by Eirini Beneki, MSc, MD, PhD(c); Kyriakos Dimitriadis, MD, PhD; Elias Zintzaras, MD, PhD; Panagiotis Kostakis, MD, PhD(c); Constantina Aggeli, MD, PhD; and Konstantinos Tsioufis, MD, PhD

Drs. Beneki, Dimitriadis, Kostakis, Aggeli, and Tsioufis are with First Cardiology Department, School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens in Athens, Greece. Dr. Zintzaras is with Department of Biomathematics, University of Thessaly School of Medicine in Larissa, Greece; Center for Clinical Evidence Synthesis, The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine in Boston, Massachusetts; and Pharmacology and Drug Development Program, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine in Boston, Massachusetts.

FUNDING: No funding was provided for this article.

DISCLOSURES: The authors declare no conflicts of interest relevant to the content of this article.

Innov Clin Neurosci. 2025;22(1–3):14–19.

---

Abstract

The presence of patent foramen ovale (PFO) has been associated with migraine. Several retrospective, nonrandomized studies support reduction of migraine frequency and severity after PFO closure. However, three randomized, controlled trials (RCTs) have not met their primary efficacy endpoints, and their reporting quality has not been assessed. The present study aims to determine the reporting quality of RCTs focusing on the PFO closure for the treatment of migraine according to the revised Consolidated Standards of Reporting Trials (CONSORT) 2010 checklist. Systematic searches of two databases (MEDLINE/PubMed and Cochrane Library) were conducted. The primary objective was to establish the mean CONSORT adherence of RCTs of PFO closure for the migraine treatment, and secondary objectives were the calculation of adherence per CONSORT item and the effect of CONSORT statement in high-ranked medical journals. A 37-item questionnaire based on the CONSORT 2010 checklist was used to assess the reporting quality. Adequate adherence to the CONSORT statement was defined as reporting over 70 percent of the items. The search identified three eligible articles for analysis. The mean adherence was 69.66±4.49 percent. Only one of the studies achieved a good reporting quality (≥75%). Twenty-six of the 37 items of the CONSORT checklist (70.3%) were reported in more than half of the studies. Quality of reporting in RCTs focusing on the PFO closure for the treatment of migraine remains unsatisfactory. Further improvement of reporting quality is essential to assess the validity of clinical research.

Keywords: CONSORT, randomized controlled trials, quality, patent foramen ovale closure, migraine

---

Migraine affects more than 10 percent of the general population between 20 and 64 years of age,¹ with a 3:1 female-to-male ratio, and 1 in 3 individuals report migraine attack preceded by an aura.² Migraine remains among the most debilitating chronic diseases, having a significantly detrimental effect on work, social activities, and family life in otherwise healthy young adults, and treatment is crucial for improving their quality of life. Medications are effective for many patients, but their potentially disabling side effects leave a large treatment gap.³

There is an increased prevalence of patent foramen ovale (PFO) in patients with migraine,⁴ and several retrospective, nonrandomized studies indicate that percutaneous PFO closure might help reduce migraine frequency and severity, particularly in patients with migraine with aura.^5–8 

Three randomized, controlled trials (RCTs), the MIST⁹, PRIMA,¹⁰ and PREMIUM¹¹ trials, that assessed the effect of PFO closure on migraine failed to reach their primary endpoints (migraine cessation and >50% reduction in migraine attacks). Thus, the percutaneous PFO closure remains controversial for the treatment of migraine. 

RCTs and, in particular, double-blind clinical trials, are considered at the top level of evidence-based medicine.¹² Transparent and well-designed, -conducted, and -reported RCTs are considered the gold standard of research for the evaluation of healthcare interventions, and their results are crucial for the formulation of the optimum therapeutic strategies.¹³ However, low-quality RCTs impede adequate understanding of clinical indications and are responsible for many misguided conclusions.¹⁴

The quality of reporting of RCTs has been addressed by an international group of experts who created the Consolidated Standards of Reporting Trials (CONSORT) statement in 1996,¹⁵ with two revisions released in 2001¹⁶ and 2010.¹⁷ There are 37 items in the CONSORT statement (numbered 1–25, with some items having subitems [ie, 1a, 1b]),which aim to provide an understanding of the trial design, conduction, analysis, and interpretation, as well as the validity of the results.¹⁸ Many journals support adherence with the CONSORT statement for amelioration of RCTs reporting.¹⁹ 

To our knowledge, no publication has evaluated the quality of RCTs focusing on percutaneous PFO closure for migraine treatment. Therefore, the aim of the present study was to evaluate the adherence of RCTs with the CONSORT statement.

