Ticagrelor is superior to Clopidogrel in the treatment of patients with acute coronary syndrome with or without ST-segment elevation: Results of the PLATO study
September 3, 2009 By Alexandra M. Palmer 
Barcelona, Spain: Results from the Study of PLATelet Inhibition and Patient Outcomes (PLATO) indicate that treatment with Ticagrelor + Aspirin in comparison with Clopidogrel + Aspirin in a broad population with ST- and non-ST-elevation acute coronary syndrome (ACS) provides significant reduction in cardiovascular (CV) and total mortality, myocardial infarction (MI), and stent thrombosis with no change in the overall risk of major bleeding. Specifically, treating 54 patients with Ticagrelor instead of with Clopidogrel for one year will prevent one event of CV death, MI or stroke. This report was presented by Lars Wallentin at the European Society of Cardiology Congress 2009.

# Introduction
Although current guidelines recommend 12 months of Aspirin and Clopidogrel, previous studies have indicated disadvantages to Clopidogrel use. Clopidogrel is associated with an increased risk of bleeding and risks of stent thrombosis and MI among patients who respond poorly to the drug. Furthermore, the efficacy of Clopidogrel is hampered by slow and variable transformation to the active metabolite and modest and variable platelet inhibition.
Contrastingly, Ticagrelor is direct acting and does not require metabolic activation. Its effect is a rapid onset of P2Y12 receptor inhibiton. Moreover, Ticagrelor produces a greater inhibition of platelet aggregation than Clopidogrel and its blockage is reversible. These perceived advantages of Ticagrelor over Clopidogrel led investigators to compare the effect of the two drugs (when used in conjunction with Aspirin) on CV death, MI, stroke and total major bleeding among patients with ACS in the PLATO trial.

# Methods and Inclusion Criteria
The PLATO trial was a global, randomized, double-blind trial involving 18,624 patients who had been hospitalized for STEMI or NSTEMI ACS, with onset during the previous 24 hours. With STEMI, the following two inclusion criteria were required: 1) Persistent STEMI or new Left bundle branch block (LBBB), 2) Primary percutaneous coronary intervention (PCI) planned. With NSTEMI ACS, at least two of the following three were required: 1) ST-segment changes on ECG indicating ischemia, 2) Positive biomarker indicating myocardial necrosis, 3) One of the following risk indicators:
- 60 years of age
- Previous MI or CABG
- CAD with 50% stenosis in 2 vessels
- Previous ischemic stroke, TIA, carotid stenosis (50%)
- Diabetes mellitus
- Peripheral artery disease
- Chronic renal dysfunction (creatinine clearance <60 mL/min)
Of the 18,624 patients, 9,333 were randomized to Ticagrelor and 9,291 to Clopidogrel. Patients in the Ticagrelor group received a 180 mg loading dose followed by 90 mg twice daily. An additional 90 mg was administered at the time of PCI.
The Clopidogrel arm was divided into two groups for treatment purposes. Clopidogrel-naive patients (those who had not received an open-label loading dose and had not been taking Clopidogrel for at least 5 days before randomization) were treated with a 300 mg loading dose followed by 75 mg daily, while patients pre-treated with Clopidogrel continued on a maintenance dose of 75 mg daily. An additional 300 mg was administered at the time of PCI.
For patients undergoing CABG, Clopidogrel administration was withheld for 5 days and Ticagrelor treatment for 1 to 3 days.
75-100 mg Aspirin was administered daily to all patients who could tolerate the drug. Those who had not previously been receiving Aspirin received 325 mg. Patients were also treated with 325 mg Aspirin daily for 6 months post-stent implantation.
Patients were exposed to the study drugs for 6-12 months. There were five different follow-up visits: 1,3,6,9, and 12 months.

