Brilinta (Ticagrelor)
Indications
Ticagrelor is a reversible, direct-acting P2Y12 antagonist with three FDA-approved indications spanning acute coronary syndromes, long-term secondary prevention, and acute non-cardioembolic ischaemic stroke. Its clinical role centres on situations where rapid, potent platelet inhibition is required and where a reversible mechanism is preferred over the irreversible thienopyridines.
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Acute Coronary Syndrome (UA / NSTEMI / STEMI) or history of MI | Adults; managed medically or with PCI/CABG. Reduces CV death, MI, stroke, and stent thrombosis | Adjunctive to aspirin | FDA Approved |
| Coronary artery disease at high cardiovascular risk, without prior MI or stroke | Adults; efficacy established in patients with type 2 diabetes (THEMIS population) | Adjunctive to aspirin | FDA Approved |
| Acute non-cardioembolic ischaemic stroke or high-risk TIA | Adults; NIHSS ≤5, or TIA with ABCD² ≥6 or ipsilateral atherosclerotic stenosis ≥50%; within 24 h of onset; no thrombolysis/thrombectomy | Adjunctive to aspirin (30-day course) | FDA Approved |
| Peripheral artery disease — symptomatic claudication, post-revascularisation | Adults; clopidogrel intolerance or hyporesponse | Substitution / adjunctive to aspirin | Off-label |
| Clopidogrel resistance / high on-treatment platelet reactivity | Post-PCI patients with CYP2C19 loss-of-function alleles | Switch from clopidogrel | Off-label |
In contemporary practice, ticagrelor is used predominantly in the first 12 months after ACS, where it — together with prasugrel — is preferred over clopidogrel based on the PLATO trial (Wallentin 2009) and reaffirmed by the 2023 ESC ACS and 2021 ACC/AHA/SCAI revascularisation guidelines. The 60 mg BID maintenance dose, derived from PEGASUS-TIMI 54, allows extended secondary prevention beyond 12 months in selected high-risk post-MI patients. The THEMIS trial (Steg 2019) extended use to patients with CAD and type 2 diabetes without prior MI, and THALES (Johnston 2020) added the acute non-cardioembolic stroke / high-risk TIA indication.
Peripheral artery disease (low-quality evidence): The EUCLID trial (Hiatt 2017) compared ticagrelor monotherapy with clopidogrel in symptomatic PAD and showed no benefit on cardiovascular events. Use is generally limited to clopidogrel intolerance.
Genotype-guided switching from clopidogrel (moderate-quality evidence): Trials including TAILOR-PCI and POPular Genetics evaluated escalation to ticagrelor or prasugrel in patients carrying CYP2C19 loss-of-function alleles after PCI. Genotype-guided strategies are addressed in the 2021 ACC/AHA/SCAI revascularisation guideline as a Class IIb recommendation.
Dosing
Ticagrelor dosing is organised by clinical scenario rather than tablet strength. All maintenance dosing is twice-daily — this is a pharmacokinetic requirement (the parent compound has a 7-hour half-life) and one of the principal practical limitations of the drug compared with once-daily clopidogrel or prasugrel.
