Size matters in STEMI: time for translation of ticagrelor?

This editorial refers to ‘P2Y₁₂ antagonists and cardiac repair post-myocardial infarction: global and regional heart function analysis and molecular assessment in pigs’ by G. Vilahur et al., pp. 1860–1870.

Both the European and the American guidelines for ST-elevation myocardial infarction (STEMI) prefer ticagrelor over clopidogrel in patients after acute coronary syndromes.^1,2 The landmark Platelet Inhibition and Patient Outcomes (PLATO) study showed the superiority of long-term ticagrelor therapy over the traditional P2Y₁₂ inhibitor, clopidogrel, in patients with acute coronary syndromes.^3,4 Since its publication, there has been a debate as to the mechanism(s) explaining the superiority of ticagrelor over clopidogrel. The original explanation was a more rapid onset and consistent platelet inhibition over time, leading to better tissue perfusion and prevention of recurrent ischaemic events, including stent thrombosis. However, preclinical models have shown that ticagrelor has additional pleiotropic effects, related to inhibition of the Equilibrative Nucleoside Transporter 1 with subsequent increase in the interstitial adenosine levels.⁵ Adenosine receptor activation in the heart leads to myocardial protection against ischaemia–reperfusion injury and limitation of infarct size.⁶ Indeed, pretreatment of rats⁷ and pigs⁸ before experimental ischaemia–reperfusion injury limits infarct size. This may suggest that patients receiving pretreatment with ticagrelor can be protected, and if they experience (additional) myocardial infarction, their infarct size will be smaller than in patients that receive clopidogrel. To answer whether ticagrelor can potentially reduce infarct size when administered after ischaemia has started (a model relevant to patients presenting with STEMI), Ye et al. administered ticagrelor or clopidogrel intraperitoneally 5 min before reperfusion to rats subjected to 30-min ischaemia followed by 24 h of reperfusion. Ticagrelor dose-dependently reduced infarct size, whereas clopidogrel had no effect.⁹

Vilahur et al.¹⁰ expand on their previous findings that the initial infarct-size-limiting effect of ticagrelor, observed after 24 h of reperfusion,⁸ was maintained for 42 days in pigs receiving a loading dose of ticagrelor before infarction and treated with the maintenance clinical dose of ticagrelor after infarction. The results are encouraging, as the protective effect was maintained in a large animal model. However, several issues have not been answered:

Is the infarct size limiting effect related to the initial loading dose before infarction, the maintenance dose of ticagrelor post-infarction or both? A smaller initial infarct would lead to better remodelling over time, and it is expected that the activation of the prosurvival kinases is higher in viable than in infarcted tissue. The current study does not address this issue. In the rat, one dose of ticagrelor administered intraperitoneally 5 min before reperfusion and oral treatment for 4 weeks, started 24 h after reperfusion (when the immediate reperfusion injury is believed to be completed), equally preserved left ventricular function and attenuated fibrosis 4 weeks after infarction, whereas clopidogrel had no effect.⁹ When pretreatment and maintenance dose of ticagrelor were combined, the effect on fibrosis was significantly greater than the effect of ticagrelor pre-loading alone and the effect on left ventricular function tended to be greater. This experiment suggests that the effects of the chronic maintenance treatment of ticagrelor after infarction are equally important and are independent of the initial infarct-size-limiting effects during the acute phase of ischaemia.

Can these favourable effects be achieved in the clinical setting? The loading and maintenance doses of ticagrelor and clopidogrel used by Vilahur et al.^8,10 are those used in the clinical setting. Yet, the body weight of the pigs (43 kg) was lower than that of the average patient. Blood levels of ticagrelor are not reported. In the rat, blood levels of ticagrelor were slightly higher than those seen in humans.^7,9 Thus, one cannot exclude off-target effects that can be achieved only with concentrations higher than those seen in the clinical setting.

In the current experiment ticagrelor increased adenosine levels.¹⁰ Adenosine receptor activation mediates the infarct-size limiting effects of ticagrelor.⁷ As adenosine receptor blockers completely block the protective effect in the experimental setting, it is unclear whether caffeine consumption could block the favourable effects of ticagrelor on protection against ischaemia–reperfusion injury and/or remodelling in the clinical setting. It has previously shown that caffeine can block the infarct-size-limiting effect of statins in the rat.¹¹

Downstream of adenosine receptor activation, ticagrelor modifies cyclooxygenase-2.⁹ Aspirin, dose-dependently, attenuates the infarct-size-limiting effects of ticagrelor.⁷ While it is well accepted by the guidelines that the maintenance dose of aspirin should be reduced in patients treated with ticagrelor,¹² the loading dose of chewable (up to 300 mg) or intravenous aspirin (up to 250 mg) have not been reduced by the current European¹ and American² guidelines. It is possible that the initial protective effects of ticagrelor are blocked by the initial systemic effect of the aspirin loading. Can it be that the lack of effect of prehospital loading with ticagrelor in the ATLANTIC trial are because the concomitant aspirin loading blocked its myocardial protective effect?¹³ It is also unclear whether the low oral maintenance dose of aspirin can attenuate the effects of ticagrelor on remodelling and inflammation, as has been shown in the preclinical setting.¹⁴ In the current experimental model, Vilahur et al.¹⁰ did not treat their pigs with aspirin, as it is recommended by the STEMI guidelines.

High doses of statins are recommended for patients with acute coronary syndromes.^1,12 Statins also protect against ischaemia–reperfusion injury.^11,15 Statins activate ecto-5ʹ nucleotidase, increasing the interstitial concentrations of adenosine. The protective effect of statin depends on adenosine receptor activation. As ticagrelor prevents the re-uptake of adenosine and statins increase the production of adenosine, an additive effect is expected. Indeed, in rodent models, the combination of statins and ticagrelor have additive effects on limiting infarct size¹⁶ and ameliorating of inflammation and the progression of atherosclerosis in diabetic mice.¹⁴ As mentioned in the Discussion section, the pigs included in the current study were not exposed to statins.¹⁰ It is yet to be shown in large animal models and in the clinical setting whether statins and ticagrelor combination has additive effects, or the signalling pathway of the adenosine receptor activation is saturated by either ticagrelor or high-dose statins alone.

Myocardial oedema 3 days after infarction was reduced only by ticagrelor.¹⁰ This can be secondary to smaller initial infarct size in the ticagrelor-treated pigs.⁸ However, ticagrelor has anti-inflammatory properties via augmenting the production of 15-epi-lipoxin-A₄.^7,9,14,16 It is unclear whether these inflammation-resolution properties contributed to amelioration of oedema.

In conclusion, the current study is promising, as the infarct-size-limiting effects of ticagrelor in a large animal models were sustained over time. It has yet to be shown that similar effects can be achieved at blood levels seen in the clinical setting and with the background of current standard of care therapy (aspirin, statins, etc.), before we can proceed with clinical trials.

Conflict of interest: Y.B. and Y.Y.: Research grants Astra Zeneca; Y.Y.: Boehringer Ingelheim Pharmaceuticals, Inc.

Funding

John S. Dunn Endowment for Cardiology Research and Education.

The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.