William A. E. Parker

Long-term antiplatelet therapy following myocardial infarction: implications of PEGASUS-TIMI 54

Dual antiplatelet therapy (DAPT) is standard treatment for patients with acute coronary syndromes (ACS), typically comprising the use of aspirin with either an irreversible thienopyridine P2Y12 inhibitor, clopidogrel or prasugrel, or reversibly binding ticagrelor. Pivotal studies led to guidelines recommending DAPT for up to 12 months post-ACS. Despite this, there remains a significant burden of coronary artery disease (CAD)-related events up to and after this period. Recent meta-analyses, including both patients with ACS and patients with stable CAD treated with DAPT following percutaneous coronary intervention, have suggested that long-term thienopyridine-based DAPT reduces the risks of myocardial infarction (MI) and stent thrombosis but may paradoxically increase all-cause mortality risk. The PEGASUS-TIMI 54 (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) study examined the effects of long-term DAPT with aspirin and ticagrelor, compared with aspirin alone, on major adverse cardiovascular events (MACE) and complications, including bleeding in patients with prior history of MI. It showed that, over a 3-year period, ticagrelor reduced the risk of MACE but increased non-fatal bleeding risk. Overall, the PEGASUS-TIMI 54 results demonstrate that patients with a history of ACS deemed to be at high risk of further ischaemic events, particularly those in whom the risks of ischaemic events and cardiovascular death outweigh the risk of life-threatening bleeding, may benefit from prolonged ticagrelor-based DAPT. Guidelines are emerging which reflect this. The relationship between aspirin and ticagrelor, particularly with regard to aspirin dosing, remains to be fully elucidated and attention has recently been turned to the option of ticagrelor monotherapy. Future studies will explore optimal individualised strategies for long-term antiplatelet therapy.

Characteristics of dyspnoea and associated clinical outcomes in the CHAMPION PHOENIX study

Dyspnoea may be induced by some reversibly-binding P2Y12 inhibitors, including cangrelor and ticagrelor. Dyspnoea was not associated with any compromise to the efficacy of ticagrelor in the PLATO study. The CHAMPION PHOENIX study (NCT01156571) compared initial treatment with cangrelor versus initial treatment with clopidogrel in patients undergoing PCI. We investigated the incidence, characteristics, and associated clinical outcomes in patients with dyspnoea in CHAMPION PHOENIX. Adverse events (AEs) of dyspnoea to 48 hours were recorded in patients randomised to cangrelor or clopidogrel in CHAMPION PHOENIX. The composite primary endpoint of death, myocardial infarction, ischaemia-driven revascularisation, or stent thrombosis as well its individual components were assessed in patients who did or did not report dyspnoea. A total of 68 (1.2 %) cangrelor-treated patients and 18 (0.3 %) clopidogrel-treated patients reported dyspnoea (p<0.001). Most dyspnoea events in cangrelor-treated patients were considered mild (71 %) or moderate (28 %) and only one event was considered severe and led to discontinuation of cangrelor. The dyspnoea events in the clopidogrel-treated patients were mild (78 %) or moderate (22 %). Characteristics of dyspnoea were consistent with those seen in the CHAMPION programme as a whole. In the modified intention-to-treat population, rates of the composite primary outcome and its individual components were not affected by the presence of dyspnoea in cangrelor-treated patients. Cangrelor-related dyspnoea is transient, usually mild or moderate, and unlikely to lead to discontinuation of therapy. The occurrence of dyspnoea does not seem to be associated with any reduction in the efficacy of cangrelor compared with clopidogrel as initial therapy in PCI patients.

