Review of the PLATO Trial

Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes

N Engl J Med 2009;361:1045-57.

Background Similar to Prasugrel, Ticagrelor is a direct-acting oral antagonist of the adenosine diphosphate receptor P2Y12. Unlike clopidogrel that requires transformation of the prodrug to the active metabolite, Ticagrelor provides faster and more consistent P2Y12 inhibition.

In the TRITON-TIMI 38 trial, Prasugrel compared to clopidogrel reduced myocardial infarction in patients with ACS but was associated with more major bleeding and subgroup interactions were evident for patients who were older, had a history of stroke or risk factors for bleeding and who were generally at higher risk for recurrent events.

The Study of Platelet Inhibition and Patient Outcomes (PLATO) sought to test the hypothesis that Ticagrelor is superior to clopidogrel for the prevention of vascular events and death in patients presenting with ACS.

Patients Eligible patients were hospitalized for ACS, with or without ST-segment elevation (STE), whose onset of symptoms occurred within the previous 24 hours. For patients without STE, at least 2 of the following criteria were required: 1) ST-segment changes on ECG indicating ischemia, 2) a positive biomarker indicating myocardial necrosis, or 3) one or more risk factors including age ≥60 years, previous MI or CABG, CAD with stenosis of ≥50% in at least 2 vessels, history of ischemic stroke, TIA, carotid stenosis, cerebral revascularization, diabetes, peripheral arterial disease or CKD based on creatinine clearance <60 ml/min. STEMI was traditionally defined. Key exclusion criteria included any contraindication against the use of clopidogrel, fibrinolytic therapy within 24 hours, a need for oral anticoagulation, an increased risk of bradycardia, and concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer.

Baseline characteristics The median age of patients was 62 years with 15% being ≥75 years and 72% were men; over 90% were white. The index event was UA or NSTEMI in approximately 60% and STEMI in 38%. Only 81% of patients underwent coronary angiography. PCI was performed in 64% of patients (was 99% in TRITON-TIMI 38) and CABG was performed in 10%. Interestingly, the majority of patients stented received only a bare metal stent (65%). 20% of patients had a prior MI, 25% had diabetes, 65% had hypertension and 36% were habitual smokers. Only 4% of patients had CKD defined as a creatinine clearance ≤60 ml/min or a history of ischemic stroke.

Procedures All drugs were administered in a double-blind, double-dummy fashion. Ticagrelor was given as a loading dose of 180 mg followed by 90 mg twice daily for all patients. For patients who had not been on clopidogrel for at least 5 days prior to randomization, a 300 mg loading dose of clopidogrel was given followed by a dose of 75 mg daily. Others in the clopidogrel group continued to receive a maintenance dose of 75 mg daily.

For patients undergoing PCI more than 24 hours after randomization, an additional dose of their study drug was given at the time of PCI, which was 300 mg of clopidogrel, at the investigator’s discretion, or 90 mg of ticagrelor. In patients undergoing CABG, it was recommended that the study drug be withheld for 5 days in the clopidogrel group and for 24 to 72 hours in the Ticagrelor group.

Outpatient visits occurred at 1, 3, 6, 9, and 12 months, with a safety follow-up visit 1 month after the end of treatment, which was scheduled to continue for 12 months. Notably, patients left the study at their 6- or 9- month visit if the targeted number of primary endpoint events had occurred by that time.

Endpoints The primary efficacy endpoint was the time to the first occurrence of a composite endpoint of death from vascular causes, myocardial infarction, or stroke. Investigators estimated that 1780 primary endpoint events would be required to achieve 90% power to detect a 13.5% relative risk reduction of the primary endpoint in the ticagrelor group, based on an event rate of 11% in the clopidogrel group at 12 months (≤9.5% vs 11%). The consistency of treatment effects over time was assessed from randomization to 30 days and from 31 to 360 days. The primary safety endpoint was the first occurrence of any major bleeding event. Treatment effect heterogeneity was explored in 25 prespecified subgroups and 8 post hoc subgroups without adjustment for multiplicity, which is standard.

