Antiplatelet therapy in ACS

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.

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.

Figure 2. Role of platelets in acute coronary syndrome pathophysiology (Adapted⁴). GPIIb-IIIa, glycoprotein IIb/IIIa receptor; vWF, von Willebrand factor.

Following immediate treatment of ACS to restore blood flow, long-term treatment aims to improve heart function and lower the risk of a heart attack, either through surgery or pharmacological management. Pharmacological treatment classes include antiplatelet therapies, thrombolytics, beta-blockers, statins, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)⁵.

Antiplatelet therapy to prevent platelet activation and aggregation is essential in the management of ACS, particularly after percutaneous coronary intervention (PCI)⁵

Antiplatelet therapy options for ACS include aspirin, which binds to cyclooxygenase-1 (COX-1) and inhibits TXA₂ synthesis, and the P2Y₁₂ inhibitors clopidogrel, ticagrelor, prasugrel and cangrelor⁵. These agents can be given as monotherapy or as dual antiplatelet therapy (DAPT) involving a combination of aspirin and a P2Y₁₂ inhibitor⁵. Other agents include the GPIIb/IIIa inhibitors eptifibatide and tirofiban and the protease-activated receptor (PAR)-1 inhibitor vorapaxar (Figure 3)⁵. Antiplatelet therapy is especially important after PCI because balloon angioplasty and stenting stretch the coronary arterial wall, leading to platelet activation, which induces inflammation and increases the risk of thrombosis⁶.

Figure 3. Therapeutic approaches for antiplatelet therapy (Adapted⁵).

Aspirin

Aspirin inhibits COX-1 in platelets, resulting in irreversible inhibition of the synthesis of TXA₂, a potent vasoconstrictor and major inducer of platelet activation and aggregation⁷. The beneficial effects of low-dose aspirin in treating ACS have been well established since the 1980s^8,9, and several randomised clinical trials have consistently demonstrated a dramatic reduction (40–50%) in the risk of subsequent myocardial infarction, stroke or vascular death among patients with ACS treated with aspirin^10–14. 

The question of the maintenance dose for aspirin has been long debated. Currently, maintenance doses range from 75–325 mg¹⁵. The only large-scale ACS randomised trial that compared lower dose (75–100 mg daily) with higher dose (300–325 mg daily) aspirin was the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events-Organisation to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) trial¹⁶. Here, 25,086 patients with ACS received either lower dose or higher dose aspirin, and there was no difference in death, myocardial infarction or stroke at 30 days (4.4% vs 4.2%, respectively)¹⁶. There was also no difference in overall bleeding events (2.3% for both aspirin doses) in the follow-up, although an increased rate of gastrointestinal bleeding in the higher dose group (0.2% vs 0.4%; P=0.04) was observed¹⁶.

P2Y₁₂ inhibitors

P2Y₁₂ inhibitors that are currently available include the orally active agents clopidogrel, ticagrelor, prasugrel and clopidogrel, and intravenously administered cangrelor (Figure 4)⁵.

Figure 4. P2Y₁₂ receptor inhibition by different antiplatelet drugs (Adapted¹⁷). cAMP, cyclic adenosine monophosphate; CYP, cytochrome P450; PKA, protein kinase A; VASP, vasodilator-stimulated phosphoprotein.

Table 1 further summarises the differences and similarities between the drug characteristics for the P2Y₁₂ inhibitors.

Table 1. Comparison of drug characteristics for P2Y₁₂ inhibitors (Adapted¹⁸).

Clopidogrel

Clopidogrel, an orally active, second-generation thienopyridine, inhibits ADP-induced platelet aggregation by inhibiting ADP binding to P2Y₁₂ receptors and blocking the subsequent activation of the glycoprotein GPIIb/IIIa complex¹⁷. Clopidogrel is a prodrug that requires a two-step metabolism for biotransformation to its active form. The enzyme cytochrome P450 mediates oxidation of clopidogrel to 2-oxoclopidogrel, followed by conversion of 2-oxoclopidogrel to an active metabolite that irreversibly inhibits the P2Y₁₂ receptor on the platelet surface¹⁹.

Clinical trials have shown that clopidogrel, an orally active irreversible P2Y₁₂ inhibitor, significantly improves outcomes for patients with ACS without increasing fatal bleeding risk^16,20,21

In the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, patients with NSTEMI treated with 75–325 mg daily aspirin were randomised to receive clopidogrel (300 mg immediately, followed by 75 mg once daily; 6,259 patients) or placebo (6,303 patients)²⁰. At 12 months, the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction or stroke was significantly lower in the clopidogrel group than in the placebo group (9.3% vs 11.4%; P<0.001) with increased major bleeding (3.7% vs 2.7%; P=0.001), but no increase in fatal bleeding or intracranial haemorrhage²⁰. A subgroup analysis involving 2,658 patients who received PCI (PCI-CURE trial) showed that clopidogrel was associated with significantly lower rates of cardiovascular death, myocardial infarction and urgent target-vessel revascularisation within 30 days of PCI, compared with placebo (4.5% vs 6.4%; relative risk [RR], 0.7; 95% confidence intervals [CI], 0.50–0.97; P=0.03)²¹.

