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Dual antiplatelet therapy in the ‘real world’
  1. Eunice N C Onwordi1,2,
  2. William AE Parker1,2,
  3. Robert F Storey1,2
  1. 1 Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
  2. 2 Cardiology and Cardiothoracic Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
  1. Correspondence to Professor Robert F Storey, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2RX, UK; r.f.storey{at}sheffield.ac.uk

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Dual antiplatelet therapy (DAPT) with aspirin and an oral P2Y12 inhibitor is a successful strategy for preventing recurrent ischaemic events following acute coronary syndromes (ACS). Clopidogrel was previously the P2Y12 inhibitor of choice but interpatient heterogeneity in levels of achieved platelet inhibition and delayed onset of action limit its efficacy. Consequently, the more potent P2Y12 inhibitors prasugrel and ticagrelor have been compared with clopidogrel in randomised controlled trials (RCT) of patients with ACS. In Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38, prasugrel significantly reduced recurrent ischaemic events in moderate to high risk patients managed with percutaneous coronary intervention (PCI) but increased major bleeding. In PLATelet inhibition and patient Outcomes  (PLATO), ticagrelor significantly reduced rates of vascular death, myocardial infarction (MI) and stroke at 12 months, without increasing overall major or fatal bleeding but with more non-coronary artery bypass grafting-related bleeding. Given their superior ischaemic risk reduction, international guidelines now preferentially recommend prasugrel and ticagrelor use in patients with ST-elevation MI (STEMI) and non-STEMI without contraindications, except in those requiring oral anticoagulant therapy.1

Scepticism over the applicability of these findings to real-world settings remains since patients in RCTs can be highly selected due to rigorous exclusion criteria. Elderly patients and others with extensive comorbidity are often under-represented, calling into question the external validity of DAPT RCTs in these high-risk groups. Such concerns may result in underuse of guideline-recommended therapy. However, the perception that DAPT RCTs are not representative of patients managed invasively for ACS may be incorrect. Complementary real-world data have supported the RCT findings. Analysis of 45 073 patients with ACS, identified from the System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry, demonstrated a lower incidence of the combined endpoint of death, MI or stroke as well as lower mortality alone in ticagrelor-treated versus clopidogrel-treated patients. As expected, rates of PCI-related bleeding and readmissions with bleeding were higher with ticagrelor.2 In our centre, we examined the outcomes of 10 793 consecutive patients with ACS undergoing coronary angiography, comparing ticagrelor and prasugrel with clopidogrel, and found that ticagrelor was associated with lower all-cause mortality (adjusted HR 0.82, 95% CI 0.71 to 0.96, p=0.01) in the entire population as well as lower rates of stent thrombosis in PCI-treated patients.3 In the STEMI subgroup, both prasugrel and ticagrelor were associated with lower mortality.

In their Heart paper, Grimaldi-Bensouda et al further explore the outcomes of patients presenting with ACS, according to choice of P2Y12 inhibitor.4 In the case-referent matched Antiplatelet agents and Recurrent Myocardial Infarction Study  (AReMIS) registry study, the incidence of recurrent fatal and non-fatal MI in ticagrelor-treated and prasugrel-treated versus clopidogrel-treated patients was compared. Ticagrelor and prasugrel use within 30 days of index ACS resulted in 35% and 29% risk reductions, respectively. Further analysis revealed that the magnitude of risk reduction was determined by the index ACS presentation and was most marked where this presentation was a first STEMI (ticagrelor OR 0.39; 95% CI 0.24 to 0.62 and prasugrel OR 0.44; 95% CI 0.26 to 0.75). This is in line with RCTs suggesting that more potent antiplatelet therapy is most effective, compared with clopidogrel, in reducing recurrent ischaemic events in higher risk patients. However, the extent of risk reduction demonstrated in AReMIS is notably more profound than in RCTs, most likely due to residual confounding since it is improbable that such analyses are able to sufficiently adjust for all confounders. Consequently, such observational analyses should be treated with caution even though they add confidence to translation of RCT findings to clinical practice.

The preferential use of newer P2Y12 inhibitors in younger patients in registries reflects clinical practice in some centres. Such tailoring of therapy may be warranted in the case of prasugrel since, in TRITON-TIMI 38, prasugrel had less clinical efficacy and was associated with more frequent major bleeding in patients ≥75 years, those with a history of cerebrovascular disease and in patients of low body weight. As such, it is either cautioned or contraindicated in these patients. On the other hand, a prespecified analysis of PLATO showed a significant reduction in the composite endpoint independent of age (≥75 vs <75 years) and no increase in overall major bleeding with ticagrelor with increasing age.5 Comorbid conditions that raise cardiovascular (CV) risk as well as bleeding risk become more prevalent with advancing age. Finding the right balance between effective thrombotic risk reduction and minimising bleeding remains challenging and likely explains the tendency of clinicians to use less potent antiplatelet therapy in high-risk patients. Real-world data on the outcomes of very elderly patients managed with ticagrelor for ACS remain relatively sparse and further studies assessing its efficacy and safety in these patients are needed.

