PLATO Substudy: Ticagrelor Reduces Mortality in NSTE-ACS Patients Regardless of Revascularization

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A subanalysis of the PLATO study suggests that ticagrelor reduces ischemic events and mortality with no difference in major bleeding compared with clopidogrel in patients with non-ST-elevation acute coronary syndromes (NSTE-ACS). In the study, published online April 11, 2014, ahead of print in the European Heart Journal, the benefits of ticagrelor were similar regardless of whether patients were or were not managed with revascularization.

In the main trial 18,624 ACS patients were randomized to receive aspirin plus ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). Overall results, published in the New England Journal of Medicine in 2009, showed that at 12 months, ticagrelor reduced the composite of cardiovascular death, MI, or stroke (primary endpoint) with no increase in major bleeding.

For the subanalysis, researchers led by Stefan K. James, MD, PhD, of Duke University Medical Center (Durham, NC), examined outcomes for the 11,080 patients in PLATO with NSTE-ACS. Of these, 5,366 did not undergo revascularization in the first 10 days.

NSTE-ACS Results Mirror Overall Outcomes

Compared with clopidogrel, ticagrelor reduced the primary efficacy endpoint (a composite of cardiovascular death, MI, and stroke), as well as the individual endpoints of MI, cardiovascular death, and all-cause mortality. Stroke rates did not differ between groups. The primary safety endpoint of PLATO—major bleeding—was similar between treatment groups, but an increase was seen in non-CABG major bleeding in the ticagrelor group (table 1).

Table 1. Outcomes at 12 Months

 

Ticagrelor
(n= 5,581)

Clopidogrel
(n = 5,499)

P Value

CV Death/MI/Stroke

10.0%

12.3%

.0013

MI

6.6%

7.7%

.0419

CV Death

3.7%

4.9%

.0070

Stroke

1.3%

1.4%

.79

All-Cause Mortality

4.3%

5.8%

.0020

PLATO Major Bleeding

13.4%

12.6%

.26

Non-CABG Major Bleeding

4.8%

3.8%

.0139


The advantage with ticagrelor for the primary composite endpoint and total mortality was maintained for the duration of the trial.

In addition, while there was no difference in the rate of PLATO life-threatening or fatal bleeding (P = .56) or intracranial bleeding (P = .13), the composite of PLATO major or minor bleeding occurred more often in the ticagrelor group compared with the clopidogrel group (HR 1.14; 95% CI 1.03-1.25; P = .0078).

Overall, event rates were considerably higher in patients who did not undergo revascularization within the first 10 days compared with those who did. However, reductions in the primary endpoint were similar for both revascularized and nonrevascularized patients treated with ticagrelor vs clopidogrel (HR 0.86 vs 0.85, respectively; interaction P = .93), as were reductions in all-cause mortality (HR 0.75 vs 0.73, respectively; interaction P = .89), which was consistent with the results of the overall trial. Likewise, the greater incidence of non-CABG-related major bleeding with ticagrelor was unaffected by treatment strategy (interaction P = .43).

Results Consistent with Guidelines

Although current guidelines advocate early invasive treatment of NSTE-ACS patients, a large proportion are managed noninvasively due in part to more comorbidities and higher bleeding risk, the study authors say. For these patients, the optimal platelet inhibition strategy has been unclear. In the TRILOGY-ACS trial, for example, NSTE-ACS patients for whom revascularization was not planned saw no significant benefit of prasugrel over clopidogrel over 2 years.

Dr. James and colleagues say that although the nonrevascularization subgroup of PLATO seems similar to the TRILOGY-ACS population, it is impossible to compare the effect of the respective new P2Y12 inhibitors across the 2 studies because TRILOGY-ACS was a prospective study while the current PLATO substudy analyzed post hoc-defined subgroups. Furthermore, the TRILOGY-ACS population was higher risk with more comorbidities, they add.

In conclusion, they say the PLATO results “harmonize with” the European Society of Cardiology guidelines, which recommend ticagrelor in all patients at moderate-to-high risk of ischemic events, regardless of initial treatment strategy.

 


Source:
Lindholm D, Varenhorst C, Cannon CP, et al. Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial. Eur Heart J. 2014;Epub ahead of print.

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Disclosures
  • The PLATO trial and substudy were funded by AstraZeneca.
  • Dr. James reports receiving research grants from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Medtronic, Terumo, and Vascular Solutions; receiving honoraria from Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, IROKO, and The Medicines Company; and serving as a consultant or on the advisory board for AstraZeneca, Eli Lilly, Medtronic, Merck, and Sanofi.

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