Methodological considerations in assessing the impact of CGRP monoclonal antibodies on blood pressure: The need for a broader perspective

We commend Van Der Arend et al. ¹ for their thorough and systematic approach in reviewing the impact of calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) on blood pressure (BP). Given the complexity of this topic, the review represents a valuable effort in synthesizing existing literature. However, we would like to highlight certain methodological aspects that may have influenced the conclusions, particularly regarding the selection criteria applied to observational studies. The review systematically excluded observational studies that did not include a control group, thereby omitting a significant portion of real-world evidence on BP changes in patients treated with CGRP-mAbs. While controlled study designs remain invaluable, real-world data serve as a crucial complement, particularly in post-marketing safety assessments. These studies are often the most pragmatic means of capturing long-term cardiovascular risks in clinical populations who may not be well represented in randomized trials. Moreover, PRISMA guidelines do not mandate the exclusion of observational studies without a control group. ² Excluding well-conducted observational studies limits the external validity of the review's findings. Additionally, the decision to include only one observational study alongside three post-hoc analyses of randomized controlled trials may have inadvertently limited the breadth of evidence considered. While post-hoc analyses can offer useful insights, they may introduce selection biases and fail to capture real-world patient variations. Given the exclusion of other observational studies, a broader scope could have enhanced the objectivity of the review, providing a more comprehensive assessment of the current evidence base.

Furthermore, while the review identifies the only included observational study as having minimal bias, several methodological aspects warrant further consideration. ³ BP measurement protocols in this study were less standardized than in some excluded studies, adjustments for baseline hypertension and cardiovascular risk factors may not have been sufficiently accounted for, loss to follow-up was considerable, and patient selection criteria could have introduced bias.

Another important consideration is that systematic reviews should acknowledge in the discussion section studies published after the initial search deadline. A recently published multicentric, real-world prospective study has further contributed to the discussion on the impact of CGRP-mAbs on BP in elderly migraineurs (≥60 years. ⁴ This study followed 155 patients receiving erenumab, galcanezumab or fremanezumab over a one-year period and demonstrated no significant systolic or diastolic BP changes at three or twelve months compared to baseline (p > 0.05), analyzing BP as a continuous variable. Additionally, the study observed an annual incidence of hypertension in the cohort of 2.5%. Although the study lacked a control group, comparisons with population-based hypertension incidence stratified by age revealed a lower-than-expected incidence. The study concluded that CGRP-mAbs did not significantly influence BP trends in elderly patients and that pre-existing hypertension was the strongest predictor of BP changes rather than the medication itself. By not considering recently published studies, the review may have inadvertently overlooked findings that could have provided additional context regarding CGRP-mAb effects on blood pressure. While adhering to predefined search periods is a necessary aspect of systematic reviews, referencing more recent studies, where relevant, can help ensure that conclusions remain reflective of the most current understanding. Some observational studies suggest that CGRP-mAbs may not significantly influence BP trends, and their inclusion in the discussion may have introduced complementary perspectives to the review’s findings. Recognizing such studies does not diminish the value of controlled trial data but rather offers an opportunity to integrate real-world insights that can refine patient risk stratification and clinical decision-making.

In conclusion, while the systematic review provides a valuable synthesis of the available literature, a more inclusive approach to study selection, particularly regarding well-conducted observational studies, could have broadened the perspective on CGRP-mAbs safety. Given the evolving nature of the evidence base, continued pharmacovigilance remains essential. While the available data, both from the included and excluded studies, offer valuable insights, they are not yet sufficient to establish definitive clinical guidance or warnings regarding the hypertensive effects of CGRP-mAbs. Long-term, real-world monitoring will be necessary to further elucidate any potential cardiovascular implications, particularly in high-risk populations. Future studies should aim to assess BP changes using standardized methodologies to enhance comparability and reliability. A comprehensive synthesis of all available data, alongside continuous post-marketing surveillance, will be key in ensuring patient safety while maintaining access to these beneficial treatments. Observational data, even without a control group, can offer insight that complement clinical trial findings, especially when interpreted within the context of population-based reference data. By integrating a wider range of real-world data, systematic reviews can better inform clinical decision-making and refine risk assessment in patients receiving CGRP-mAbs.