Methods

The present article constitutes an evaluation of the reporting quality of RCTs for percutaneous PFO closure in patients with migraine, based on the CONSORT statement. Two authors (EB and KD) conducted a literature search, data extraction, and quality assessment independently. Any disagreements between the reviewers were resolved by consensus, if possible, and a third author (PK) acted as an arbitrator for items where consensus could not be reached. 

Selection of studies. The PubMed/MEDLINE and Cochrane Library databases were used in an electronic structured literature search to identify studies for inclusion. The search strategy identified reports on RCTs involving patients with migraine and PFO who were randomized to transcatheter device closure of PFO or medical treatment to investigate the effect of percutaneous PFO closure for migraine. 

As a search criterion, the combination of the following terms were used: (((percutaneous transcatheter patent foramen ovale closure OR percutaneous transcatheter PFO closure OR percutaneous transcatheter patent foramen ovale repair OR percutaneous transcatheter PFO repair) OR (medical treatment OR medical management OR medical therapy OR antiplatelet agents OR antiplatelet drugs OR platelet aggregation inhibitors OR platelet antiaggregants OR platelet antagonists OR aspirin OR ASA OR acetylsalicylic acid OR clopidogrel)) AND (migraine disorder OR migraine headache OR migraine with aura OR migraine without aura OR migraine attack)). In PubMed, the following filters were also used: article type: RCT, article language: English, and species: humans.

To determine study eligibility, we first conducted visual inspection of the study title, then the abstract, and lastly, the full manuscript. Trials were eligible if they had randomly assigned human subjects to at least two treatment arms and included patients who received either percutaneous transcatheter device closure of PFO or medical treatment for migraine management. Retrieved RCTs were manually searched for relevant references.

Nonhuman studies, reviews and systematic reviews, meta-analyses, nonrandomized studies, follow-up studies of previously published trials, studies with crossover design, economic analyses, safety analyses, dose-comparison studies, small pilot studies, ex vivo studies, abstracts, study protocols, editorials, and articles not in English were excluded.

Reporting assessment tool. The revised CONSORT checklist was used, which includes a 37-item questionnaire.²⁰ The CONSORT elaboration and explanation statement guided the process.²⁰ CONSORT offers recommendations for each part of an RCT, including title, introduction, methods, results, discussion, and other information, covering all aspects of an optimal clinical trial.²⁰

Methodological evaluation. During the evaluation, the following procedures were followed:

• All items were investigated in terms of whether they were reported and not if they actually were carried out during the trial. Namely, each item was characterized as a “yes” if it was clearly and adequately reported or as a “no” if it was partially unclear or not reported at all.
• Alternative responses (apart from “yes” or “no”) or unclear responses to each question were coded as negative responses. Regarding items on the CONSORT checklist with statements such as “When applicable” (7b), “If done” (11a), or “If relevant” (11b), they were checked as “nonapplicable” if the answer was a definite yes or no; then, the answers of these items were analyzed accordingly.
• When an item was reported in a different section of the trial (title, abstract, methods, results, discussion, supplementary material), it was considered a positive response.
• The revised CONSORT 2010 checklist was used for all extracted articles, regardless of article publication date. 

Additional information extracted included the publication year and journal ranking (5-year impact factor [IF] published in 2022 by Clarivate Analytics via Journal Citation Reports). 

Outcome measures and statistical analysis. The mean CONSORT adherence of the included RCTs was the primary outcome. Adherence with the CONSORT items of over 75 percent was regarded as an adequate cutoff in a number of studies.^21–23 Thus, adherence of 75 percent or greater was compatible with good reporting quality, while adherence of less than 75 percent was suboptimal. Τhe percentage of studies that addressed 75 percent or more of the 37 checklist items was calculated. 

