Evidence for intensive platelet inhibition in ACS
Dual antiplatelet therapy (DAPT) with aspirin and a thienopyridine is generally regarded as a cornerstone of treatment in the management of acute coronary syndromes (ACS) due to its efficacy in reducing the rate of ischaemic events. At a symposium held during the European Society of Cardiology (ESC) Congress 2019 and the World Congress of Cardiology (WCC) 2019 in Paris, France, experts reviewed the evidence behind intensive platelet inhibition in the treatment of ACS, with particular emphasis on the use of ticagrelor.
PLATO trial: One decade on
“To date, 85 published manuscripts and 90 presented abstracts have arisen from the PLATO study, which involved 257 unique co-authors from at least 35 countries,” said Professor Lars Wallentin of the Uppsala University, Uppsala, Sweden. “In the 10 years since results of the PLATO study were published, we have continued to refine the use of DAPT to optimize outcomes in ACS.”
Rationale for targeting P2Y12 receptor for platelet inhibition
An essential part of the platelet activation process is the interaction between adenosine diphosphate (ADP) and the platelet P2Y12 receptor – a key receptor involved in the activation of the glycoprotein IIb/IIIa receptor. The activation of the glycoprotein IIb/IIIa receptor in turn leads to prolonged platelet aggregation. [J Thromb Thrombolysis 2012;33:143-153] As activation of the P2Y12 receptor results in a powerful amplification of these processes, the introduction of P2Y12 receptor antagonists would thus have significant inhibitory effects on platelet function, regardless of the activating stimuli. [Curr Pharm Des 2006;12:1255-1259] “This phenomenon makes the P2Y12 receptor an ideal target for platelet inhibition therapy,” said Professor Robert Storey of the University of Sheffield, UK.
Describing how the degree of P2Y12 receptor blockade closely mirrors the inhibition of platelet aggregation, Storey noted that the increase in receptor blockage corresponds with an increase in inhibition of platelet aggregation. “While we do not know the optimal level of P2Y12 receptor blockade required to effectively inhibit platelet function, there is data to suggest that blockade of at least 80 percent of P2Y12 receptors will provide strong inhibition of platelet aggregation,” he said. [Thromb Haemost 2010;103:1201-1217]
DAPT a cornerstone of treatment in ACS
In 2007, the TRITON-TIMI 38 investigators concluded that greater inhibition of ADP-induced platelet aggregation by prasugrel is more effective at preventing ischaemic events than the inhibition conferred by a standard regimen of clopidogrel in patients with ACS. [N Engl J Med 2007;357:2001-2015] A further study – PRINCIPLE-TIMI 44 – showed that a 60 mg loading dose of prasugrel resulted in greater platelet inhibition than a 600 mg loading dose of clopidogrel (p<0.0001). [Circulation 2007;116:2923-2932]
The PEGASUS-TIMI 54 trial, which enrolled more than 21,000 patients with a history of MI and risk factors, demonstrated that DAPT with ticagrelor 60 mg BID or 90 mg BID resulted in statistically significant reductions in major cardiovascular (CV) thrombotic events. [Am Heart J 2014;167:437-444] “A subsequent substudy showed that peak and trough platelet inhibition was similar in patients who received either dose of ticagrelor, thus explaining the efficacy of the lower dose,” said Storey. [J Am Coll Cardiol 2016;67:1145-1154]
DAPT with aspirin and ticagrelor has been shown to increase bleeding time in healthy volunteers. [Platelets 2013;24:615-624] There is evidence that higher aspirin doses can markedly reduce the effects of ticagrelor on haemostasis, thereby leading to increased bleeding risk in ticagrelor-treated ACS patients. [Platelets 2019;30:148-157] “Further research is required to assess how different regimens can improve the balance of clinical efficacy and safety, and on how to individualize therapy,” suggested Storey.