A well-documented risk factor for MI is chronic kidney disease (CKD), the prevalence of which increases dramatically with age. CKD is defined as a creatinine clearance (CrCl) of <60 mL/min for ≥3 months. It is present in up to 40% of patients presenting with MI and is an independent risk factor for bleeding, recurrent ischaemic events and all-cause mortality.6 The mechanisms driving these worse outcomes are not fully understood but may include accelerated atherosclerosis, inflammation, increased platelet reactivity and adverse changes in blood coagulability.7 Hypertension is more prevalent in CKD and patients tend to be older, factors that undoubtedly increase the associated CV risk.

In PLATO, subgroup analysis demonstrated greater absolute risk reduction with ticagrelor in those with moderate CKD compared with those without.7 A lower admission CrCl was associated with increased major bleeding overall but no significant difference in rates of major bleeding by antiplatelet therapy. However, the numbers of patients with advanced CKD in PLATO were few and those with end-stage renal failure were excluded. Unexpectedly, ticagrelor treatment was associated with a slight and reversible excess in creatinine levels compared with clopidogrel. The mechanisms underlying this are unclear but, importantly, the transient rises in creatinine were not associated with an increase in adverse events.

In their Heart paper, Edfors et al explore outcomes following DAPT for acute MI in relation to renal function.8 Data from 45 206 unselected consecutive patients from the SWEDEHEART registry presenting with MI and discharged alive on DAPT with aspirin and ticagrelor or clopidogrel were analysed with respect to a composite of death, readmission with stroke or MI at 1 year. Individual components of the primary outcome as well as in-hospital bleeding and readmission with bleeding were also evaluated. CKD (estimated glomerular filtration rate (eGFR) 30–60 and eGFR <30 mL/min) was associated with a higher incidence of the combined endpoint at 12 months. Ticagrelor treatment was associated with a lower risk of the combined endpoint across all eGFR subgroups: eGFR >60 mL/min: HR 0.87 (95% CI 0.76 to 0.99), eGFR 30–60 mL/min: HR 0.82 (95% CI 0.70 to 0.97), eGFR <30 mL/min: HR 0.95 (95% CI 0.69 to 1.29). This trend was not significant in advanced CKD (eGFR <30 mL/min) but patient numbers in this group were few and CIs wide, suggesting insufficient power to detect potential differences between the groups. There was no sign of interaction between renal function and treatment regarding the primary outcome. Bleeding risk, including PCI-related bleeding, was significantly higher with ticagrelor across all eGFR subgroups. Limitations of the study include analysis based on intended treatment rather than necessarily actual treatment. If antiplatelet therapy was altered or discontinued after discharge, this would not have been taken into account. However, given the large numbers of patients in the registry and well-documented tolerability of the different drugs, it is unlikely that the conclusions would be substantially changed if medication alterations had been accounted for.

These findings support those of the PLATO substudy demonstrating an even greater benefit of ticagrelor in patients with CKD7 and are further supported by analysis of patients with CKD 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 trial.6 Given the large number of unselected patients with ACS with moderate CKD in the SWEDEHEART registry, clinicians may have more confidence using ticagrelor in this setting. However, the clinical benefit of ticagrelor in unselected patients with an eGFR <30 mL/min remains uncertain.

Optimal antithrombotic therapy in ACS remains a subject of debate and the balance between ischaemic risk reduction and bleeding is often fine. In this edition of Heart, evaluation of registry data sheds further light on the effects of DAPT in the real world and compares favourably with the outcomes seen in RCTs. This may alleviate clinician concerns and support further uptake of guideline-recommended therapy. Still, little is known about the clinical effects of ticagrelor in dialysis-dependent patients and the very elderly so more research is needed in these groups.

References

Footnotes

  • Contributors ENCO drafted the article which was critically revised by RFS and WAEP.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests RFS: institutional research grants/support from AstraZeneca and PlaqueTec; consultancy fees from AstraZeneca, Actelion, Avacta, Bayer, Bristol Myers Squibb/Pfizer, Idorsia, Novartis, PlaqueTec, and The Medicines Company; speaker fees from AstraZeneca and Bayer.

  • Patient consent Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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