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| ACS — UA / NSTEMI / STEMI (medically managed or PCI) | 180 mg PO loading | 90 mg PO BID × 12 months | 90 mg BID | Co-administer with daily ASA 75–100 mg Initial ASA load typically 162–325 mg per ACS protocol |
| Post-ACS — long-term secondary prevention beyond 12 months | De-escalate from 90 mg BID | 60 mg PO BID | 60 mg BID | PEGASUS-TIMI 54 regimen Reassess bleeding/ischaemic balance annually |
| CAD without prior stroke/MI (high CV risk; THEMIS population) | No loading dose | 60 mg PO BID | 60 mg BID | Net clinical benefit greatest in prior-PCI subgroup (THEMIS-PCI) |
| Acute ischaemic stroke (NIHSS ≤5) or high-risk TIA | 180 mg PO loading within 24 h of onset | 90 mg PO BID × 30 days | 90 mg BID | Co-administer with ASA 300–325 mg load on day 1, then 75–100 mg daily THALES regimen; not for cardioembolic stroke; thrombolysis/thrombectomy excluded |
| Patient unable to swallow tablets (NG tube, post-arrest) | Crush 180 mg load — mix with water; administer via NG tube (CH8 or greater) and flush | 90 mg BID crushed | 90 mg BID | Bioequivalent to whole tablet; modestly faster Tmax (~1 h vs ~1.5 h) |
Special populations
| Population | Adjustment | Rationale |
|---|---|---|
| Renal impairment (any stage) | No dose adjustment | <1% renal excretion of unchanged drug; ticagrelor is not dialysable |
| End-stage renal disease on dialysis | No adjustment; safety/efficacy not established in this population | PLATO/PEGASUS/THEMIS/THALES did not enrol dialysis patients |
| Mild hepatic impairment (Child-Pugh A) | No adjustment | Modest exposure increase; not clinically meaningful |
| Moderate hepatic impairment (Child-Pugh B) | Use with caution; weigh risks and benefits | Limited data; probable increase in exposure |
| Severe hepatic impairment (Child-Pugh C) | Avoid use | Likely substantial increase in exposure; not studied |
| Elderly (≥75 years) | No specific adjustment | No overall safety/efficacy difference observed; use bleeding risk score (e.g., PRECISE-DAPT) |
| Low body weight (<60 kg) | No adjustment | Unlike prasugrel, no weight-based dose threshold |
| Paediatric (<18 years) | Not established | Safety and efficacy not established; HESTIA in sickle cell disease did not demonstrate benefit |
Switching between P2Y12 inhibitors
| Switch direction | Approach | Setting |
|---|---|---|
| Clopidogrel → ticagrelor | 180 mg loading dose, then 90 mg BID — without interruption of antiplatelet effect | Acute / early phase escalation |
| Prasugrel → ticagrelor | 180 mg loading dose 24 h after last prasugrel dose | Acute switch (e.g., for thrombocytopenia) |
| Ticagrelor → clopidogrel (de-escalation) | Per protocol approaches: 600 mg clopidogrel load 24 h after last ticagrelor dose, then 75 mg daily | Chronic phase (TROPICAL-ACS de-escalation strategy) |
| Ticagrelor → prasugrel | 60 mg prasugrel load 24 h after last ticagrelor dose | Acute switch (rare; e.g., dyspnoea intolerance) |
• BID compliance is the single largest practical limitation. If adherence is uncertain, clopidogrel or prasugrel may give better real-world platelet inhibition than missed ticagrelor doses.
• Maintenance aspirin must not exceed 100 mg/day. Higher aspirin doses reduced ticagrelor efficacy in the PLATO US subgroup — this is one of the FDA boxed warnings.
• Hold for 5 days before non-emergent surgery with a major risk of bleeding. Despite reversible binding, washout still requires approximately 5 days for adequate platelet recovery.
• If a dose is missed, the patient should take the next scheduled dose at its usual time — doses are not doubled.
Pharmacology
Mechanism of Action
Ticagrelor is a cyclopentyltriazolopyrimidine that binds reversibly to the platelet P2Y12 ADP receptor. By blocking P2Y12 signalling, it prevents amplification of platelet activation downstream of GPIIb/IIIa complex formation, reducing aggregation and thrombus growth at sites of arterial injury. Two features distinguish it from the thienopyridines (clopidogrel, prasugrel). First, ticagrelor itself is pharmacologically active — no hepatic bioactivation is required, although the major circulating active metabolite AR-C124910XX (equipotent at P2Y12, exposure approximately 30–40% of parent) contributes to the antiplatelet effect. This avoids the variability seen with clopidogrel in patients carrying CYP2C19 loss-of-function alleles. Second, binding is reversible: platelet function recovers as drug levels fall, giving a more predictable washout profile than the irreversible thienopyridines. A proposed off-target effect — inhibition of the equilibrative nucleoside transporter ENT1 with consequent rise in extracellular adenosine — has been advanced in the mechanistic literature to explain ticagrelor-related dyspnoea and ventricular pauses, though this is not described in the FDA prescribing information.
