Abstract
To the Editor,
We thank the authors for their comments on our study. We appreciate their recognition of the clinical importance of this question and welcome the opportunity to discuss the methodology, interpretation, and limitations of the study. In our original paper, we described the limitations and criticisms the authors raise. We agree that the observed association between low-dose aspirin (81 mg daily) and lower rates of reported pseudoarthrosis should be interpreted cautiously. Accordingly, we framed our findings as hypothesis-generating rather than as direct evidence of a protective effect of aspirin and explicitly advocated for no changes to clinical practice without further prospective studies, which are required to draw causal conclusions. We described limitations of the exposure definition and agree with the authors’ observation that defining aspirin use within three months of surgery may introduce bias related to accurate medication documentation, healthcare utilization, or follow-up practices. In a large dataset such as the one employed in our study, such factors are difficult to fully adjust for and may lead to residual confounding. We would note, however, that our sensitivity analyses using clopidogrel, an antiplatelet agent with a comparable cardiovascular indication and follow-up profile, and ibuprofen showed no analogous association, which argues against healthcare-contact differences or exposure-definition bias as the sole explanation for our findings. Future investigations with granular details on the timing of re-initiating home aspirin medication would provide additional insight.
We agree that the lack of a dose-dependent relationship warrants cautious interpretation of the apparent benefit observed in the 81 mg aspirin cohort. We emphasized that the potential biological mechanisms we offered to explain these findings remain speculative. We concur that, absent a dose-response gradient and given the potential for healthcare-contact differences, our findings are most conservatively interpreted suggesting the absence of a harmful association between aspirin and pseudoarthrosis, rather than as evidence of a fusion-promoting effect. The authors also note that our outcome definition warrants consideration. As we discuss in our manuscript, the use of ICD coding presents a significant limitation in that the specific radiographic or clinical criteria used by each spine surgeon assigning the diagnostic code for pseudoarthrosis are unknown. Similarly, re-operation was included as a complementary outcome measure, and we explicitly discuss that coding for additional spinal fusion cannot definitively distinguish revision spinal fusion surgery performed for index-level nonunion versus adjacent segment disease in the setting of successful index fusion. Given the widespread use of aspirin among spinal fusion patients, our intention was to contribute preliminary evidence to an understudied area. We agree that an active-comparator, new-user design, or a comparison of aspirin continuers with discontinuers, would help disentangle a medication effect from treatment-selection bias and healthcare-contact differences, and we view these as valuable directions for future work. We hope that our preliminary, hypothesis-generating study provides a foundation for future prospective studies incorporating standardized assessment of non-union, precise medication exposure timing, and detailed follow-up to determine whether the observed association reflects a potential biological effect of aspirin on bony fusion or if there remains residual confounding.
Sincerely.
Kevin T. Kim, MD and Timothy Chryssikos, MD, PhD