The CURRENT–OASIS 7 trial investigated optimal clopidogrel and aspirin dosing¹⁶. In this study 25,086 patients with ACS were randomised to receive either the standard dose of clopidogrel (300 mg loading dose, then 75 mg daily) or double-dose clopidogrel (300 mg loading dose, 150 mg daily for 6 days, then 75 mg daily)¹⁶. Similar reductions in the primary composite endpoint of cardiovascular mortality, stroke or myocardial infarction at 30 days were seen with double-dose and standard-dose clopidogrel (4.2% vs 4.4%, respectively; hazard ratio [HR], 0.94; 95% CI, 0.83–1.06; P=0.30); however, double-dose clopidogrel was associated with higher rates of major bleeding (2.5% vs 2.0%; HR, 1.24; 95% CI, 1.05–1.46; P=0.01)¹⁶.

The main drawbacks associated with the use of clopidogrel are its slow onset of action and high interindividual variability in the response²². It is estimated that the percentage of nonresponders is around 25% and this nonresponsiveness is associated with a threefold increase in adverse outcomes²³. Clopidogrel resistance is multifactorial²⁴, but genetic polymorphisms in the metabolic activation of clopidogrel (e.g., cytochrome P450 2C19) and drug–drug interactions at this level (e.g., between proton pump inhibitors [PPIs] and clopidogrel) are both associated with decreased clopidogrel efficacy²³. Therefore, it is important to consider clopidogrel resistance in some patients and establish strategies to manage this problem (e.g., genotyping, platelet aggregability tests, use of alternative antiplatelet drugs).

Prasugrel

Prasugrel is a third-generation, orally active thienopyridine that is more readily metabolised to its active metabolite, compared with clopidogrel²⁴. This translates into a faster onset of action, lower interindividual variability of pharmacological response and, most importantly, greater antithrombotic efficacy²⁵.

Prasugrel has a faster onset of action and greater antithrombotic efficacy than clopidogrel in patients aged <75 years or weighing >60 kg and with no history of stroke^25,26

In the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimising Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction) study, 13,608 patients presenting with ACS, for whom PCI was planned, were randomised to receive either prasugrel (60 mg loading dose, then 10 mg daily maintenance dose) or clopidogrel (300 mg loading dose, then 75 mg daily maintenance dose) for a median of 14.5 months²⁶. A significantly greater reduction in the primary composite outcome of cardiovascular mortality, nonfatal myocardial infarction or nonfatal stroke was seen in those treated with prasugrel, compared with clopidogrel (9.9% vs 12.1%; HR, 0.81; 95% CI, 0.73–0.90; P<0.001), primarily due to a reduction in myocardial infarction²⁶. On the other hand, the greater mean inhibition of platelet function led to an increase in major bleeding in participants who received prasugrel (2.4% vs 1.8%; HR, 1.32; 95% CI, 1.03-–1.68; P=0.03)²⁶. Specifically, a post hoc analysis of the TRITON-TIMI 38 study showed no net clinical benefit of prasugrel for patients aged 75 years or older (HR, 0.99; 95% CI, 0.81–1.21; P=0.92) or weighing <60 kg (HR, 1.03; 95% CI, 0.69–1.53; P=0.89) and net harm for those with a history of stroke or transient ischaemic attack (HR, 1.54; 95% CI, 1.02–2.32; P=0.04)²⁶. When the US Food and Drug Administration (FDA) approved prasugrel in July 2009, it prohibited prescribing it to patients with a history of stroke or TIA^27–29.

Ticagrelor

Unlike clopidogrel and prasugrel, ticagrelor is not a thienopyridine. Ticagrelor is an orally active, direct-acting, third-generation reversible antagonist of the P2Y₁₂ receptor³⁰. It is associated with faster onset and a longer half-life than clopidogrel^18,30.

Ticagrelor is an orally active, reversible P2₁₂ inhibitor with a faster onset of action, longer half-life and greater antithrombotic efficacy in ACS than clopidogrel^18,30,31

The PLATO (Study of Platelet Inhibition and Patient Outcomes) trial randomised 18,624 patients admitted for ACS to receive either ticagrelor (180 mg loading dose, then 90 mg twice daily) or clopidogrel (300–600 mg loading dose, then 75 mg daily)³¹. The primary composite outcome was cardiovascular mortality, stroke or myocardial infarction. At 12 months’ follow-up, ticagrelor was associated with a significantly greater reduction in the primary outcome, compared with clopidogrel (9.8% vs 11.7%; HR, 0.84; 95% CI, 0.77–0.92; P<0.001)³¹. Ticagrelor was also associated with significantly greater reductions in secondary endpoints, compared with clopidogrel, as well as a greater reduction in all-cause mortality (4.5% vs 5.9%; HR, 0.78; 95% CI, 0.69–0.89; P<0.001)³¹. No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs 3.8%; P=0.03)³¹.

