Response letter regarding Letters to the Editor from Rao et al. and Proietti et al

Dear Editor:

We acknowledge the letters from Drs. Rao and Chan for highlighting the limitations pertinent to clinical applicability of our findings, and Drs. Proietti, Thanassoulis and Essebag for sharing their case of a patient that suffered a stroke following CIED implantation.¹ The former expresses concern regarding the potential for misclassification bias due to differential diligence in diagnosing PFO already at high risk for cardioembolism. The latter suggests that characteristics of the PFO themselves like the size and degree of shunting may impact the risk attributable to PFOs.

We reviewed all transthoracic (TTE) and transesophageal echocardiograms (TEE) reports available for patients that had CIEDs implanted at Mayo Clinic Rochester between January 1, 2000, and October 25, 2010, for mention of PFO and if the PFO was definite or could not be conclusively confirmed or refuted. Only conclusive PFOs whether with TEE, color Doppler, or agitated saline contrast were considered eligible for the PFO group, and the cases with inconclusive reports were excluded from analysis. Because many patients had multiple echocardiograms with more than one clinical indication listed in the reports and with over 6000 patients (with some patients with more than 40 echo reports to review), we were unable to systematically analyze the clinical indications for the studies performed. We speculate that agitated saline contrast was used either as a reflex when PFO was suspected on color Doppler exam, presence of a mobile interatrial septum or atrial septal aneurysm, or as a standard practice for comprehensive evaluations by certain echocardiographers, and on a more routine basis during comprehensive TEEs.

It is noteworthy that we excluded all cases where PFO diagnosis was made within 30 days after a stroke/TIA event, biasing our results towards null. If we had included the possible/probable PFO (74 patients) and post stroke/TIA diagnoses of PFO (11 patients) the PFO rate would have increased to 7.3% as opposed to 6% (still lower than expected 10% to 15%).² It is also worth noting that although there probably was an underdiagnosis of PFOs in our study, random underdiagnoses alone would only bias towards null by counting some PFO-related stroke/TIA events in the non-PFO group. Only a systematic misclassification by more thorough evaluation for PFO among patients with future stroke/TIA events based on unmeasurable prior concern would bias towards a false positive association. We are unable to quantify such a bias related to differential use of agitated saline contrast. However, patients suffering stroke/TIA subsequent to CIED implantation did have higher rates of prior TEE evaluations (32.7% versus 12.1%). This difference in TEE rates was presumably partially in context of prior stroke/TIA symptoms. The bias due to this would be in the order of an absolute 2% difference in stroke/TIA in the PFO versus non-PFO group, compared to 14.8% observed in our study. Moreover, we adjusted for prior stroke/TIA in our multivariable proportional-hazards analysis.

We are not as surprised by the rate of warfarin use being 32% in our “real-world” population, when the atrial fibrillation was clinically diagnosed in 45%.³ Some patients, despite the overall mean CHA₂DS₂-VASc score of 3 would have a low score to not warrant anticoagulation, while others might have personal or other clinical reasons to not use warfarin. We would like to emphasize that in our subgroup analysis, PFO was associated with increased risk of stroke whether atrial fibrillation, high CHA₂DS₂-VASc score, or baseline warfarin use was present or not.

In our study on CIED patients, congestive heart failure (present in 46% of the study population) was not associated with stroke/TIA (p=0.27), and PFO association with stroke/TIA was independent of congestive heart failure. We have further analyzed our PFO cohort and found no significant difference at baseline to longest term follow up with respect to EF% and RVSP.⁴ Estimated RVSP was 41.7 ± 12.8 mm Hg at baseline and 42.1 ± 14.1 mm Hg at follow up (p=0.60). EF% at baseline was 45.5 ± 17.6 mmHg vs. 46.4 ± 17.0 mmHg at follow up (p = 0.20). Furthermore, neither RVSP (HR- 0.99; p = 0.55) or EF (HR: 1.02; p = 0.153) were associated with an increase in stroke/TIA on univariate analysis.⁴ Defibrillators were implanted in 43% patients while the rest had pacemakers. Further, among patients who had a PFO diagnosis, defibrillation coils were not associated with risk of stroke/TIA (p=0.65).⁵

In summary, we agree with caution against over interpretation of our findings in clinical situations. However, until a prospective evaluation can provide further data, when a PFO is documented we would urge physicians to consider our findings for an informed discussion when recommending endovascular lead implantation.