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Antiplatelet therapy in ACS: Choices and Controversies

Antiplatelet therapy in ACS

Read time: 110 mins
Last updated:6th Jun 2022
Published:17th Dec 2021

Antiplatelet therapy is a cornerstone of acute coronary syndrome (ACS) management. Discover:

  • The currently available antiplatelet therapies for patients with ACS
  • The challenges in antiplatelet therapy selection for ACS
  • The ESC and ACC/AHA guideline recommendations in our infographics

Antiplatelet therapies in acute coronary syndrome

Acute coronary syndrome (ACS) is an umbrella term for conditions characterised by a sudden reduction or occlusion of blood supply to the heart. ACS presentations include unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). Unstable angina and NSTEMI are grouped together as NSTE-ACS. The most common symptom of ACS is chest pain or discomfort; however, signs and symptoms may vary significantly depending on age, sex and other medical conditions.

ACS is a common cause of mortality and morbidity worldwide (Figure 1)1.

Amongst cardiovascular diseases (CVDs), ACS is the most common cause of death and predictions suggest that the burden will increase globally2

The total number of disability-adjusted life years (DALYs) due to ACS has risen steadily since 1990, reaching 182 million (95% uncertainty intervals [UI], 170 to 194 million) DALYs and 9.14 million (95% UI, 8.40 to 9.74 million) deaths in 20192. The Global Burden of Disease (GBD) Study 2019 estimated 197 million (95% UI, 178 to 220 million) prevalent cases of ACS in 20192.

T1_Anti-Platelet_Fig1.png

Figure 1. Proportion of global cardiovascular disease deaths in 2019 by underlying causes (Adapted2).

ACS results primarily from disruption of atherosclerotic plaques, which leads to thrombus formation and acute obstruction of coronary blood flow (Figure 2). Disruption of the atherosclerotic plaque can be caused by plaque rupture or plaque erosion. Both causes of disruption result in exposure of thrombogenic material within the plaque, including collagen and von Willebrand factor (vWF), which stimulate platelet adhesion3. The next step in the pathogenesis of ACS is platelet activation and release of vasoactive substances (thromboxane A2 (TXA2), adenosine diphosphate (ADP), serotonin, epinephrine, and thrombin), which promote interactions between adherent platelets, as well as further recruitment and activation of circulating platelets3. Binding of ADP to platelet P2Y12 receptors activates the glycoprotein IIb/IIIa receptor (GPIIb-IIIa). Activated GPIIb/IIIa binds to the extracellular ligands, fibrinogen and vWF, leading to platelet aggregation and eventually to thrombus formation3.

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ESC and ACC guideline recommendations for antiplatelet therapy

The European Society of Cardiology (ESC) recommendations for antiplatelet therapy are available in three separate documents:

  1. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation45
  2. 2020 ESC guidelines for the management of patients with acute coronary syndrome without persistent ST-segment elevation15
  3. Focused update on dual antiplatelet therapy (DAPT) guidelines46

The American College of Cardiology (ACC) have produced the following guidelines in collaboration with the American Heart Association (AHA):

  1. 2013 ACC/AHA guideline for the management of ST-elevation myocardial infarction27
  2. 2014 ACC/AHA guideline for non–ST-elevation acute coronary syndromes28
  3. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with acute coronary syndrome38

The ESC and ACC/AHA guidelines consider antiplatelet therapy a cornerstone in the treatment of patients with ACS47. However, it is important to highlight the need to tailor treatments according to thrombosis risk versus bleeding risk (Figure 6).

T1_Anti-Platelet_Fig6.png

Figure 6. Determinants of antithrombotic treatment in acute coronary syndrome (Adapted15). ACS, acute coronary syndrome; CABG, coronary artery bypass graft; CCS chronic coronary syndrome; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; NSTE-ACS, non-ST segment elevation-acute coronary syndrome; STEMI, ST segment elevation myocardial infarction.

Current guidelines recommend that all patients with ACS, whether STEMI or NSTE-ACS, should start aspirin therapy, unless there are contraindications such as risk of life-threatening bleeding or hypersensitivity15

ESC and ACC/AHA guidelines differ slightly in the dose of aspirin recommended (150–300 mg or 162–325 mg, respectively)15,27,28. A second antithrombotic agent should also be considered for extended long-term secondary prevention in patients with a high risk of ischaemic events and without increased risk of major or life-threatening bleeding (Class IIa recommendation)27,45.