ADME profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability ~36% (range 30–42%); median Tmax 1.5 h (parent), 2.5 h (active metabolite); high-fat meal increases AUC ~21% without clinically relevant impact | Onset of platelet inhibition within hours; faster and more potent IPA at 2 h than 600 mg clopidogrel |
| Distribution | Steady-state Vd ~88 L; protein binding >99% (parent and active metabolite) | Extensive tissue distribution; not dialysable; clinically significant drug-drug protein-displacement interactions are unlikely |
| Metabolism | Hepatic; CYP3A4 is the major enzyme, with CYP3A5 contributing; ticagrelor is a weak P-gp substrate and weak inhibitor of CYP3A4 and P-gp | Susceptible to interactions with strong CYP3A inhibitors and inducers; raises digoxin levels via P-gp inhibition |
| Elimination | Predominantly hepatic/biliary; mean radioactivity recovery ~84% (58% faeces, 26% urine); <1% renal excretion of unchanged drug; t½ ~7 h (parent), ~9 h (active metabolite) | No dose adjustment for any stage of renal impairment; severe hepatic impairment is an “avoid” recommendation |
Reviews by Husted/van Giezen and Cattaneo et al. propose that ticagrelor inhibits ENT1, raising extracellular adenosine. This is the leading mechanistic explanation for three features uncommon with clopidogrel: dyspnoea, asymptomatic ventricular pauses on Holter monitoring, and possible adenosine-mediated cardiovascular effects. Patients tolerating clopidogrel may not tolerate ticagrelor for this reason.
Side Effects
Frequency data below are from the FDA prescribing information, which draws on PLATO (n=18,624; ACS; 12 months) for the 90 mg BID dose, PEGASUS-TIMI 54 (n=21,162; post-MI; median 33 months) for the 60 mg BID dose, THEMIS (n=19,220; CAD plus T2DM) for chronic 60 mg BID, and THALES (n=11,016; minor stroke/high-risk TIA; 30 days) for 90 mg BID. Bleeding rates depend heavily on the bleeding definition used — PLATO criteria, TIMI, GUSTO, or BARC.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dyspnoea | ~14% (PLATO 13.8%, PEGASUS 14.2%); ~21% in THEMIS | Distinct from cardiopulmonary causes; usually mild to moderate; often resolves on continued treatment; a PLATO pulmonary-function substudy showed no adverse effect on lung function Discontinuation due to dyspnoea: 0.9% (PLATO), 1.0% (THALES), 4.3% (PEGASUS), 6.9% (THEMIS) |
| Bleeding (any, PLATO criteria, including minor) | PLATO 11.6% major; non-CABG major+minor ~7.7% | Overall PLATO-defined major bleeding similar to clopidogrel; non-CABG bleeding higher with ticagrelor PEGASUS TIMI major+minor: 11 events/1000 patient-years (60 mg) vs 5 placebo |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Non-CABG major bleeding (PLATO criteria) | 4.5% vs 3.8% clopidogrel | Statistically increased with ticagrelor; non-CABG TIMI major bleeding 2.8% vs 2.2% |
| Dizziness | PLATO 4.5%; PEGASUS 4.5% | Consider orthostatic vitals; may overlap with bradyarrhythmia |
| Nausea (PLATO) / Diarrhoea (PEGASUS) | Nausea 4.3% (PLATO); diarrhoea 3.3% (PEGASUS) | Take with food if prominent; do not add a PPI purely for tolerance |
| Increase in serum creatinine >50% | PLATO 7.4% (vs 5.9% clopidogrel); PEGASUS ~4% | Generally non-progressive and reversible on discontinuation; treatment groups did not differ for renal-related serious adverse events in PLATO |
| Bradyarrhythmias / ventricular pauses >3 s on Holter | 6.0% (acute phase) vs 3.5% clopidogrel; 2.2% vs 1.6% at 1 month | From PLATO Holter substudy; mostly nocturnal, asymptomatic, transient Patients with sick sinus syndrome or 2nd/3rd degree AV block without pacemaker were excluded from trials |
