Antiplatelet therapy in ACS

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 ACC and AHA have also produced the 2021 guideline for coronary artery revascularization⁴⁷, which is an update of the 2011 and 2015 guidelines. The 2021 update also replaces some sections of the 2013 guideline for ST-elevation myocardial infarction²⁷ (STEMI) and the 2014 guideline for non-ST-elevation acute coronary syndrome²⁸ (NSTE-ACS).

The ESC and ACC/AHA guidelines consider antiplatelet therapy a cornerstone in the treatment of patients with ACS⁴⁸. However, it is important to highlight the need to tailor treatments according to thrombosis risk versus bleeding risk (Figure 6).

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 inhibitors^27,45:

• ATLANTIC trial investigating ticagrelor pretreatment in patients with STEMI⁴⁹
• ACCOAST trial investigating pasugrel pretreatment in patients with NSTE-ACS⁵⁰

Neither the ATLANTIC nor the ACCOAST trial showed any benefit of pretreatment with ticagrelor or prasugrel, respectively. For patients with STEMI, there is general consensus that P2Y₁₂ inhibitor treatment should be initiated as early as possible, although ESC guidelines recommend delaying treatment if a diagnosis of STEMI is not clear or the anatomy is not known^27,45. For patients with NSTE-ACS, ACC/AHA guidelines recommend initiating therapy before percutaneous coronary intervention (PCI)²⁸. The latest ESC guidelines no longer recommend pretreatment with P2Y₁₂ inhibitors for patients with NSTE-ACS in whom coronary anatomy is not known and PCI is planned, but allow for clinical judgement based on bleeding risk¹⁵.

Before the ESC guidelines were updated in 2020, ESC and ACC/AHA were in agreement that either prasugrel or ticagrelor were the P2Y₁₂ inhibitors of choice for ACS⁴⁸. Clopidogrel was recommended only in the event that prasugrel or ticagrelor were contraindicated or bleeding risk was unacceptably high. The 2020 ESC guidelines incorporated the findings of the ISAR-REACT-5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) trial, which showed that prasugrel was superior to ticagrelor in reducing ischaemic risk without increasing bleeding risk in patients with ACS^15,51. Overall, the 2020 ESC guidelines for NSTE-ACS recommend greater individualisation of antiplatelet treatment based on ischaemic/thrombotic events and bleeding complications and advise on long-term oral anticoagulation management¹⁵.

The new key recommendations of the 2020 ESC guidelines for antiplatelet therapy in patients with NSTE-ACS are¹⁵:

• Prasugrel should be considered in preference to ticagrelor for NSTE-ACS patients who proceed to PCI.
• Routine pretreatment with a P2Y₁₂ receptor inhibitor is not recommended for patients in whom the coronary anatomy is not known and early invasive management is planned; however, it may be considered in patients who do not have a high bleeding risk.
• De-escalation of P2Y₁₂ inhibitor treatment (e.g. with a switch from prasugrel or ticagrelor to clopidogrel) may be considered as an alternative DAPT strategy, especially for ACS patients deemed unsuitable for potent platelet inhibition. De-escalation may be based on clinical judgment or guided by platelet function testing or CYP2C19 genotyping, depending on the patient’s risk profile and availability of respective assays (Figure 7).
• In patients with atrial fibrillation (AF) (CHA2DS2-VASc score ≥1 in men and ≥2 in women), after a short period of triple antithrombotic therapy (TAT) (up to 1 week from the acute event), dual antithrombotic therapy (DAT) is recommended as the default strategy using a non-vitamin K antagonist oral anticoagulant (NOAC) at the recommended dose for stroke prevention and single oral antiplatelet agent (preferably clopidogrel).
• Discontinuation of antiplatelet treatment in patients treated with oral anticoagulants (OACs) is recommended after 12 months.
• DAT with an OAC and either ticagrelor or prasugrel may be considered as an alternative to TAT with an OAC, aspirin, and clopidogrel in patients with a moderate or high risk of stent thrombosis, irrespective of the type of stent used.

Figure 7. De-escalation or escalation of P2Y₁₂ inhibitor treatment in patients undergoing percutaneous coronary intervention (Adapted⁵²). ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention; PFT, platelet function testing.

Download this infographic that summarises the 2020 ESC and 2021 ACC/AHA guidelines for antiplatelet therapy in ACS.

Challenges in antiplatelet therapy selection in ACS

Selection of P2Y₁₂ inhibitor

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 PCI^53–56

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 events^15,51. The 2021 ACC/AHA guideline for coronary artery revascularization has not adopted this recommendation and continues to allow for the use of either prasugrel or ticagrelor⁴⁷.

