding, 5.9% in the clopidogrel group vs 1.2% in the placebo group [difference, 4.8% {95% CI, −0.7% to 10.3%}]; P = .11). The rate of patients with any adverse event throughout the study period was similar between groups (16.7% [14 patients] in the clopidogrel group vs 21.8% [19 patients] in the placebo group [difference, −5.2% [95% CI, −17.0% to 6.6%]; P = .44).

Table Graphic Jump LocationTable 4.  Adverse Events at 3-Month Follow-up

Dual antiplatelet therapy (aspirin + clopidogrel) following transcatheter ASD closure was associated with a statistically significant reduction in the occurrence and number of new-onset migraine headaches within the 3 months following the procedure. Among patients with migraine attacks, those on dual antiplatelet therapy tended to experience less-severe migraine attacks. No significant increase in adverse events was observed with the use of dual vs single antiplatelet therapy.

Transcatheter ASD closure has been well established as the treatment of choice for most patients with hemodynamically significant ASD. This treatment offers a very high success rate together with an extremely low rate of complications (including cerebrovascular events), and the minimally invasive approach, when compared with surgery, allows a much more rapid recovery.14 This combination of high success rate, low rate of complications, and more rapid recovery rate is of particular importance considering that most adult patients receiving this treatment are of the working age. However, a limitation of transcatheter ASD closure is the occurrence of migraine attacks—affecting approximately 15% patients and extending to approximately 1 week per month during the first months following the procedure.110 This limitation represents a significant burden of medical consultations in addition to missed work or school days and reduced productivity. The present study, which to our knowledge is the first randomized trial in this field, confirmed prior observations on the incidence of migraine attacks following transcatheter ASD closure and demonstrated the usefulness of dual antiplatelet therapy for preventing and reducing, by more than 50%, the burden of such migraine episodes following the procedure. However, the reduction in monthly migraine days in the entire study population (0.4 days in the clopidogrel broup vs 1.4 days in the placebo group) may appear modest due to the high number of patients with no migraine headaches after the procedure. Moreover, the addition of clopidogrel therapy reduced the severity of migraine episodes, with no patient in the dual antiplatelet therapy group presenting moderately or severely disabling headache episodes compared with more than one-third of the patients receiving single antiplatelet therapy (aspirin only). No increase in adverse events was observed with the addition of clopidogrel. Whether the optimal duration of clopidogrel treatment should be 3 months or longer following ASD closure will need to be determined in future studies. Also, no loading dose of clopidogrel was used in this trial; the potential additional effect of a loading dose of clopidogrel on the prevention of migraine headaches following ASD closure needs to be further evaluated.

An association between interatrial shunts and migraine has been put forward in various observational studies,1517 and a significant reduction of migraine attacks following percutaneous shunt closure has also been suggested.15,16 The randomized trials evaluating the effects of atrial shunt closure on patients with migraine headaches have provided controversial results, with negative or borderline primary outcomes and some positive secondary outcomes like in the PRIMA trial.18,19 Although the pathophysiology linking interatrial shunts and chronic migraine headaches is probably different from the one linking ASD closure with new-onset migraines, the results of this trial should be considered when designing or analyzing the results of past, current, and future studies assessing the efficacy of interatrial shunt closure for the treatment of migraines. The addition of clopidogrel to the treatment of patients allocated to the transcatheter shunt closure group must be considered as a potential confounding factor that may lead to overestimating the real effect of shunt closure in such patients. Spencer et al20 showed a significant positive effect of clopidogrel therapy on migraine patients with a patent foramen ovale before transcatheter closure. Migraine trials in this setting should consider adjusting for clopidogrel therapy in case of unbalanced treatment between groups.

The effects of a specific antithrombotic regimen, such as the use of clopidogrel on the occurrence of migraine attacks, provide further insight into the potential role of platelet-coagulation activation and prothrombotic status in the pathogenesis of migraine. The association between migraine and ischemic stroke has been well established,21,22 and several studies have linked migraine attacks with abnormalities of platelet morphology and function and also with coagulation disorders.2326 Some studies have shown a reduction in migraine attacks with the use of anticoagulation or antiplatelet (clopidogrel) therapy in specific subsets of patients,20,26 but 2 randomized studies failed to demonstrate a significant effect of warfarin or clopidogrel on migraine attacks.27,28 The present study showed that in the presence of a specific trigger, clopidogrel may be highly effective in the prevention of migraine attacks. The occurrence of increased platelet aggregation following ASD closure has been demonstrated,29 and this may have increased the release of substances such as serotonin or proinflammatory cytokines like interleukins 1, 6, and 8 and tumor necrosis factor α, which have been linked to migraine attacks.2325