Secondary outcomes were the adherence to the CONSORT statement per item (items reported in ≥75% or <75% of the studies were defined as adequately or inadequately reported, respectively). We also ranked the included articles according to IF, and we examined whether journals with a high IF presented high adherence with the CONSORT statement. The statistical analysis was made on the IBM SPSS v.21 package. The cutoff point was set at the two-sided 0.05 level for statistical significance. 

Ethics statement. Approval from an ethics committee was not needed since we analyzed existing data from publicly available sources.

Results 

Initially, 1,163 studies were obtained through the selected databases. Following evaluation of title and abstracts, 27 potentially eligible articles were identified. Finally, the full text of these studies were examined, and three studies were included for further assessment. Figure 1 describes the search strategy in a flow diagram.

CONSORT adherence. The mean adherence to the CONSORT statement for RCTs was calculated at 69.66 percent, with a standard deviation (SD) of 4.49 percent (median: 69.66%, minimum and maximum adherence: 64% and 75%, respectively). Among the studies, only one (PRIMA trial) registered a good reporting quality (75% of the CONSORT items). There were no RCTs with a CONSORT adherence less than 50 percent. The mean proportion of adherence to the CONSORT statement for each study is presented in Table 1 and Figure 2. All CONSORT items and the frequency of adherence to the individual criterion are shown in Table 2 and Figure 3.

Among the 37 checklist items, 19 (51.4%) were reported in all (100%) of the articles. Twenty-six items (70.3%) were reported in more than half of the studies. With the exception of item 2b (“Specific objectives or hypotheses”), subjectively assessed items (Introduction and Discussion) were adequately reported in all three trials (100% CONSORT adherence). The majority of the Results items had adequate adherence, whereas randomization items were not sufficiently reported overall. Item 24 (“Where the full protocol can be assessed, if available”) was reported in only one study. Items 3a [“Description of trial design (such as parallel, factorial) including allocation ratio”] and 7a (“How sample size was determined”) were reported in all studies.

Impact of CONSORT in high-ranked journals. Each one of the RCTs used in the analysis was published in a high-ranked medical journal (IF>30). However, none of the studies reported all 37 items (Table 3).

Discussion

The present study evaluated the reporting quality of RCTs of percutaneous PFO closure for migraine treatment according to the 2010 CONSORT statement. To our knowledge, this is the first application of CONSORT analysis to RCTs testing percutaneous PFO closure versus medical treatment in patients with migraine. We analyzed three RCTs including 484 randomized participants. Only one of the RCTs showed CONSORT adherence of 75 percent. 

The overall CONSORT adherence was not optimal, with a mean adherence of 69.6 percent. Although CONSORT items are not weighted differently in the overall score, caution is needed when interpreting underreported items that do not directly impact the interpretation of results in the assessment of RCT reporting quality. In our analysis, item 24 (“Where the full trial protocol can be assessed, if available”) had an overall adherence rate of 33 percent, as only one RCT had referred it. However, it is worth noting that important items, such as items 8a (“Method used to generate the random allocation sequence”), 8b [“Type of randomization; details of any restriction (such as blocking and block size)”] and 10 (“Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions”) were also not reported in 100 percent of the articles. Methodological items are of crucial importance in the quality assessment of RCTs,²⁴ and their inadequate reporting lowers the grade of acquired evidence.²⁵ Additionally, inadequate reporting of item 19 (“All important harms or unintended effects in each group”) could potentially misguide medical practice. In contrast, it is quite encouraging that other important items, such as items 3a [“Description of trial design (such as parallel, factorial) including allocation ratio”] and 5 (“The interventions for each group with sufficient details to allow replication, including how and when they were actually administered”) were reported in 100 percent of the articles. 

In our study, all reports were published in high-ranked medical journals. As these journals usually receive and select RCTs with the utmost quality, it can be expected that these trials have a higher adherence to the CONSORT checklist. However, only one RCT (PRIMA trial) achieved a CONSORT adherence score of 75 percent. None of the studies achieved a CONSORT adherence score of 100 percent, but it is worth noting that all CONSORT adherence scores were above 60 percent. 