Choices for Potent Platelet Inhibition in Patients With Diabetes Mellitus

Article, see p 780 Diabetes mellitus provides challenges to clinicians seeking to optimize the efficacy of pharmacological therapies for the management and prevention of atherothrombotic events. On the one hand, it drives the progression of atherosclerosis, leading to the highly thrombogenic rupture and erosion of plaques, at the same time as increasing the thrombogenicity of blood through modulation of platelet reactivity, enhancement of plasma coagulability, and impairment of endogenous fibrinolysis.1 On the other hand, it is associated with reduced pharmacodynamic action of traditional oral antiplatelet therapies (aspirin and clopidogrel) through increased platelet turnover and, in the case of clopidogrel, impairment of hepatic active metabolite generation, thus rendering these therapies less effective despite the clinical imperative for more effective treatment.1 It was therefore inevitable that more effective treatments should be developed for patients who have diabetes mellitus, and others at high risk of atherothrombotic events, as well. This concept is well illustrated in the work of Franchi and colleagues2 who, in this issue of Circulation , have compared the pharmacodynamic properties of prasugrel and ticagrelor in patients with diabetes mellitus. A key component of the rationale for comparing the effects of prasugrel and ticagrelor in patients who have diabetes mellitus is the different patterns of benefits seen in the diabetes subgroups in the pivotal phase 3 studies of these drugs in comparison with clopidogrel.3,4 With prasugrel, a particularly marked early benefit in reduced thrombotic events was seen in the diabetes subgroup, whereas, with ticagrelor, there was a more progressive accrual of benefit over 1 year, including progressive reduction in mortality. However, differences in study design can explain much of the difference in the patterns of early benefit: the clopidogrel regimen was substantially different between the 2 studies, with prasugrel being compared with a 300-mg loading …

Choosing a perspective on mortality with DAPT

This editorial refers to ‘Causes of late mortality with dual antiplatelet therapy after coronary stents’[†][1], by L. Mauri et al ., on page 378 and ‘Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome’,[‡][2] by M.T. Roe et al ., on page 412. Dual antiplatelet therapy (DAPT, a combination of aspirin and a P2Y12 inhibitor), typically for up to 1 year, has been shown to be of benefit in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) and stable coronary artery disease (SCAD). After this period, however, there remains a significant incidence of ischaemic events, particularly in high-risk patients, and extending the duration of DAPT has been explored as a potential way of reducing these further. The DAPT study randomized, at 12 months after PCI, 9961 patients treated with drug-eluting stents (DES; the primary analysis cohort) and 1287 patients treated with bare-metal stents to a further 18 months of thienopyridine (clopidogrel in 65%, prasugrel in 35%) or placebo.1 The co-primary outcomes of stent thrombosis and major adverse cardiovascular/cerebrovascular events (MACCE) were both significantly less frequent in the extended DAPT group. Moderate or severe, but not fatal, bleeding was also significantly higher in this group. This was perhaps as expected; however, an unanticipated finding was of higher non-cardiovascular causes of death [1.1% vs. 0.6%, hazard ratio (HR) 1.80, P = 0.01] in the DES cohort treated with extended DAPT. There were more cancer-related deaths in the thienopyridine group, although a greater number of patients with previously diagnosed malignancy entered into this arm. There … [1]: #fn-2 [2]: #fn-3

Pharmacodynamic Effects of a 6-Hour Regimen of Enoxaparin in Patients Undergoing Primary Percutaneous Coronary Intervention (PENNY PCI Study)

Delayed onset of action of oral P2Y 12 inhibitors in ST-elevation myocardial infarction (STEMI) patients may increase the risk of acute stent thrombosis. Available parenteral anti-thrombotic strategies, to deal with this issue, are limited by added cost and increased risk of bleeding. We investigated the pharmacodynamic effects of a novel regimen of enoxaparin in STEMI patients undergoing primary percutaneous coronary intervention (PPCI). Twenty patients were recruited to receive 0.75 mg/kg bolus of enoxaparin (pre-PPCI) followed by infusion of enoxaparin 0.75 mg/kg/6 h. At four time points (pre-anti-coagulation, end of PPCI, 2–3 hours into infusion and at the end of infusion), anti-Xa levels were determined using chromogenic assays, fibrin clots were assessed by turbidimetric analysis and platelet P2Y 12 inhibition was determined by VerifyNow P2Y12 assay. Clinical outcomes were determined 14 hours after enoxaparin initiation. Nineteen of 20 patients completed the enoxaparin regimen; one patient, who developed no-reflow phenomenon, was switched to tirofiban after the enoxaparin bolus. All received ticagrelor 180 mg before angiography. Mean (± standard error of the mean) anti-Xa levels were sustained during enoxaparin infusion (1.17 ± 0.06 IU/mL at the end of PPCI and 1.003 ± 0.06 IU/mL at 6 hours), resulting in prolonged fibrin clot lag time and increased lysis potential. Onset of platelet P2Y 12 inhibition was delayed in opiate-treated patients. No patients had thrombotic or bleeding complications. In conclusion, enoxaparin 0.75 mg/kg bolus followed by 0.75 mg/kg/6 h provides sustained anti-Xa levels in PPCI patients. This may protect from acute stent thrombosis in opiate-treated PPCI patients who frequently have delayed onset of oral P2Y 12 inhibition.

