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Published on : Jan 09, 2020 | Views : 2391 | Downloads : 13

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Presented by - Dr. Harshal Pamecha Resident in cardiology CMCH Journal club
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The study of PLATelet inhibition and patient Outcomes (PLATO) Trial
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Background.. Direct acting Not a prodrug; does not require metabolic activation Rapid onset of inhibitory effect on the P2Y12 receptor Greater inhibition of platelet aggregation than clopidogrel Reversibly bound Degree of inhibition reflects plasma concentration Faster offset of effect than clopidogrel Functional recovery of all circulating platelets TICAGRELOR (AZD 6140): AN ORAL REVERSIBLE P2Y12 ANTAGONIST
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Background.. In STEMI and UA/NSTEMI, current guidelines recommend 12 months of aspirin and clopidogrel Efficacy of clopidogrel is hampered by slow and variable transformation to the active metabolite (e.g. 2C19) modest and variable platelet inhibition risk stent thrombosis and MI in poor responders Irreversible effect – and increased risk of bleeding if urgent CABG is required
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Background...
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Plato - a global trial PLATO was a multicenter, randomized, double blind trial. from 862 centers in 43 countries from October 2006 through July 2008. The follow-up period ended in February 2009
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PLATO inclusion criteria Hospitalisation for STEMI or NSTEMI ACS, with onset during the previous 24 hours With STEMI, the following two inclusion criteria were required Persistent STEMI or new LBBB Primary PCI planned With NSTEMI ACS, at least two of the following three were required ST-segment changes on ECG indicating ischaemia Positive biomarker indicating myocardial necrosis One of the following risk indicators ≥60 years of age Previous MI or CABG CAD with ≥50% stenosis in ≥2 vessels Previous ischaemic stroke, TIA, carotid stenosis (≥50%) Diabetes mellitus Peripheral artery disease Chronic renal dysfunction (creatinine clearance <60 mL/min)
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PLATO exclusion criteria Any contraindication against the use of clopidogrel, fibrinolytic therapy within 24 hours before randomization, A need for oral anticoagulation therapy, An increased risk of Bradycardia, Concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer.
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PLATO – STUDY DESIGN NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) 6–12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding
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PLATO Study treatment In patients undergoing CABG, it was recommended that the study drug be withheld — in the clopidogrel group, for 5 days, and in the ticagrelor group, for 24 to 72 hours. All patients received acetylsalicylic acid (aspirin) at a dose of 75 to 100 mg daily. For those who had not previously been receiving aspirin, 325 mg was the preferred loading dose; 325 mg was also permitted as the daily dose for 6 months after stent placement. Outpatient visits were scheduled at 1, 3, 6, 9, and 12 months with a safety follow-up visit 1 month after the end of treatment. Initially, patients were to be assessed by means of Holter monitoring for 7 days after randomization, until a repeat assessment at 1 month had been obtained for 2000 of the enrolled patients.
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PLATO END POINTS Death from vascular causes was defined as death from cardiovascular causes or cerebrovascular causes and any death without another known cause. We defined major life-threatening bleeding as fatal bleeding, intracranial bleeding, intrapericardial bleeding with cardiac tamponade, hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery, a decline in the hemoglobin level of 5.0 g per deciliter or more, or the need for transfusion of at least 4 units of red cells. We defined other major bleeding as bleeding that led to clinically significant disability (e.g., intraocular bleeding with permanent vision loss) or bleeding either associated with a drop in the hemoglobin level of at least 3.0 g per deciliter but less than 5.0 g per deciliter or requiring transfusion of 2 to 3 units of red cells. We defined minor bleeding as any bleeding requiring medical intervention but not meeting the criteria for major bleeding.
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RESULTS The two treatment groups were well balanced with regard to all baseline characteristics (Table 1) and non study medications and procedures (Table 2). Both groups started the study drug at a median of 11.3 hours (interquartile range, 4.8 to 19.8) after the start of chest pain. In the clopidogrel group, 79.1% of patients received at least 300 mg, and 19.6% at least 600 mg, of clopidogrel between the time of the index event and up to 24 hours after randomization. Premature discontinuation of the study drug was slightly more common in the ticagrelor group than in the clopidogrel group (in 23.4% of patients vs. 21.5%). The overall rate of adherence to the study drug, was 82.8%, and the median duration of exposure to the study drug was 277 days.
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Table 1
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Table 1
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Table 1
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Table 2
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Table 2
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Table 2
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efficacy The primary end point occurred significantly less often in the ticagrelor group than in the clopidogrel group (in 9.8% of patients vs. 11.7% at 12 months; P<0.001 T(able 3 and Fig. 1). The difference in treatment effect was apparent within the first 30 days of therapy and persisted throughout the study period. the composite end point of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events (14.6% vs. 16.7%, P<0.001); Myocardial infarction alone (5.8% vs. 6.9%, P = 0.005); and death due to vascular causes (4.0% vs. 5.1%, P = 0.001). reduction in the rate of death from any cause with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001).
