antiplatelets

mechanism

• ASA — irreversibly inhibits cyclooxygenase-1 (COX-1), blocking thromboxane A₂ synthesis and platelet aggregation
• Clopidogrel — thienopyridine prodrug; irreversibly blocks the P2Y12 ADP receptor after hepatic activation via CYP2C19/3A4
• Ticagrelor (Brilinta) — cyclopentyl-triazolo-pyrimidine; reversibly and non-competitively binds P2Y12; does not require hepatic activation
• Prasugrel (Effient) — thienopyridine prodrug; irreversibly blocks P2Y12; faster onset and more consistent platelet inhibition than clopidogrel

---

comparison

Feature	ASA	Clopidogrel	Ticagrelor	Prasugrel
Binding	Irreversible (COX-1)	Irreversible (P2Y12)	Reversible (P2Y12)	Irreversible (P2Y12)
Prodrug	No	Yes (CYP2C19)	No	Yes (not CYP2C19-dependent)
Loading dose	162 mg (ACS) or 325 mg (pre-PCI)	300–600 mg	180 mg	60 mg
Maintenance	81 mg daily	75 mg daily	90 mg BID (ACS) or 60 mg BID (extended)	10 mg daily
Onset (loading)	~1 hour	2–6 hours	~30 minutes	~30 minutes
Offset (hold pre-op)	7 days	5 days	3–5 days	7 days
Affected by CYP2C19	No	Yes	No	No
PPI interaction	No	Yes (avoid omeprazole; use pantoprazole)	No	No

---

key points

P2Y12 inhibitor selection in ACS

• Ticagrelor or prasugrel preferred over clopidogrel for ACS managed with PCI — both reduce MACE vs clopidogrel at the cost of more bleeding (PLATO (2009), TRITON-TIMI 38 (2007))
• ISAR-REACT 5 (2019) — prasugrel showed a 26% relative risk reduction over ticagrelor in composite CV outcome (driven by nonfatal MI) with no difference in major bleeding; both agents considered equally preferred by CCS 2023
• Prasugrel benefit demonstrated only in ACS with PCI — no benefit over clopidogrel for medically managed ACS (TRILOGY (2012))
• Ticagrelor efficacy extends to medically managed ACS and post-CABG patients (PLATO subgroups)

ASA dosing

• Maintenance: 81 mg daily for all indications — higher doses offer no additional efficacy but reduce adherence
• ACS loading: 162 mg chewed/crushed, then 81 mg daily indefinitely
• Pre-PCI (ASA-naive): 325 mg chewed/crushed
• ASA efficacy of ticagrelor may be lost with ASA doses >150 mg daily (PLATO subanalysis)
• Primary prevention: ASA not routinely recommended regardless of sex, age, or diabetes (CCS/CAIC 2023)

clopidogrel-specific

• Prodrug requiring CYP2C19 activation → variable response; CYP2C19 loss-of-function alleles reduce efficacy
• Routine genotyping not recommended
• PPI interaction: omeprazole and esomeprazole are strong CYP2C19 inhibitors → use pantoprazole when PPI required
• Switching from ticagrelor to clopidogrel in early post-ACS: give 300–600 mg loading dose; later switching: 75 mg daily directly
• DAPT for acute high-risk TIA or minor ischaemic stroke: clopidogrel 300–600 mg load + ASA 160 mg load → clopidogrel 75 mg + ASA 81 mg for 21 days → ASA monotherapy

ticagrelor-specific

• Dyspnoea in ~14% (adenosine-mediated vagal C-fibre stimulation) — usually mild, often resolves on treatment
• Bradycardia and ventricular pauses reported — use caution with baseline bradycardia or heart block
• Contraindicated with strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir) or inducers (rifampin, phenytoin)
• Small increases in creatinine, uric acid, and gout

---

DAPT duration

after ACS with PCI (CCS 2023)