| Hyperuricaemia / gout | PLATO gout 0.6% (each group); PEGASUS gout 1.5% vs 1.1% | Mean urate rise ~0.6 mg/dL on 90 mg, ~0.2 mg/dL on 60 mg; reversible on discontinuation |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Major bleeding (TIMI major, PLATO trial) | 7.9% vs 7.7% clopidogrel (overall) | Throughout therapy | Hold drug; supportive care; platelet transfusion is unlikely to be of clinical benefit (FDA PI); ticagrelor is not dialysable; consider PCC for life-threatening bleeding |
| Intracranial haemorrhage (PLATO non-CABG) | 0.3% vs 0.2% clopidogrel | Throughout therapy | Permanent discontinuation; contraindicated for re-initiation; emergency neuroimaging and neurosurgical input |
| Fatal bleeding (PLATO non-CABG) | 0.2–0.3% (similar across groups) | Any time | Resuscitation; root-cause review (mistimed elective surgery, drug interaction, missed contraindication) |
| GUSTO severe bleeding (THALES, 30 days) | 0.5% vs 0.1% placebo | Within first 30 days | Discontinue drug; assess for reversible causes; emergency management |
| Symptomatic bradyarrhythmia / high-grade AV block | Postmarketing reports | Days to weeks | 12-lead ECG; Holter; consider switch to alternative P2Y12 inhibitor |
| Anaphylaxis / angioedema | Postmarketing — rare | Hours to days | Emergency care; permanent discontinuation; switch to chemically unrelated agent (clopidogrel) |
| Thrombotic thrombocytopenic purpura (TTP) | Postmarketing — rare | Within 2 weeks of exposure (case reports) | Discontinue immediately; haematology consult; plasma exchange |
| Central sleep apnoea / Cheyne-Stokes respiration | Postmarketing — uncommon | Variable | Sleep study if suspected; consider switch to alternative P2Y12 inhibitor if confirmed |
| Reason for discontinuation | Incidence | Context |
|---|---|---|
| Dyspnoea | PLATO 0.9%; THALES 1.0%; PEGASUS 4.55%; THEMIS 6.9% | Most distinctive cause across trials; usually mild but persistent; key counselling priority |
| Bleeding | PEGASUS KM 6.2% (60 mg); higher with concomitant anticoagulation | Causes higher in patients with prior bleeding or on anticoagulants |
| Bradyarrhythmia / pauses | Low absolute rates | Mostly asymptomatic Holter findings; symptomatic withdrawal uncommon |
| Other (rash, GI intolerance, gout flare) | Variable; small contributors to total withdrawal | Usually permits switch to clopidogrel without recurrence |
Dyspnoea is the most clinically meaningful tolerability issue. Pragmatic workflow: (1) confirm it is ticagrelor-related — new onset, no exertional pattern, normal SpO₂, no congestion; (2) rule out unmasked heart failure or pulmonary embolism; (3) reassure most cases improve over weeks and continue ticagrelor without interruption if tolerable (FDA PI); (4) for intolerable dyspnoea after the acute phase, switch to clopidogrel or prasugrel rather than allowing self-discontinuation. Dyspnoea typically resolves within days of stopping the drug.
Drug Interactions
Ticagrelor is metabolised primarily by CYP3A4 (with CYP3A5 contributing) and is itself a weak inhibitor of CYP3A4 and P-glycoprotein. Clinically important interactions cluster around these pathways, plus the predictable additive bleeding risks shared by all antiplatelet and anticoagulant agents.
Unlike clopidogrel (where omeprazole and esomeprazole reduce active metabolite formation via CYP2C19), ticagrelor does not require CYP2C19 activation. PPIs can be used freely with ticagrelor and are recommended in patients with GI bleeding risk factors per current guidelines.
