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Presenter | see Discussant report
Lars Wallentin, FESC (Sweden)
List of Authors:
Lars Wallentin, Richard C. Becker, Andrzej Budaj, Christopher P Cannon, Håkan Emanuelsson, Claes Held, Jay Horrow, Steen Husted, Stefan James, Hugo Katus, Kenneth M Mahaffey, Benjamin M Scirica, Allan Skene, Philippe Gabriel Steg, Robert F. Storey, and Robert A. Harrington for the PLATO investigators.
Ticagrelor versus clopidogrel in patients with acute coronary syndromes: the PLATelet inhibition and patient Outcomes (PLATO) trial.
Current clinical practice guidelines for patients with acute coronary syndrome recommend dual antiplatelet treatment with aspirin and clopidogrel. The efficacy of clopidogrel is hampered by slow and variable transformation of the prodrug to the active metabolite, modest and variable platelet inhibition, increased risk of bleeding and increased risk of stent thrombosis and myocardial infarction in poor responders. Ticagrelor is an oral reversible direct acting P2Y12-inhibitor providing faster and greater platelet inhibition than clopidogrel.
The PLATO trial was a multicenter double-blind randomized trial, comparing treatment with ticagrelor (180 mg loading dose followed by 90 mg twice daily) to treatment with clopidogrel (300 to 600 mg loading dose followed by 75 mg daily) for prevention of cardiovascular events. We included 18,624 patients admitted either with ST-elevation ACS intended for primary PCI (38%) or with non-ST-elevation ACS intended for an invasive or medical approach (62%). Prior to randomization 94% were treated with aspirin; 46% with clopidogrel. The patients were treated for an average of 278 days (minimum 6 and maximum 12 months). The follow-up was complete in 99.97% with only 5 patients lost to follow-up.
The primary composite of death from vascular causes (CV) death, myocardial infarction (MI) and stroke was reduced from 11.7% to 9.8% (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). In the predefined hierarchical testing of secondary endpoints there were reductions of the composites of total death, MI and stroke from 12.3% to 10.2% (P=0.0001), CV-death, MI, stroke, severe recurrent, recurrent ischemia, transient ischemic attack (TIA) and other arterial thrombotic events from 16.7% to 14.6% (P<0.001), MI alone from 6.9% to 5.8% (P=0.005) and CV-death from 5.1% to 4.0% (P=0.001). Total mortality was reduced from 5.9% to 4.5%, (P<0.001). There was no difference in total major bleeding, 11.6% vs. 11.2% (P=0.434), but higher occurrence of non-CABG related major bleeding 4.5% vs. 3.8% (p=0.026). Episodes of dyspnoea were more common with ticagrelor, 14.2%, than clopidogrel, 9.2%, which led to discontinuation of treatment in respectively 1.0% and 0.3%. There was no difference in other important side effects.
Treatment with ticagrelor instead of clopidogrel in a broad spectrum of patients with acute coronary syndrome provides a clinically important reduction in mortality and myocardial infarction without an increase in total major bleeding, but with a rise in non-procedure related bleeding.
Discussant | see Presenter abstract
Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLATO trial presented by Lars Wallentin, ESC Congress Barcelona 2009.
The new reversible oral P2Y12 receptor antagonist, ticagrelor, was compared to the ‘classic’ irreversible P2Y12 blocker clopidogrel in 18,264 patients with acute coronary syndromes (ACS) comprising a broad population with non-ST- or ST-elevation myocardial infarction (MI). Ticagrelor was superior to clopidogrel in terms of preventing the combination of cardiovascular death/ MI/stroke without causing a significant increase in major bleedings. Also, cardiovascular mortality, total mortality and the incidence of stent thrombosis were significantly reduced. There was an increased risk of non-procedure-related bleedings in the ticagrelor group. Ticagrelor has the potential to improve prognosis in patients with ACS.
Comments: The investigators should be congratulated for this well-designed and nicely conducted landmark study. Overall, treating 54 patients for one year with ticagrelor instead of clopidogrel prevented one event of cardiovascular death, MI or stroke. MI and Bleeding. The authors used the new global MI definition and the trial design has been described previously (S James et al, Am Heart J 2009; 157: 599-605). A new definition of bleedings was used in PLATO. This definition seems appropriate and as good as the other 8-10 bleeding definitions that have been used in previous trials. There was no significant difference in PLATO or TIMI major bleedings between the two groups. However, there was an increased risk of non-CABG bleedings in the ticagrelor group, whereas the incidence of CABG-related bleedings did not differ. Patients with active bleeding, a bleeding history or severe anemia were excluded from the study, and therefore the bleeding profile of ticagrelor should also be tested in ‘real’ world ACS patients. One of the major advantages of reversible inhibition of P2Y12 is indeed the possibility of reducing bleeding during surgery, and therefore it is not surprising that ticagrelor was not associated with an increased incidence of CABG related bleeds. Dosing and duration. The dose of ticagrelor was chosen according to phase 2 trials (DISPERSE and DISPERSE-2) and clopidogrel was dosed according to guidelines. The inclusion of non-naïve clopidogrel patients in the study is appropriate as this is the real world, and because sub-analysis on these patients might provide useful information. Patients were included within the first 24 hours of ACS. In this phase, the risk of events is high, thus perphaps favouring the fast onset of strong platelet inhibition obtained with ticagrelor. The ESC Guidelines recommend dual anti-platelet therapy for 12 months in ACS. In PLATO, duration of treatment was 6 to 12 months. There was a significantly lower incidence of ischaemic events in the ticagrelor group both within the first 30 days and also in the period from 1 to 12 months. There is currently no evidence to recommend dual anti-platelet therapy beyond 12 month in ACS. Side effects and compliance
The authors report an increase in the levels of uric acid, and also an increased frequency of dyspnoea and brady-arrhythmias in the ticagrelor group. Some of the side effects have been described in phase 2 studies with ticagrelor and were expected. No severe new side effects seemed to occur and only few patients had to stop ticagrelor due to side effects. The study drugs were discontinued prematurely in 23.4 and 21.5% of the patients in the ticagrelor and the clopidogrel groups, respectively.
Ticagrelor does not require metabolic activation, causes stronger platelet inhibition and has a fast onset of action. However, the reversible receptor binding and a 12 h half-life necessitate twice-daily dosing, which might be a problem in patients who are not fully compliant. The investigators reported that compliance was approximately 83% in each group. Implementation of ticagrelor might be troublesome in patients who are unable to fully adhere to the prescribed drug therapy, because insufficient platelet inhibition increases the risk of stent thrombosis and other ischaemic events.