The ISAR-REACT-5 study, published in 2019, was the first randomised trial to compare ticagrelor with prasugrel⁵¹. 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 bleeding⁵¹. 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 debate^53–55.

Find out more in our expert roundtable discussion on the 2020 ESC guidelines

Several concerns on the implications of the ISAR-REACT 5 study have been raised^53–56:

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 pretreatment⁵⁶.
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 prasugrel⁵⁶.
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 discrepancies^57,58, the true medication adherence in the trial may have been lower than that reported⁵⁵.
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.

More controversies also stem from the results of a prespecified ISAR-REACT 5 subgroup analysis of ticagrelor versus prasugrel efficacy according to diabetic status⁵⁹. In this subgroup of patients with high ischaemic risk and poor antiplatelet response, the efficacy of prasugrel and ticagrelor in reducing ischaemic events (a composite of death, myocardial infarction or stroke) was comparable up to 1 year after randomisation.

Whilst the ISAR-REACT 5 study supports the concept of individualised care for NSTE-ACS patients undergoing PCI, more data are needed to support a preferred drug or strategy⁵⁴

Guidelines from the National Institute of Health and Care Excellence (NICE) in the UK also considered the evidence provided by the ISAR-REACT 5 trial​​. For patients with STEMI, NICE recommends prasugrel if PCI is planned and the patients are not on oral anticoagulant therapy⁶⁰. If medical management is planned, NICE recommends ticagrelor in preference to prasugrel, or clopidogrel if bleeding risk is high⁶⁰. For patients with NSTE-ACS undergoing PCI, NICE acknowledges the ISAR-REACT 5 findings favouring prasugrel over ticagrelor, but for practical reasons, recommends ticagrelor or clopidogrel⁶⁰. The rationale for this is that in the UK,​ there can be delays of up to 72 hours before coronary angiography is performed⁶⁰. This may preclude the use of prasugrel because, in the UK, it is not licenced for use before coronary anatomy is known​​⁶⁰. ACC/AHA and Australian/New Zealand guidelines have not been updated since publication of the ISAR REACT 5 study and do not specify a preference of prasugrel over ticagrelor among patients with confirmed ACS at intermediate to very high- risk of recurrent ischaemic events^61,62.

Overall, while clinical guidelines are updated and improved as new information emerges, concerns raised by experts in the field should be taken seriously and discussed openly

Find out more in our expert roundtable discussion on the 2020 ESC guidelines

Test yourself with our Patient Focus case studies presented by experts

De-escalation of DAPT

The latest ESC guidelines state that de-escalation of P2Y₁₂ inhibitor treatment (e.g. with a switch from prasugrel or ticagrelor to clopidogrel) may be considered as an alternative DAPT strategy, especially for ACS patients deemed unsuitable for potent platelet inhibition¹⁵. There are many variables that should be considered when favouring de-escalation of DAPT (Figure 8)¹⁵.

Figure 8. Variables that should be considered for favouring de-escalation of DAPT (Adapted¹⁵).

However, it is important to note that there is a potential for increased ischaemic risk with a uniform de-escalation of P2Y₁₂ receptor inhibition after PCI, particularly if performed early (<30 days) after the index event⁶³. Indeed, dedicated large-scale trials on a uniform and unguided DAPT de-escalation are lacking, and the available data on uniform de-escalation are conflicting^63,64.

DAPT de-escalation guided by either platelet function testing or CYP2C19-directed genotyping may be considered as an alternative to 12 months of potent platelet inhibition, especially for patients deemed unsuitable for maintained potent platelet inhibition^65,66

After deciding to de-escalate to clopidogrel, it is possible to do this either by giving a loading dose or not⁶³. There have not been any randomised trials powered for clinical outcomes investigating this, but expert consensus papers give recommendations based on pharmacodynamic studies. Whether or not a loading dose is given is based on the timing of de-escalation and the P2Y₁₂ inhibitor used prior to de-escalation (Figure 9). When de-escalating in the early phase (≤30 days from the index event), a 600 mg loading dose of clopidogrel should be administered 24 h after the last dose of prasugrel or ticagrelor⁵². In a sub-analysis of the POPULAR Genetics trial, this method seemed safe with no bleeding and thrombotic events in 172 patients who switched to clopidogrel within seven days after STEMI⁶⁶. When de-escalating from ticagrelor to clopidogrel in the late phase (>30 days from the index event), a 600 mg loading dose 24 h after the last dose of ticagrelor is recommended, while it is not recommended to use a new loading dose when switching from prasugrel to clopidogrel in the late phase⁶⁷. If de-escalating due to bleeding or bleeding concerns, a 75 mg clopidogrel dose could be considered instead of a loading dose irrespective of the phase or initial P2Y₁₂ inhibitor^68,69.

