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Identification of cardiovascular risk factors as the strongest predictors of recurrent neurological events in cryptogenic stroke patients with a patent foramen ovale (PFO) suggests that that the heart defect is not always the key player in future risk, according to a substudy of the CLOSURE I trial published in the August 2014 issue of JACC: Cardiovascular Interventions. 

The finding underlines the need for careful risk stratification of PFO patients before considering percutaneous closure, the authors say.  

Diabetes, A-fib, Index TIA All Independent Predictors

Baseline BMI, history of diabetes, hypertension, ischemic heart disease, and index TIA (vs stroke) were identified as risk factors for recurrent neurological events. On multivariable analysis, however, only diabetes, index TIA, and detection of A-fib after randomization were independent predictors. Furthermore, diabetes and A-fib were specifically associated with future stroke, while index TIA was linked only to recurrent TIA (table 1).

Table 1: Multivariable Predictors of Neurological Events

In addition, a large majority of patients (85.6%) had a RoPE (Risk of Paradoxical Embolism study) score of greater than 5, indicating that their cryptogenic stroke was more likely to be related to their PFO. The rate of recurrent neurological events was more than 3-fold lower in this group than in patients with a score of 5 or less (4.2% vs 14.5%; P < .0001). 

“To what degree stroke can be attributed to PFO in [the absence of an identifiable cause] is a matter of debate,” the authors say, but “the association of cardiovascular risk factors such as diabetes with recurrent events within this analysis implies that subclinical atherosclerosis and noncardioembolic causes of neurologic events may have been present in many patients presumed to have had PFO-mediated events.” 

Patient Selection Key to Potential Benefit of PFO Closure  

If percutaneous closure is approved for cryptogenic stroke, Dr. Mauri and colleagues suggest, “patient selection might be improved by more stringently considering the burden of conventional vascular risk factors that to a large degree drive the RoPE score. Additional trials may be required to demonstrate treatment efficacy in this more focused population (eg, excluding patients with lower scores).” 

In an accompanying editorial, Alex Abou-Chebl, MD, of Baptist Neurosciences Associates (Louisville, KY), seconds the importance of proper patient selection. He also echoes the authors’ suspicion that many TIAs in the trial may not have been ischemic events but rather ‘mimics’ such as migraine, epilepsy, or psychiatric conditions. 

“Not only are these patients important to exclude from future trials, but they likely represent a large proportion of patients who are referred for PFO closure in the real world,” he says, adding that future trials should include only patients whose stroke or TIA has been confirmed by neuroimaging. 

In a telephone interview with TCTMD, David E. Thaler, MD, of Tufts Medical Center (Boston, MA), said that another problematic issue is what he called “outcome selection.” The events captured under the rubric of ‘recurrent stroke’ are due to disparate mechanisms, he explained, so a single treatment modality for all would be unlikely. 

RoPEing Off PFO Risk

Dr. Thaler said the study helps independently validate the RoPE score in terms of its ability to discriminate between patients whose PFO is or is not likely to have been relevant to their index cryptogenic stroke. It is also broadly consistent with the RoPE-defined predictors of recurrence for different scores, he noted, adding that the ultimate goal is to combine these dimensions to help identify patients for whom PFO closure offers more benefit than medical therapy alone.

Robert J. Sommer, MD, of Columbia University Medical Center (New York, NY), related being somewhat let down by the current analysis, calling it little more than a focused re-presentation of the trial data. However, he told TCTMD in a telephone interview, it reiterates the need to carefully screening PFO patients prior to any intervention to rule out other potential sources of cryptogenic stroke.

Identification of A-fib as a major risk factor for recurrent events is hardly surprising, Dr. Sommer commented, and today patients are routinely monitored for the condition before PFO closure is considered. Clouding the picture is the fact that in CLOSURE I the STARFlex device itself appeared to contribute to the incidence of A-fib, he observed, although other closure devices have not been similarly implicated. 

Dr. Sommer acknowledged the potential role of the RoPE score and risk prediction in patient selection, although he noted that some have interpreted them to suggest that PFO closure is not warranted in patients with a high score and very low recurrence risk. However, he pointed out, an annual risk of about 1% in a very young PFO patient is as consequential as a much higher risk in a 70-year-old.

Sources: 
1. Elmariah S, Furlan AJ, Reisman M, et al. Predictors of recurrent events in patients with cryptogenic stroke and patent foramen ovale within the CLOSURE I (Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale) trial. J Am Coll Cardiol Intv. 2014;7;913-920.

2. Abou-Chebl A. The paradox of paradoxical embolism and recurrent stroke [editorial]. J Am Coll Cardiol Intv. 2014;7:921-922.

Disclosures:

• The CLOSURE I trial was supported by NMT Medical.
• Dr. Mauri reports receiving institutional research support from multiple device and pharmaceutical companies and serving as a consultant to Biotronik and St. Jude Medical.
• Drs. Abou-Chebl and Thaler report no relevant conflicts of interest.
• Dr. Sommer reports holding an equity interest in Coherex and serving as an investigator for the REDUCE trial, sponsored by St. Jude Medical.
  
  

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