# Results
Compared to Clopidogrel, Ticagrelor was associated with an absolute reduction in the pre-specified primary efficacy endpoint of CV death + MI + stroke. The rate of occurrence of the composite endpoint at 12 months was as follows: Clopidogrel 11.7%, n=1,014; Ticagrelor 9.8%, n=864 (HR 0.84, 95% CI 0.77-0.92), p=0.0003.
The rate of the primary efficacy endpoint was monitored over time and the following results were obtained: day 1-30, Clopidogrel 5.43%, Ticagrelor 4.77% (HR 0.88, 95% CI 0.77-1.00), p=0.045; days 31-360: Clopidogrel 6.60%, Ticagrelor 5.28% (HR 0.80, 95% CI 0.70-0.91), p<0.001.
The primary safety endpoint was the time to major bleeding. The difference in time to major bleeding was not statistically significant between the two treatment arms.
Clopidogrel and Ticagrelor did however differ in their effect on non-CABG and CABG-related major bleeding. These bleeding types were sub-categorized into PLATO and TIMI major bleeding.
Secondary endpoints included MI and CV death. Analysis of these variables at 12 months also favored Ticagrelor over Clopidogrel. Rate of incidence of MI was 6.9% (n=593) for Clopidogrel and 5.8% (n=504) for Ticagrelor. HR 0.84 (95% CI 0.75-0.95), p=0.005. For CV death, the following incidence rates were noted: Clopidogrel 5.1%, n=442;  4.0%, n=353 (HR 0.79, 95% CI 0.69-0.91), p=0.001.
In addition, rate of total death + MI + stroke at 12 months was lower in the Ticagrelor arm: Clopidogrel 12.3%, n=1,065; Ticagrelor 10.2%, n=901 (HR 0.84, 95% CI 0.77-0.92), p<0.001. Rate of CV death + MI + stroke + ischemia + TIA + arterial thrombotic events demonstrated similar incidence rates at 12 months: Clopidogrel 16.7%, n=1,456; Ticagrelor 14.6%, n=1,290 (HR 0.88, 95% CI 0.81-0.95), p<0.001.
Patients treated with Ticagrelor also saw a lower rate of total death at 12 months (4.5%, n=399), compared to patients who were administered Clopidogrel (5.9%, n=506); HR 0.78 (95% CI 0.69-0.89), p<0.001.
There was no significant difference in the incidence rate of stroke between the two treatment groups at 12 months.
An evaluation of stent thrombosis among patients with any stent during the study demonstrated a higher rate of occurrence among patients treated with Clopidogrel versus those administered Ticagrelor. Three different classifications of stent thrombosis were considered: 1) definite stent thrombosis, 2) probable or definite stent thrombosis and 3) possible, probable, definite stent thrombosis. Incidence of definite stent thrombosis was 1.9% (n=106) for Clopidogrel and 1.3% (n=71) for Ticagrelor; HR 0.67 (95% CI 0.50-0.91), p=0.009. Probable or definite stent thrombosis was observed in 2.8% (n=158) of Clopidogrel-treated patients and 2.1% (n=118) of Ticagrelor-treated patients; HR 0.75 (95% CI 0.59-0.95), p=0.02. Clopidogrel was associated with a 3.6% (n=202) incidence rate of possible, probable, definite stent thrombosis, while the rate was 2.8% (n=155) for Ticagrelor; HR 0.77 (95% CI 0.62-0.95), p=0.01. Time-at-risk was calculated from the first stent insertion in the study or date of randomization.
Other findings included a higher percentage of patients presenting with dyspnea in the Ticagrelor arm (13.8%) compared to the Clopidogrel-treated patients (7.8%), p<0.001. With discontinuation of study treatment these values dropped to 0.9% for Ticagrelor and 0.1% for Clopidogrel (p<0.001).
Additional analysis illustrated a greater number of Clopidogrel-treated patients presenting with neoplasms during treatment (0.4%) compared to those administered Ticagrelor (0.2%), p=0.02, but there was no significant difference between the number of patients with neoplasms in general or with malignant neoplasms.

# Conclusions, Discussion, Interpretation
In summary, based on 1,000 patients admitted to the hospital for ACS, using Ticagrelor instead of Clopidogrel for 12 months resulted in:
- 14 fewer deaths
- 11 fewer myocardial infarctions
- 68 fewer cases with stent thrombosis
- No increase in bleedings requiring transfusion
- 9 patients may switch to thienopyridine treatment because of reversible symptoms of dyspnea
Results from the PLATO trial are novel in that they introduce Ticagrelor as a drug that expands on the benefits of Clopidogrel and Prasugrel, two antiplatelet agents previously tested in ACS patients undergoing PCI. Prasugrel, a strong P2Y12 receptor inhibitor like Ticagrelor, was tested against Clopidogrel in the TRITON-TIMI 38 study. Like Ticagrelor, Prasugrel demonstrated a lower risk of MI and stent thrombosis, compared to Clopidogrel. Contrasting to the favorable bleeding outcomes related to treatment with Ticagrelor, however, Prasugrel was associated with increased bleeding rates compared to Clopidogrel.
Since Clopidogrel is recommended under current guidelines for the prevention of ischemic events, stent thrombosis and death in the acute and long-term treatment of ACS patients, it is probable that the results from PLATO will have an effect on clinical practice. However, the fact that strict enrollment criteria are used in clinical trials must still be taken into consideration. The results observed here may not be applicable to all patients in clinical practice.

# Sponsorship
The study was sponsored by AstraZeneca.

# ClinicalTrials.gov Number
NCT00391872

# Sources
- Lars Wallentin, M.D., Ph.D., Richard C. Becker, M.D., Andrzej Budaj, M.D., Ph.D., Christopher P. Cannon, M.D., Hakan Emanuelsson, M.D., Ph.D., Claes Held, M.D., Ph.D., Jay Horrow, M.D., Steen Husted, M.D., D.Sc., Stefan James, M.D., Ph.D., Hugo Katus, M.D., Kenneth W. Mahaffey, M.D.,Benjamin Scirica, M.D., M.P.H., Allan Skene, Ph.D., Philippe Gabriel Steg, M.D., Robert F. Storey, M.D., D.M., and Robert A. Harrington, M.D., for the PLATO investigators. Ticagrelor compared with Clopidogrel in Patients with Acute Coronary Syndromes - the PLATO trial. As presented at ESC 2009.
- Lars Wallentin, M.D., Ph.D., Richard C. Becker, M.D., Andrzej Budaj, M.D., Ph.D., Christopher P. Cannon, M.D., Hakan Emanuelsson, M.D., Ph.D., Claes Held, M.D., Ph.D., Jay Horrow, M.D., Steen Husted, M.D., D.Sc., Stefan James, M.D., Ph.D., Hugo Katus, M.D., Kenneth W. Mahaffey, M.D.,Benjamin Scirica, M.D., M.P.H., Allan Skene, Ph.D., Philippe Gabriel Steg, M.D., Robert F. Storey, M.D., D.M., Robert A. Harrington, M.D., for the PLATO investigators. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. New England Journal of Medicine. 30 August 2009.
- PLATelet inhibition and patient outcomes (PLATO - Presented at ESC 2009)

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