Which calcitonin gene-related peptide (CGRP) antagonist is the most effective?

Comparative Effectiveness of CGRP Antagonists for Migraine Prevention

No single CGRP antagonist has demonstrated clear superiority over others in terms of efficacy for migraine prevention, but CGRP monoclonal antibodies (mAbs) may offer slightly better efficacy compared to gepants, with selection depending on patient-specific factors including administration preference, cost, and tolerability. 1

Efficacy Comparison

• CGRP antagonists include two main classes: monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) and small molecule antagonists/gepants (atogepant, rimegepant) 1, 2
• Low-certainty evidence suggests CGRP-mAbs may reduce migraine frequency compared to other preventive treatments like valproate (0.76 fewer days per month) 1
• CGRP-mAbs may reduce migraine frequency (0.80 fewer days per month) and acute medication intake (1.02 fewer days per month) compared to topiramate 1
• CGRP-mAbs probably reduce discontinuations due to adverse events (162 fewer events per 1000 treated people) compared to topiramate (moderate-certainty evidence) 1
• There is no direct comparative evidence showing superiority of one CGRP-mAb over another in terms of efficacy 1

Safety and Tolerability

• Adverse event profiles are generally mild across CGRP antagonists, with most common side effects including injection-site pain (for mAbs), upper respiratory tract infection, and nausea 1
• Erenumab has been associated with risk for development or worsening of hypertension in post-marketing studies 1
• Constipation is one of the most common adverse events with erenumab that may influence treatment decisions 3
• CGRP-mAbs have demonstrated a favorable safety profile with adverse event rates similar to placebo in clinical trials 4, 3
• Discontinuation rates due to adverse events are generally low with CGRP antagonists 1, 4

Administration Considerations

• CGRP-mAbs are administered via subcutaneous injection (except eptinezumab which is intravenous) typically monthly or quarterly 1
• Gepants (atogepant and rimegepant) are administered orally 1
• Patients generally prefer oral treatments over injectables (moderate-certainty evidence) 1
• Route of administration is probably as important as effect on migraine frequency in patient preferences (moderate-certainty evidence) 1

Cost Considerations

• CGRP-mAbs and gepants are substantially more expensive than other migraine preventive medications 1
• Annual costs for CGRP-mAbs range from $7,071 to $22,790 compared to much lower costs for traditional preventives like metoprolol ($123), propranolol ($393), valproate ($274), venlafaxine ($378), and amitriptyline ($67) 1
• CGRP-mAbs (erenumab and fremanezumab) may have intermediate value compared to no preventive treatment (low-certainty evidence) 1
• Gepants (atogepant and rimegepant) may have low value compared to no preventive treatment (low-certainty evidence) 1

Treatment Algorithm

1. First-line options (based on current guidelines):

   • Beta-blockers (metoprolol or propranolol)
   • Valproate (except in women of childbearing potential)
   • Venlafaxine
   • Amitriptyline 1

2. Second-line options (if first-line fails or is not tolerated):

   • CGRP antagonists (either mAbs or gepants) 1
   • When selecting a CGRP antagonist:
     • For patients prioritizing convenience and ease of administration: Consider oral gepants (atogepant or rimegepant) 1
     • For patients with poor medication adherence: Consider monthly injectable CGRP-mAbs 1, 2
     • For patients with severe, frequent migraines: Consider CGRP-mAbs which may offer slightly better efficacy 1

3. Third-line option:

   • Topiramate (if both first-line and CGRP antagonists fail) 1

Special Considerations

• Combination therapy with both a CGRP-mAb (erenumab) and a gepant (rimegepant) has been reported in case studies, showing potential benefit without increased adverse events 5
• CGRP antagonists are contraindicated in pregnancy; women of childbearing potential should use appropriate contraception 6, 7
• CGRP-mAbs have a longer half-life (approximately 28 days for erenumab) compared to gepants, which may influence treatment decisions for patients requiring drug discontinuation 7
• Patients with significant cardiovascular risk factors should be monitored when using CGRP antagonists due to the vasodilatory effects of CGRP 7, 2

In conclusion, while no single CGRP antagonist has demonstrated clear superiority, treatment selection should be guided by patient-specific factors including administration preference, cost considerations, and individual tolerability profiles.