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efficacy The rate of stroke did not differ significantly between the two treatment groups, although there were more hemorrhagic strokes with ticagrelor than with clopidogrel (23 [0.2%] vs. 13 [0.1%], nominal P = 0.10). Among patients who received a stent during the study, the rate of definite stent thrombosis was lower in the ticagrelor group than in the clopidogrel group (1.3% vs. 1.9%, P = 0.009). The results regarding the primary end point did not show significant heterogeneity in three exceptions. The benefit of ticagrelor appeared to be attenuated in patients weighing less than the median weight for their sex (P = 0.04 for the interaction), those not taking lipid-lowering drugs at randomization (P = 0.04 for the interaction), and those enrolled in North America (P = 0.045 for the interaction).
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Table 3
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Table 3
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Fig 1
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Fig 2 The ticagrelor and clopidogrel groups did not differ significantly with regard to the rates of major bleeding as defined in the trial (11.6% and 11.2%, respectively; P = 0.43) (Fig. 2 and Table 4). BLEEDING
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bleeding There was also no significant difference in the rates of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) criteria (7.9% with ticagrelor and 7.7% with clopidogrel, P = 0.57) or fatal or life-threatening bleeding (5.8% in both groups, P = 0.70). The two treatment groups did not differ significantly in the rates of CABG-related major bleeding or bleeding requiring transfusion of red cells. However, in the ticagrelor group, there was a higher rate of non–CABG-related major bleeding according to the study criteria (4.5% vs. 3.8%, P = 0.03) and the TIMI criteria (2.8% vs. 2.2%, P = 0.03) (Fig. 3) With ticagrelor as compared with clopidogrel, there were more episodes of intracranial bleeding (26 [0.3%] vs. 14 [0.2%], P = 0.06), including fatal intracranial bleeding (11 [0.1%] vs. 1 [0.01%], P = 0.02).
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Other adverse events Dyspnea was more common in the ticagrelor group than in the clopidogrel group (in 13.8% of patients vs. 7.8%) (Table 4). Few patients discontinued the study drug because of dyspnea (0.9% of patients in the ticagrelor group and 0.1% in the clopidogrel group). Holter monitoring was performed for a median of 6 days during the first week in 2866 patients and was repeated at 30 days in 1991 patients. There was a higher incidence of ventricular pauses in the first week, but not at day 30, in the ticagrelor group than in the clopidogrel group (Table 4). Pauses were rarely associated with symptoms; the two treatment groups did not differ significantly with respect to the incidence of syncope or pacemaker implantation (Table 4). Discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (in 7.4% of patients vs. 6.0%, P<0.001) (Table 2). The levels of creatinine and uric acid increased slightly more during the treatment period with ticagrelor than with clopidogrel (Table 4).
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Table 4
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Table 4
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Table 4
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discussion PLATO shows that treatment with ticagrelor as compared with clopidogrel in patients with acute coronary syndromes significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke. A similar benefit was seen for the individual components of death from vascular causes and myocardial infarction, but not for stroke. The beneficial effects of ticagrelor were achieved without a significant increase in the rate of major bleeding. The benefits of ticagrelor over clopidogrel were seen in patients who had an acute coronary syndrome with or without ST-segment elevation.
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discussion Previous trials have shown benefits of clopidogrel in the same clinical settings. The advantages were seen regardless of whether patients had received appropriate initiation of treatment with the currently recommended higher loading dose of clopidogrel and regardless of whether invasive or noninvasive management was planned. The treatment effects were the same in the short term (days 0 to 30) and in the longer term (days 31 to 360). This duration of treatment benefit has also been shown with clopidogrel. Thus, ticagrelor appears to expand on the previously demonstrated benefits of clopidogrel across the spectrum of acute coronary syndromes.
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discussion The incremental reduction in the risk of coronary thrombotic events (i.e., myocardial infarction and stent thrombosis) through more-intense P2Y12 inhibition with ticagrelor is consistent with similar effects of prasugrel. Although the rates of major bleeding were not lower with ticagrelor than with clopidogrel, but those were also not associated with an increase in the rate of any major bleeding. contrast to the experience with prasugrel, which is also a more effective platelet inhibitor than clopidogrel but is irreversible, there was no increased risk of CABG-related bleeding with ticagrelor As with prasugrel, non–procedure-related bleeding (spontaneous bleeding), including gastrointestinal and intracranial bleeding, was more common with ticagrelor than with clopidogrel.
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Conclusion Although the rare episodes of intracranial bleeding were often fatal, the rates of nonintracranial fatal bleeding, death from vascular causes, and death from any other cause were lower in the ticagrelor group than in the clopidogrel group, resulting in an overall reduction in the mortality rate with ticagrelor. In conclusion, in patients who had 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.
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Thank you...