At present, percutaneous PFO closure cannot be recommended for the prevention of migraine in patients with PFO.²⁶ However, only three small RCTs to assess the effect of PFO closure on migraine headache in patients refractory to medical treatment have been published. Although they failed to meet their primary endpoints, they showed a significant benefit of PFO closure in most of their secondary endpoints, especially in patients with migraine with aura. Also, a pooled analysis of the RCTs using the Amplatzer PFO Occluder (Abbott; US) showed the safety of PFO closure, which significantly reduced mean monthly migraine days and monthly migraine attacks and resulted in a greater number of patients who experienced complete migraine cessation.²⁷ Currently, the Relief Migraine Trial is evaluating the safety and efficacy of transcatheter PFO closure of PFO with the GORE® CARDIOFORM Septal Occluder (W. L. Gore & Associates, Inc.; Newark, DE) for the relief of migraine headaches (ClinicalTrials.gov Identifier: NCT03821129). Thus, the possibility of PFO closure to reduce migraine frequency continues to be researched. 

As current medical therapies for migraine are often ineffective or poorly tolerated^28,29 and given the safety of PFO closure, more properly designed and reported RCTs need to be undertaken to identify the patients who might be most responsive to PFO closure. It is, therefore, of paramount importance to ensure adequate reporting quality of relevant RCTs by recommending that authors adhere to the CONSORT statement. Furthermore, journal endorsement of the CONSORT statement might influence the reporting quality of RCTs. 

Strengths and limitations. This study had several strengths. First, it included articles published in medical journals that clinicians can find in the PubMed/MEDLINE and Cochrane Library databases. Also, as the above-mentioned search engines are open databases and the CONSORT statement is freely accessible, the methodology of this study is easily reproducible.

The present study, however, has some limitations. The number of studies was low because only three RCTs to assess PFO closure efficacy for migraine treatment were available, and one is currently being conducted. Also, we were obligated to engage in an arbitrary assumption, namely, the 75-percent threshold used for both studies and items to define good and adequate reporting, respectively (based on previous publications).^30,31 Furthermore, investigators were unblinded to the study information and all items were rated as equal, while one author could argue that certain items were more important than others or that there were several subjectively assessed items. Furthermore, the limitations of the CONSORT statement must be considered. As it was designed to assess the quality of reporting RCTs overall and not the actual performance of the trial procedures, a method of a trial that is not reported does not mean that it has not been performed. In addition, each item in the CONSORT checklist carries significant weight. Hence, the whole score might not show the overall quality of the reported RCTs. 

It is strongly recommended that investigators adhere to the CONSORT statement when reporting their RCTs. Thereby, RCT reports based on CONSORT statement criteria can be improved specifically in the areas of methodology, results, and discussion, and they will contribute in the development of evidence-based guidelines.

Conclusion

This study shows that the quality of reporting according to the CONSORT statement of all RCTs evaluating PFO closure efficacy and safety for migraine treatment is inadequately reported. Future investigators should ensure that the quality of reporting satisfies the current expected standards through the use of the CONSORT statement checklist.