Scenario	Recommendation
Standard	DAPT for 12 months: ASA 81 mg + ticagrelor 90 mg BID or prasugrel 10 mg daily (preferred over clopidogrel 75 mg)
High bleeding risk	Short DAPT (1–3 months) then SAPT (ASA or P2Y12 inhibitor monotherapy)
Not high bleeding risk at 1 year	Consider extending DAPT up to 3 years
De-escalation (after ≥30 days)	Switch potent P2Y12 inhibitor → clopidogrel 75 mg, or discontinue P2Y12 inhibitor → P2Y12 monotherapy or ASA monotherapy

after elective PCI

Scenario	Recommendation
Standard	DAPT for 6 months: ASA 81 mg + clopidogrel 75 mg
High bleeding risk	Shortened to 1 month (BMS) or 3 months (DES), then SAPT
High thrombotic risk, low bleeding risk	Extend DAPT up to 3 years

medically managed ACS (no PCI)

• DAPT for minimum 3 months and preferably 12 months
• Ticagrelor preferred over clopidogrel (PLATO); prasugrel not beneficial (TRILOGY)

beyond 12 months — options at the 1-year decision point

• Default: de-escalate to ASA monotherapy
• Extended DAPT: ASA + clopidogrel 75 mg or ticagrelor 60 mg BID for up to 3 years — reduces thrombotic events, increases bleeding, no mortality benefit (DAPT (2014), PEGASUS (2015))
• Dual pathway inhibition: ASA + rivaroxaban 2.5 mg BID — reduces CV death, MI, stroke (ARR 1.3%) with increased major bleeding (ARI 1.2%) but no increase in fatal or intracranial bleeding (COMPASS (2017))

---

high bleeding risk factors

Major	Minor
End-stage CKD (eGFR <30 mL/min/1.73m²)	Moderate CKD (eGFR 30–59)
Haemoglobin <110 g/L	Haemoglobin 110–129 g/L (men); 110–119 g/L (women)
Spontaneous bleeding with hospitalisation/transfusion <6 months	Spontaneous bleeding with hospitalisation/transfusion <12 months
Prior spontaneous or traumatic ICH <12 months, or stroke <6 months	Any prior ischaemic stroke
Anticipated long-term anticoagulants	Long-term NSAIDs or steroids
Moderate-severe thrombocytopenia (platelets <100 × 10⁹/L)	Age >75
Chronic bleeding diathesis
Active malignancy within 12 months
Liver cirrhosis

---

de-escalation strategies

De-escalation of antiplatelet therapy within the first 30 days post-ACS is not recommended. Beyond 30 days:

• Potent P2Y12 → clopidogrel: TOPIC (2017) and TALOS-AMI (2021) — switching to clopidogrel-based DAPT at 30 days reduces major bleeding with similar ischaemic outcomes
• Short DAPT → P2Y12 monotherapy: TWILIGHT (2019) — 3 months DAPT then ticagrelor monotherapy reduced bleeding vs continued DAPT; non-inferior for MACE
• Short DAPT → ASA or P2Y12 monotherapy: MASTER DAPT (2021) — 1 month DAPT then monotherapy in high bleeding risk patients; similar ischaemic outcomes, less bleeding

---

concomitant anticoagulation

See anticoagulants for full detail. Key principles for patients with AF + ACS/PCI:

• Stratify stroke risk: if CHADS₂ = 0 and age <65 → no OAC indication → manage as standard DAPT
• If OAC indicated: initiate triple therapy (OAC + ASA 81 mg + clopidogrel 75 mg), DOAC preferred over warfarin
• Discontinue ASA within 1–30 days → dual pathway therapy (OAC + clopidogrel 75 mg) for up to 1 year
• At 1 year: discontinue P2Y12 inhibitor → OAC alone
• Use clopidogrel as the P2Y12 inhibitor (not ticagrelor or prasugrel) to minimise bleeding
• Stable AF + CAD ≥1 year from ACS/PCI: OAC alone is sufficient (AFIRE (2019))

---

perioperative management

non-cardiac surgery timing after PCI

Stent type	Elective NCS	Semi-urgent NCS
BMS	Delay ≥1 month	Delay ≥1 month
DES	Delay ≥3 months (elective PCI) or ≥6 months (ACS)	Delay ≥1 month
Post-ACS (any)	Delay ≥12 months if possible	≥3 months of DAPT if within 6–12 weeks of PCI

holding antiplatelets pre-operatively

Drug	Non-cardiac surgery	CABG
ASA	Continue for low-moderate bleeding risk surgery; hold 7 days for high-risk	Continue (including ACS patients)
Clopidogrel	Hold 5 days	Hold 5 days (elective); hold 48–72h minimum (semi-urgent)
Ticagrelor	Hold 3–5 days	Hold 48–72h minimum (semi-urgent); 5 days (elective)
Prasugrel	Hold 7 days	Hold 5 days minimum (semi-urgent); 7 days (elective)