Recommendations for the use of P2Y12 inhibitors in ACS

There is limited evidence for the optimal timing of initiating antiplatelet therapy with P2Y12 inhibitors in patients presenting with ACS. Only two clinical trials have investigated pretreatment (initiation of treatment before angiography) with P2Y12 inhibitors27,45:

  • ATLANTIC trial investigating ticagrelor pretreatment in patients with STEMI48
  • ACCOAST trial investigating pasugrel pretreatment in patients with NSTE-ACS49
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Challenges in antiplatelet therapy selection in ACS

There are multiple factors that should be considered when selecting a P2Y12 inhibitor for a given patient. These include patient characteristics and comorbidities, weighting of benefit versus side effects, potential drug-drug interactions and pharmacokinetics. These factors should be considered alongside label indications and clinical guideline recommendations. Whilst clinical guidelines have been immensely improved over the decades, shortcomings can compromise optimal care.

Since publication of the 2020 ESC NSTE-ACS guidelines, leading cardiology experts have voiced concerns on the evidence for the recommendation favouring prasugrel over ticagrelor in patients with NSTE-ACS who proceed to PCI52–55

The 2020 European Society of Cardiology (ESC) guidelines on non-ST-segment elevation acute coronary syndromes (NSTE-ACS) gave a strong level of recommendation (IIa) in favour of prasugrel over ticagrelor in patients with NSTE-ACS who proceed to percutaneous coronary intervention (PCI)15. This recommendation was based on a prospective head-to-head study, ISAR-REACT 5, which concluded that prasugrel was superior to ticagrelor at preventing major adverse ischaemic events15,50.

The ISAR-REACT-5 study, published in 2019, was the first randomised trial to compare ticagrelor with prasugrel50. Patients with ACS undergoing invasive therapy were randomised to receive ticagrelor (loading dose 180 mg, maintenance dose 90 mg twice daily; n = 2012) or prasugrel (loading dose 60 mg, maintenance dose 10 mg daily; n = 2006) and were followed up for 1 year. The maintenance dose of prasugrel was reduced to 5 mg for patients older than 75 years or who weighed less than 60 kg. Patients with a history of stroke, TIA or intracranial haemorrhage were excluded. The primary outcome of death, myocardial infarction or stroke at 1 year occurred in 9.3% of the ticagrelor group and 6.9% of the prasugrel group (P=0.006) with no significant difference in bleeding50. The 2020 ESC guidelines gave a strong level of recommendation (IIa) in favour of prasugrel over ticagrelor in patients with NSTE-ACS who proceed to PCI15. Since publication of the 2020 ESC guidelines, however, leading cardiology experts have voiced concerns about recommendations based only on the ISAR-REACT 5 study, suggesting that equipoise remains between the ticagrelor- and prasugrel-based strategies and more data are needed to settle the debate52–54.

Several concerns on the implications of the ISAR-REACT 5 study have been raised52–55:

  1. The ISAR-REACT 5 trial did not directly compare ticagrelor with prasugrel; rather, it was a comparison of treatment strategies for patients with NSTE-ACS, as all patients received ticagrelor pretreatment, whereas patients with NSTE-ACS did not receive prasugrel pretreatment55.
  2. In addition to its open-label design, the trial was performed in only two countries with an imbalance in enrolling centres (21 centres in Germany and 2 centres in Italy), which could have some impact on the outcomes, however minor.
  3. At discharge, about 19% of patients in each group did not receive the assigned drug for various reasons. After discharge 15% of patients on ticagrelor and 12% on prasugrel discontinued treatment. This rate of discontinuation may have affected the final results by overestimating the beneficial effect of prasugrel55.
  4. After discharge, physicians prescribed commercially available ticagrelor or prasugrel, and patients had to purchase the drugs themselves. No specific method for verifying adherence, such as pill count or medication event monitoring systems, was reported. As patient-reported drug adherence has been previously shown to have significant discrepancies56,57, the true medication adherence in the trial may have been lower than that reported54.
  5. More patients in the prasugrel group (233) than those in the ticagrelor group (23) were excluded from the safety endpoint analysis, raising questions about the safety profile of prasugrel, compared with ticagrelor.
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Evidence for antiplatelet therapy in NSTE-ACS

Patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) account for approximately two-thirds of all hospital admissions for ACS69,70.

Dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitor is recommended for patients with NSTE-ACS for 12 months, unless there are contraindications or an unacceptably high risk of bleeding15,60

Ticagrelor has a faster and more consistent onset of action, compared with clopidogrel, in addition to a quicker offset of action with a more rapid recovery of platelet function​​71. Ticagrelor was found to be more effective than clopidogrel in patients with moderate-to-high risk NSTE-ACS in the PLATO trial​72.