The TWILIGHT study compared ticagrelor alone and in combination with aspirin in high-risk patients after coronary intervention³². Among high-risk patients who underwent PCI and completed 3 months of DAPT, ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin, with no higher risk of death, myocardial infarction or stroke³².

Cangrelor

Cangrelor is a direct, reversible, short-acting P2Y₁₂ receptor inhibitor that has been evaluated during PCI for stable chronic coronary syndrome (CCS) and ACS in clinical trials comparing it with clopidogrel, administered before PCI [Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PCI)] or after PCI (CHAMPION PLATFORM and CHAMPION PHOENIX)^33–35. A meta-analysis of these trials showed a benefit with respect to major ischaemic endpoints that was counter-balanced by an increase in minor bleeding complications³³. Moreover, the benefit of cangrelor with respect to ischaemic endpoints was attenuated in CHAMPION PCI with upfront administration of clopidogrel, while data for its use in conjunction with ticagrelor or prasugrel treatment are limited³³. Given its proven efficacy in preventing intraprocedural and postprocedural stent thrombosis in P2Y₁₂ receptor inhibitor-naive patients, cangrelor may be considered on a case-by-case basis in P2Y₁₂ receptor inhibitor-naive patients with unstable angina or NSTEMI (NSTE-ACS) undergoing PCI³⁶.

Dual antiplatelet therapy (DAPT)

Although there are several potential combinations of antiplatelet therapy, the term and acronym DAPT has been used to refer specifically to the combination of aspirin and a P2Y₁₂ receptor inhibitor (clopidogrel, prasugrel or ticagrelor). DAPT provides greater platelet inhibition and has been shown to reduce recurrent major ischaemic events in patients with ACS^5,30,37; however, DAPT also increases the risk of bleeding. There is general agreement that DAPT should be continued for 6–12 months after placement of a coronary stent³⁸. The risks and benefits of extending DAPT treatment beyond six months have been investigated in several clinical trials³⁸. Of these trials, the DAPT trial is the largest and the only double-blind trial to assess the risks and benefits of continuing DAPT for more than one year after placement of a drug-eluting stent³⁹. This trial found that extending DAPT for 30 months significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding (Figure 5)³⁹.

Figure 5. Results of the DAPT study on patients who had received drug-eluting stents (Adapted³⁹). Cumulative incidence of stent thrombosis (left panel) and major adverse cardiovascular and cerebrovascular events (right panel). HR, hazard ratio.

The use of DAPT necessitates balancing the benefits of decreased ischaemic risk against the increased risk of bleeding³⁸

Decisions about treatment with and duration of DAPT require a thoughtful assessment of the benefit/risk ratio, integration of study data and consideration of patient preference. For example, a longer duration of DAPT generally results in decreased ischaemic risk, compared with a shorter duration of DAPT, at the expense of increased bleeding risk⁴⁰. The use of more potent P2Y₁₂ inhibitors (ticagrelor or prasugrel) in place of clopidogrel also results in decreased ischaemic risk and increased bleeding risk⁴⁰. In general, shorter duration DAPT can be considered for patients at lower ischaemic risk with high bleeding risk, whereas longer duration DAPT may be reasonable for patients at higher ischaemic risk with lower bleeding risk¹⁵.

Factors that increase ischaemic risk and may favour longer duration DAPT are³⁸:

• Advanced age
• ACS presentation
• Multiple prior MIs
• Extensive CAD
• Diabetes mellitus
• CKD

Similarly, factors that increase the risk of stent thrombosis and may favour longer duration DAPT are³⁸:

• ACS presentation
• Diabetes mellitus
• Left ventricular ejection fraction <40%
• First-generation drug-eluting stent
• Stent undersizing
• Stent underdeployment
• Small stent diameter
• Greater stent length
• Bifurcation stents
• In-stent restenosis

Conversely, factors that increase bleeding risk and favour shorter-duration DAPT are³⁸:

• History of prior bleeding
• Oral anticoagulant therapy
• Female sex
• Advanced age
• Low body weight
• Chronic kidney disease
• Diabetes mellitus
• Anaemia
• Chronic steroid or NSAID therapy

Tools to assess the benefit/risk of extending the duration of DAPT include the DAPT study score and the Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score^41,42. A high DAPT score ≥2 in patients who have received a 12-month course of DAPT without experiencing ischaemic or bleeding events favours prolongation to 30 months⁴². Conversely, a high PRECISE-DAPT score of ≥25 at the index event signifies a high risk of bleeding and a potential benefit from shortened DAPT duration⁴³.

In the STOPDAPT-2 trial (Short and Optimal Duration of Dual Antiplatelet Therapy-2), 1-month DAPT followed by clopidogrel monotherapy as compared with 12-month DAPT with aspirin and clopidogrel substantially reduced major bleeding events without an increase in cardiovascular events⁴⁴. Therefore, 1-month DAPT followed by clopidogrel monotherapy might be an option in patients with high bleeding risk, although more data are needed.

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

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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.