PLATO Substudy: Ticagrelor Associated with Less Bleeding, Infection, Death than Clopidogrel after CABG

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Compared with clopidogrel, ticagrelor is associated with fewer deaths among patients with acute coronary syndromes (ACS) requiring coronary artery bypass grafting (CABG). In a substudy of the PLATO trial, published online September 26, 2012, ahead of print in the Journal of the American College of Cardiology, this lower mortality rate was explained not only by lower rates of cardiovascular deaths, but also by a reduction in bleeding and infections contributing to death.

In PLATO, 18,624 patients with ACS were randomized to ticagrelor (180-mg loading dose and 90 mg twice daily thereafter), or clopidogrel (300- to 600-mg loading dose and 75 mg once daily thereafter). Overall, 10% (n = 1,899) underwent CABG post-randomization. Of this group, those receiving ticagrelor had about half the total and cardiovascular 12-month mortality of those given clopidogrel.

For the substudy led by Christoph Varenhorst, MD, PhD, of the Uppsala Clinical Research Center (Uppsala, Sweden), causes of death in 87 patients of the 1,261who underwent CABG within 7 days of stopping the study drug were classified as vascular or nonvascular. The investigators also identified bleeding or infection events that may have contributed to death.

Survival Advantage for Ticagrelor

Rates of vascular death were greater among patients treated with clopidogrel vs. ticagrelor. Causes of vascular death that were more common with clopidogrel than ticagrelor included MI (14 vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death (9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2), although none of the differences were statistically significant. There also was a trend toward a higher rate of nonvascular death with clopidogrel (table 1).

Table 1. Types of Death Following CABG: Ticagrelor vs. Clopidogrel

 

Ticagrelor
(n = 632)

Clopidogrel
(n = 629)

P Value

Total Death

4.6%

9.2%

0.0018

Vascular Death

4.0%

7.5%

0.0092

Nonvascular Death

0.6%

1.7%

0.0748

Abbreviation: CABG, coronary artery bypass grafting.

Bleeding as the primary or contributing cause of death occurred more frequently within the first month after CABG. At 12 months from the CABG procedure, the cumulative incidence of death due to bleeding (primary or contributing cause) and death due to infection (primary or contributing cause) was higher in patients randomized to clopidogrel than with ticagrelor (table 2).

Table 2. Cumulative Death: Ticagrelor vs. Clopidogrel

 

HR (95% CI)

P Value

Bleeding

0.33 (0.15-0.70

< 0.01

Infection

0.36 (0.14-0.93)

< 0.05


Ticagrelor Drug of Choice When CABG Is Anticipated

“The lower rate of bleeding- and infection-related fatalities with ticagrelor favors the use of ticagrelor for ACS patients where urgent or elective surgical intervention like CABG is required,” Dr. Varenhorst wrote in an e-mail correspondence with TCTMD. “As the need for CABG is difficult to predict before performing a coronary angiogram, these results speak in favor of ticagrelor as a first-line immediate treatment in most patients with ACS in the acute phase when the extent of coronary lesions are unknown. In clinical reality, where many CABG procedures are performed on an emergent basis, the faster offset of antiplatelet effect with ticagrelor as compared to clopidogrel (approximately 3 days vs. 5 days) might be beneficial.”

Also in an e-mail correspondence with TCTMD, David Schneider, MD, of the University of Vermont (Burlington, VT), expressed similar views. “For clinicians, both the CABG substudy and this analysis support the use of ticagrelor in ACS patients, particularly if they might require surgery. Very few interventions have been shown to have such a marked effect on outcome in selected patients.”

Greater Inhibition of Platelet Aggregation

“The most likely reason [for the lower mortality rate with ticagrelor] is that ticagrelor yields greater inhibition of platelet aggregation than clopidogrel, leading to less thrombotic complications, such as MI and stent thromboses (as seen in the PLATO results),” said Dr. Varenhorst. “In addition, our results indicate that if there is bleeding, the reversibility of the platelet-inhibitory effect with ticagrelor might lead to less severe complications, such as fatalities.”

With regard to the difference in nonvascular death, Dr. Varenhorst observed that “previous [findings suggest] a raised risk of septic infections during clopidogrel treatment, which also was seen in the PLATO trial. Thus, there could be a raised vulnerability to septic infections during clopidogrel treatment that is not seen with ticagrelor, [perhaps because] it is not a thienopyridine.” he continued: “There has also been speculation about the importance of other mechanisms, such as ticagrelor being an inhibitor of adenosine reuptake by erythrocytes and other cells, as adenosine is involved in several physiologic pathways that influence recovery of cardiac function after ischemia and also inflammatory responses.”

The reversible binding of ticagrelor may be a key mechanism,” suggested Dr. Schneider, adding that it might relate to both the thrombotic and bleeding events. “Because of redistribution, new platelets that are more reactive are likely to be inhibited by ticagrelor, an effect that should not occur with clopidogrel. Similarly, when bleeding occurs, the dissociation of ticagrelor may limit the extent of bleeding, particularly when profound inhibition occurs. Infection may be related to bleeding or to effects of ticagrelor on inflammatory response, perhaps mediated by platelets, or direct effects of ticagrelor on other immune functions.”

Dr, Schneider added that there may be a pleiotropic effect of ticagrelor, yet to be defined, involving “the reversible binding, or some combination of these mechanisms.”

 


Source:
Varenhorst C, Alström, U, Scirica BM, et al. Factors contributing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery. J Am Coll Cardiol. 2012;Epub ahead of print.

 

 

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Disclosures
  • The study was supported by AstraZeneca.
  • Dr. Varenhorst reports receiving a research grant from AstraZeneca and serving on the speakers’ bureaus for AstraZeneca, Eli Lilly, and The Medicines Company.
  • Dr. Schneider reports receiving honoraria from AstraZeneca, BMS, and Sanofi-Aventis and research funding from BMS and Sanofi-Aventis.

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