Apart from its antiplatelet effects, clopidogrel has also proven antioxidant and anti-inflammatory properties.30 Several studies have also shown improved endothelial function and nitric oxide bioavailability with the use of clopidogrel.3133 The vasoprotective effects through adenosine phosphate receptor blockade may also have played a role in the prevention of migraine attacks.34 Further studies to evaluate the pathophysiology linking clopidogrel with antimigraine effects are warranted. Also, it remains to be elucidated whether the effects of clopidogrel on migraine attacks are a class effect or specific to that medication.

Limitations

No platelet reactivity examinations were performed to evaluate clopidogrel resistance,35 and thus it remains unknown whether the patients with migraine attacks in the dual antiplatelet group had some degree of clopidogrel resistance. These results were obtained in patients undergoing ASD closure with the Amplatzer Septal Occluder device and may not apply to other transcatheter ASD closure devices. Migraine headaches following ASD closure may decrease over time36; studies with a longer-term follow-up are needed to determine the transient vs permanent behavior of new-onset migraine headaches after ASD closure.

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.

Corresponding Author: Josep Rodés-Cabau, MD, Quebec Heart and Lung Institute, Laval University, Quebec City, QC G1V 4G5, Canada (josep.rodes@criucpq.ulaval.ca).

Published Online: November 9, 2015. doi:10.1001/jama.2015.13919.

Author Contributions: Dr Rodés-Cabau and Ms Côté had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Rodés-Cabau.

Acquisition, analysis, or interpretation of data: Rodés-Cabau, Horlick, Ibrahim, Cheema, Labinaz, Nadeem, Osten, Coté, Marsal, Rivest, Marrero, Houde.

Drafting of the manuscript: Rodés-Cabau, Coté, Marsal.

Critical revision of the manuscript for important intellectual content: Rodés-Cabau, Horlick, Ibrahim, Cheema, Labinaz, Nadeem, Osten, Marsal, Rivest, Marrero, Houde.

Statistical analysis: Coté, Marsal.

Obtained funding: Rodés-Cabau.

Administrative, technical, or material support: Rodés-Cabau, Ibrahim, Cheema, Labinaz, Nadeem, Osten, Marsal, Rivest.

Study supervision: Rodés-Cabau, Horlick, Ibrahim, Nadeem, Osten, Marrero, Houde.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Horlick reports receipt of honoraria for lectures outside the submitted work from St Jude Medical and an institutional unrestricted grant for research, education, and administrative support from St Jude Medical. The other authors report no disclosures.

Funding/Support: This study was funded by unrestricted grants from Sanofi and St Jude Medical and a grant from the Foundation of the Quebec Heart and Lung Institute.

Role of the Funder/Sponsor: There was no role of any organization or sponsor in any of the following: design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, and approval of the manuscript, and decision to submit the manuscript for publication.