Monitoring
Routine therapeutic drug monitoring is not used. Bedside platelet function tests (VerifyNow, Multiplate) are not recommended for routine ticagrelor management — the evidence from ARCTIC, ANTARCTIC, and TROPICAL-ACS does not support tailoring therapy by platelet reactivity outside research settings.
-
Bleeding signs & symptoms
Every visit
Routine Ask about bruising, gingival bleeding, epistaxis, melena, haematuria, menorrhagia. Inspect mucous membranes. Reinforce when to seek emergency care (red or brown urine; tarry stools; sudden severe headache). -
Haemoglobin / haematocrit
Baseline, then with symptoms
Trigger-based Recheck for unexplained fatigue, dyspnoea, drop in BP, or visible bleeding. Occult GI loss is the commonest cause of asymptomatic anaemia on DAPT. -
Platelet count
Baseline, then with symptoms
Trigger-based TTP is rare but life-threatening; check urgently if new bruising or neurological symptoms. Note that ticagrelor can cause false-negative results in functional HIT tests (e.g., heparin-induced platelet aggregation); PF4 antibody testing is not affected. -
Renal function (eGFR, creatinine)
Baseline, then annually
Routine Modest creatinine rises are common and usually benign; treatment groups in PLATO did not differ for renal-related serious adverse events. Hold and reassess during severe sepsis or acute decompensation. -
Liver function (AST, ALT)
Baseline, then with symptoms
Trigger-based Recheck if jaundice, abdominal pain, or unexplained fatigue. Severe hepatic impairment is an “avoid” recommendation. -
Serum uric acid
In patients with prior gout
Trigger-based Mean urate increase ~0.6 mg/dL on 90 mg, ~0.2 mg/dL on 60 mg. Continue or initiate urate-lowering therapy if symptomatic. -
ECG / Holter
Triggered by symptoms
Trigger-based Indicated for syncope, presyncope, or new bradycardia — especially in patients with sinus node disease or on negative chronotropes (beta-blocker, non-DHP CCB). -
Adherence assessment
Every visit
Routine Twice-daily dosing is the highest-risk adherence challenge. Use pill counts, refill data, or patient-reported missed doses. Consider de-escalation to clopidogrel if adherence is consistently poor. -
Bleeding risk reassessment (PRECISE-DAPT, DAPT score)
At 6 and 12 months post-ACS
Routine Drives decisions on duration extension, de-escalation, or shortening of DAPT. Integrate with ischaemic risk (e.g., complex PCI, multi-vessel disease, recurrent events).
Hold ticagrelor for 5 days before non-emergency surgery (FDA PI). For urgent CABG, expect substantial bleeding when surgery occurs within 24–72 h of last dose — have platelets and prothrombin complex available. Bentracimab, a ticagrelor-binding monoclonal antibody fragment, has positive Phase 3 (REVERSE-IT) data and a BLA under FDA review, but is not approved as of this update.
Contraindications & Cautions
Bleeding: Ticagrelor, like other antiplatelet agents, can cause significant, sometimes fatal bleeding. Do not use in patients with active pathological bleeding or a history of intracranial haemorrhage. Do not start in patients undergoing urgent CABG. If possible, manage bleeding without discontinuing the drug, as stopping it increases the risk of subsequent cardiovascular events.
Aspirin maintenance dose: In patients with ACS, concomitant maintenance aspirin doses above 100 mg/day reduce ticagrelor effectiveness and should be avoided. Maintenance daily aspirin must not exceed 100 mg.