Figure 9. De-escalation dosing recommendation for clopidogrel (Adapted⁵²). IE, index event.

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 ACS^70,71.

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 bleeding^15,61

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​​⁷². Ticagrelor was found to be more effective than clopidogrel in patients with moderate-to-high risk NSTE-ACS in the PLATO trial​⁷³.

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) trial⁷⁴. 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 bleeding⁷⁴. This was true for both ticagrelor doses tested (90 mg and 60 mg) (Figure 10)⁷⁴.

Figure 10. Kaplan–Meier rates of cardiovascular death, myocardial infarction and stroke during the three years follow up in the PEGASUS-TIMI 54 trial (Adapted⁷⁴). 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 clopidogrel^26,75​​. 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.

Table 2. Antiplatelet dosing regimen for patients with NSTE-ACS (Adapted¹⁵). Note: see guidelines for full notes on dosing recommendations. iv, intravenous.

It has been proposed that, because of its association with major bleeding⁷⁶, the ADP-binding enzyme creatine kinase (CK) should be estimated in studies of patients treated for NSTE-ACS^77,78. Major bleeding is one of the most common non-cardiac causes of mortality in NSTE-ACS. Therefore, it is important to identify patients at risk for haemorrhagic complications when designing a treatment plan with antiplatelet therapy. In this context, the application of the Academic Research Consortium for High Bleeding Risk (ARC-HBR) could be a useful tool^79,80. Table 3 shows the major and minor criteria for high bleeding risk according to the ARC-HBR at the time of percutaneous coronary intervention. Bleeding risk is considered high if at least one major or two minor criteria are met¹⁵.

Table 3. Major and minor criteria for high bleeding risk according to the Academic Research Consortium for High Bleeding Risk (ARC-HBR) at the time of percutaneous coronary intervention in patients with NSTE-ACS. Bleeding risk is high if at least one major or two minor criteria are met (Adapted¹⁵). CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular filtration rate; OAC, oral anti-coagulant; PCI, percutaneous coronary intervention.

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 offered⁶⁰:

• 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 placebo⁸¹. 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 haemorrhage⁸¹. These results were further confirmed by the COMMIT study⁸².

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)⁸³.

Prasugrel in STEMI

In the TRITON-TIMI 38 trial, 3,534 patients had STEMI^26,75. 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)^26,75. 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 less⁷⁵. 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)⁷⁵.

Overall, prasugrel is a more efficacious and reasonably safe antiplatelet therapy in patients with STEMI treated with PCI, compared with clopidogrel⁷⁵. 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 kg^27,45.

Ticagrelor in STEMI

Ticagrelor was compared with clopidogrel in patients with ACS in the Platelet Inhibition and Patient Outcomes (PLATO) Study³¹. Patients were randomised to receive either ticagrelor (180 mg loading, 90 mg twice daily maintenance) or clopidogrel (300–600 mg loading, 75 mg daily). Overall, the results for the STEMI subgroup analysis of PLATO were consistent with the main trial^31,84. Of the 18,624 patients, 7,544 patients were diagnosed with STEMI (or left bundle-branch block)⁸⁴. At 12 months, the primary endpoint was reduced in the ticagrelor and clopidogrel groups, but the difference was not statistically significant (10.8 vs 9.4%; P=0.07)⁸⁴. When patients with a final diagnosis of STEMI (not just at presentation) were included, however, the primary endpoint was reduced further in the ticagrelor group and the difference between the groups was significantly different (9.3 vs 11.0%; P=0.02)⁸⁴. Ticagrelor also had a significantly greater effect than clopidogrel in reducing several of the secondary endpoints in the STEMI population, including a composite of cardiovascular death and myocardial infarction (8.4 vs 10.2%, P=0.01); all arterial thrombotic events (13.3% vs 15.0%; P=0.03); the incidence of myocardial infarction alone (4.7% vs 5.8%; P=0.03); and definite stent thrombosis (1.6 vs 2.4%; P=0.03)⁸⁴.

Compared with the CURE trial and TRITON-TIMI 38 studies, the results of PLATO are notable because stronger platelet inhibition from ticagrelor did not result in increased bleeding⁸⁴. This, together with the reduction in mortality, led to an indication of preference for ticagrelor over clopidogrel in the 2016 ACC Guidelines³⁸.

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