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

Princess Igwe, Mercer University College of Pharmacy

The American Heart Association states that atrial septal defect (ASD) is a common adult congenital heart condition that affects the septum separating the two upper chambers (atria) of the heart. It is suggested that this defect allows oxygen-rich blood to leak into the oxygen-poor blood chambers in the heart (called a left-to-right atrial shunt), which is then pumped into the lungs. [1] The American College of Cardiology/American Heart Association (ACC/AHA) states that atrial septal defects may lead to right ventricular volume overload, pulmonary over-circulation, atrial arrhythmias and right-sided heart failure. [2]

The ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease recommend that patients with hemodynamically significant ASD should undergo ASD closure, regardless of symptoms, in order to prevent long-term complications. [2]

Migraine headaches are thought to be associated with congenital heart defects such as ASD and ASD closure may result in aggravation of these migraines. [3]


Title: Effect of Clopidogrel and Aspirin vs Aspirin Alone on Migraine Headaches After Transcatheter Atrial Septal Defect Closure
Design Randomized, double-blind clinical trial; N= 171
Objective To assess the efficacy of clopidogrel, used in addition to taking aspirin, for the prevention of migraine attacks following atrial septal defect (ASD) closure
Study Groups Dual antiplatelet therapy (aspirin + clopidogrel, n= 84) vs single antiplatelet therapy (aspirin + placebo, n= 87)
Methods The study was conducted in six centers in Canada and included patients aged 18 years and older with a clinical indication for transcatheter ASD closure. Patients received aspirin (80 mg/day) plus placebo, or aspirin (80 mg/day) plus clopidogrel (75 mg/day). Treatment was initiated within 24 hours prior to ASD closure and continued for three 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 one- and three-month follow-up using a structured migraine headache questionnaire.
Duration December 2008 to February 2015
Primary Outcome Measure Monthly number of migraine days within the three months following ASD closure in the entire study population
Baseline Characteristics   Aspirin + Clopidogrel (n= 84) Aspirin + Placebo (n= 87)
Age, mean (SD), yr 49 (16) 48 (15)
Male sex 36 (42.9) 29 (33.3)
ASD size, mean (SD), mm Measured by TEE: 15.7 (5.7) Measured by TEE: 16.9 (5.7)
Measured by balloon: 20.3 (6.3) Measured by balloon: 21.7 (5.3)
Device size, median (IQR), mm 1 (1-1) 1     (1-1)
Values are reported as No. (%) unless otherwise indicated.; SD= standard deviation; IQR= interquartile range; TEE= transesophageal echocardiography
Results   Aspirin + Clopidogrel Aspirin + Placebo Difference (95% CI) p-value
Migraine days, mean (SD) [95% CI]:        
Days per mo (primary outcome) 0.4 (1.4) [0.07 to 0.69] 1.4 (4.1) [0.54 to 2.26] −1.02 (−1.94 to −0.10) 0.04
Total migraine days at 3 mo 1.0 (4.1) [0.12 to 1.88] 3.8 (10.6) [1.5 to 5.95] −2.74 (−5.14 to −0.34) < 0.001
New-onset migraine attacks, No. (%): 8 (9.5) 19 (21.8) −12.3% (−23.0% to −1.6%) 0.03
With aura 3 (37.5) 11 (57.9) −20.4% (−60.6% to 19.8%) 0.33
Adverse Events Common Adverse Events:
Adverse Events Aspirin + Clopidogrel Aspirin + Placebo Difference (95% CI) p-value
Transient ischemic attack 0 1 (1.2) −1.1 (−3.4 to 1.1) > 0.99
Minor bleeding 5 (5.9) 1 (1.2) 4.8 (−0.7 to 10.3)  0.11
Access site complications 0 1 (1.2) −1.1 (−3.4 to 1.1) > 0.99
Phlebitis 0 1 (1.2) −1.1 (−3.4 to 1.1) > 0.99
Atrial fibrillation 2 (2.4 5 (5.8) −3.4 (−9.2 to 2.5) 0.44
Palpitations 4 (4.8) 6 (6.9) −2.1 (−9.1 to 4.9) 0.75
Vertigo 0 2 (2.3) −2.3 (−5.4 to 0.9) 0.49
Cutaneous rash 3 (3.6) 2 (2.3) 1.3 (−3.8 to 6.3) 0.68
Serious Adverse Events: One patient (1.2%) in the placebo group experienced a transient ischemic attack.
Percentage that Discontinued due to Adverse Events: The treatment was temporarily or definitely stopped by the investigator in 9 patients (5.3%).
Study Author Conclusions 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 three months. Further studies are needed to assess generalizability and durability of this effect.

The study demonstrates that clopidogrel in addition to aspirin reduces the number of monthly migraine days within three months after transcatheter ASD closure (0.4 days) compared to aspirin alone (1.4 days). It is also concluded that clopidogrel plus aspirin lowers the incidence of migraine attacks (9.5%) compared to aspirin alone (21.8%) after the procedure. [4]

Given the incidence of migraine headache after transcatheter ASD closure (affecting approximately 15% of patients), it is reasonable to utilize dual antiplatelet therapy as a treatment option for this subset of patients. However, characteristics of patients used in this study should be considered and good clinical judgment should be implemented in order to formulate a treatment plan for each individual patient.


  1. American Heart Association. Atrial Septal Defect (ASD). Available at: http://www.heart.org/HEARTORG/Conditions/CongenitalHeartDefects/AboutCongenitalHeartDefects/Atrial-Septal-Defect-ASD_UCM_307021_Article.jsp#.Vl8Cb7iDGko. Accessed December 1, 2015.
  2. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: Executive Summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2008;118(23):2395-451.
  3. Gupta V. Patent Foramen Ovale/Atrial Septal Defect Closure and Migraine: Searching the Rationale for the Procedure. Journal of the American College of Cardiology. 2005;46(4):737-738. doi:10.1016/j.jacc.2005.05.029.
  4. Rodés-Cabau J, Horlick E, Ibrahim R, et al. Effect of Clopidogrel and Aspirin vs Aspirin Alone on Migraine Headaches After Transcatheter Atrial Septal Defect Closure: The CANOA Randomized Clinical Trial. JAMA. 2015;314(20):2147-2154. doi:10.1001/jama.2015.13919.



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