Absolute contraindications (FDA prescribing information, Section 4)
- History of intracranial haemorrhage at any point
- Active pathological bleeding (e.g., active peptic ulcer haemorrhage, intracranial haemorrhage)
- Hypersensitivity to ticagrelor or any excipient (including angioedema)
Avoid use (FDA-recommended; not formal Section 4 contraindications)
- Severe hepatic impairment (Child-Pugh C): likely substantial increase in ticagrelor exposure; not studied (FDA PI Warnings & Precautions 5.6)
- Concomitant strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, atazanavir, telithromycin): substantial increase in ticagrelor exposure (FDA PI Drug Interactions 7.1)
- Concomitant strong CYP3A inducers (rifampin, phenytoin, carbamazepine, phenobarbital): substantial reduction in ticagrelor exposure with loss of efficacy (FDA PI Drug Interactions 7.2)
- Patients undergoing urgent CABG: do not initiate (boxed warning)
Relative contraindications — specialist input recommended
- Cardioembolic stroke or moderate-to-severe stroke (NIHSS >5): THALES did not enrol these patients, and use is not recommended in this population
- Patients receiving thrombolysis or thrombectomy within 24 h of randomisation: excluded from THALES; use not established
- Concomitant oral anticoagulation (AF, mechanical valve, recurrent VTE): 2023 ESC ACS guideline favours clopidogrel + DOAC over ticagrelor + DOAC in AF + ACS/PCI; cardiology input required
- Sick sinus syndrome, second- or third-degree AV block, or bradycardia-related syncope without pacemaker: excluded from pivotal trials and at increased risk of bradyarrhythmias
- Severe asthma or advanced COPD: dyspnoea may be misattributed; have low threshold to switch if intolerable
- Moderate hepatic impairment (Child-Pugh B): limited data; weigh risks and benefits
- Planned non-emergent surgery within 5 days: defer initiation or hold drug
- Pregnancy: available case reports have not identified harm, but animal studies showed structural abnormalities at high maternal doses; reserve for situations where benefit clearly outweighs risk
- Lactation: ticagrelor and metabolites present in rat milk; breastfeeding not recommended (FDA PI 8.2)
Use with caution
- Elderly (≥75 years): reassess net benefit at 6 and 12 months
- Prior gout / hyperuricaemia: continue urate-lowering therapy; counsel on flare risk
- Recent or planned spinal/epidural anaesthesia: risk of spinal haematoma; coordinate with anaesthesia
- Concomitant SSRI/SNRI or chronic NSAID: consider PPI; reassess GI bleeding risk factors
- Active or recent peptic ulcer disease: treat H. pylori, optimise PPI, reassess net benefit
Patient Counselling
Purpose of therapy
Explain that ticagrelor is a blood-thinning medicine that reduces the risk of another heart attack, stroke, or death from cardiovascular causes after ACS, after stenting, or in selected high-risk patients. It works by stopping platelets from clumping together at the site of damaged blood vessels. It is almost always used together with low-dose aspirin — this combination is called dual antiplatelet therapy (DAPT). Stopping ticagrelor too early is one of the most common causes of stent thrombosis, a life-threatening blockage of a stent. Patients should never stop the drug without speaking to their cardiologist first.
How to take
Ticagrelor is taken twice daily, roughly 12 hours apart, with or without food. Pair the doses with a regular daily anchor (e.g., breakfast and dinner) to support adherence. If a dose is missed, take the next scheduled dose at its usual time — do not double up. Tablets may be swallowed whole or crushed, mixed with water, and drunk; the same approach can be used through a nasogastric tube. Continue low-dose aspirin (81 mg in the United States, 75 mg in the United Kingdom) every day — do not increase the aspirin dose, as higher doses reduce ticagrelor’s benefit. The course duration depends on the indication: typically 12 months after ACS, then either de-escalation or extension based on risk; 30 days after acute non-cardioembolic stroke or high-risk TIA. Bring a list of all medicines, including over-the-counter products and herbal remedies, to every clinic visit.
Sources
- U.S. Food and Drug Administration. BRILINTA (ticagrelor) tablets — Prescribing Information (revised 02/2021). AstraZeneca. accessdata.fda.gov/drugsatfda_docs/label/2021/022433s031lbl.pdf Primary regulatory source for indications, dosing, boxed warnings, contraindications, and adverse-reaction frequencies.
- European Medicines Agency. Brilique (ticagrelor) Summary of Product Characteristics. ema.europa.eu/en/medicines/human/EPAR/brilique European prescribing reference; useful for dosing nuances and additional warnings.
- U.S. FDA. Drugs@FDA database, BRILINTA (ticagrelor) approval history. accessdata.fda.gov/scripts/cder/daf/ Tracks labelling changes, including the THALES stroke indication added November 2020.
- Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes (PLATO). N Engl J Med. 2009;361(11):1045-1057. doi.org/10.1056/NEJMoa0904327 Pivotal ACS trial — basis for the 90 mg BID indication and the comparative-effectiveness benchmark over clopidogrel.
- Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction (PEGASUS-TIMI 54). N Engl J Med. 2015;372(19):1791-1800. doi.org/10.1056/NEJMoa1500857 Established the 60 mg BID extended secondary-prevention regimen in stable post-MI patients.
- Steg PG, Bhatt DL, Simon T, et al. Ticagrelor in patients with stable coronary disease and diabetes (THEMIS). N Engl J Med. 2019;381(14):1309-1320. doi.org/10.1056/NEJMoa1908077 Trial behind the CAD-with-T2DM indication; defines the population in which net clinical benefit is favourable.
- Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA (THALES). N Engl J Med. 2020;383(3):207-217. doi.org/10.1056/NEJMoa1916870 Foundation for the acute non-cardioembolic stroke / high-risk TIA indication.
- Schüpke S, Neumann FJ, Menichelli M, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes (ISAR-REACT 5). N Engl J Med. 2019;381(16):1524-1534. doi.org/10.1056/NEJMoa1908973 Investigator-initiated head-to-head trial showing prasugrel superior to ticagrelor on the composite endpoint without an increase in BARC 3-5 bleeding (5.4% vs 4.8%).
- Hiatt WR, Fowkes FGR, Heizer G, et al. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease (EUCLID). N Engl J Med. 2017;376(1):32-40. doi.org/10.1056/NEJMoa1611688 Negative PAD trial — supports limiting off-label use to specific clinical scenarios.
- Bonaca MP, Bhatt DL, Oude Ophuis T, et al. Long-term tolerability of ticagrelor for the secondary prevention of major adverse cardiovascular events: a secondary analysis of the PEGASUS-TIMI 54 trial. JAMA Cardiol. 2016;1(4):425-432. doi.org/10.1001/jamacardio.2016.1017 Source for PEGASUS discontinuation rates, including dyspnoea (KM 4.55%) and bleeding (KM 6.2%) on 60 mg BID.
- Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44(38):3720-3826. doi.org/10.1093/eurheartj/ehad191 Current European recommendations on P2Y12 selection, DAPT duration, and de-escalation strategies.
- Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization. J Am Coll Cardiol. 2022;79(2):e21-e129. doi.org/10.1016/j.jacc.2021.09.006 US revascularisation guidance; addresses genotype-guided therapy and DAPT recommendations after PCI.
- Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update. Stroke. 2019;50(12):e344-e418. doi.org/10.1161/STR.0000000000000211 Foundation document for short-course DAPT in minor stroke / high-risk TIA.
- Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27(4):259-274. doi.org/10.1111/j.1755-5922.2009.00096.x Detailed mechanism review covering reversible P2Y12 binding and ENT1 inhibition.
- Cattaneo M, Schulz R, Nylander S. Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance. J Am Coll Cardiol. 2014;63(23):2503-2509. doi.org/10.1016/j.jacc.2014.03.031 Reviews the off-target adenosine effects underlying dyspnoea and bradyarrhythmia.
- Teng R, Mitchell PD, Butler K. Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers. Eur J Clin Pharmacol. 2013;69(3):477-487. doi.org/10.1007/s00228-012-1369-4 Source for the simvastatin/lovastatin 40 mg cap recommendation.
- Kubica J, Adamski P, Ostrowska M, et al. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction (IMPRESSION). Eur Heart J. 2016;37(3):245-252. doi.org/10.1093/eurheartj/ehv547 Documents the morphine-ticagrelor absorption interaction relevant to STEMI loading.
- Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with severe renal impairment. Br J Clin Pharmacol. 2010;70(1):65-77. doi.org/10.1111/j.1365-2125.2010.03669.x Underpins the no-renal-adjustment recommendation across all stages including dialysis.