The long-term use of antiplatelet therapy in patients with prior myocardial infarction has been investigated in the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial73. Here, the hypothesis that long-term therapy with ticagrelor added to low-dose aspirin would reduce the risk of major adverse cardiovascular events among stable patients with a history of myocardial infarction was tested. Results showed that, in patients with a myocardial infarction more than 1 year previously, long-term treatment with ticagrelor significantly reduced the risk of cardiovascular death, myocardial infarction or stroke and increased the risk of major bleeding73. This was true for both ticagrelor doses tested (90 mg and 60 mg) (Figure 10)73.

T1_Anti-Platelet_Fig10.png

Figure 10. Kaplan–Meier rates of cardiovascular death, myocardial infarction and stroke during the three years follow up in the PEGASUS-TIMI 54 trial (Adapted73). CI, confidence interval; HR, hazard ratio.

Prasugrel also has a faster onset and is more potent than clopidogrel25. The TRITON-TIMI 38 trial demonstrated that patients receiving prasugrel had fewer recurrent cardiovascular events and less stent thrombosis but more bleeding complications, compared with clopidogrel26,74​​. Therefore, the 2016 ACC/AHA guidelines recommend that it is reasonable to choose prasugrel over clopidogrel for maintenance therapy in patients treated with DAPT after stent implantation, unless they are at high risk of bleeding or have contraindications38. ​On the other hand, results from TRITON-TIMI 38 trial showed that prasugrel increased the risk of major and fatal bleeding in patients with prior stroke or TIA26. In addition, the study showed no apparent benefit for the use of prasugrel over clopidogrel in patients aged above 75 years or with low body weight (<60 kg)26.

On the basis of these studies, clopidogrel is generally used when ticagrelor or prasugrel are not suitable, for example, in those with an indication for oral anticoagulation and in those with prior intracranial bleeding15​. Clopidogrel is used in combination with aspirin at a maintenance dose of 75 mg daily in patients with NSTE-ACS15.

Recommended doses of antiplatelet drugs are shown in Table 2.

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Evidence for antiplatelet therapy in STEMI

Antiplatelet therapy is an essential component of ST-elevation myocardial infarction (STEMI) management.

Current guidelines state that people with acute STEMI who are having primary PCI should be offered59:

  • Prasugrel, as part of dual antiplatelet therapy (DAPT) with aspirin, if they are not already taking an oral anticoagulant
  • Clopidogrel, as part of DAPT with aspirin, if they are already taking an oral anticoagulant

Clopidogrel in STEMI

Clopidogrel use in STEMI was first evaluated in the CLARITY-TIMI 28 study in 2005, which randomised 3,491 patients with STEMI treated with a fibrinolytic agent and aspirin (150–325 mg loading, then 75–162 mg daily) to clopidogrel (300 mg loading, then 75 mg daily) or placebo80. At 30 days, clopidogrel reduced the composite endpoint (cardiovascular death, recurrent myocardial infarction, recurrent ischaemia needing PCI) by 20%, with similar rates of major bleeding and intracranial haemorrhage80. These results were further confirmed by the COMMIT study81.

After establishing the clinical benefits of DAPT with clopidogrel, more trials revealed variability in individual responses, leading to suboptimal responses. These can be due to genetic factors, clinical factors (drug interactions, poor absorption), or cellular factors (P2Y12 pathway upregulation)82.

Prasugrel in STEMI

In the TRITON-TIMI 38 trial, 3,534 patients had STEMI26,74. Prasugrel was associated with a greater improvement than clopidogrel in the primary endpoint at 15 months (10 vs 12.4%, HR 0.79, P=0.02), significantly greater reduction in both secondary endpoints (urgent target vessel revascularisation and stent thrombosis)26,74. However, it is important to note that in the main TRITON-TIMI 38 study, the reported benefits came at the expense of significantly increased major bleeding (2.4 vs 1.8%, HR 1.32; 95% CI, 1.03–1.68), life-threatening bleeding and even fatal bleeding26. In an important subsequent analysis of the main trial, there was no accrued clinical benefit from prasugrel in the following groups: history of stroke or transient ischemic attack (TIA), age 75 years or greater, and weight 60 kg or less74. Those with stroke or TIA were harmed by prasugrel administration (HR 1.54, 95% CI 1.02–2.32), including increased intracranial haemorrhage (2.3% vs none on clopidogrel, P=0.02)74.

Overall, prasugrel is a more efficacious and reasonably safe antiplatelet therapy in patients with STEMI treated with PCI, compared with clopidogrel74. However, prasugrel is contraindicated in patients with a history of stroke or TIA. It is generally not recommended for people age 75 years or older or who weigh <60 kg27,45.

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