• Restart antiplatelet therapy within 24 hours post-surgery once haemostasis is achieved
• Perioperative ASA initiation to reduce CV events is not recommended (POISE-2 (2014))
• In patients with prior PCI undergoing NCS, perioperative ASA likely benefits more than harms (POISE-2 PCI subgroup: prevents 59 MIs per 1000, causes 8 major bleeds per 1000)

---

adverse effects

• All agents: bleeding (major, GI, intracranial), bruising
• ASA: dyspepsia, GI bleeding (dose-related), aspirin-induced asthma, allergic reactions
• Clopidogrel: rash (uncommon); rare blood dyscrasias (agranulocytosis, TTP)
• Ticagrelor: dyspnoea (~14%), bradycardia/ventricular pauses, ↑ creatinine, ↑ uric acid/gout
• Prasugrel: ↑ fatal bleeding vs clopidogrel (0.4% vs 0.1%), ↑ CABG-related bleeding (NNH = 10)

---

key trials summary

Trial	Year	N	Intervention	Key result
CURE	2001	12,562	Clopidogrel + ASA vs ASA in NSTE-ACS	20% RRR in CV death/MI/stroke; ↑ major bleeding
PLATO	2009	18,624	Ticagrelor vs clopidogrel in ACS	HR 0.84 for CV death/MI/stroke; NNT 52; ↑ non-CABG bleeding
TRITON-TIMI 38	2007	13,608	Prasugrel vs clopidogrel in ACS + PCI	ARR 2.2% for CV death/MI/stroke; NNT 46; ↑ major/fatal bleeding
ISAR-REACT 5	2019	4,018	Prasugrel vs ticagrelor in ACS + PCI	Prasugrel: ARR 2.4% for composite CV outcome; no bleeding difference
TRILOGY	2012	7,243	Prasugrel vs clopidogrel in medically managed ACS	No benefit for prasugrel; similar bleeding
PEGASUS-TIMI 54	2015	21,162	Ticagrelor 60/90 mg BID vs placebo (1–3 yr post-MI)	ARR 1.3% for CV death/MI/stroke (60 mg); ↑ TIMI major bleeding
DAPT	2014	9,961	30 vs 12 months DAPT post-DES	↓ stent thrombosis and MACE; ↑ moderate-severe bleeding; no CV mortality benefit
TWILIGHT	2019	7,119	3-month DAPT → ticagrelor mono vs continued DAPT	↓ bleeding; non-inferior for MACE
MASTER DAPT	2021	4,579	1-month DAPT → mono vs ≥3-month DAPT (high bleeding risk)	Similar ischaemic outcomes; ↓ bleeding
COMPASS	2017	27,395	Rivaroxaban 2.5 mg BID + ASA vs ASA in stable CVD	ARR 1.3% for CV death/MI/stroke; ↑ major bleeding (ARI 1.2%); ↓ mortality
POISE-2	2014	10,010	Perioperative ASA vs placebo in NCS	No ↓ MI/death; ↑ major bleeding
POPular AGE	2020	1,002	Clopidogrel vs ticagrelor/prasugrel in ≥70 yr NSTE-ACS	Less bleeding with clopidogrel; similar net clinical benefit

---

what NOT to do

• Do not use ASA for primary prevention in patients without established atherosclerotic disease
• Do not use prasugrel in medically managed ACS (no benefit), prior stroke/TIA (net harm), or in patients ≥75 or <60 kg without careful consideration
• Do not use omeprazole or esomeprazole with clopidogrel — use pantoprazole
• Do not de-escalate antiplatelet therapy within the first 30 days post-ACS
• Do not use ticagrelor or prasugrel (instead of clopidogrel) in combination with OAC — bleeding risk is unacceptable
• Do not use doses of ASA >150 mg daily with ticagrelor (may lose efficacy benefit)
• Do not initiate ASA perioperatively to reduce cardiovascular events in non-cardiac surgery