UOS Cefalee e Neurosonologia, Neurologia, Policlinico Universitario Campus Bio-Medico di Roma, Roma, Italy.
Servizio di Statistica medica, Fondazione Fatebenefratelli per la Ricerca e la Formazione Sanitaria e Sociale, Roma, Italy.
Headache. 2019 Sep;59(8):1300-1309. doi: 10.1111/head.13617. Epub 2019 Aug 27.
To clarify whether the clinical response after the first 2 cycles with Onabotulinumtoxin A can accurately predict the long-term response.
Onabotulinumtoxin-A (OBT-A) is an approved preventive treatment option for chronic migraine (CM). Nowadays, it remains to be clarified if the treatment has to be prolonged for at least an entire year (4 injections every 3 months - ie, quarterly, as proposed in the PREEMPT trials) or it can be halted after the second or third injection if not clinically effective.
We conducted a multicenter observational cohort study based on real-life data on the usage of OBT-A in CM patients from 2 Italian headache centers, Roma Campus Bio-Medico and Milano Besta, adopting the whole 4-injections protocol. We performed a retrospective analysis of medical records of consecutive patients treated in the 2 centers. The main statistical analysis aimed to evaluate longitudinal measures related to headache (monthly headache frequency, monthly number of analgesic drugs, MIDAS). We hypothesized from our clinical practice with OBT-A that only 2 cycles of treatment were not enough to actually define the non-responder status to botulinum toxin A and that probably a longer time of treatment is needed to get the condition of long-term (delayed) responder.
We considered 115 patients from the 2 centers: 53 in Roma and 62 in Milano. Regarding the main analysis, a clear improvement in each measure was obtained at the 6 months assessment and maintained up to 12 months. Comparing patients with <30% and ≥30% reduction in headache frequency between T0 and T2 or T4 (respectively, "Non-Responders" and "Responders"), we found that the agreement between the classification Responders/Non-Responders at T2 and T4 was not very high (79/104 = 76.0%, with a "moderate" Cohen's Kappa of 0.51), suggesting that the status at T4 is not fully predictable by the status at T2 (λ = 0.47). Responders for headache frequency at T4 were 54.8%. Among Responders at T2, Responders at T4 were 47/62 = 75.8% (95% CI: 64.5%, 85.5%), while among Non-Responders at T2, Responders at T4 were 10/42 = 23.8% (95% CI: 11.9%, 38.1%). Similarly, even when considering the 50% reduction in painkillers consumption or in MIDAS total score between T0 and T2 as possible prognostic factors, the changes occurring at T4 are not strongly predictable by those at T2.
A ≥30% reduction in headache frequency at T2 cut-off is not adequate in predicting a late response to treatment: more than a quarter of excluded patients would miss a clinical improvement with an ongoing treatment, while in a similar percentage of Responders the treatment would lose efficacy. Results from our real-life study suggest that we possibly have to postpone the definition of Responder/Non-Responder to OBT-A at least after 1 year of treatment (4 cycles).
明确在接受奥那博林毒素 A 治疗的前 2 个周期后的临床反应是否能准确预测长期反应。
奥那博林毒素 A（OBT-A）是慢性偏头痛（CM）的一种经批准的预防性治疗选择。目前，仍需明确是否必须将治疗延长至少整整一年（每 3 个月注射 4 次，即每季度一次，如 PREEMPT 试验所建议），或者如果临床无效，在第二次或第三次注射后可以停止治疗。
我们基于来自 2 个意大利头痛中心 Roma Campus Bio-Medico 和 Milano Besta 的 CM 患者使用 OBT-A 的真实数据进行了一项多中心观察性队列研究，采用了完整的 4 次注射方案。我们对 2 个中心连续治疗的患者的病历进行了回顾性分析。主要统计分析旨在评估与头痛相关的纵向指标（每月头痛频率、每月镇痛药数量、MIDAS）。根据我们在 OBT-A 治疗方面的临床实践，我们假设仅 2 个周期的治疗不足以真正确定对肉毒杆菌毒素 A 的无反应状态，可能需要更长的时间才能达到长期（延迟）反应者的状态。
我们从 2 个中心考虑了 115 名患者：罗马 53 名，米兰 62 名。在主要分析中，在 6 个月评估时，每个指标都明显改善，并持续到 12 个月。将头痛频率减少<30%和≥30%的患者（分别为“无反应者”和“反应者”）与 T0 和 T2 或 T4 时进行比较，我们发现 T2 和 T4 时的分类反应者/无反应者之间的一致性不是很高（79/104=76.0%，Cohen's Kappa 为 0.51，属于“中等”），表明 T4 时的状态不能完全由 T2 时的状态预测（λ=0.47）。T4 时头痛频率的反应者为 54.8%。在 T4 时的反应者中，T2 时的反应者为 47/62=75.8%（95%CI：64.5%，85.5%），而 T2 时的无反应者中，T4 时的反应者为 10/42=23.8%（95%CI：11.9%，38.1%）。同样，即使将 T0 和 T2 之间止痛药消耗减少 50%或 MIDAS 总分减少作为可能的预后因素，T4 时发生的变化也不能很好地预测 T2 时的变化。
T2 时头痛频率减少≥30%作为预测治疗后期反应的标准并不充分：超过四分之一被排除的患者会错过持续治疗带来的临床改善，而在类似比例的反应者中，治疗会失去疗效。我们的真实研究结果表明，我们可能至少要在治疗 1 年后（4 个周期）才能推迟确定 OBT-A 的反应者/无反应者。