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Dowson  A, Mullen  MJ, Peatfield  R,  et al.  Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation. 2008;117(11):1397-1404.
PubMed   |  Link to Article
Hildick-Smith  D.Percutaneous closure of patent foramen ovale in migraine with aura—a randomized prospective study (PRIMA trial). Transcatheter Cardiovascular Therapeutics Meeting, Washington, DC, March 2014. http://www.sac.org.ar/wp-content/uploads/2014/09/tct-2014-prima-a-prospective-randomized-trial.pdf. Accessed October, 2, 2015.
Spencer  BT, Qureshi  Y, Sommer  RJ.  A retrospective review of clopidogrel as primary therapy for migraineurs with right to left shunt lesions. Cephalalgia. 2014;34(11):933-937.
PubMed   |  Link to Article
Kurth  T, Diener  HC.  Migraine and stroke: perspectives for stroke physicians. Stroke. 2012;43(12):3421-3426.
PubMed   |  Link to Article
Mawet  J, Kurth  T, Ayata  C.  Migraine and stroke: in search of shared mechanisms. Cephalalgia. 2015;35(2):165-181.
PubMed   |  Link to Article
Borgdorff  P, Tangelder  GJ.  Migraine: possible role of shear-induced platelet aggregation with serotonin release. Headache. 2012;52(8):1298-1318.
PubMed   |  Link to Article
Sarchielli  P, Alberti  A, Coppola  F,  et al.  Platelet-activating factor (PAF) in internal jugular venous blood of migraine without aura patients assessed during migraine attacks. Cephalalgia. 2004;24(8):623-630.
PubMed   |  Link to Article
Danese  E, Montagnana  M, Lippi  G.  Platelets and migraine. Thromb Res. 2014;134(1):17-22.
PubMed   |  Link to Article
Maggioni  F, Bruno  M, Mainardi  F, Lisotto  C, Zanchin  G.  Migraine responsive to warfarin: an update on anticoagulant possible role in migraine prophylaxis. Neurol Sci. 2012;33(6):1447-1449.
PubMed   |  Link to Article
Wammes-van der Heijden  EA, Smidt  MH, Tijssen  CC, van’t Hoff  AR, Lenderink  AW, Egberts  AC.  Effect of low-intensity acenocoumarol on frequency and severity of migraine attacks. Headache. 2005;45(2):137-143.
PubMed   |  Link to Article
Chambers  JB, Seed  PT, Ridsdale  L.  Clopidogrel as prophylactic treatment for migraine: a pilot randomised, controlled study. Cephalalgia. 2014;34(14):1163-1168.
PubMed   |  Link to Article
Pan  G, Xie  ZF, Zhang  Y, Long  SC, Xu  XP, Zhang  ZW.  Platelet activation through the efficacy of aspirin in congenital heart disease patients undergoing transcatheter closure of atrial septal defects or ventricular septal defects. Genet Test Mol Biomarkers. 2014;18(12):832-838.
PubMed   |  Link to Article
Heitzer  T, Rudolph  V, Schwedhelm  E,  et al.  Clopidogrel improves systemic endothelial nitric oxide bioavailability in patients with coronary artery disease: evidence for antioxidant and antiinflammatory effects. Arterioscler Thromb Vasc Biol. 2006;26(7):1648-1652.
PubMed   |  Link to Article
Warnholtz  A, Ostad  MA, Velich  N,  et al.  A single loading dose of clopidogrel causes dose-dependent improvement of endothelial dysfunction in patients with stable coronary artery disease: results of a double-blind, randomized study. Atherosclerosis. 2008;196(2):689-695.
PubMed   |  Link to Article
Giachini  FR, Leite  R, Osmond  DA,  et al.  Anti-platelet therapy with clopidogrel prevents endothelial dysfunction and vascular remodeling in aortas from hypertensive rats. PLoS One. 2014;9(3):e91890.
PubMed   |  Link to Article
Zhang  YZ, Chen  BL, Zhang  W, Cao  X.  Non-antiplatelet effect of clopidogrel: improving endothelial function in Chinese healthy subjects with different CYP2C19 genotype. Clin Exp Pharmacol Physiol. 2015;42(1):22-26.
PubMed   |  Link to Article
Tietjen  GE.  The role of the endothelium in migraine. Cephalalgia. 2011;31(6):645-647.
PubMed   |  Link to Article
Linden  MD, Tran  H, Woods  R, Tonkin  A.  High platelet reactivity and antiplatelet therapy resistance. Semin Thromb Hemost. 2012;38(2):200-212.
PubMed   |  Link to Article
Voet  A, Luermans  JG, Thijs  V,  et al.  New-onset and persistent migraine early after percutaneous atrial septal defect closure disappear at follow-up. Acta Clin Belg. 2008; 63(4):262-268.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Flowchart of the CANOA Study Population

ASD indicates atrial septal defect.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Timing of the First and Subsequent Migraine Attacks During the 3 Months Following ASD Closure

The first vertical column of data markers on the left indicates day 1. Day 0 was the day of ASD closure.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Baseline and Procedural Characteristics of the Study Population
Table Graphic Jump LocationTable 2.  Occurrence and Number of New-Onset Migraine Attacks Within the 3 Months Following ASD Closure
Table Graphic Jump LocationTable 3.  Migraine Characteristics in Patients With Migraine Headaches
Table Graphic Jump LocationTable 4.  Adverse Events at 3-Month Follow-up

