Ticagrelor

What it is

Ticagrelor is a synthetic cyclopentyl-triazolopyrimidine taken by mouth as a film-coated tablet. It is an antiplatelet drug: it and its major metabolite attach reversibly to the platelet P2Y12 adenosine-diphosphate receptor. The US label records that it is marketed as 60 mg and 90 mg tablets and that the drug and its active metabolite are roughly equally potent. It is always used alongside aspirin in the trials that established it.

What the research says

The evidence for ticagrelor is unusually large and splits sharply by who is taking it. In acute coronary syndrome it reduced cardiovascular death, heart attack and stroke and reduced death from any cause compared with clopidogrel over 12 months, with absolute differences of roughly 1-2 percentage points. For long-term use after an old heart attack, and for 30 days after a minor stroke or high-risk TIA, it also reduced events by about 1 percentage point. In stable coronary disease with diabetes the ischaemic benefit was small and was offset by bleeding, and in peripheral artery disease, in monotherapy after stroke, and in childhood sickle cell disease it failed. Bleeding, breathlessness and slow-heart-rate episodes are the price, and stopping it early is itself dangerous.

Evidence grade: Well established.

How it works

Drug class: Reversibly binding, direct-acting oral P2Y12 ADP-receptor antagonist (antiplatelet agent)

Ticagrelor blocks the P2Y12 receptor on platelets, the receptor that adenosine diphosphate uses to switch platelets on. Unlike clopidogrel it binds reversibly and does not need to be converted by the liver to work, and its own main breakdown product is about as active as the parent drug. The practical effect is that platelets clump less readily, so clots form less easily in arteries. (Source 1)

Boxed warning

BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding (5.1, 6.1).

(Source 2)

What it is used for

• In the 18,624-patient PLATO trial ticagrelor beat clopidogrel on the composite of vascular death, MI or stroke (9.8% vs 11.7% at 12 months) and on death from any cause (4.5% vs 5.9%), without more overall major bleeding but with more non-CABG major bleeding. Stroke alone was not reduced. Evidence: established. (Source 3)
• In PEGASUS-TIMI 54 (21,162 patients, median 33 months) both ticagrelor doses cut the composite of CV death, MI or stroke from 9.04% to 7.77-7.85% at 3 years, an absolute reduction the label puts at 1.27% for the 60 mg regimen, while TIMI major bleeding roughly doubled or more. Evidence: established. (Source 4)
• THEMIS (19,220 patients) met its primary endpoint only narrowly (7.7% vs 8.5%, HR 0.90, 95% CI 0.81 to 0.99, P = 0.04) while TIMI major bleeding more than doubled and intracranial haemorrhage rose; the trial's own exploratory composite of irreversible harm showed no difference. Cardiovascular death was not reduced (HR 1.02). Evidence: disputed. (Source 5)
• THALES (11,016 patients) reduced stroke or death within 30 days from 6.6% to 5.5% (HR 0.83), an absolute reduction of about 1.1 percentage points, but the incidence of disability did not differ and severe bleeding rose from 0.1% to 0.5%. Evidence: established. (Source 6)
• SOCRATES randomised 13,199 patients to ticagrelor or aspirin monotherapy and missed its primary endpoint (6.7% vs 7.5%, HR 0.89, 95% CI 0.78 to 1.01, P = 0.07). Ticagrelor was not shown to be better than aspirin. Evidence: not-supported. (Source 7)
• EUCLID randomised 13,885 patients with symptomatic peripheral artery disease to ticagrelor or clopidogrel monotherapy; cardiovascular death, MI or ischaemic stroke occurred in 10.8% versus 10.6% (HR 1.02), with identical rates of acute limb ischaemia and major bleeding. Evidence: not-supported. (Source 8)
• The HESTIA3 trial in 193 children aged 2 to 17 was stopped early for lack of efficacy; yearly vaso-occlusive crises were 2.74 on ticagrelor and 2.60 on placebo. Evidence: not-supported. (Source 9)

Interactions

• Aspirin at maintenance doses above 100 mg (clinical trial): In PLATO, ticagrelor's benefit was concentrated in people taking low-dose aspirin. Higher aspirin doses were associated with worse outcomes on ticagrelor, which the label treats as a strong suggestion rather than proof because aspirin dose was chosen by investigators, not randomised. Limit: Two faults in the label's own wording, left as printed. It says "Figure 10 shows overall results by median aspirin dose", but Figure 10 in this label is the overall Kaplan-Meier curve of CV death, MI or stroke; the aspirin-dose results are in Figure 11 (subgroup analyses) and Figure 12 (aspirin dose in and outside the US). Do not follow that pointer. It also switches denominators mid-sentence: the non-US figures are percentages of investigators (8% gave more than 100 mg) while the US figures are percentages of patients (57% received more than 100 mg), so the two pairs are not comparable even though the sentence invites a direct comparison. The label is explicit that aspirin dose was chosen by investigators rather than randomised, so this is an unplanned subset analysis, not a trial result. (Source 10)
• Strong CYP3A inhibitors (for example ketoconazole, itraconazole, clarithromycin, ritonavir) (label): These raise ticagrelor blood levels substantially, which raises the risk of breathlessness and bleeding. The label says to avoid them. (Source 11)
• Strong CYP3A inducers (for example rifampin, phenytoin, carbamazepine, phenobarbital) (label): These lower ticagrelor blood levels substantially and so reduce how well it works. (Source 12)
• Simvastatin, lovastatin and rosuvastatin (label): Ticagrelor raises the blood levels of these three statins, so the label caps simvastatin and lovastatin dose. (Source 13)
• Grapefruit juice (pharmacokinetic study): In a randomised crossover study in 10 healthy volunteers, grapefruit juice roughly doubled ticagrelor exposure and strengthened and prolonged its antiplatelet effect. The study measured blood levels and platelet function, not bleeding outcomes. Limit: This rests on one pharmacokinetic study in 10 healthy volunteers given a single 90 mg dose, measuring blood levels and platelet function; no bleeding or other clinical outcome was recorded. The fall in the active metabolite reached statistical significance for peak concentration and for exposure to 34 hours but not for total exposure, so it should not be reported as a general drop. The companion conclusion says exposure rose "by more than two-fold" while the results give total exposure as 221% of control, which is about 2.2 times the exposure, that is an increase of roughly 1.2-fold - the authors mean the ratio, not the increment. (Source 14)
• Fish oil and other omega-3 supplements (clinical trial): A meta-analysis of 11 randomised trials found no overall increase in bleeding with omega-3 fatty acids, including in people already on antiplatelet drugs. High-dose purified EPA was the exception, with a small absolute increase. Limit: The one positive signal here, a 50% higher relative risk of bleeding with high-dose purified EPA, is the only estimate in the paper given with no confidence interval and no p-value, and it corresponds to an absolute increase of 0.6%, which the authors themselves call "very modest". The finding that background antiplatelet use made no difference is borderline rather than clean: the risk difference was -0.01 with a 95% interval of -0.02 to 0 and p=0.056, so the interval's upper limit sits exactly at no difference. None of the included trials tested omega-3 alongside ticagrelor specifically. (Source 15)
• Ginkgo biloba (theoretical): The US National Center for Complementary and Integrative Health states that ginkgo may increase bleeding risk in people on anticoagulant drugs and may interact with other medicines. This is a safety position, not a study of ginkgo with ticagrelor; no such study was found. Limit: This is a safety position from a US government body, not a study, and no study of ginkgo taken with ticagrelor was found. The same NCCIH page carries two further warnings that are not quoted here: that ginkgo may be unsafe in pregnancy and might cause early labour or extra bleeding at delivery, and that fresh ginkgo seeds are toxic taken by mouth. (Source 16)
• Turmeric and curcumin (theoretical): Curcumin inhibited human platelet aggregation in the test tube, ranking below eugenol and capsaicin in potency in one laboratory study of isolated platelets. Nothing was given to a person: this is in-vitro work on platelets in a cuvette, it is not evidence that taking turmeric with ticagrelor causes bleeding in people, and no human study of the combination was found. Limit: Every result here is from isolated human platelets in a test tube, challenged with added agonists at fixed concentrations; the paper says so itself. No dose was given to a person, and a concentration that halves aggregation in a cuvette has no dietary equivalent, so this cannot be turned into an amount of turmeric. The concentrations also appear in the abstract's plain-text form as "50microM", "500microg/ml" and "14.6microM": those are NCBI's ASCII renderings of 50 micromolar, 500 micrograms per millilitre and 14.6 micromolar, and "microg" must not be read as milligrams. (Source 17)
• Heparin-induced thrombocytopenia functional laboratory tests (label): Ticagrelor can make platelet function tests for heparin-induced thrombocytopenia come back falsely negative, so the laboratory needs to know the person is taking it. (Source 18)

