Door Still Not Shut on CLOSURE I

The debate over percutaneous closure of patent foramen ovale (PFO) to prevent recurrent stroke is still going strong, as evidenced by new correspondence published in the June 14, 2012, issue of the New England Journal of Medicine. The letters take issue with the negative CLOSURE I trial.

Final results of CLOSURE I, published in March 2012 in the New England Journal of Medicine, showed that PFO closure failed to prevent recurrent stroke or mortality in 909 patients with PFO and either cryptogenic stroke or transient ischemic attack (TIA) at 87 US and Canadian sites. Patients were randomly assigned to medical therapy (aspirin 325 mg daily, warfarin target INR 2.0-3.0, or both) or percutaneous PFO closure with the StarFlex device (NMT Medical, Boston, MA) plus antiplatelet therapy (clopidogrel 75 mg daily for 6 months and aspirin 325 mg daily for 2 years).

By the end of follow-up, the primary composite endpoint (stroke or TIA at 2 years, mortality at 30 days, or neurologic mortality from 31 days to 2 years) was numerically lower in the device closure group, driven by a slight improvement in TIAs. Stroke rates, meanwhile, were almost identical.

Many Issues for Discussion

In the first of 3 letters, Carlos Guijarro, MD, PhD, of Hospital Universitario Fundación Alcorcón (Madrid, Spain), notes several issues with CLOSURE I. First, the number of patients with cryptogenic stroke was unclear, as some may have in fact had lacunar strokes. He also comments that the estimated reduction in stroke risk among patients with shunts of moderate or substantial size is 35%, and “the decision to include patients at low risk may have diluted the actual protective effect of the device in patients at higher risk.”

Lastly, Dr. Guijarro notes that warfarin was apparently withdrawn from some closure patients while its use was allowed in some patients in the medical therapy group. “Patent foramen ovale closure is associated with a risk of atrial fibrillation that is 8 times as high as that among patients assigned to medical therapy,” he writes. “This issue may be critical, since double antiplatelet therapy has been shown to be inferior to warfarin in patients with atrial fibrillation.”

Ignacio Cruz-Gonzalez, MD, PhD, of University Hospital of Salamanca (Salamanca, Spain), Ignacio Inglessis-Azuaje, MD, and Igor F. Palacios, MD, both of Massachusetts General Hospital (Boston, MA), point out that CLOSURE I “demonstrates the importance of patient selection (ie, excluding patients with alternative causes of stroke) and the need to concentrate the use of these interventions at high-volume centers with low rates of procedural complications and high success rates.”

Their letter highlights the exclusion of patients with large redundant atrial septal aneurysms, despite such aneurysms being an important risk factor for recurrent embolism. They also point out that the STARFlex device is no longer available, and the complication rate is much higher and the success rate lower in CLOSURE I than has been previously reported. Finally, they comment that because the study was underpowered, the possibility that closure may in fact provide benefit cannot be ruled out.

In the final letter, Sourbha Dani, MD, Aniruddha Singh, MD, and Nitin Trivedi, MD, of Saint Vincent Hospital (Worcester, MA), cite the lack of information regarding diabetes in CLOSURE I patients as well as the use of long-term anticoagulation therapy in patients with atrial fibrillation.

“Diabetes is an established risk factor for stroke and death from stroke,” they write. “A difference in the prevalence of diabetes between the two groups could have influenced the results of the analysis.”

Focusing on Patient Selection

In his reply, Dr. Furlan emphasizes that the inclusion and exclusion criteria of the study reflect clinical practice at the time. Moreover, he notes, “excluding patients with any risk factors would have made recruitment even more difficult.”

Dr. Furlan agrees with Dr. Guijarro that “subcortical lacunes . . . are less specific than cortical infarcts for cardioembolic stroke.” However, he counters that after MRI analysis, only 12% of 886 patients imaged showed a single diffusion-positive lacune at baseline (no difference between device and medical therapy groups) and only 4% showed any subcortical microvascular changes at baseline.

In addition, he postulates that rates of recurrent stroke and TIA would be even lower in a more selective group of PFO patients, making it even more difficult to recruit a large enough population. “For example, in order to detect a 50% difference in our primary outcome, we would have required 1,600 participants,” Dr. Furlan writes. “Similarly, in order to confirm the nonsignificant difference favoring implantation of a device in CLOSURE I . . . more than 4,000 patients would be required.”

Diabetes is a nonissue, he says, as less than 5% overall had the disease. Also, patients who required long-term warfarin therapy were excluded from CLOSURE I as were those with known atrial fibrillation.

Ultimately, the findings from CLOSURE I emphasize the need to “severely restrict potential selection criteria” when considering closure among PFO patients, Dr. Furlan concludes. “The challenge remains to achieve a satisfactory demonstration of superiority of a device over medical therapy in any patient population.”

 

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Sources:
1. Guijarro C. Device closure for stroke with patent foramen ovale [letter to the editor]. N Engl J Med. 2012;366:2322.

2. Cruz-Gonzalez I, Inglessis-Azuaje I, Palacios I. Device closure for stroke with patent foramen ovale [letter to the editor]. N Engl J Med. 2012;366:2322-2323.

3. Dani S, Singh A, Trivedi N. Device closure for stroke with patent foramen ovale [letter to the editor]. N Engl J Med. 2012;366:2323.

4. Furlan AJ. Device closure for stroke with patent foramen ovale [author reply]. N Engl J Med. 2012;366:2323-2324.

5. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366:991-999.

 

 

Related Stories:

• CLOSURE I Published as Similar PFO Trials Forge Ahead
• Final Results Provide CLOSURE on Device Therapy for PFOs, Cryptogenic Stroke
• Coming to Grips with CLOSURE I: PFO Device Plus Medical Therapy Not Superior to Medical Therapy Alone

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