Results Summary
What was the research about?
A patent foramen ovale, or PFO, is a small hole between the top two chambers of the heart that didn’t close correctly after birth. PFOs can raise the risk for stroke. For adults ages 18–60, about 10 percent of strokes caused by a blocked artery are related to a PFO. Among these patients, questions remain about what treatment works best to prevent future strokes.
In this study, the research team analyzed data from six clinical trials to compare two treatments for preventing future strokes among patients who had experienced a PFO-related stroke:
- Medicines alone. Patients take medicines to prevent blood clots.
- Surgical procedure to close the PFO, plus medicines. A doctor inserts a medical device through a vein to the PFO. The device closes the PFO and remains in the heart permanently. Patients also take medicines to prevent blood clots.
The research team looked at the risk of future strokes and at safety risks like serious adverse events. A serious adverse event occurs when medical care causes harm, such as having bleeding when taking blood thinners. The team also looked at treatment effects based on how likely it was that the PFO caused patients’ strokes. To determine likelihood, the team used existing scoring systems.
What were the results?
Compared with patients who took medicines alone, patients who also had surgery had a lower risk of future strokes.
Patients whose PFO was likely the cause of their stroke had a lower risk of future strokes with surgery plus medicines than with medicine alone, compared with patients whose PFO was not likely the cause of their stroke, based on the scoring systems.
Patients who had surgery had a higher risk of irregular heartbeat events within 45 days of surgery. But most patients’ heartbeats went back to normal over time. Other safety outcomes like bleeding or blood clots didn’t differ between the two treatments.
Who was in the study?
The study included data from 3,740 patients across six trials. The trials took place around the world from 2000 to 2017. Patients in the trials were ages 18 and older and had experienced a PFO-related stroke. The average age was 46, and 55 percent were men.
What did the research team do?
The research team combined and analyzed data from the six trials. The trials included patients with a PFO who had a stroke. Combining data from multiple trials provides more reliable results than data from single trials.
Researchers from the six trials provided input during this study.
What were the limits of the study?
The study couldn’t look at whether another stroke caused more disability, because some kinds of data were missing, such as how much help people needed at home.
Future research could compare how different medicines and types of medical devices reduce patients’ risk of having a stroke.
How can people use the results?
Patients who had a PFO-related stroke and their doctors can use these results when considering treatments for preventing future strokes.
Professional Abstract
Objective
To evaluate the effectiveness of medical therapy alone versus patent foramen ovale (PFO) closure plus medical therapy to prevent recurrent stroke, overall and across patient subgroups, in patients with PFO-associated cerebral ischemic events
Study Design
| Design Element | Description |
|---|---|
| Design | Individual participant-level data meta-analysis |
| Population |
3,740 patients ages 18 and older with PFO-associated cerebral ischemic events who participated in 1 of 6 published randomized controlled trials conducted worldwide from 2000 to 2017 Researchers stratified the subgroup analysis by:
|
| Interventions/ Comparators |
|
| Outcomes |
Primary: recurrent ischemic stroke |
| Timeframe | Median follow-up of 57 months across studies |
This individual participant-level data meta-analysis compared the effectiveness and safety of medical therapy alone versus PFO closure plus medical therapy in preventing recurrent stroke in patients with PFO-associated cerebral ischemic events.
Researchers invited investigators from six randomized controlled trials conducted between 2000 and 2017 to pool their data sets for re-analysis, while retaining the original trial randomization assignments. The meta-analysis included data from 3,740 patients ages 18 and older who had PFO-associated cerebral ischemic events. Among trial participants, the average age was 46, and 55% were male.
Researchers assessed differential effects of treatment across subgroups based on:
- The risk of paradoxical embolism (RoPE) score, which uses age and cardiovascular risk factors to estimate the probability that a PFO caused a stroke.
- The PFO-Associated Stroke Causal Likelihood (PASCAL) classification system. This system combines the RoPE score with high-risk PFO features, such as shunt size and presence of an atrial septal aneurysm, to classify the likelihood that a PFO caused a stroke as unlikely, possible, or probable.
Investigators from the randomized clinical trials provided input during the study.
Results
Recurrent ischemic stroke risk. Compared with patients who received medical therapy alone, patients who received PFO closure plus medical therapy had a lower risk of recurrent ischemic stroke (adjusted hazard ratio [aHR]=0.41; 95% confidence interval [CI]: 0.27, 0.60; p<0.001).
Patients with high RoPE scores had a greater absolute risk reduction (ARR) for recurrent ischemic stroke with PFO closure plus medical therapy than with medical therapy alone, compared to patients with low RoPE scores (ARR=2.1%; 95% CI: 1.0, 3.1 versus ARR=1.1%; 95% CI: -0.9, 3.1). Similarly, patients classified as possible and probable using the PASCAL system had a clinically and statistically significant risk reduction for recurrent ischemic stroke (respectively, ARR=2.1%; 95% CI: 0.6, 3.6; and ARR=2.1%; 95% CI: 0.9, 3.4), while patients classified as unlikely had no risk reduction in recurrent ischemic stroke (ARR=-0.7%; 95% CI: -4.0, 2.6).
Safety outcomes. Compared with patients who received medical therapy alone, patients who received PFO closure plus medical therapy had a significantly higher risk of atrial fibrillation (adjusted relative risk=4.54; 95% CI: 2.78, 7.39). However, 46% of atrial fibrillation events happened within the first 45 days and did not cause permanent harm. No significant differences were found in risk for other safety outcomes.
Limitations
Because functional outcomes data were missing, the study could not assess the risk of recurrent stroke causing worsening disability.
Conclusions and Relevance
In this study, PFO closure plus medical therapy was associated with reductions in risk for recurrent ischemic stroke. In subgroup analyses, reductions were primarily seen among those patients at higher risk for their PFO causing a stroke, based on RoPE scores and PASCAL classification.
Future Research Needs
Future research could compare different medical therapies and different closure devices for patients with PFO-associated cerebral ischemic events.
Final Research Report
This project's final research report is expected to be available by November 2023.
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PROSPERO RecordID: 186537
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Peer-Review Summary
Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.
The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments.
Peer reviewers commented and the researchers made changes or provided responses. Those comments and responses included the following:
- The reviewers lauded the researchers for completing this individual patient data meta-analysis of stroke treatment studies designed to optimize selection of therapies to prevent recurrent stroke events. There were no significant concerns.
- The reviewers did ask why the researchers established a score of 7 to delineate high and low probability of the reason for a stroke on the Risk of Paradoxical Embolism (RoPE) score. The researchers explained that 7 was the median score in the original database of patients, although they acknowledged that RoPE scores for patients in randomized clinical trials were lower than 7. The researchers explained that patients with RoPE scores below 7 showed less evident benefit from antithrombotic therapy.
- The reviewers asked why the researchers did not explore treatment response heterogeneity based on different antithrombotic treatments. The researchers explained that most of the studies they exampled did not randomize patients to specific antithrombotic therapies, resulting in the potential for unmeasured confounding in a treatment response heterogeneity analysis.