References

1. Lipton RB, Liberman JN, Kolodner KB, et al. Migraine headache disability and health-related quality-of-life: a population-based case-control study from England. Cephalalgia. 2003;23(6):441–450.
2. Pringsheim T, Davenport W, Mackie G, et al. Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci. 2012;39(2 Suppl 2):S1–59.
3. Pozo-Rosich P, Lucas C, Watson DPB, et al. Burden of migraine in patients with preventive treatment failure attending European Headache Specialist Centers: real-world evidence from the BECOME Study. Pain Ther. 2021;10(2):1691–1708. 
4. Schwedt TJ, Demaerschalk BM, Dodick DW. Patent foramen ovale and migraine: a quantitative systematic review. Cephalalgia. 2008;28(5):531–540.
5. Wilmshurst PT, Nightingale S, Walsh KP, et al. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons. Lancet. 2000;356(9242):1648–1651.
6. Slavin L, Tobis JM, Rangarajan K, et al. Five-year experience with percutaneous closure of patent foramen ovale. Am J Cardiol. 2007;99(9):1316–1320.
7. Post MC, Thijs V, Schonewille WJ, et al. Embolization of pulmonary arteriovenous malformations and decrease in prevalence of migraine. Neurology. 2006;66(2):202–205.
8. Trabattoni D, Brambilla M, Canzano P, et al. Migraine in patients undergoing PFO closure: characterization of a platelet-associated pathophysiological mechanism: the LEARNER Study. JACC Basic Transl Sci. 2022;7(6):525–540.
9. 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. Erratum in: Circulation. 2009;1;120(9):e71–e72. 
10. Mattle HP, Evers S, Hildick-Smith D, et al. Percutaneous closure of patent foramen ovale in migraine with aura, a randomized controlled trial. Eur Heart J. 2016;37(26):2029–2036.
11. Tobis JM, Charles A, Silberstein SD, et al. Percutaneous closure of patent foramen ovale in patients with migraine: the PREMIUM Trial. J Am Coll Cardiol. 2017;70(22):2766–2774. 
12. Hariton E, Locascio JJ. Randomised controlled trials – the gold standard for effectiveness research: study design: randomised controlled trials. BJOG. 2018;125(13):1716.
13. Burns PB, Rohrich RJ, Chung KC. The levels of evidence and their role in evidence-based medicine. Plast Reconstr Surg. 2011;128(1):305–310.
14. Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Lancet. 2009;374(9683):86–89.
15. Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting of randomised controlled trials. The CONSORT statement. JAMA. 1996; 276(8):637–639. 
16. Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet. 2001;357(9263):1191–1194.
17. Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332.
18. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. Int J Surg. 2012;10(1):28–55. 
19. Stevens A, Shamseer L, Weinstein E, et al. Relation of completeness of reporting of health research to journals’ endorsement of reporting guidelines: systematic review. BMJ. 2014;348:g3804.
20. Hopewell S, Clarke M, Moher D, et al. CONSORT for reporting randomized controlled trials in journal and conference abstracts: explanation and elaboration. PLoS Med. 2008;5(1):e20. 
21. Ziogas DC, Zintzaras E. Analysis of the quality of reporting of randomized controlled trials in acute and chronic myeloid leukemia, and myelodysplastic syndromes as governed by the CONSORT statement. Ann Epidemiol. 2009;19(7):494–500. 
22. Kober T, Trelle S, Engert A. Reporting of randomized controlled trials in Hodgkin lymphoma in biomedical journals. J Natl Cancer Inst. 2006;98(9):620–625. 
23. Rikos D, Dardiotis E, Tsivgoulis G, et al. Reporting quality of randomized-controlled trials in multiple sclerosis from 2000 to 2015, based on CONSORT statement. Mult Scler Relat Disord. 2016;9:135–139. 
24. Higgins JPT, Thomas J, Chandler J, et al, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Cochrane; 2011. 
25. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401–406.
26. Kavinsky CJ, Szerlip M, Goldsweig AM, et al. SCAI guidelines for the management of patent foramen ovale. J Soc Cardiovasc Angiogr Interv. 2022;1(4):100039.
27. Mojadidi MK, Kumar P, Mahmoud AN, et al. Pooled analysis of PFO occluder device trials in patients with PFO and migraine. J Am Coll Cardiol. 2021;77(6):667–676.
28. Lipton RB, Buse DC, Serrano D. Examination of unmet treatment needs among persons with episodic migraine: results of the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2013;53(8):1300–1311.
29. Diener HC, Charles A, Goadsby PJ, et al. New therapeutic approaches for the prevention and treatment of migraine. Lancet Neurol. 2015;14(10):1010–1022. 
30. Beneki E,Vrysis C, Zintzaras E, et al. Analysis of the quality of reporting of randomized controlled trials in anticoagulant versus antiplatelet medication for venous thromboembolism prophylaxis as governed by the CONSORT statement. J Thromb Thrombolysis. 2021;52(1):138–147. 
31. Vrysis C, Beneki E, Zintzaras E, et al. Assessment of the reporting quality of randomised controlled trials for vitamin D supplementation in autoimmune thyroid disorders based on the CONSORT statement. Endocrine. 2023; 80(2):346–354.