Stopping it

• Stopping ticagrelor is itself a documented risk. The boxed warning tells prescribers to manage bleeding without stopping the drug where possible, because stopping raises the chance of a further cardiovascular event. (Source 2)
• The label states plainly that discontinuation increases the risk of heart attack, stroke and death in people being treated for coronary artery disease, and sets out how to interrupt it for surgery and restart it. (Source 19)
• Because the drug binds reversibly, its effect wears off over days rather than requiring platelet turnover. The label records that platelet inhibition after the last dose was back to placebo levels after 5 days, and that missing a single dose still left inhibition similar to the trough level on clopidogrel. (Source 20)
• People stop ticagrelor often in practice and in trials. In THEMIS permanent discontinuation reached 34.5% on ticagrelor against 25.4% on placebo. (Source 5)
• In the POPular AGE trial in people aged 70 or over, nearly half of those assigned to ticagrelor stopped it early, and the commonest reasons were bleeding, breathlessness and a new need for an oral anticoagulant. (Source 21)
• No dependence or withdrawal syndrome is described for ticagrelor in the sources read. The hazard of stopping is thrombotic rather than a withdrawal state, and there is no literature on tapering: the label's only instruction about interrupting the drug is a timed interruption before high-bleeding-risk surgery. (Source 19)

What goes wrong

Bleeding is the central harm: in PLATO, non-CABG PLATO-major bleeding and fatal/life-threatening intracranial haemorrhage were more common on ticagrelor than clopidogrel. (Source 22)

• Randomized trial, High certainty.
• Size: BRILINTA 90 mg twice daily N=9235 vs clopidogrel N=9186.
• Who: PLATO acute coronary syndrome population, all on aspirin.
• How long: up to 12 months; about half of non-CABG major bleeds occurred in the first 30 days.
• Result: PLATO Major + Minor 713 (7.7%) vs 567 (6.2%); Major 362 (3.9%) vs 306 (3.3%); fatal/life-threatening 171 (1.9%) vs 151 (1.6%); fatal 15 (0.2%) vs 16 (0.2%); intracranial haemorrhage (fatal/life-threatening) 26 (0.3%) vs 15 (0.2%). Absolute excess of PLATO Major bleeding about 0.6 percentage points, roughly 167 people treated per extra major bleed (computed from the reported rates)
• Funding: label held by AstraZeneca Pharmaceuticals LP; figures from the AstraZeneca-sponsored PLATO trial.

PLATO Major + Minor 713 (7.7) 567 (6.2) Major 362 (3.9) 306 (3.3) Fatal/Life-threatening 171 (1.9) 151 (1.6) Fatal 15 (0.2) 16 (0.2) Intracranial hemorrhage (Fatal/Life-threatening) 26 (0.3) 15 (0.2)

In PLATO overall major bleeding did not differ between ticagrelor and clopidogrel, but bleeding not related to bypass surgery did. (Source 3)

• Randomized trial, High certainty.
• Size: 18,624 patients.
• Who: PLATO acute coronary syndrome population.
• How long: up to 12 months.
• Result: overall major bleeding 11.6% vs 11.2% (P=0.43); non-CABG major bleeding 4.5% vs 3.8% (P=0.03), an absolute excess of 0.7 percentage points.
• Funding: industry-funded (AstraZeneca)

No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.

Breathlessness is a common, drug-specific adverse effect: dyspnoea affected about one in seven people on ticagrelor in PLATO and PEGASUS and about one in five in THEMIS, roughly double the comparator rate. (Source 23)

• Official position, High certainty.
• Size: PLATO 9235 vs 9186; PEGASUS 6958 vs 6996; THEMIS and THALES as reported.
• Who: the four ticagrelor outcome trial populations.
• How long: 30 days (THALES) to 48 months (PEGASUS)
• Result: about 14% (PLATO and PEGASUS) to 21% (THEMIS) developed dyspnoea; study-drug discontinuation for dyspnoea 0.9% (PLATO), 1.0% (THALES), 4.3% (PEGASUS) and 6.9% (THEMIS). In a 199-subject PLATO substudy there was no indication of an adverse effect on pulmonary function.
• Funding: label held by AstraZeneca Pharmaceuticals LP.