References

Rodés-Cabau  J, Molina  C, Serrano-Munuera  C,  et al.  Migraine with aura related to the percutaneous closure of an atrial septal defect. Catheter Cardiovasc Interv. 2003;60(4):540-542.
PubMed   |  Link to Article
Fernández-Mayoralas  DM, Fernández-Jaén  A, Muñoz-Jareño  N, Gutiérrez-Larraya  F, Calleja-Pérez  B, San Antonio Arce  V.  Migraine symptoms related to the percutaneous closure of an ostium secundum atrial septal defect: report of four paediatric cases and review of the literature. Cephalalgia. 2007;27(6):550-556.
PubMed   |  Link to Article
Mortelmans  K, Post  M, Thijs  V, Herroelen  L, Budts  W.  The influence of percutaneous atrial septal defect closure on the occurrence of migraine. Eur Heart J. 2005;26(15):1533-1537.
PubMed   |  Link to Article
Yew  G, Wilson  NJ.  Transcatheter atrial septal defect closure with the Amplatzer septal occluder: five-year follow-up. Catheter Cardiovasc Interv. 2005;64(2):193-196.
PubMed   |  Link to Article
Wei  SH, Fan  PC, Kuo  PH, Chiou  LC, Wang  JK.  Calcitonin gene-related peptide and size of the atrial septal defect in new-onset migraine after transcatheter closure: results of a preliminary study. Headache. 2012;52(6):985-992.
PubMed   |  Link to Article
Castellini  P, Lambru  G, Manzoni  GC, Torelli  P.  Atrial septal defect closure and migraine with aura: is there a correlation? Neurol Sci. 2009;30(4):339-342.
PubMed   |  Link to Article
Sharifi  M, Dehghani  M, Mehdipour  M, Al-Bustami  O, Emrani  F, Burks  J.  Intense migraines secondary to percutaneous closure of atrial septal defects. J Interv Cardiol. 2005;18(3):181-183.
PubMed   |  Link to Article
Wilmshurst  PT, Nightingale  S, Walsh  KP, Morrison  WL.  Clopidogrel reduces migraine with aura after transcatheter closure of persistent foramen ovale and atrial septal defects. Heart. 2005;91(9):1173-1175.
PubMed   |  Link to Article
Rodés-Cabau  J, Mineau  S, Marrero  A,  et al.  Incidence, timing, and predictive factors of new-onset migraine headache attack after transcatheter closure of atrial septal defect or patent foramen ovale. Am J Cardiol. 2008;101(5):688-692.
PubMed   |  Link to Article
Kato  Y, Kobayashi  T, Ishido  H, Hayashi  T, Furuya  D, Tanahashi  N.  Migraine attacks after transcatheter closure of atrial septal defect. Cephalalgia. 2013;33(15):1229-1237.
PubMed   |  Link to Article
Headache Classification Subcommittee of the International Headache Society.  The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004; 24(suppl 1): 9-160.
PubMed
Kazmouz  S, Kenny  D, Cao  QL, Kavinsky  CJ, Hijazi  ZM.  Transcatheter closure of secundum atrial septal defects. J Invasive Cardiol. 2013;25(5):257-264.
PubMed
Palta  M. Quantitative Methods in Population Health: Extensions of Ordinary Regression. Hoboken, NJ: Wiley; 2003.
Du  ZD, Hijazi  ZM, Kleinman  CS, Silverman  NH, Larntz  K; Amplatzer Investigators.  Comparison between transcatheter and surgical closure of secundum atrial septal defect in children and adults: results of a multicenter nonrandomized trial. J Am Coll Cardiol. 2002;39(11):1836-1844.
PubMed   |  Link to Article
Lip  PZ, Lip  GY.  Patent foramen ovale and migraine attacks: a systematic review. Am J Med. 2014;127(5):411-420.
PubMed   |  Link to Article
Luermans  JG, Post  MC, Temmerman  F,  et al.  Is a predominant left-to-right shunt associated with migraine?: a prospective atrial septal defect closure study. Catheter Cardiovasc Interv. 2009;74(7):1078-1084.
PubMed   |  Link to Article
Kato  Y, Hayashi  T, Kobayashi  T, Tanahashi  N.  Migraine prevalence in patients with atrial septal defect. J Headache Pain. 2013;14:63.
PubMed   |  Link to Article
Dowson  A, Mullen  MJ, Peatfield  R,  et al.  Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation. 2008;117(11):1397-1404.
PubMed   |  Link to Article
Hildick-Smith  D.Percutaneous closure of patent foramen ovale in migraine with aura—a randomized prospective study (PRIMA trial). Transcatheter Cardiovascular Therapeutics Meeting, Washington, DC, March 2014. http://www.sac.org.ar/wp-content/uploads/2014/09/tct-2014-prima-a-prospective-randomized-trial.pdf. Accessed October, 2, 2015.
