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| __NOTOC__
| | #REDIRECT [[Ticagrelor#Clinical Studies]] |
| {{Ticagrelor}}
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| {{CMG}}; {{AE}} {{JH}}
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| ==Indications and Usage==
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| ===Clinical Studies===
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| The clinical evidence for the effectiveness of BRILINTA is derived from PLATO, a randomized double-blind study comparing BRILINTA (N=9333) to clopidogrel (N=9291), both given in combination with aspirin and other standard therapy, in patients with acute coronary syndromes (ACS). Patients were treated for at least 6 months and for up to 12 months. Study endpoints were obtained until the study was complete, even if drug was discontinued.
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| Patients who presented within 24 hours of onset of the most recent episode of chest pain or symptoms were randomized to receive BRILINTA or clopidogrel. Patients who had already been treated with clopidogrel could be enrolled and randomized to either study treatment. Patients could be included whether there was intent to manage the ACS medically or invasively, but patient randomization was not stratified by this intent. Subjects in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if previous clopidogrel therapy had not been given prior to randomization. Patients undergoing PCI could receive an additional 300 mg of clopidogrel at investigator discretion. All subjects randomized to BRILINTA received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. Concomitant aspirin was recommended at a loading dose of 160-500 mg. A daily maintenance dose of aspirin 75-100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local judgment.
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| Because of ticagrelor’s metabolism by CYP3A enzymes, the protocol recommended limiting the maximum dosage of simvastatin and lovastatin to 40 mg in both study arms. Because of an increased bleeding risk, the study excluded patients with previous intracranial hemorrhage, a gastrointestinal bleed within the past 6 months, or other factors that predispose to bleeding.
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| PLATO patients were predominantly male (72%) and Caucasian (92%). About 43% of patients were >65 years and 15% were >75 years.
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| The study’s primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke. The components were assessed as secondary endpoints.
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| Median exposure to study drug was 277 days. About half of the patients received pre-study clopidogrel and about 99% of the patients received aspirin at some time during PLATO. About 35% of patients were receiving a statin at baseline and 93% received a statin sometime during PLATO.
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| Table 4 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. Separate secondary endpoint analyses are shown for the overall occurrence of CV death, MI, and stroke and overall mortality.
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| **************
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| The difference between treatments on the composite resulted from effects on CV death and MI; each was statistically significant when considered as a secondary endpoint and there was no beneficial effect on strokes. For all-cause mortality the benefit was also statistically significant (p = 0.0003) with a hazard ratio of 0.78.
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| Among 11289 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=0.0091). The results were similar for drug-eluting and bare metal stents.
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| The Kaplan-Meier curve (Figure 7) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke in the overall study.
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| Figure 7 - Time to First Occurrence of CV death, MI, or Stroke in PLATO
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| ************************
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| The curves separate by 30 days (RRR 12%) and continue to diverge throughout the 12 month treatment period (RRR 16%).
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| A wide range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcome. Many of these are shown in Figure 8. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Most of the analyses show effects consistent with the overall results, but there are two marked exceptions: a finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin. These are considered further below.
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| Most of the characteristics shown are baseline characteristics, but some reflect post-randomization determinations (e.g., final diagnosis, aspirin maintenance dose, use of PCI). Patients were not stratified by initial diagnosis, but the effect in the unstable angina subset (determined after randomization) appeared smaller than the effect in the NSTEMI and STEMI subsets. The results in the subsets based on final diagnosis (STEMI, NSTEMI and unstable angina) are also presented in Figure 8.
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| Figure 8 - Subgroup analyses of PLATO
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| ******************************
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| Regional Differences
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| 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.
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| A wide variety of baseline and procedural differences between the US and non-US (including intended invasive vs. planned medical management, use of GPIIb/IIIa inhibitors, use of drug eluting vs. bare-metal stents) were examined to see if they could account for regional differences, but with one exception, aspirin maintenance dose, these differences did not appear to lead to differences in outcome.
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| Aspirin Dose
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| The PLATO protocol left the choice of aspirin maintenance dose up to the investigator and use patterns were very different in the US and elsewhere, with about 8% of non-US investigators using aspirin doses above 100 mg, and about 2% using doses above 300 mg, in contrast with US practice, where 57% of patients received doses above 100 mg and 54% received doses above 300 mg. Overall results favored BRILINTA when used with low maintenance doses (≤ 100 mg) of aspirin, and results analyzed by aspirin dose were similar in the US and elsewhere. Figure 8 shows overall results by median aspirin dose. Table 5 shows results by region and dose.
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| Table 5 - PLATO: CV Death, MI, Stroke by maintenance aspirin dose in the US and outside the US
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| *************************
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| Like any unplanned subset analysis, especially one where the characteristic is not a true baseline characteristic (but may be determined by usual investigator practice), the above analyses must be treated with caution. It is notable, however, that aspirin dose predicts outcome in both regions with a similar pattern, and that the pattern is similar for the two major components of the primary endpoint, CV death and non-fatal MI.
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| Despite the need to treat such results cautiously, there appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. Higher doses do not have an established benefit in the ACS setting, and there is a strong suggestion that use of such doses reduces the effectiveness of BRILINTA.
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| <u>Pharmacogenetics</u>
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| In a genetic substudy of PLATO (n=10,285), the effects of BRILINTA compared to clopidogrel on thrombotic events and bleeding were not significantly affected by CYP2C19 genotype.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = BRILINTA (TICAGRELOR) TABLET [ASTRAZENECA LP] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f7b3f443-e83d-4bf2-0e96-023448fed9a8 | publisher = | date = | accessdate = 26 February 2014 }}</ref>
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| ==References==
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| <ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = BRILINTA (TICAGRELOR) TABLET [ASTRAZENECA LP] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f7b3f443-e83d-4bf2-0e96-023448fed9a8 | publisher = |date = | accessdate = 26 February 2014 }}</ref>
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| {{Reflist|2}}
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| {{Antithrombotics}}
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| [[Category:ADP receptor inhibitors]]
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| [[Category:Triazolopyrimidines]]
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| [[Category:Organofluorides]]
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| [[Category:Alcohols]]
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| [[Category:AstraZeneca]]
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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