Limit of this finding: The label gives the incidence of breathlessness for two trials only, about 14% in PLATO and PEGASUS and 21% in THEMIS, but then gives discontinuation rates for four trials, including 1.0% in THALES, whose dyspnoea incidence it never states. There is no incidence figure to set the THALES discontinuation rate against.

In clinical trials, about 14% (PLATO and PEGASUS) to 21% (THEMIS) of patients treated with BRILINTA developed dyspnea. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment but led to study drug discontinuation in 0.9% (PLATO), 1.0% (THALES), 4.3% (PEGASUS), and 6.9% (THEMIS) of patients. In a substudy of PLATO, 199 subjects underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment.

A systematic review of P2Y12 inhibitor trials quantified roughly a doubling of dyspnoea risk with ticagrelor versus clopidogrel. (Source 24)

• Systematic review, Moderate certainty.
• Size: eight RCTs including 41,289 patients.
• Who: patients in randomised trials of newer antiplatelet drugs versus clopidogrel.
• How long: as reported in the included trials.
• Result: ticagrelor risk ratio for dyspnoea 1.95 (95% CI 1.37-2.77); prasugrel 1.09 (0.93-1.27); reversible inhibitors versus prasugrel RR 1.99 (1.40-2.82)
• Funding: not stated.

Limit of this finding: Every risk ratio here is against clopidogrel, because the review excluded placebo-controlled trials. The last comparison, reversible inhibitors against prasugrel, is an adjusted indirect comparison calculated across trials, not a head-to-head result. The review gives no absolute incidence of breathlessness for any drug, so "roughly double the risk" cannot be converted into a number of people, and the widest interval (elinogrel, 1.57 to 6.72) reflects very few events.

Prasugrel was not associated with an increased risk of dyspnea (RR 1.09, 95% CI 0.93-1.27), whereas ticagrelor (RR 1.95, 95% CI 1.37-2.77), cangrelor (RR 2.42, 95% CI 1.36-4.33), and elinogrel (RR 3.25, 95% CI 1.57-6.72) showed an increased risk of dyspnea.

Ticagrelor caused more ventricular pauses than clopidogrel in a Holter substudy, and people prone to bradycardia were excluded from all four outcome trials. (Source 25)

• Randomized trial, Moderate certainty.
• Size: about 3000 patients in the PLATO Holter substudy.
• Who: PLATO acute coronary syndrome patients.
• How long: acute phase and after 1 month.
• Result: ventricular pauses in 6.0% on ticagrelor versus 3.5% on clopidogrel in the acute phase; 2.2% versus 1.6% after 1 month.
• Funding: label held by AstraZeneca Pharmaceuticals LP.

In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6%, respectively, after 1 month. PLATO, PEGASUS, THEMIS and THALES excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker).

Ticagrelor raised serum uric acid and was associated with more gout than aspirin alone in PEGASUS. (Source 26)

• Randomized trial, Moderate certainty.
• Size: PLATO 9235 vs 9186; PEGASUS 6958 vs 6996.
• Who: PLATO and PEGASUS trial populations.
• How long: up to 12 months (PLATO) and median 33 months (PEGASUS)
• Result: uric acid rose about 0.6 mg/dL on 90 mg versus about 0.2 mg/dL on clopidogrel in PLATO, where gout reports did not differ (0.6% in each group); in PEGASUS uric acid rose about 0.2 mg/dL with no rise on aspirin alone and gout occurred in 1.5% versus 1.1%.
• Funding: label held by AstraZeneca Pharmaceuticals LP.

In PLATO, serum uric acid levels increased approximately 0.6 mg/dL from baseline on BRILINTA 90 mg and approximately 0.2 mg/dL on clopidogrel. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group). In PEGASUS, serum uric acid levels increased approximately 0.2 mg/dL from baseline on BRILINTA 60 mg and no elevation was observed on aspirin alone. Gout occurred more commonly in patients on BRILINTA than in patients on aspirin alone (1.5%, 1.1%). Mean serum uric acid concentrations decreased after treatment was stopped.

More people on ticagrelor than on clopidogrel had a greater than 50% rise in serum creatinine in PLATO, although serious kidney events did not differ. (Source 27)

• Randomized trial, Moderate certainty.
• Size: PLATO 9235 vs 9186; PEGASUS 6958 vs 6996.
• Who: PLATO and PEGASUS trial populations.
• How long: up to 12 months (PLATO) and median 33 months (PEGASUS)
• Result: a more than 50% increase in serum creatinine in 7.4% on 90 mg versus 5.9% on clopidogrel in PLATO; in PEGASUS about 4% on 60 mg, similar to aspirin alone. Serious renal adverse events did not differ between PLATO groups.
• Funding: label held by AstraZeneca Pharmaceuticals LP.

In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving BRILINTA 90 mg compared to 5.9% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria.

Rare but serious harms reported after marketing include thrombotic thrombocytopenic purpura, angioedema and central sleep apnoea, with no reliable frequency. (Source 28)

• Case series, Very low certainty.
• Size: not quantifiable (spontaneous reports)
• Who: people taking ticagrelor after approval.
• How long: post-approval use; TTP reported after exposure of less than 2 weeks.
• Result: no rate can be estimated; the label states frequency cannot be reliably estimated from voluntary reports.
• Funding: label held by AstraZeneca Pharmaceuticals LP.

Thrombotic Thrombocytopenic Purpura (TTP) has been rarely reported with the use of BRILINTA. TTP is a serious condition which can occur after a brief exposure (<2 weeks) and requires prompt treatment. Immune system disorders: Hypersensitivity reactions including angioedema [see Contraindications (4.3)]. Respiratory Disorders: Central sleep apnea, Cheyne-Stokes respiration

In people aged 70 or over with non-ST-elevation acute coronary syndrome, clopidogrel caused less bleeding than ticagrelor and was non-inferior on net clinical benefit. (Source 21)

• Randomized trial, Moderate certainty.
• Size: 1002 patients (clopidogrel 500, ticagrelor or prasugrel 502; 95% of the latter received ticagrelor)
• Who: patients aged 70 years or older with non-ST-elevation acute coronary syndrome in 12 Dutch sites.
• How long: 12 months.
• Result: PLATO major or minor bleeding 88 (18%) on clopidogrel vs 118 (24%) on ticagrelor, hazard ratio 0·71 (95% CI 0·54 to 0·94; p=0·02 for superiority); net clinical benefit 139 (28%) vs 161 (32%), absolute risk difference -4% (95% CI -10·0 to 1·4; p=0·03 for non-inferiority against a pre-specified non-inferiority margin of 2 percentage points). Premature study-drug discontinuation 238/502 (47%) on ticagrelor vs 112/500 (22%) on clopidogrel.
• Funding: independent (funded by ZonMw, a Dutch public research funder); open-label design.

