Assessing the occurrence of hypertension in patients receiving calcitonin gene-related peptide monoclonal antibodies for episodic and chronic migraine: a systematic review and meta-analysis

Calcitonin gene-related peptide (CGRP) monoclonal antibodies in the treatment of episodic and chronic migraine was invetigated. A comprehensive literature search was conducted in Ovid Medline, Web of Science and Embase databases from their inception until April 2024 for randomized controlled trials comparing CGRP monoclonal antibodies with placebo or other active treatments in adults with episodic or chronic migraine. The primary outcome assessed was the incidence of hypertension, and secondary outcomes were tolerability, acceptability and adverse events. Data analysis was performed using a random-effects model, and the strength of evidence was evaluated using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach. A total of eleven studies involving 9729 participants were found eligible and included for data analysis. The results revealed that the pooled odds ratio for the incidence of hypertension in patients receiving CGRP monoclonal antibodies compared to placebo was (95% confidence interval (CI): 0.60, 2.21; I2 = 32%), suggesting no significant increase in hypertension risk. Moreover, no significant differences were observed in tolerability or acceptability between the CGRP monoclonal antibody and placebo groups. However, the overall risk of total adverse events was significantly higher in the CGRP monoclonal antibody group (odds ratio (OR): 1.13; 95% CI: 0.97, 1.33; I2 = 56%; p = 0.01). These findings indicate that CGRP monoclonal antibodies are well-tolerated and present a generally safe option for treating episodic and chronic migraine. Although there was no significant increase in the incidence of hypertension, a slight rise in overall adverse events was observed. Consequently, CGRP monoclonal antibodies may be considered a viable treatment option for patients who have not found other treatments effective or tolerable, or who have contraindications to alternative therapies. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (http://www.crd.york.ac.uk, registration number: CRD42024554897).

Headache; Migraine; CGRP monoclonal antibodies; Hypertension; Meta-analysis

[1] Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet. 2017; 390: 1211–1259.

[2] Collaborators GBDN. Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology. 2019; 18: 459–480.

[3] Petrun AM, Selinsek J, Mekis D. Neurological complication during pregnancy, delivery and puerperium requiring intensive therapy management. Signa Vitae. 2024; 20: 17–25.

[4] Datta A, Gupta S, Maryala S, Aggarwal V, Chopra P, Jain S. Erenumab for episodic migraine. Pain Management. 2022; 12: 587–594.

[5] Mulleners WM, Kim BK, Láinez MJA, Lanteri-Minet M, Pozo-Rosich P, Wang S, et al. Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. The Lancet Neurology. 2020; 19: 814–825.

[6] Ferrari MD, Diener HC, Ning X, Galic M, Cohen JM, Yang R, et al. Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial. The Lancet. 2019; 394: 1030–1040.

[7] Van Der Arend BWH, Van Veelen N, De Ruijter JET, Olsen MH, MaassenVanDenBrink A, Terwindt GM. Safety considerations in the treatment with anti-CGRP(R) monoclonal antibodies in patients with migraine. Frontiers in Neurology. 2024; 15: 1387044.

[8] Stewart LA, Clarke M, Rovers M, Riley RD, Simmonds M, Stewart G, et al. Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement. JAMA. 2015; 313: 1657–1665.

[9] Chen CH. Revision and validation of a scale to assess pregnancy stress. Journal of Nursing Research. 2015; 23: 25–32.

[10] Ashina M, Doležil D, Bonner JH, Zhou L, Klatt J, Picard H, et al. A phase 2, randomized, double-blind, placebo-controlled trial of AMG 301, a pituitary adenylate cyclase-activating polypeptide PAC1 receptor monoclonal antibody for migraine prevention. Cephalalgia. 2021; 41: 33–44.

[11] Ashina M, Lanteri-Minet M, Pozo-Rosich P, Ettrup A, Christoffersen CL, Josiassen MK, et al. Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): a multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial. The Lancet Neurology. 2022; 21: 597–607.

[12] Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. The Lancet Neurology. 2015; 14: 1081–1090.

[13] Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J, Fan X, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology. 2009; 73: 970–977.

[14] Croop R, Madonia J, Stock DA, Thiry A, Forshaw M, Murphy A, et al. Zavegepant nasal spray for the acute treatment of migraine: a Phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial. Headache. 2022; 62: 1153–1163.

[15] Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. The Lancet Neurology. 2014; 13: 885–892.

