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Letter by Neugebauer et al Regarding Article, "Recent Nationwide Impact of Mechanical Thrombectomy on Decompressive Hemicraniectomy for Acute Ischemic Stroke".

To the Editor: We read the important article by Rumalla et al with great interest. Although it seems intuitive that early reperfusion therapy of large vessel occlusion reduces the rates of hemicraniectomy, it is not easy to demonstrate a causal link between those 2 procedural stroke interventions, not even with a large patient cohort, such as the presented one. We wish to comment on 2 aspects of this contribution, the statistical analysis, and the use of hemicraniectomy as outcome in the analyses. First, their description of statistical methods seems rather minimal. A major limitation in observational data is confounding by indication, for which the authors did not seem to account. Covariate adjustment, instrumental variable regression, or propensity score matching would be expected, considering the described setting. While multiple covariates were included in the logistic regression model, stepwise backward variable selection based on P values was performed without including unbalanced covariates in the null-model as would be expected when performing covariate adjustment. As adjustment of confounders is pivotal to prevent erroneous association between exposure and outcome and considering the large sample size, it remains unclear why variables were preselected instead of performing selection on the full set of candidate variables. Furthermore, multivariable analysis using backward selection is path-dependent, that is, the variable that is excluded in a first step determines the P values of all other variables in the next step. As a model with further variables could have altered the result dramatically, it is not clear why variables with P>0.05 were, despite the large sample size, not included in the selection process. This is of special interest, as thrombectomy was only borderline significant in the selection process with P=0.049. Furthermore, it remains unclear how appropriate stratum, cluster, and discharge weights were defined. For descriptive analyses, χ tests were used to compare baseline values (T1), ignoring the underlying continuous nature of some of the baseline variables, such as age, without stating the reason for the specific categorization taken. We would, therefore, like to ask why there was no adjustment for baseline imbalances and whether the above-mentioned limitations of the statistical analyses were considered? Second, the rate of hemicraniectomy is not an adequate outcome measure to assess the effect of thrombectomy in large hemispheric stroke. Hemicraniectomy is a procedure and not a biological outcome, and it is wrong with regard to content to postulate a doseresponse relationship between both treatments. The correct outcome measure is the rate of malignant infarction. Because hemicraniectomy is underutilized in any case, it does not reflect the rate of malignant infarction, not even as a surrogate. Most importantly, the rate of hemicraniectomy is influenced by the expected outcome and the goal of care. In 2014, the positive but also disappointing results of the DESTINY-II trial (Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery II) were published. In older patients with malignant infarction, hemicraniectomy caused high rates of moderate-severe and severe disability. At the same time, it was practically impossible to achieve functional independency. Outcome in older patients was clearly worse than in younger patients in whom, however, moderate-severe disability is still the most likely outcome after hemicraniectomy. In this regard, the question of what is perceived a good or acceptable outcome is of utmost interest and strongly interferes with the rate of hemicraniectomy. In 2015, after long years of academic discussion, general opinion moved towards not conceiving moderate-severe-disability as an acceptable outcome. For us, it rather seems that the rates of hemicraniectomy declined in 2016 (Figure 3D) as a consequence of a shift in attitudes towards acceptable outcome, don’t they? In conclusion, the results of the present study can be at high risk of bias and may not be conclusive on the relationship between thrombectomy and hemicraniectomy. In our opinion, it remains premature to claim having captured a causal link.