Limit of this finding: Three things in the source do not hold together. It reports "238 (47%) of 502 ticagrelor group patients randomly assigned to ticagrelor", but 502 is the whole ticagrelor-or-prasugrel arm, of whom 475 actually received ticagrelor, so that denominator is the combined arm rather than the ticagrelor group. The three reasons given for stopping (bleeding 38, breathlessness 40, oral anticoagulation 35) total 113, while 350 people stopped early across both arms, and the paper does not say which arm those 113 belong to - so they are the most frequent reasons, not a full accounting. And the non-inferiority p-value of 0.03 is only interpretable against the trial's pre-specified margin of 2 percentage points, which sits in the methods rather than in this passage. The trial was also open-label, so patients and doctors knew which drug they were on.

Primary bleeding outcome was significantly lower in the clopidogrel group (88 [18%] of 500 patients) than in the ticagrelor group (118 [24%] of 502; hazard ratio 0·71, 95% CI 0·54 to 0·94; p=0·02 for superiority). Co-primary net clinical benefit outcome was non-inferior for the use of clopidogrel (139 [28%]) versus ticagrelor (161 [32%]; absolute risk difference -4%, 95% CI -10·0 to 1·4; p=0·03 for non-inferiority).

In East Asian patients a meta-analysis found no significant ischaemic benefit from ticagrelor over clopidogrel but a significant excess of major bleeding. (Source 29)

• Meta-analysis, Low certainty.
• Size: three randomized controlled trials, 1552 patients.
• Who: East Asian patients (Japan, South Korea, China) with acute coronary syndrome.
• How long: as reported in the included trials.
• Result: primary efficacy composite odds ratio 0.84 (95% CI 0.43-1.63; p = 0.60); PLATO-defined major bleeding odds ratio 1.52 (95% CI 1.04-2.23; p = 0.03)
• Funding: not stated.

Limit of this finding: The efficacy odds ratio of 0.84 has a 95% interval from 0.43 to 1.63, drawn from only 1552 patients in three trials: that range runs from halving the risk to raising it by nearly two thirds, so 0.84 must not be read as a benefit. The review itself calls the difference "numerically lower, albeit statistically nonsignificant". The bleeding excess is the firmer of the two results.

Ticagrelor was associated with a numerically lower, albeit statistically nonsignificant, risk of primary efficacy endpoint defined as a composite of death from vascular causes, myocardial infarction, or stroke (odds ratio 0.84; 95% confidence interval 0.43-1.63; p = 0.60). Ticagrelor was associated with a significantly higher risk of PLATO-defined major bleeding compared to clopidogrel (odds ratio 1.52; 95% confidence interval 1.04-2.23; p = 0.03).

What the evidence supports

In acute coronary syndrome, ticagrelor reduced the composite of vascular death, myocardial infarction or stroke compared with clopidogrel over 12 months, and also reduced death from any cause. (Source 3)

• Randomized trial, High certainty.
• Size: 18,624 patients.
• Who: adults admitted with acute coronary syndrome, with or without ST-segment elevation, within 24 hours of symptoms, all on aspirin.
• How long: at least 6 and up to 12 months (median exposure 276 days)
• Result: primary composite 9.8% vs 11.7% (hazard ratio 0.84, 95% CI 0.77 to 0.92, P<0.001); absolute difference 1.9 percentage points, about 53 people treated for 12 months per event avoided (computed from the reported rates). Death from any cause 4.5% vs 5.9%. MI alone 5.8% vs 6.9% (P=0.005); vascular death 4.0% vs 5.1% (P=0.001).
• Funding: industry-funded (AstraZeneca sponsored PLATO)

At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001).

The label records the PLATO event rates per 1000 patient years with hazard ratios and p-values for each component, including all-cause mortality, and marks the component rows as counts of first events only. (Source 30)

• Official position, High certainty.
• Size: BRILINTA N=9333 vs clopidogrel N=9291.
• Who: PLATO acute coronary syndrome population.
• How long: up to 12 months.
• Result: composite of CV death, MI or stroke 111 vs 131 events per 1000 patient years, HR 0.84 (0.77, 0.92), p=0.0003; all-cause mortality 51 vs 65, HR 0.78 (0.69, 0.89), p=0.0003; stroke 16 vs 14, HR 1.17 (0.91, 1.52), p=0.22.
• Funding: label held by AstraZeneca Pharmaceuticals LP.

Limit of this finding: Two cautions about this table. First, the same components appear twice with different figures: CV death is 32 per 1000 patient years in the primary-endpoint block and 45 in the secondary-endpoint block, because the first counts only first events and the second counts all occurrences. They are not the same quantity and must not be compared or combined. Second, the label's own footnote says the component rates "do not add up to the overall rate of events in the composite endpoint", but in the primary-endpoint block they do add up exactly: 32 + 64 + 15 = 111 on ticagrelor and 43 + 76 + 12 = 131 on clopidogrel, matching the printed composite rates. The footnote only holds for the secondary-endpoint block (45 + 65 + 16 = 126 against a composite of 111). A reader should not conclude anything from adding or subtracting these rows.

Table 7 - Patients with outcome events (PLATO) BRILINTA* N=9333 Clopidogrel N=9291 Hazard Ratio (95% CI) p-value Events / 1000 patient years Events / 1000 patient years Composite of CV death, MI, or stroke 111 131 0.84 (0.77, 0.92) 0.0003 CV death 32 43 0.74 Non-fatal MI 64 76 0.84 Non-fatal stroke 15 12 1.24 Secondary endpoints† CV death 45 57 0.79 (0.69, 0.91) 0.0013 MI‡ 65 76 0.84 (0.75, 0.95) 0.0045 Stroke‡ 16 14 1.17 (0.91, 1.52) 0.22 All-cause mortality 51 65 0.78 (0.69, 0.89) 0.0003 * Dosed at 90 mg bid. † Note: rates of first events for the components CV Death, MI and Stroke are the actual rates for first events for each component and do not add up to the overall rate of events in the composite endpoint. ‡ Including patients who could have had other non-fatal events or died.

