Can metoprolol or apixaban (Eliquis) cause distal toe discoloration and cold toes in an older adult with peripheral vascular disease?

Can Metoprolol or Eliquis Cause Distal Toe Discoloration and Cold Toes?

Metoprolol can cause cold toes and may contribute to discoloration in patients with peripheral vascular disease, while apixaban (Eliquis) does not directly cause these symptoms but may unmask underlying vascular pathology through its anticoagulant effects.

Metoprolol and Peripheral Vascular Effects

Direct Vasoconstriction Risk

• Metoprolol is associated with peripheral vasoconstriction and cold extremities, particularly in patients with pre-existing peripheral arterial disease 1, 2.
• In hypertensive patients, beta-blockers cause cold extremities in approximately 50% of cases, compared to only 5% with other antihypertensive agents like methyldopa 2.
• A network meta-analysis of 57,026 patients found that peripheral vasoconstriction occurred in 7% of patients on beta-blockers versus 4.6% in controls (P < 0.001), with significant heterogeneity among different beta-blockers 1.

Important Distinction: Metoprolol is NOT Contraindicated

Despite causing cold extremities, metoprolol is generally safe in peripheral arterial disease and does not worsen limb outcomes 3:

• In a double-blind RCT of 128 patients with intermittent claudication and hypertension, metoprolol was well-tolerated over 48 weeks, and maximal walking distance actually improved by 17% (though this was not statistically significant, P < 0.12) 3.
• In 1,873 patients with critical limb-threatening ischemia receiving endovascular therapy, beta-blockers did not worsen clinical outcomes 3.
• In a registry of 1,273 patients with severe lower extremity artery disease (65% with critical limb ischemia), death and amputation rates did not differ between those on beta-blockers versus those without 3.

Clinical Context: When Cold Toes Are Concerning

The key distinction is between benign vasospastic symptoms versus embolic disease 4:

• Cold extremities from metoprolol represent vasospasm without tissue damage—uncomfortable but not limb-threatening 5, 2.
• Blue toe syndrome (sudden unilateral cyanotic discoloration with palpable pedal pulses) indicates atherosclerotic embolization and requires urgent vascular imaging 4.
• If your patient has sudden onset, unilateral discoloration with normal pulses, this is NOT a metoprolol side effect—it's embolic disease requiring duplex ultrasound of the entire arterial tree 4.

Practical Management Algorithm

If the patient reports cold toes bilaterally without tissue changes:

• This is likely metoprolol-related vasospasm 1, 2.
• Consider switching to nebivolol, which improved pain-free walking distance by 34% (P < 0.003) versus metoprolol's 17% in patients with claudication 3, 6.
• Nebivolol has vasodilatory properties through nitric oxide-mediated mechanisms and is preferred in peripheral arterial disease 6.

If the patient has unilateral discoloration, especially with recent onset:

• This suggests blue toe syndrome (cholesterol embolization) rather than drug effect 4.
• Check for recent vascular procedures, catheterization, or trauma 4.
• Obtain duplex ultrasound from aorta to pedal vessels to identify embolic source 4.
• Ankle-brachial index is typically normal (>0.8) in blue toe syndrome because proximal vessels remain patent 4.

Apixaban (Eliquis) and Toe Discoloration

Direct Effects

Apixaban does not cause peripheral vasoconstriction or cold extremities—this is not a recognized adverse effect of direct oral anticoagulants.

Indirect Unmasking of Pathology

However, anticoagulation can reveal underlying vascular disease through two mechanisms:

1. Prevention of compensatory thrombosis: In patients with severe arterial stenosis, small thrombi may partially maintain perfusion; anticoagulation removes this compensation, potentially worsening ischemia.

2. Hemorrhagic complications: In patients with critical limb ischemia and tissue breakdown, anticoagulation may worsen local bleeding into ischemic tissue, causing discoloration.

Critical Caveat: Purple Toe Syndrome

If the patient is on warfarin (not apixaban), sudden purple toe discoloration represents cholesterol embolization paradoxically worsened by warfarin 4:

• Warfarin initiation or dose increases should be avoided in acute blue toe syndrome 4.
• This does NOT apply to apixaban, which does not have this association.

Diagnostic Approach in Your Patient

Given the context of an older adult with peripheral vascular disease:

1. Determine onset pattern: Gradual bilateral coldness suggests metoprolol; sudden unilateral discoloration suggests embolization 4, 2.

2. Check pedal pulses: Palpable pulses with discoloration = blue toe syndrome; absent pulses = acute limb ischemia 4.

3. Measure ankle-brachial index: Normal ABI (>0.8) with toe discoloration confirms blue toe syndrome; low ABI (<0.5) suggests critical ischemia 3, 4.

4. Assess for neuropathy: Diabetic patients may have "masked" peripheral arterial disease without typical claudication symptoms, presenting directly with toe necrosis after minor trauma 3.

Bottom Line Recommendation

For bilateral cold toes without tissue loss: This is metoprolol-related vasospasm. Switch to nebivolol if symptoms are bothersome, as it provides equivalent blood pressure control with superior peripheral vascular effects 3, 6.

For unilateral discoloration with palpable pulses: This is blue toe syndrome requiring urgent duplex ultrasound and vascular surgery consultation, regardless of medications 4.

Apixaban is not the culprit for cold toes or discoloration—continue it for its indicated purpose (likely atrial fibrillation or venous thromboembolism prevention).