What is ticagrelor, including its mechanism, indications, dosing, contraindications, side effects, and alternatives?

What is Ticagrelor

Ticagrelor is an oral, reversible P2Y12 receptor antagonist used as antiplatelet therapy in acute coronary syndromes that provides superior reduction in cardiovascular death and myocardial infarction compared to clopidogrel, without increasing major bleeding. 1

Mechanism of Action

Ticagrelor belongs to the cyclopentyl-triazolopyrimidine class and acts as a direct, reversible inhibitor of the P2Y12 receptor on platelets 1. Unlike clopidogrel and prasugrel (thienopyridines), ticagrelor:

• Binds reversibly to the P2Y12 receptor at a location distinct from the ADP binding site, blocking ADP-mediated platelet activation through a noncompetitive, allosteric mechanism 1
• Does not require hepatic conversion to an active metabolite, resulting in rapid and predictable onset of action 1
• Achieves platelet inhibition within 30 minutes that exceeds levels obtained with 300-600 mg clopidogrel loading doses 1, 2
• Reaches peak inhibitory effect approximately 2 hours after administration 1, 2

Clinical Indications

Ticagrelor is indicated for acute coronary syndromes (both ST-elevation and non-ST-elevation MI) to reduce thrombotic cardiovascular events 1. The American College of Chest Physicians recommends ticagrelor over clopidogrel for ACS patients based on superior outcomes 2.

Dosing Regimen

Standard Dosing

• Loading dose: 180 mg (not 90 mg, which is the maintenance dose) 2
• Maintenance dose: 90 mg twice daily for 12 months 1, 2
• Extended treatment beyond 12 months: 60 mg twice daily may be considered in high thrombotic risk patients without increased bleeding risk 2

Critical Aspirin Dosing Consideration

The aspirin dose used with ticagrelor must not exceed 100 mg daily, with 81 mg being the preferred maintenance dose 2, 3. Higher aspirin doses reduce ticagrelor's efficacy, as demonstrated by the geographic interaction in the PLATO trial where North American patients (using higher aspirin doses) showed diminished benefit 3.

Clinical Evidence: The PLATO Trial

The landmark PLATO trial enrolled 18,624 patients with ACS and demonstrated 1, 3:

Primary Efficacy Outcomes at 12 Months

• Composite endpoint (CV death/MI/stroke): 9.8% vs 11.7% with clopidogrel (HR 0.84,95% CI 0.77-0.92, P<0.001) 1, 3
• Myocardial infarction: 5.8% vs 6.9% (P=0.005) 1, 3
• Cardiovascular death: 4.0% vs 5.1% (HR 0.79, P=0.001) 3
• All-cause mortality: 5.0% vs 6.1% (P=0.05) 1
• Definite stent thrombosis: 1.6% vs 2.4% (HR 0.60, P=0.03) 1

Bleeding Safety

Major bleeding rates were similar between ticagrelor and clopidogrel (9.0% vs 9.2%, P=0.76) in the STEMI population 1. Overall PLATO-defined major bleeding showed no significant increase (11.6% vs 11.2%, P=0.43) 4.

Side Effects and Contraindications

Common Side Effects 1

• Dyspnea occurs in 10-15% of patients, typically within the first week, usually mild and dose-related 1, 2
• Asymptomatic bradycardia with ventricular pauses 1
• Modest increase in uric acid levels 1

The mechanism for dyspnea and bradycardia likely relates to ticagrelor's capacity to inhibit adenosine reuptake by erythrocytes, increasing circulating adenosine levels 1.

Drug Interactions

Ticagrelor is metabolized predominantly by CYP3A4 and is a weak inhibitor of CYP3A4 and P-glycoprotein 1, 2. Key interactions include:

• Simvastatin exposure increases 56-81% when combined with ticagrelor due to CYP3A4 inhibition; similar effects expected with lovastatin 1
• Atorvastatin shows minimal interaction (23% increase in Cmax, not statistically significant) 1
• Can increase levels of dabigatran due to P-gp inhibition 2

Perioperative Management

Ticagrelor should be withheld for at least 5 days before surgery to allow adequate platelet function recovery 2. In the PLATO-CABG substudy, patients who underwent CABG showed:

• Lower cardiovascular death with ticagrelor: 4.1% vs 7.9% (P<0.01) 1
• Lower all-cause mortality: 4.7% vs 9.7% (P<0.01) 1
• No increase in CABG-related bleeding 1

This contrasts with clopidogrel, which requires longer discontinuation periods 3.

Alternatives and Switching Strategies

Primary Alternatives

• Clopidogrel (75 mg daily): Less potent, requires hepatic activation, more variable response due to genetic polymorphisms 1, 5
• Prasugrel: Another irreversible P2Y12 inhibitor with different risk-benefit profile 3

Switching from Ticagrelor to Clopidogrel

When de-escalating from ticagrelor to clopidogrel, administer a 600 mg loading dose of clopidogrel after discontinuing ticagrelor, followed by 75 mg daily 2, 5. This loading dose is necessary because:

• Ticagrelor is more potent and binds differently to the P2Y12 receptor 5
• Clopidogrel requires hepatic conversion and has slower onset 5
• The 600 mg dose achieves faster platelet inhibition than 300 mg 5

Special Population: Atrial Fibrillation with PCI

Clopidogrel is preferred over ticagrelor in most patients with atrial fibrillation requiring oral anticoagulation due to lower bleeding risk, though ticagrelor may be reasonable in high ischemic/low bleeding risk patients 2.

Common Pitfalls to Avoid

1. Using aspirin doses >100 mg daily with ticagrelor reduces efficacy 2, 3
2. Confusing the 90 mg dose as a loading dose when it is actually the maintenance dose; loading dose is 180 mg 2
3. Combining ticagrelor with high-dose simvastatin or lovastatin without dose adjustment due to significant drug interaction 1
4. Failing to wait 5 days before surgery for adequate platelet recovery 2
5. Not recognizing that ticagrelor requires twice-daily dosing due to its 7-hour half-life 2