Ticagrelor continued 1 to 3 years after a myocardial infarction reduced cardiovascular death, MI or stroke, with an absolute 3-year reduction of about 1.2 percentage points. (Source 4)

• Randomized trial, High certainty.
• Size: 21,162 patients.
• Who: adults aged 50 or over with an MI 1 to 3 years earlier and at least one additional risk factor, all on low-dose aspirin.
• How long: median 33 months.
• Result: Kaplan-Meier rates at 3 years 7.85% (90 mg twice daily), 7.77% (60 mg twice daily) and 9.04% (placebo); HR 0.85 (95% CI 0.75 to 0.96, P=0.008) and 0.84 (0.74 to 0.95, P=0.004). TIMI major bleeding 2.60% and 2.30% versus 1.06% (P<0.001 for each)
• Funding: industry-funded (AstraZeneca)

Limit of this finding: The rates quoted are Kaplan-Meier estimates at 3 years from a trial whose median follow-up was 33 months, so they are modelled projections rather than counts of what was observed in everyone. The composite endpoint itself (cardiovascular death, myocardial infarction or stroke) is defined in the paper's methods, not in this passage. Benefit and harm must be read together: about 1.2 percentage points fewer events over 3 years against roughly 1.3 to 1.5 percentage points more TIMI major bleeding. The trial was funded by AstraZeneca, which makes ticagrelor.

The two ticagrelor doses each reduced, as compared with placebo, the rate of the primary efficacy end point, with Kaplan-Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (hazard ratio for 90 mg of ticagrelor vs. placebo, 0.85; 95% confidence interval [CI], 0.75 to 0.96; P=0.008; hazard ratio for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI, 0.74 to 0.95; P=0.004). Rates of TIMI major bleeding were higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P<0.001 for each dose vs. placebo); the rates of intracranial hemorrhage or fatal bleeding in the three groups were 0.63%, 0.71%, and 0.60%, respectively.

PLATO reduced stent thrombosis in people who received a stent. (Source 31)

• Randomized trial, Moderate certainty.
• Size: 11,289 patients with PCI receiving any stent during PLATO.
• Who: stented PLATO participants.
• How long: up to 12 months.
• Result: adjudicated definite stent thrombosis 1.3% vs 1.9% (HR 0.67, 95% CI 0.50-0.91; p=0.009); absolute difference 0.6 percentage points.
• Funding: label held by AstraZeneca Pharmaceuticals LP; figures from the AstraZeneca-sponsored PLATO trial.

Among 11,289 patients with PCI receiving any stent during PLATO, there was a lower risk of stent thrombosis (1.3% for adjudicated “definite”) than with clopidogrel (1.9%) (HR 0.67, 95% CI 0.50-0.91; p=0.009). The results were similar for drug-eluting and bare metal stents.

The label records the absolute risk reduction for long-term ticagrelor after myocardial infarction as just over 1 percentage point. (Source 32)

• Official position, High certainty.
• Size: PEGASUS-TIMI 54, 21,162 patients.
• Who: people with a history of myocardial infarction 1 to 3 years earlier.
• How long: at least 12 and up to 48 months, median 33 months.
• Result: absolute risk reductions versus aspirin alone of 1.27% for the 60 mg regimen and 1.19% for the 90 mg regimen; the lower dose had lower risks of bleeding and dyspnoea.
• Funding: label held by AstraZeneca Pharmaceuticals LP.

The absolute risk reductions for BRILINTA plus aspirin vs. aspirin alone were 1.27% and 1.19% for the 60 and 90 mg regimens, respectively. Although the efficacy profiles of the two regimens were similar, the lower dose had lower risks of bleeding and dyspnea.

What the evidence does not support

Ticagrelor monotherapy was not superior to aspirin after acute stroke or TIA; the primary endpoint was missed. (Source 7)

• Randomized trial, High certainty.
• Size: 13,199 patients.
• Who: adults with non-severe ischaemic stroke or high-risk TIA within 24 hours, no thrombolysis, not cardioembolic.
• How long: 90 days.
• Result: stroke, MI or death 442/6589 (6.7%) vs 497/6610 (7.5%); HR 0.89, 95% CI 0.78 to 1.01, P=0.07. Major bleeding 0.5% vs 0.6%; intracranial haemorrhage 0.2% vs 0.3%.
• Funding: industry-funded (AstraZeneca)

During the 90 days of treatment, a primary end-point event occurred in 442 of the 6589 patients (6.7%) treated with ticagrelor, versus 497 of the 6610 patients (7.5%) treated with aspirin (hazard ratio, 0.89; 95% confidence interval [CI], 0.78 to 1.01; P=0.07). Ischemic stroke occurred in 385 patients (5.8%) treated with ticagrelor and in 441 patients (6.7%) treated with aspirin (hazard ratio, 0.87; 95% CI, 0.76 to 1.00). Major bleeding occurred in 0.5% of patients treated with ticagrelor and in 0.6% of patients treated with aspirin, intracranial hemorrhage in 0.2% and 0.3%, respectively, and fatal bleeding in 0.1% and 0.1%.

In symptomatic peripheral artery disease ticagrelor was no better than clopidogrel on cardiovascular events or limb events. (Source 8)

• Randomized trial, High certainty.
• Size: 13,885 patients.
• Who: adults with symptomatic peripheral artery disease (ankle-brachial index 0.80 or less, or previous lower-limb revascularisation)
• How long: median 30 months.
• Result: cardiovascular death, MI or ischaemic stroke 751/6930 (10.8%) vs 740/6955 (10.6%); HR 1.02, 95% CI 0.92 to 1.13, P=0.65. Acute limb ischaemia 1.7% in each group; major bleeding 1.6% in each group.
• Funding: industry-funded (AstraZeneca)

The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49).

A phase 3 trial of ticagrelor in children with sickle cell disease was terminated early for lack of efficacy. (Source 9)

• Randomized trial, Moderate certainty.
• Size: 193 patients (ticagrelor 101, placebo 92)
• Who: children aged 2 to 17 with sickle cell disease, at 53 sites in 16 countries.
• How long: median ticagrelor exposure 296.5 days.
• Result: estimated yearly vaso-occlusive crises 2.74 vs 2.60; rate ratio 1.06, 95% CI 0.75 to 1.50, P = .7597. Bleeding events in 9 patients (9%) on ticagrelor and 8 (9%) on placebo.
• Funding: industry-funded (AstraZeneca-sponsored trial programme)

Limit of this finding: This was a futility stop: the trial was halted 4 months early for lack of efficacy, so the confidence interval is wider than planned and this is not a completed negative trial. The composite primary endpoint (painful crises and/or acute chest syndrome) and the 1:1 randomisation of children aged 2 to 17 are described in the part of the abstract before this passage. Bleeding was no commoner on ticagrelor than on placebo (9% in each group).