Spencer  BT, Qureshi  Y, Sommer  RJ.  A retrospective review of clopidogrel as primary therapy for migraineurs with right to left shunt lesions. Cephalalgia. 2014;34(11):933-937.
PubMed   |  Link to Article
Kurth  T, Diener  HC.  Migraine and stroke: perspectives for stroke physicians. Stroke. 2012;43(12):3421-3426.
PubMed   |  Link to Article
Mawet  J, Kurth  T, Ayata  C.  Migraine and stroke: in search of shared mechanisms. Cephalalgia. 2015;35(2):165-181.
PubMed   |  Link to Article
Borgdorff  P, Tangelder  GJ.  Migraine: possible role of shear-induced platelet aggregation with serotonin release. Headache. 2012;52(8):1298-1318.
PubMed   |  Link to Article
Sarchielli  P, Alberti  A, Coppola  F,  et al.  Platelet-activating factor (PAF) in internal jugular venous blood of migraine without aura patients assessed during migraine attacks. Cephalalgia. 2004;24(8):623-630.
PubMed   |  Link to Article
Danese  E, Montagnana  M, Lippi  G.  Platelets and migraine. Thromb Res. 2014;134(1):17-22.
PubMed   |  Link to Article
Maggioni  F, Bruno  M, Mainardi  F, Lisotto  C, Zanchin  G.  Migraine responsive to warfarin: an update on anticoagulant possible role in migraine prophylaxis. Neurol Sci. 2012;33(6):1447-1449.
PubMed   |  Link to Article
Wammes-van der Heijden  EA, Smidt  MH, Tijssen  CC, van’t Hoff  AR, Lenderink  AW, Egberts  AC.  Effect of low-intensity acenocoumarol on frequency and severity of migraine attacks. Headache. 2005;45(2):137-143.
PubMed   |  Link to Article
Chambers  JB, Seed  PT, Ridsdale  L.  Clopidogrel as prophylactic treatment for migraine: a pilot randomised, controlled study. Cephalalgia. 2014;34(14):1163-1168.
PubMed   |  Link to Article
Pan  G, Xie  ZF, Zhang  Y, Long  SC, Xu  XP, Zhang  ZW.  Platelet activation through the efficacy of aspirin in congenital heart disease patients undergoing transcatheter closure of atrial septal defects or ventricular septal defects. Genet Test Mol Biomarkers. 2014;18(12):832-838.
PubMed   |  Link to Article
Heitzer  T, Rudolph  V, Schwedhelm  E,  et al.  Clopidogrel improves systemic endothelial nitric oxide bioavailability in patients with coronary artery disease: evidence for antioxidant and antiinflammatory effects. Arterioscler Thromb Vasc Biol. 2006;26(7):1648-1652.
PubMed   |  Link to Article
Warnholtz  A, Ostad  MA, Velich  N,  et al.  A single loading dose of clopidogrel causes dose-dependent improvement of endothelial dysfunction in patients with stable coronary artery disease: results of a double-blind, randomized study. Atherosclerosis. 2008;196(2):689-695.
PubMed   |  Link to Article
Giachini  FR, Leite  R, Osmond  DA,  et al.  Anti-platelet therapy with clopidogrel prevents endothelial dysfunction and vascular remodeling in aortas from hypertensive rats. PLoS One. 2014;9(3):e91890.
PubMed   |  Link to Article
Zhang  YZ, Chen  BL, Zhang  W, Cao  X.  Non-antiplatelet effect of clopidogrel: improving endothelial function in Chinese healthy subjects with different CYP2C19 genotype. Clin Exp Pharmacol Physiol. 2015;42(1):22-26.
PubMed   |  Link to Article
Tietjen  GE.  The role of the endothelium in migraine. Cephalalgia. 2011;31(6):645-647.
PubMed   |  Link to Article
Linden  MD, Tran  H, Woods  R, Tonkin  A.  High platelet reactivity and antiplatelet therapy resistance. Semin Thromb Hemost. 2012;38(2):200-212.
PubMed   |  Link to Article
Voet  A, Luermans  JG, Thijs  V,  et al.  New-onset and persistent migraine early after percutaneous atrial septal defect closure disappear at follow-up. Acta Clin Belg. 2008; 63(4):262-268.
PubMed   |  Link to Article
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Multimedia

Supplement 1.

Trial Protocol

Supplemental Content
Supplement 2.

eTable 1. Occurrence and Number of New-Onset Migraine Attacks in Those Patients Compliant With the Allocated Treatment (n=155)

eTable 2. Migraine Characteristics in Those Patients Compliant With the Allocated Treatment Who Presented With Migraine Attacks Post-ASD Closure (n=26)

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