In a reproductive‑age woman taking an estrogen‑containing oral contraceptive, is ubrogepant (Ubrelvy) associated with lower cardiovascular risk than rizatriptan for acute migraine treatment?

Ubrelvy (Ubrogepant) Is Safer Than Rizatriptan for Women on Oral Contraceptives

Yes, a patient on estrogen-containing oral contraceptives is at substantially lower cardiovascular risk taking ubrelvy (ubrogepant) compared to rizatriptan, and ubrelvy should be the preferred acute migraine treatment in this population. 1

Why Ubrelvy Is Preferred: Absence of Cardiovascular Risk

Triptans Carry Cardiovascular Contraindications

• Rizatriptan and other triptans cause vasoconstriction through 5-HT1B receptor agonism, which can precipitate arterial thrombotic events including myocardial infarction and stroke. 1
• Triptans are relatively contraindicated in patients with cardiovascular risk factors, and women on combined oral contraceptives already carry elevated baseline cardiovascular risk. 1
• The combination of oral contraceptives plus migraine increases stroke risk 2-16 fold, creating a high-risk substrate where additional vasoconstrictive agents should be avoided. 2

Ubrogepant Has No Cardiovascular Mechanism

• Ubrogepant is a CGRP receptor antagonist that blocks migraine pain signaling without causing vasoconstriction. 3, 1
• No cardiovascular risks have been identified with ubrogepant in clinical trials, making it safe for patients with underlying cardiovascular risk factors. 1
• The most common adverse events with ubrogepant are nausea (2.1-4.1%), somnolence, and dry mouth—none of which are cardiovascular in nature. 3

The Compounding Cardiovascular Risk in Women on Oral Contraceptives

Oral Contraceptives Independently Increase Arterial Thrombosis

• Current users of combined oral contraceptives have significantly elevated risk of both myocardial infarction and stroke compared to non-users. 2
• The risk is greatest for ischemic stroke, which is the same arterial event that triptans can precipitate through vasoconstriction. 2
• Women with migraine taking combined hormonal contraceptives experience a 2-16 fold increased stroke risk, demonstrating a synergistic rather than additive interaction. 2, 4

Multiple Risk Factors Act Multiplicatively

• Cardiovascular risk factors do not simply add—they multiply. A woman with migraine, on oral contraceptives, using a triptan faces exponentially higher stroke risk than any single factor alone. 4
• Women ≥35 years who smoke ≥15 cigarettes daily and use oral contraceptives face unacceptable cardiovascular risk, illustrating how combined risk factors create dangerous clinical scenarios. 4, 5

Efficacy Comparison: Triptans vs. Ubrogepant

Triptans Are More Effective, But the Risk-Benefit Ratio Shifts

• Most triptans demonstrate higher odds ratios for pain freedom at 2 hours compared to ubrogepant (OR range: 1.54-3.05 favoring triptans). 1
• Rizatriptan specifically shows superior efficacy compared to ubrogepant for both pain freedom and pain relief at 2 hours. 1
• However, the lack of cardiovascular risk with ubrogepant makes it the preferred choice when baseline cardiovascular risk is elevated, as in women on oral contraceptives. 1

Ubrogepant Provides Acceptable Efficacy Without Cardiovascular Risk

• Ubrogepant 50 mg and 100 mg both demonstrate statistically significant superiority over placebo for pain freedom at 2 hours (19.2% and 21.2% vs. 11.8%, P<0.002). 3
• Freedom from most bothersome symptom at 2 hours was achieved in 38.6% (50 mg) and 37.7% (100 mg) vs. 27.8% with placebo (P=0.002). 3

Clinical Decision Algorithm

Step 1: Identify Baseline Cardiovascular Risk

• All women on combined oral contraceptives have elevated baseline cardiovascular risk due to estrogen-mediated prothrombotic effects. 2, 6
• Additional risk factors that further elevate risk include:
  • Age ≥35 years 4, 5
  • Smoking (any amount) 2, 4
  • Hypertension 2, 7
  • Migraine with aura (absolute contraindication to oral contraceptives) 4, 5
  • Diabetes, dyslipidemia, or obesity 2, 7

Step 2: Select Acute Migraine Treatment Based on Risk Profile

• For women on oral contraceptives without additional risk factors:

  • First-line: Ubrogepant (no cardiovascular risk) 1
  • Second-line: Triptans may be considered, but ubrogepant is safer 1

• For women on oral contraceptives WITH additional cardiovascular risk factors (age ≥35, smoking, hypertension, etc.):

  • Ubrogepant is strongly preferred 1
  • Triptans should be avoided due to compounding cardiovascular risk 1

Step 3: Consider Contraceptive Modification

• Women with migraine with aura must discontinue combined oral contraceptives immediately, as this combination carries unacceptable stroke risk. 4, 5
• Progestin-only pills, levonorgestrel IUDs, and etonogestrel implants are Category 1 (no restrictions) for women with migraine and carry no stroke risk. 4, 7

Common Pitfalls to Avoid

Do Not Assume All Acute Migraine Treatments Are Equivalent

• The cardiovascular safety profile differs dramatically between triptans (vasoconstrictive) and CGRP antagonists (non-vasoconstrictive). 1
• Prescribing rizatriptan to a woman on oral contraceptives adds triptan-mediated vasoconstriction to estrogen-mediated prothrombotic state, creating unnecessary risk. 2, 1

Do Not Overlook the Synergistic Nature of Cardiovascular Risk Factors

• Migraine + oral contraceptives = 2-16 fold increased stroke risk (not simply additive). 2, 4
• Adding a vasoconstrictive triptan to this baseline further amplifies risk in a multiplicative fashion. 4, 1

Do Not Ignore Absolute Contraindications

• Migraine with aura is an absolute contraindication to combined oral contraceptives, regardless of age or other factors. 4, 5
• If a patient develops migraine with aura while on oral contraceptives, discontinue the contraceptive immediately and switch to progestin-only methods. 4