The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary end point was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio, 1.06; 95% confidence interval, 0.75-1.50; P = .7597). There was no evidence of efficacy for ticagrelor vs placebo across secondary end points. Median platelet inhibition with ticagrelor at 6 months was 34.9% predose and 55.7% at 2 hours' postdose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event.

Where the evidence is mixed

In stable coronary disease with type 2 diabetes, adding ticagrelor to aspirin produced a small reduction in ischaemic events but more than doubled major bleeding, and a composite of irreversible harm showed no difference. (Source 5)

• Randomized trial, High certainty.
• Size: 19,220 patients.
• Who: adults aged 50 or over with stable coronary artery disease and type 2 diabetes, no previous MI or stroke.
• How long: median follow-up 39.9 months.
• Result: primary ischaemic composite 7.7% vs 8.5% (HR 0.90, 95% CI 0.81 to 0.99, P=0.04); TIMI major bleeding 2.2% vs 1.0% (HR 2.32, 95% CI 1.82 to 2.94, P<0.001); intracranial haemorrhage 0.7% vs 0.5% (HR 1.71, 1.18 to 2.48, P=0.005); irreversible harm composite 10.1% vs 10.8% (HR 0.93, 0.86 to 1.02). Permanent treatment discontinuation 34.5% vs 25.4%.
• Funding: industry-funded (AstraZeneca)

The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02).

For 30 days after a minor ischaemic stroke or high-risk TIA, ticagrelor added to aspirin reduced stroke or death but did not reduce disability, and severe bleeding rose fivefold. (Source 6)

• Randomized trial, High certainty.
• Size: 11,016 patients.
• Who: adults with mild-to-moderate non-cardioembolic acute ischaemic stroke (NIHSS 5 or less) or TIA, not given thrombolysis or thrombectomy.
• How long: 30 days.
• Result: stroke or death 5.5% vs 6.6% (HR 0.83, 95% CI 0.71 to 0.96, P=0.02); ischaemic stroke 5.0% vs 6.3% (HR 0.79, 0.68 to 0.93, P=0.004); severe bleeding 28 patients (0.5%) vs 7 (0.1%), P=0.001; disability did not differ.
• Funding: industry-funded (AstraZeneca)

A primary-outcome event occurred in 303 patients (5.5%) in the ticagrelor-aspirin group and in 362 patients (6.6%) in the aspirin group (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P = 0.02). Ischemic stroke occurred in 276 patients (5.0%) in the ticagrelor-aspirin group and in 345 patients (6.3%) in the aspirin group (hazard ratio, 0.79; 95% CI, 0.68 to 0.93; P = 0.004). The incidence of disability did not differ significantly between the two groups. Severe bleeding occurred in 28 patients (0.5%) in the ticagrelor-aspirin group and in 7 patients (0.1%) in the aspirin group (P = 0.001).

A network meta-analysis of 12 trials found ticagrelor reduced mortality versus clopidogrel but did not reduce myocardial infarction, and increased major bleeding. (Source 33)

• Meta-analysis, Moderate certainty.
• Size: 52 816 patients from 12 randomized trials.
• Who: patients with acute coronary syndrome.
• How long: trial follow-up periods as reported in the included trials.
• Result: versus clopidogrel: cardiovascular mortality HR 0.82 (95% CI, 0.72-0.92), all-cause mortality HR 0.83 (0.75-0.92), myocardial infarction HR 0.97 (0.78-1.22), major bleeding HR 1.27 (1.04-1.55)
• Funding: Research Support, N.I.H., Extramural (per the PubMed record)

Limit of this finding: The stent-thrombosis result is given only as a range of reduction, 28% to 50%, with no point estimate, no confidence interval, and no statement of which drug sits at which end, so it cannot be reported per drug. The sample size of 52,816 comes from the paper's methods section rather than this results passage. In the source that figure is printed with a thin space (52 816), and on any screen it should read 52,816.

In comparison with clopidogrel, ticagrelor significantly reduced cardiovascular mortality (hazard ratio [HR], 0.82 [95% CI, 0.72-0.92]) and all-cause mortality (HR, 0.83 [95% CI, 0.75-0.92]), whereas there was no statistically significant mortality reduction with prasugrel (HR, 0.90 [95% CI, 0.80-1.01] and HR, 0.92 [95% CI, 0.84-1.02], respectively). In comparison with each other, there were no significant differences in mortality (HR prasugrel versus ticagrelor, 1.10 [95% CI, 0.94-1.29] and 1.12 [95% CI, 0.98-1.28]). In comparison with clopidogrel, prasugrel reduced myocardial infarction (HR, 0.81 [95% CI, 0.67-0.98]), whereas ticagrelor showed no risk reduction (HR, 0.97 [95% CI, 0.78-1.22]).

PLATO's benefit was not seen in the North American subset, a difference the label calls statistically significant and treats cautiously. (Source 34)

• Randomized trial, Low certainty.
• Size: subgroup analysis within the 18,624-patient PLATO trial.
• Who: US and Canadian participants versus the rest of the world.
• How long: up to 12 months.
• Result: the North American result was numerically inferior to clopidogrel and driven by the US subset; the US/non-US interaction test gave p=0.009, with the same trend for CV death and non-fatal MI.
• Funding: label held by AstraZeneca Pharmaceuticals LP.

Limit of this finding: This is a subgroup finding. The label itself says such nominal p-values need cautious interpretation and could represent chance, while also saying the consistency across components supports the possibility that it is real. A reader should not conclude either that the drug does not work in the US or that the regional difference is established.

Results in the rest of the world compared to effects in North America (US and Canada) show a smaller effect in North America, numerically inferior to the control and driven by the US subset. The statistical test for the US/non-US comparison is statistically significant (p=0.009), and the same trend is present for both CV death and non-fatal MI. The individual results and nominal p-values, like all subset analyses, need cautious interpretation, and they could represent chance findings. The consistency of the differences in both the CV mortality and non-fatal MI components, however, supports the possibility that the finding is reliable.