Results A total of 18,624 patients from 862 sites in 43 countries were enrolled. There were 9,333 patients assigned to the Ticagrelor group and 9,291 assigned to clopidogrel. The median duration of therapy was 277 days (approximately 9 months). Ticagrelor significantly reduced the primary composite endpoint compared to clopidogrel (9.8% vs 11.7%; HR 0.84; 95% CI 0.77-0.92; P<0.001). This reduction was driven by significant differences in both the rates of nonfatal MI between groups (5.8% vs 6.9%; HR 0.84; 95% CI 0.75-0.95; P=0.005) and death from vascular causes (4.0% vs 5.1%; p=0.001). There was no significant difference in stroke (1.5% vs 1.3%; p=0.22). There was a statistically significant difference in all-cause death (4.5% vs 5.9%; p<0.001) but this should be interpreted cautiously as the trial was underpowered for detection of a smaller, more feasible difference in this endpoint (i.e. based on the event rate in control group, approximately 48,000 patients would be needed to detect a 10% difference in all-cause death with 80% power).

In the prespecified landmark analysis, benefit from ticagrelor was observed from randomization through day 30 (4.8% vs 5.4%; P=0.045) and from 31 days onward (5.3% vs 6.6%; p<0.001).

Also of note, there was a statistically significant reduction in stent thrombosis. For the primary safety endpoint, Ticagrelor did not significantly increase major bleeding (11.6% vs 11.2%; HR 1.04, 95% CI 0.95-1.13; p=0.43); however, it did significantly increase Non-CABG related major bleeding (4.5% vs 3.8%; p=0.03).

Of particular importance for contemporary clinical practice, Ticagrelor significantly increased shortness of breath (13.8% vs 7.8%; p<0.001). This side effect is commonly encountered in the clinical setting and requires careful consideration.

Less striking treatment response variation was observed for ticagrelor in this trial than for prasugrel in TRITON-TIMI 38. Most importantly, there was no observed difference in the treatment effect for patients based on “planned treatment approach” and thus, for patients reflective of those enrolled in the trial, ticagrelor is more effective than clopidogrel whether patients undergo PCI or not.

For the subgroups presented in the Figure 2 of the supplement, a significant interaction was noted based on region of enrollment with patients in North America seemingly doing worse with ticagrelor. It should be noted that such patients accounted for only 10% of total enrollment; however, the interaction p value was strong 0.05. It is hard to explain this interaction beyond the play of chance.

The strongest interaction signal involved patients categorized according to whether they were above or below the sex-specific median weight (82 kg for men and 71 kg for women). Lower weight patients were at higher risk of events but the treatment effect was significantly reduced compared to their higher weight counterparts with an interaction p value for this subgroup of 0.04. This interaction signal is consistent with what was observed in TRITON-TIMI 38.

Finally, patients 75 or above accounted for 15% of the overall cohort and predictably experienced a significantly higher rate of the primary endpoint but the difference in the effect was much less than half of what it was compared to lower risk patients under 75 years. In this case the interaction p value was only 0.22 due to low power. This signal was also consistent with TRITON-TIMI 38.

Conclusions In patients with ACS regardless of management strategy (early invasive vs conservative) and whether revascularization is performed or not, ticagrelor reduced the rate of cardiovascular events; including nonfatal MI and death due to vascular causes. For patients similar to those enrolled in PLATO, approximately 50 patients would need to be treated with ticagrelor instead of clopidogrel to prevent 1 person from having a nonfatal MI or dying from a vascular cause; approximately 140 patients would need to be treated to cause 1 person to have a non-CABG-related major bleeding event.

The benefit from Ticagrelor is realized early in treatment (0-30 days) and beyond (>31 days onward) as demonstrated by the landmark analysis in this study. Patients above 75 benefit less with Ticagrelor as do patients who are low weight based on sex-specific norms. Dyspnea is a frequently occurring side effect of Ticagrelor.