ULTRA-LOW-DOSE TWICE-DAILY ASPIRIN IMPROVES HEMOSTASIS AND MAINTAINS PLATELET INHIBITION IN ACUTE CORONARY SYNDROME PATIENTS RECEIVING TICAGRELOR

The PLATO study suggested that higher aspirin doses may be inferior in ticagrelor treated patients with acute coronary syndromes (ACS). Reducing bleeding risk whilst maintaining antithrombotic benefits would improve outcomes. We characterised a novel regimen of ultra-low-dose aspirin given twice

Study of Two Dose Regimens of Ticagrelor Compared with Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease (STEEL-PCI)

Background: Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndromes but has not been assessed in patients undergoing percutaneous coronary intervention for stable coronary artery disease. We compared the pharmacodynamic effects of ticagrelor and clopidogrel in this stable population. Methods: One hundred eighty aspirin-treated stable coronary artery disease patients, who were planned to undergo elective percutaneous coronary intervention in a single center, were randomized 1:1:1 to either a standard clopidogrel regimen or 1 of 2 regimens of ticagrelor, either 90 mg (T90) or 60 mg twice daily (T60), both with a 180 mg loading dose. Cellular adenosine uptake was assessed, at the time of the procedure and pre- and postdose at 1 month, by adding adenosine 1 µmol/L to aliquots of anticoagulated whole blood and mixing with a stop solution at 0, 15, 30, and 60 seconds, then measuring residual plasma adenosine concentration by high-performance liquid chromatography. Systemic plasma adenosine concentration and platelet reactivity were assessed at the same timepoints. High-sensitivity troponin T was measured pre- and 18 to 24 hours postpercutaneous coronary intervention. Results: One hundred seventy-four patients underwent an invasive procedure, of whom 162 received percutaneous coronary intervention (mean age 65 years, 18% female, 21% with diabetes mellitus). No effect on in vitro adenosine uptake was seen postdose at 1 month for either ticagrelor dose compared with clopidogrel (residual adenosine at 15 seconds, mean±SD: clopidogrel 0.274±0.101 µmol/L; T90 0.278±0.134 µmol/L; T60 0.288±0.149 µmol/L; P=0.37). Similarly, no effect of ticagrelor on in vitro adenosine uptake was seen at other timepoints, nor was plasma adenosine concentration affected (all P>0.1). Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel (VerifyNow P2Y12 reaction units, 1 month, mean±SD: predose, T60: 62±47, T90: 40±38, clopidogrel 181±44; postdose, T60: 34±30, T90: 24±21, clopidogrel 159±57; all P<0.0001 for ticagrelor versus clopidogrel). High platelet reactivity was markedly less with both T60 and T90 compared with clopidogrel (VerifyNow P2Y12 reaction units>208, 1 month postdose: 0%, 0%, and 21%, respectively). Median (interquartile range) high-sensitivity troponin T increased 16.9 (6.5–46.9) ng/L for clopidogrel, 22.4 (5.5–53.8) ng/L for T60, and 17.7 (8.1–43.5) ng/L for T90 (P=0.95). There was a trend toward less dyspnea with T60 versus T90 (7.1% versus 19.0%; P=0.09). Conclusions: Maintenance therapy with T60 or T90 had no detectable effect on cellular adenosine uptake at 1 month, nor was there any effect on systemic plasma adenosine levels. Both regimens of ticagrelor achieved greater and more consistent platelet inhibition than clopidogrel but did not appear to affect troponin release after percutaneous coronary intervention. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02327624.