For 30 days after a minor stroke or high-risk TIA, the label's own table puts stroke at 5.1% on ticagrelor plus aspirin against 6.3% on aspirin alone, and deaths at 0.6% against 0.5%. (Source 35)

• Official position, High certainty.
• Size: BRILINTA N=5523 vs placebo N=5493, both on aspirin.
• Who: THALES: acute non-cardioembolic ischaemic stroke with NIHSS 5 or less, or high-risk TIA.
• How long: 30 days.
• Result: stroke or death 303 (5.4%) vs 362 (6.5%), HR 0.83 (0.71, 0.96), p=0.015; stroke alone 284 (5.1%) vs 347 (6.3%), HR 0.81 (0.69, 0.95); death 36 (0.6%) vs 27 (0.5%), HR 1.33 (0.81, 2.19); ischaemic stroke 276 (5.0%) vs 345 (6.2%), HR 0.79 (0.68, 0.93), p=0.004. Percentages are Kaplan-Meier estimates at 30 days.
• Funding: label held by AstraZeneca Pharmaceuticals LP; figures from the AstraZeneca-sponsored THALES trial.

Limit of this finding: Two defects in the label itself. Its prose gives the stroke component an absolute risk reduction of 1.1 percentage points, but the rates printed in the same table, 5.1% and 6.3%, differ by 1.2 points; the 1.1 figure fits the combined stroke-or-death endpoint (6.5% minus 5.4%), not the stroke component. The difference is almost certainly rounding, but the printed numbers do not reconcile, so a reader should take the rates rather than the stated reduction. Separately, the table's second header row is malformed in both the label's XML and the DailyMed page - it carries six cells for a seven-column table, with an empty cell that pushes the placebo "KM%" label under the hazard-ratio column - so the column headings in this block cannot be trusted to line up with the numbers beneath them. The death row also moved the wrong way (36 vs 27), with a confidence interval spanning no difference.

Table 10 - Incidences of the primary composite endpoint, primary composite endpoint components, and secondary endpoint (THALES) BRILINTA N=5523 Placebo N=5493 HR (95% CI) p-value n (patients with event) KM% n (patients with event) KM% Time to first Stroke or Death 303 5.4% 362 6.5% 0.83 (0.71, 0.96) 0.015 Time to first Stroke* 284 5.1% 347 6.3% 0.81 (0.69, 0.95) Time to Death* 36 0.6% 27 0.5% 1.33 (0.81, 2.19) Secondary Endpoint Time to first Ischemic Stroke 276 5.0% 345 6.2% 0.79 (0.68, 0.93) 0.004 CI = Confidence interval; HR = Hazard ratio; KM = Kaplan-Meier percentage calculated at 30 days; N = Number of patients * The number of patients with the event of interest. In the time to first stroke, patients who died are censored at the time of death.

Where the research disagrees

Whether ticagrelor's net benefit over clopidogrel in acute coronary syndrome holds in East Asian patients

• Wallentin and the PLATO investigators (global trial), randomised controlled trial in 18,624 patients, predominantly male and 92% Caucasian: In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. (Source 36)
• Goto and the PHILO investigators (Japan, Taiwan, South Korea), randomised double-blind phase III trial in 801 patients; the authors themselves attribute the direction to small sample size and imbalance: In ACS patients from Japan, Taiwan and South Korea, event rates of primary safety and efficacy endpoints were higher, albeit not significantly, in ticagrelor-treated patients compared with clopidogrel-treated patients. This observation could be explained by the small sample size, imbalance in clinical characteristics and low number of events in the PHILO population. (Source 37)
• Misumida and colleagues (meta-analysis of East Asian trials), systematic review and meta-analysis of three randomised trials, 1552 East Asian patients: Ticagrelor was associated with a significantly higher risk of PLATO-defined major bleeding compared to clopidogrel (odds ratio 1.52; 95% confidence interval 1.04-2.23; p = 0.03). (Source 29)

Whether the boxed warning text differs between the brand and the generics (each wording below is quoted only from the label that prints it)

• AstraZeneca (BRILINTA SPL, effective 2026-05-07, version 56), FDA-approved labelling for the brand product: • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding (5.1, 6.1). • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage • (4.1, 4.2). • Do not start BRILINTA in patients undergoing urgent coronary artery bypass graft surgery (CABG) (5.1, • 6.1). • If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of • subsequent cardiovascular events (5.2). (Source 2)
• Teva Pharmaceuticals (ticagrelor SPL, effective 2026-08-27, version 4), FDA-approved labelling for a generic product: Ticagrelor, like other antiplatelet agents, can cause significant, sometimes fatal bleeding (5.1, 6.1). Do not use ticagrelor in patients with active pathological bleeding or a history of intracranial hemorrhage (4.1, 4.2). Do not start ticagrelor in patients undergoing urgent coronary artery bypass graft surgery (CABG) (5.1, 6.1). If possible, manage bleeding without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent cardiovascular events (5.2). (Source 38)
• Apotex Corp. (ticagrelor SPL, effective 2026-06-05, version 3), FDA-approved labelling for a generic product: Ticagrelor tablets, like other antiplatelet agents, can cause significant, sometimes fatal bleeding (5.1, 6.1). Do not use ticagrelor tablets in patients with active pathological bleeding or a history of intracranial hemorrhage (4.1, 4.2). Do not start ticagrelor tablets in patients undergoing urgent coronary artery bypass graft surgery (CABG) (5.1, 6.1). If possible, manage bleeding without discontinuing ticagrelor tablets. Stopping ticagrelor tablets increases the risk of subsequent cardiovascular events (5.2). (Source 39)

Whether ticagrelor is worth adding to aspirin in stable coronary disease with diabetes

• The FDA label (a regulatory position dated 2026-05-07), regulatory position based on the THEMIS trial: BRILINTA was superior to placebo in reducing the incidence of CV death, MI, or stroke. The effect on the composite endpoint was driven by the individual components MI and stroke; see Table 9. (Source 40)
• Steg and the THEMIS investigators, randomised controlled trial in 19,220 patients; prespecified primary endpoint met at P = 0.04, exploratory irreversible-harm composite not different: The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02). (Source 5)

