Patent foramen ovale and the risk of cryptogenic stroke
In the RESPECT trial (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment),2 which used the Amplatzer PFO closure device, there was no increased incidence of atrial fibrillation in the device group compared with the control group. Therefore, it is not appropriate to combine the results of the CLOSURE trial with the results of the RESPECT trial and PC trial,4 both of which used the Amplatzer device.
Our patients want to know what the potential risks and benefits will be if they get their PFO closed with a specific device. They don’t want to know the average risk between two different devices.
However, if you do a meta-analysis of the RESPECT and PC trials, which used the same Amplatzer PFO occluder device, and combine the number of patients studied to increase the statistical power, then the benefit of PFO closure is significant even with an intention-to-treat analysis. By combining the two studies that assessed the same device, you reach a completely different interpretation than if you do a meta-analysis including the CLOSURE trial, which showed no benefit.
The medical community should not uncritically accept meta-analysis methodology. It is a marvelous case example of how scientific methods can be inappropriately used and two diametrically opposed conclusions reached if the meta-analysis combines two different types of devices vs a meta-analysis of just the Amplatzer device.
If we combine the numbers from the RESPECT and PC trials, there were 23 strokes in 691 patients (3.3%) in the medical groups and 10 strokes in 703 patients (1.4%) who underwent PFO closure. By chi square analysis of this intention-to-treat protocol, PFO closure provides a statistically significant reduction in preventing recurrent stroke (95% confidence interval 0.20–0.89, P = .02).
From the patient’s perspective, what is important is this: If I get my PFO closed with an Amplatzer PFO occluder device, what are the risks of the procedure, and what are the potential benefits compared with medical therapy? We can now answer that question definitively. I tell my patients, “The risks of the procedure are remarkably low (about 1%) in experienced hands, and the benefit is that your risk of recurrent stroke will be reduced 73%2 compared with medical therapy.” In the RESPECT Trial, the as-treated cohort consisted of 958 patients with 21 primary end-point events (5 in the closure group and 16 in the medical-therapy group). The rate of the primary end point was 0.39 events per 100 patient-years in the closure group vs 1.45 events per 100 patient-years in the medical-therapy group (hazard ratio 0.27; 95% confidence interval 0.10–0.75; P = .007).
Not all cryptogenic strokes in people who have a PFO are caused by paradoxical embolism. PFO may be an innocent bystander. In addition, not all people who have a paradoxical embolism will have a recurrent stroke. For example, if a young woman presents with a PFO and stroke, is it possible that she can prevent another stroke just by stopping her birth-control pills and not have her PFO closed? What is the risk of recurrent stroke if she were to become pregnant? We do not know the answers to these questions.
Your patients do not want to wait to find out if they are going to have another stroke. The meta-analysis of the randomized clinical trials for paradoxical embolism demonstrates that the closure devices are safe and effective. The FDA should approve the Amplatzer PFO occluder with an indication to prevent recurrent stroke in patients with PFO and an initial cryptogenic event.
