What are the potential side effects of dual antiplatelet therapy (DAPT) with medications such as aspirin and P2Y12 inhibitors (e.g. clopidogrel, ticagrelor, prasugrel)?

Side Effects of Dual Antiplatelet Therapy (DAPT)

Bleeding is the most significant and common side effect of DAPT, occurring in 4.5-10% of patients depending on the specific P2Y12 inhibitor used, with prasugrel and ticagrelor causing more bleeding than clopidogrel. 1

Major Bleeding Risks by Medication

Prasugrel-Specific Bleeding Rates

• Non-CABG major or minor bleeding occurs in 4.5% of prasugrel patients versus 3.4% with clopidogrel, with life-threatening bleeding in 1.3% versus 0.8% respectively 1
• Fatal bleeding occurs in 0.3% of prasugrel patients compared to 0.1% with clopidogrel 1
• CABG-related major bleeding is dramatically higher with prasugrel at 14.1% versus 4.5% with clopidogrel, making it critical to discontinue prasugrel at least 7 days before any planned surgery 1
• Intracranial hemorrhage occurs in 0.3% of patients on prasugrel, which is particularly concerning in patients with prior stroke or TIA (who should never receive prasugrel) 1

High-Risk Patient Populations for Bleeding

• Patients ≥75 years on prasugrel have a 9.0% bleeding rate versus 6.9% on clopidogrel, with fatal bleeding occurring in 1.0% versus 0.1% 1
• Patients weighing <60 kg on prasugrel experience 10.1% bleeding versus 6.5% on clopidogrel 1
• Ticagrelor increases non-CABG major bleeding compared to clopidogrel (4.5% vs 3.8%) with more fatal intracranial bleeds (0.1% vs 0.01%) 2

Gastrointestinal Complications

GI Bleeding Patterns

• Gastrointestinal hemorrhage occurs in 1.5% of prasugrel patients versus 1.0% with clopidogrel 1
• The incidence of upper and lower GI bleeding is similar (approximately 50% each) in DAPT patients, contrary to the common assumption that DAPT primarily causes upper GI bleeding 3
• DAPT patients have higher rates of bleeding from upper GI inflammation (OR 13.98,95% CI 1.40-140.36) and paradoxically may have no identifiable bleeding source in 22.8% of cases versus 5.3% in non-DAPT patients 3

GI Protection Strategy

• Proton pump inhibitors (PPIs) are recommended for all patients on DAPT to reduce gastrointestinal bleeding risk 4, 5
• PPIs are particularly critical for patients with history of GI bleeding, advanced age, concurrent anticoagulants, steroids, NSAIDs, or Helicobacter pylori infection 4

Non-Bleeding Adverse Effects

Common Side Effects (Occurring in >2.5% of Patients)

• Hypertension (7.5%), hypercholesterolemia/hyperlipidemia (7.0%), headache (5.5%), back pain (5.0%), dyspnea (4.9%), nausea (4.6%), dizziness (4.1%), and fatigue (3.7%) occur commonly with prasugrel 1
• Epistaxis is notably common, occurring in 6.2% of prasugrel patients versus 3.3% with clopidogrel 1

Rare but Serious Complications

• Thrombotic thrombocytopenic purpura (TTP) has been reported with prasugrel, requiring immediate recognition and treatment 1
• Severe thrombocytopenia occurs in 0.06% of prasugrel patients 1
• Hypersensitivity reactions including anaphylaxis and angioedema occur in 0.36% and 0.06% of patients respectively 1

Potential Malignancy Signal

• Newly diagnosed malignancies were reported in 1.6% of prasugrel patients versus 1.2% with clopidogrel, with differences primarily in colon and lung cancers 1
• Colorectal malignancies occurred in 0.3% of prasugrel patients versus 0.1% with clopidogrel, though causality remains unclear and may relate to increased detection during bleeding investigations 1

Bleeding Risk Stratification and Mitigation

Identifying High Bleeding Risk

• Use the PRECISE-DAPT score to quantify bleeding risk: scores ≥25 indicate high bleeding risk (calculated using age, creatinine clearance, hemoglobin, white blood cell count, and previous spontaneous bleeding) 4, 6
• High bleeding risk is also defined as prior intracranial hemorrhage/stroke, recent GI bleeding, anemia from possible GI blood loss, liver failure, bleeding diathesis, extreme frailty, or dialysis-dependent renal failure 4

Strategies to Reduce Bleeding

• Use radial arterial access instead of femoral access for coronary procedures when performed by an experienced radial operator 4, 2
• Maintain aspirin at the lowest effective dose of 75-100 mg daily (not higher doses) when combined with any P2Y12 inhibitor 4, 5
• Consider shortening DAPT duration to 6 months in patients who develop high bleeding risk after stent placement 4, 5
• Never discontinue DAPT within the first month after stent placement, even for elective surgery, as this dramatically increases thrombotic risk 4, 5, 2

Critical Contraindications to Avoid Harm

Absolute Contraindications for Prasugrel

• Never give prasugrel to patients with prior stroke or TIA—this is a Class III: Harm recommendation with documented increased cerebrovascular event risk 5, 2, 1
• Prasugrel is contraindicated in patients with active pathological bleeding 1

Relative Contraindications and Dose Adjustments

• Prasugrel is generally not recommended for patients ≥75 years except in high-risk patients with diabetes or prior MI, where it may be considered 1
• Consider prasugrel dose reduction to 5 mg daily for patients <60 kg body weight 1
• Avoid prasugrel in patients likely to undergo urgent CABG, and discontinue at least 7 days before any planned surgery 1

Drug Discontinuation Patterns

• The rate of drug discontinuation due to adverse reactions is 7.2% for prasugrel versus 6.3% for clopidogrel, with bleeding being the most common reason (2.5% vs 1.4%) 1
• Premature discontinuation of DAPT increases the risk of stent thrombosis, myocardial infarction, and death 5, 7