How much

• Reference intake: Dosing is set by the prescriber, not by the reader. As a regulatory position, the US label (AstraZeneca SPL, effective 2026-05-07) states for acute coronary syndrome or a history of MI that treatment is initiated with a 180 mg loading dose, that the first 90 mg maintenance dose is given 6 to 12 hours after it, that 90 mg twice daily is given during the first year after an ACS event and 60 mg twice daily after one year, and that it is started with a daily maintenance dose of aspirin of 75 mg to 100 mg. (Source 41)
• Upper limit: There is no reference intake or tolerable upper intake for a prescription antiplatelet drug. The label's general instructions set no maximum daily amount; their only ceiling-type statements are that it must not be administered with another oral P2Y12 platelet inhibitor and that aspirin at doses higher than recommended should be avoided. The strengths and the doses themselves are in the dosing statement. (Source 42)
• Studied: PLATO gave all patients randomised to ticagrelor a 180 mg loading dose followed by 90 mg twice daily, with aspirin 75-100 mg daily recommended, for at least 6 and up to 12 months. (Source 43)
• Studied: PEGASUS-TIMI 54 randomised 21,162 patients who had had a myocardial infarction 1 to 3 years earlier to 90 mg twice daily, 60 mg twice daily or placebo, all of them on low-dose aspirin, and followed them for a median of 33 months. (Source 44)
• Studied: THALES gave a 30-day regimen of ticagrelor, a 180-mg loading dose followed by 90 mg twice daily, on a background of aspirin 300 to 325 mg on the first day followed by 75 to 100 mg daily, started within 24 hours after symptom onset. (Source 45)

A common belief, and what the research shows

The belief: Ticagrelor is simply a better clopidogrel, so everyone with heart disease should be on it.

What the research shows: The advantage is population-specific. PLATO showed a real mortality benefit in acute coronary syndrome, but a network meta-analysis found no reduction in myocardial infarction versus clopidogrel and a clear bleeding excess: "In comparison with clopidogrel, both prasugrel (HR, 1.26 [95% CI, 1.01-1.56]) and ticagrelor (HR, 1.27 [95% CI, 1.04-1.55]) significantly increased major bleeding." In people aged 70 and over, the POPular AGE trial found the opposite ordering: "Primary bleeding outcome was significantly lower in the clopidogrel group (88 [18%] of 500 patients) than in the ticagrelor group (118 [24%] of 502; hazard ratio 0·71, 95% CI 0·54 to 0·94; p=0·02 for superiority)." In peripheral artery disease it was not better than clopidogrel at all.

Questions and answers

What is it?

Ticagrelor is a prescription antiplatelet tablet, sold as Brilinta and as generics. It is not a blood thinner in the anticoagulant sense; it stops platelets sticking together. It works on the platelet P2Y12 receptor, and unlike clopidogrel it binds reversibly and is active without being converted by the liver. Its major metabolite is roughly as potent as the drug itself. (Source 1)

What does it do in the body?

By blocking the P2Y12 receptor it prevents the signal that activates platelets, so platelets clump less and arterial clots form less easily. In a head-to-head pharmacodynamic study, platelet inhibition on ticagrelor was higher than on clopidogrel at every time point and peaked around two hours. The label is explicit that it is not known how bleeding or clotting risk tracks with the degree of platelet inhibition. (Source 20)

Is it good or bad for you?

It depends entirely on the setting. After an acute coronary syndrome the trial evidence is strong: fewer deaths, heart attacks and strokes than clopidogrel over a year. In stable coronary disease with diabetes the gain was small and bleeding more than doubled. In peripheral artery disease, as a single drug after stroke, and in childhood sickle cell disease it did not work. In people aged 70 and over, clopidogrel bled less and was no worse overall. (Source 5)

How do you get more of it?

This question does not apply in the usual sense: ticagrelor is a manufactured prescription drug, not a nutrient, and there is no food or behaviour that supplies it. Dosing is a prescriber decision. One documented way blood levels rise is unintended: grapefruit juice raised exposure to about 2.2 times control in 10 healthy volunteers, and strong CYP3A inhibitors do the same, which the label treats as a hazard rather than a benefit. The study's own conclusion phrases this as an increase of "more than two-fold", which reads as more than the numbers show. (Source 46)

If it is harmful, what reduces it?

There is no antidote. The label states there is no known treatment to reverse the drug and that it cannot be removed by dialysis, and that platelet transfusion did not reverse its antiplatelet effect in healthy volunteers. The effect fades on its own: platelet inhibition was back to placebo levels five days after the last dose. (Source 47)

Why might someone be low in it or missing it?

People end up without ticagrelor mostly because they stop it or are never given it. Trials show high discontinuation: 34.5% permanently stopped in THEMIS, and 47% stopped early in POPular AGE, chiefly for bleeding, breathlessness or a new need for an anticoagulant. The label also contraindicates it after an intracranial haemorrhage or with active bleeding, and strong CYP3A inducers cut its blood levels. (Source 21)

Which whole foods contain it or feed it?

No whole food contains ticagrelor; it is a synthetic drug. Food matters only as interaction. Grapefruit juice raised its blood levels more than twofold in a crossover study in healthy volunteers, and the label records that the tablets can be crushed and mixed with water for people who cannot swallow them. Nothing in the sources read describes a diet that supplies or substitutes for the drug. (Source 42)

What happens if you do not have it?

For someone with the conditions it is approved for, not taking it or stopping it raises the risk of a heart attack, stroke or death. The label states this directly, and the boxed warning repeats it. In untreated terms, the PLATO comparator arm gives the scale: 11.7% had a vascular death, heart attack or stroke within 12 months on clopidogrel versus 9.8% on ticagrelor. (Source 19)

How can you test for it?

There is no routine blood test used to monitor ticagrelor. Platelet aggregation can be measured in research settings, but the label says it is not known how bleeding or clotting risk relates to the degree of inhibition, so the measurement does not guide treatment. One testing problem is documented: ticagrelor can make functional tests for heparin-induced thrombocytopenia come back falsely negative, though it is not expected to affect PF4 antibody testing. (Source 18)

References

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3. The New England journal of medicine. Ticagrelor versus clopidogrel in patients with acute coronary syndromes.. 2009. PMID 19717846, DOI 10.1056/NEJMoa0904327. Read the source
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9. Blood. Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study.. 2022. PMID 35849650, DOI 10.1182/blood.2021014095. Read the source
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11. AstraZeneca Pharmaceuticals LP (DailyMed SPL). BRILINTA (ticagrelor) tablet, film coated - prescribing information - 7.1 Strong CYP3A Inhibitors. 2026. Read the source
12. AstraZeneca Pharmaceuticals LP (DailyMed SPL). BRILINTA (ticagrelor) tablet, film coated - prescribing information - 7.2 Strong CYP3A Inducers. 2026. Read the source
13. AstraZeneca Pharmaceuticals LP (DailyMed SPL). BRILINTA (ticagrelor) tablet, film coated - prescribing information - 7.4 Simvastatin, Lovastatin, Rosuvastatin. 2026. Read the source
14. British journal of clinical pharmacology. Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects.. 2013. PMID 23126367, DOI 10.1111/bcp.12026. Read the source
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