[16] Goadsby PJ, Reuter U, Hallstrom Y, Broessner G, Bonner JH, Zhang F, et al. A controlled trial of erenumab for episodic migraine. New England Journal of Medicine. 2017; 377: 2123–2132.

[17] Reuter U, Lucas C, Dolezil D, Hand AL, Port MD, Nichols RM, et al. Galcanezumab in patients with multiple previous migraine preventive medication category failures: results from the open-label period of the CONQUER trial. Advances in Therapy. 2021; 38: 5465–5483.

[18] Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia. 2018; 38: 1442–1454.

[19] Takeshima T, Sakai F, Hirata K, Imai N, Matsumori Y, Yoshida R, et al. Erenumab treatment for migraine prevention in Japanese patients: Efficacy and safety results from a Phase 3, randomized, double-blind, placebo-controlled study. Headache. 2021; 61: 927–935.

[20] Muñoz-Vendrell A, Campoy S, Caronna E, Alpuente A, Torres-Ferrus M, Nieves Castellanos C, et al. Effectiveness and safety of anti-CGRP monoclonal antibodies in patients over 65 years: a real-life multicentre analysis of 162 patients. The Journal of Headache and Pain. 2023; 24: 63.

[21] Barbanti P, Aurilia C, Egeo G, Proietti S, D’Onofrio F, Torelli P, et al. Ultra-late response (>24 weeks) to anti-CGRP monoclonal antibodies in migraine: a multicenter, prospective, observational study. Journal of Neurology. 2024; 271: 2434–2443.

[22] Barbanti P, Aurilia C, Egeo G, Proietti S, Torelli P, d’Onofrio F, et al. Impact of multiple treatment cycles with anti-CGRP monoclonal antibodies on migraine course: focus on discontinuation periods. Insights from the multicenter, prospective, I-GRAINE study. Journal of Neurology. 2024; 271: 2605–2614.

[23] Aggarwal P, Goyel V, Mathur S, Sachdev V. Effect of stainless-steel crown and preformed zirconia crown on the periodontal health of endodontically treated primary molars correlating with IL-1β: an in vivo study. Journal of Clinical Pediatric Dentistry. 2022; 46: 199–203.

[24] Chhabra N, Mead-Harvey C, Dodoo CA, Iser C, Taylor H, Chaudhary H, et al. Blood pressure elevation in erenumab-treated patients with migraine: a retrospective real-world experience. Headache. 2024; 64: 233–242.

[25] de Vries Lentsch S, van der Arend BWH, Maassen VanDenBrink A, Terwindt GM. Blood pressure in patients with migraine treated with monoclonal Anti-CGRP (Receptor) antibodies: a prospective follow-up study. Neurology. 2022; 99: e1897–e1904.

[26] Guerzoni S, Castro FL, Brovia D, Baraldi C, Pani L. Evaluation of the risk of hypertension in patients treated with anti-CGRP monoclonal antibodies in a real-life study. Neurological Sciences. 2024; 45: 1661–1668.

[27] Anderson EM, Luu M, Kamrava M. Pathologic primary tumor factors associated with risk of pelvic and paraaortic lymph node involvement in patients with endometrial adenocarcinoma. European Journal of Gynaecological Oncology. 2023; 44: 37–42.

[28] Falkenberg K, Bjerg HR, Olesen J. Two-hour CGRP infusion causes gastrointestinal hyperactivity: possible relevance for CGRP antibody treatment. Headache. 2020; 60: 929–937.

[29] Ailani J, Kaiser EA, Mathew PG, McAllister P, Russo AF, Vélez C, et al. Role of calcitonin gene-related peptide on the gastrointestinal symptoms of migraine-clinical considerations: a narrative review. Neurology. 2022; 99: 841–853.

[30] Favoni V, Giani L, Al-Hassany L, Asioli GM, Butera C, de Boer I, et al. CGRP and migraine from a cardiovascular point of view: what do we expect from blocking CGRP? The Journal of Headache and Pain. 2019; 20: 27.

[31] Tassorelli C, Diener HC, Silberstein SD, Dodick DW, Goadsby PJ, Jensen RH, et al. Guidelines of the international headache society for clinical trials with neuromodulation devices for the treatment of migraine. Cephalalgia. 2021; 41: 1135–1151.

[32] Hamilton KT, Robbins MS. Migraine treatment in pregnant women presenting to acute care: a retrospective observational study. Headache. 2019; 59: 173–179.