Changing clinical outcomes with more intensive platelet inhibition
In the CURE trial, investigators showed that DAPT with clopidogrel and aspirin resulted in beneficial effects in patients with non─ST-elevation ACS. The benefits in CV death, MI and stroke were consistent among patients undergoing percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) surgery, and medical therapy. As the study also showed a higher rate of life-threatening bleeding among patients undergoing CABG who were randomized to receive clopidogrel (5.6 percent vs 4.2 percent for placebo), the investigators concluded that the potential risks and benefits of initiating clopidogrel should be considered on an individual basis. [N Engl J Med 2001;345:494-502; Circulation 2004;110:1202-1208]
In the TRITON-TIMI 38 trial, patients randomized to receive DAPT with prasugrel had more significant reductions in rates of CV death, MI and stroke than those who received clopidogrel. [N Engl J Med 2007;357:2001-2015] “However, as is expected with more intensive platelet inhibition, there was a significant increase in major bleeding and non-CABG bleeding in the prasugrel group,” highlighted Professor Christopher Paul Cannon of the Harvard Medical School in Boston, Massachusetts, US.
Ticagrelor plus aspirin efficacious in ACS with or without ST-segment elevation
“The PLATO trial was carried out to investigate if ticagrelor was superior to clopidogrel for the prevention of vascular events and death in ACS patients with or without ST-segment elevation. At the time, clopidogrel plus aspirin was the recommended DAPT for these patients,” said Cannon. [N Engl J Med 2009;361:1045-1057]
At 12 months, the primary endpoint – a composite of death from vascular causes, MI or stroke – had occurred in 9.8 percent vs 11.7 percent of patients in the ticagrelor vs clopidogrel group (p<0.001). (Figure 1) The rate of all-cause mortality was also reduced with ticagrelor (4.5 percent vs 5.9 percent with clopidogrel; p<0.001).
“What really stood out was the consistency of the findings in terms of reduction of CV death,” said Cannon. The authors noted that the improved survival rates with ticagrelor may be due to decreased risk of thrombotic events without a concomitant increase in risk of major bleeding normally observed with other antithrombotic treatments in patients with ACS. [N Engl J Med 2009;361:1045-1057]
“The long-term benefits of intensive platelet inhibition with ticagrelor were illustrated in PEGASUS-TIMI 54 trial. When compared with placebo through 3 years, both doses of ticagrelor [90 mg BID and 60 mg BID] significantly reduced the rate of the primary composite endpoint of CV death, MI or stroke among stable patients with a history of MI,” said Cannon. (Figure 2) [N Engl J Med 2015;372:1791-1800]
According to the 2017 ESC focused update on DAPT in coronary artery disease, ticagrelor plus aspirin therapy has a Class I recommendation for the treatment of patients with ACS regardless of initial treatment strategy – including patients pre-treated with clopidogrel – unless otherwise contraindicated. [Eur Heart J 2018;39:213-260]
Intensive platelet inhibition in various clinical settings
“A systematic review and meta-analysis showed early benefits of potent P2Y12 inhibition for primary PCI in patients with ST-segment elevation MI,” said Professor Stefan James of the Uppsala University, Uppsala, Sweden. “These early benefits included improved coronary reperfusion, as well as lower rates of major adverse cardiac events and MI requiring bailout with glycoprotein IIb/IIIa inhibitors.” [EuroIntervention 2018;14:78-85]
In PLATO, the benefits of using ticagrelor in DAPT were consistent across various subgroups of patients, including the elderly (age ≥75 years), patients with diabetes, and those with prior stroke or transient ischaemic attack (TIA). [N Engl J Med 2009;361:1045-1057] “We have also shown a lower cumulative incidence of all-cause mortality in patients with or without prior stroke or TIA who were treated with ticagrelor vs clopidogrel,” said James. (Figure 3) [Circulation 2012;125:2914-2921]
“The SWEDEHEART study showed an increase in the use of ticagrelor in Sweden in the last few years, whereas the use of clopidogrel and prasugrel has dropped. Of 28,639 patients admitted for ACS between January 2012 and December 2013, 44 percent had been prescribed ticagrelor at discharge,” said James. “SWEDEHEART also showed that the risk of both death and major bleeding were lower in ticagrelor-treated patients vs patients treated with other antiplatelet agents.” [Eur Heart J 2016;2:5-12]
“In general, potent platelet inhibition appears to have the same benefits in clinical practice as those demonstrated in the pivotal trials,” concluded James.