From the Guidelines
Ticagrelor carries the highest bleeding risk among ticagrelor, clopidogrel (Plavix), and aspirin, followed by clopidogrel, with aspirin having the lowest risk. According to the most recent guideline 1, dual antiplatelet therapy with aspirin and an oral P2Y12 inhibitor is indicated for at least 12 months as the default strategy in patients with acute coronary syndromes (ACS) who are not at high bleeding risk. The 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with ACS recommends several strategies to reduce bleeding risk in patients with ACS who have undergone percutaneous coronary intervention (PCI) and require antiplatelet therapy, including the use of a proton pump inhibitor in patients at risk for gastrointestinal bleeding.
Some key points to consider when evaluating the bleeding risk of these medications include:
- Ticagrelor is a potent, direct-acting P2Y12 inhibitor that provides more consistent platelet inhibition than clopidogrel, but this increased efficacy comes with approximately 30-40% higher rates of non-procedure-related bleeding, as noted in the PLATO study 2.
- Clopidogrel is a prodrug requiring liver metabolism for activation, resulting in more variable antiplatelet effects but generally lower bleeding risk than ticagrelor.
- Aspirin, which works by inhibiting cyclooxygenase and preventing thromboxane A2 production, has the most favorable bleeding profile of the three but is also the least potent antiplatelet agent.
- When these medications are used in combination (dual antiplatelet therapy), bleeding risk increases substantially, with the highest risk period for bleeding typically within the first month of therapy, as noted in the 2010 ACCF/ACG/AHA expert consensus document 3.
- Patients with a history of bleeding disorders, recent surgery, advanced age, renal impairment, or those taking anticoagulants concurrently are at particularly elevated risk and require careful monitoring for bleeding complications.
In terms of specific bleeding risks, the PLATO study 2 found that ticagrelor was associated with a higher rate of non–CABG-related major bleeding (4.5% versus 3.8%, P<0.03) compared to clopidogrel. However, there were no significant differences between the ticagrelor and clopidogrel groups in rates of major bleeding (the primary safety endpoint) or TIMI major bleeding. The 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline 1 recommends aspirin discontinuation 1 to 4 weeks after PCI with continued use of a P2Y12 inhibitor (preferably clopidogrel) in patients who require long-term anticoagulation.
From the Research
Bleeding Risk Comparison
- The bleeding risk of ticagrelor, clopidogrel (Plavix), and aspirin has been studied in various clinical trials 4, 5, 6, 7, 8.
- In the PLATO trial, ticagrelor was associated with a significantly higher rate of non-CABG-related TIMI major bleeding compared to clopidogrel 4.
- However, a retrospective cohort study found no difference in the risk of major bleeding between ticagrelor and clopidogrel after PCI for ACS 8.
- Aspirin is commonly used in combination with either clopidogrel or ticagrelor, and low-dose aspirin (75 to 160 mg/day) is recommended to minimize the risk of gastrointestinal bleeding 5.
Efficacy and Safety
- Ticagrelor has been shown to be more effective than clopidogrel in reducing cardiovascular events and mortality in patients with ACS 5, 7, 8.
- However, the choice of antiplatelet agent should be made on an individual patient basis, taking into account the patient's risk factors and potential side effects 4, 6.
- Prasugrel and ticagrelor have different side effect profiles, and ongoing trials will help establish the most effective dual antiplatelet therapy regimens 4.