View source for 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

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''September 3, 2009 By Alexandra M. Palmer'' [mailto:apalmer@perfuse.org]

'''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-naïve 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; [[Ticagrelor] 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]]

*6–8 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.

*[http://www.cardiosource.com/clinicaltrials/trial.asp?trialID=1855 PLATelet inhibition and patient outcomes (PLATO - Presented at ESC 2009)]

==PowerPoint Presentation==
[[Media:PLATO-1.ppt]]

[[Category:News]]