Response to Letters by Asil et al and Hildick-Smith and Meier
We would like to thank both Dr Asil and Dr Hildick-Smith and their colleagues for their appreciative comments and their interest in the CODICIA study, as well as for the interesting questions they have raised.
Dr Asil et al cite previous reports suggesting that MBS at rest may be of more clinical relevance than the magnitude of RLS during Valsalva maneuver. Were this found to be the case, this would be particularly interesting as RLS evaluation at rest is less prone to intra- and interobserver variability than the use of the Valsalva maneuver.
As recorded in the paper, RLS in the CODICIA study was evaluated using TCD both at rest and during Valsalva maneuver. As requested by Asil and his colleagues, we set out below the correlation found between MBS detection during Valsava maneuver and at rest (Table). Stroke recurrence event rates, based on the MBS groups defined from the maximum number of microbubble signals both during Valsalva maneuver and at rest in the whole population (n=486) and in the younger group (n=229), are also presented in the Figure. No significant differences were obtained at rest in comparison with the main results described in the CODICIA study in spite of a slightly increased risk of stroke recurrence when only the curtain pattern at rest was considered.
In our opinion, TCD MBS detection during Valsalva maneuver has greater relevance1 because it is a marker of the presence of ASA and of PFO magnitude. Although there is a correlation between the magnitude of RLS at rest and during Valsalva maneuver in the present study, which is similar to previous studies by our group,1 we believe that classification at rest underestimates the magnitude of the shunt, mixes severe with middle and even absent RLS, and fails to detect some massive RLS (Table).
We agree with Dr Hildick-Smith and Meier that only a study that eliminates PFO from half of a randomized cohort can demonstrate the importance of PFO in stroke recurrence. The COCICIA study prospectively included an unbiased group of patients, reflecting the stroke population attended in our daily clinical practice. As can be observed in the Figure, as well as in the COCIDIA article,2 only about half the patients had a massive RLS. Although this was not randomized, and this did not form part of the design of the study, it is seen that both groups of patients (those with and without PFO treatment) had subgroups which received the 2 treatment options (antiplatelet and anticoagulation). PFO occlusion was performed in only 3 of the 486 patients included in the study. None suffered stroke recurrence and no differences in the overall results were detected when these patients were excluded from the analysis.
Whether or not PFO closure is a justified technique in the treatment of stroke still remains to be determined. The low incidence of recurrence in CODICIA (about 2% a year), together with the absence of conclusive supporting evidence from other published studies, makes it difficult to understand why this semi-invasive procedure is so popularly used outside the context of clinical trials. We believe that in the future we may well establish that PFO closure is a worthwhile technique for a highly specific group of stroke patients and in our opinion the approach proposed by Kent el al3 that the causal link between PFO and stroke be established is promising.
We too are looking forward to the results of the CLOSURE and PC trials and trust that further light will be shed on this interesting question.
Serena J, Segura T, Perez-Ayuso MJ, Bassaganyes J, Molins A, Davalos A. The need to quantify right-to-left shunt in acute ischemic stroke: a case-control study. Stroke. 1998; 29: 1322–1328.
Serena J, Marti-Fàbregas J, Santamarina E, Rodríguez JJ, Perez-Ayuso MJ, Masjuan J, Segura T, Gállego J, Dávalos A; on behalf of the CODICIA (Right-to-Left Shunt in Cryptogenic Stroke) Study; for the Stroke Project of the Cerebrovascular Diseases Study Group, Spanish Society of Neurology. Recurrent stroke and massive right-to-left shunt: results from the prospective Spanish multicenter (CODICIA) study. Stroke. 2008; 39 (12): 3131–3136.