The search for optimal dual antiplatelet therapy after PCI: fine-tuning of initiation and duration

Download the Issue @ a Glance podcast Subscribe to the EHJ Podcast The field of percutaneous coronary intervention (PCI) remains extremely active and fruitful, with major advances involving revascularization strategies and techniques including bioabsorbable stents1 and heated debates on when to start and the duration of antithrombotic therapy.2,3 ‘The Year in Cardiology 2015: Coronary Intervention’4 by Philippe Gabriel Steg, Paris, France summarizes the advances in 2015 with a particular focus on bleeding and methods to decrease those risks,5–7 for instance by radial access, as well as on newer generation drug-eluting stents (DES) and bioresorbable scaffolds. Dual antiplatelet therapy (DAPT) is further discussed extensively by Gilles Montalescot and colleagues from the Pitié-Salpêtrière Hospital in Paris, France in the review article ‘Oral dual antiplatelet therapy: what have we learnt from recent trials?’8 Indeed, since the publication of the ESC Guidelines on stable coronary disease9 and on ST-segment elevation myocardial infarction,10 several trials and registries have been published. The most recent ESC Guidelines on non ST-segment elevation myocardial infarction (NSTEMI) recommend 12 months of DAPT after PCI.11 Nevertheless, both when to start and the optimal duration of DAPT are still very controversial. The benefit–risk ratio of DAPT pre-treatment appears to depend on the type of acute coronary syndrome (ACS), the time elapsing to angiography, and the onset of action of the drug. In stable patients undergoing PCI with the latest generation DES, treatment should be for at least 6 months. Shorter courses of therapy may be necessary, if surgery is planned or with concomitant oral anticoagulation. Longer courses of therapy may be reasonable in patients at low bleeding risk who are tolerating DAPT well. For patients with ACS, prolonged DAPT is beneficial and reasonable, if tolerated. Individualized management of DAPT must be seen as a dynamic prescription with regular re-evaluations of the risk/benefit to the patient according to changes in his/her clinical profile. This important topic is further discussed In a meta-analysis ‘State-of-the-art review of optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: conceptual evolution based on emerging evidence’ by Gregg W. Stone from the Columbia University Medical Center in New York.12 Of 6852 publications retrieved, 23 were considered relevant, including 11 randomized controlled trials (RCTs) and 12 meta-analyses. The benefit–risk ratio of prolonged DAPT appears to be better in patients with compared with those without prior MI. On the basis of these findings, the authors advise—as proposed earlier13—a personalized approach when deciding upon the optimal duration of DAPT after DES, wherein the individualized risks of ischaemic vs. bleeding events are carefully considered for each patient. The duration of DAPT is further pursued in an ESC FAST TRACK manuscript entitled ‘Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial’ by Gerard Helft from the Institut de cardiologie Pitié-Salpêtrière in Paris, France.3 In this manuscript, the hypothesis was tested of whether on a background of aspirin continuing clopidogrel would be superior to stopping it at 12 months following DES implantation. A total of 1799 patients who had received at least one DES for stable coronary artery disease or an acute coronary syndrome were included. Of those, 1385 free of major cardiovascular or cerebrovascular events or major bleeding and on aspirin and clopidogrel 12 months after stenting were eligible for randomization between continuing clopidogrel 75 mg daily, i.e. extended-DAPT group, or discontinuing clopidogrel, i.e. aspirin group. Owing to slow recruitment, the study was stopped after enrolment of 1385 patients after a median follow-up of almost 3 years. The primary outcome of death, myocardial infarction, stroke, or major bleeding occurred in 5.8% in the extended-DAPT group and 7.5% in the aspirin group which did not reach significance. Rates of death were 2.3% in the extended-DAPT group and 3.5% in the aspirin group, and rates of major bleeding were also identical. The authors conclude that extended DAPT did not achieve superiority in reducing net adverse clinical events compared with 12 months of DAPT after DES placement. The manuscript is accompanied by an Editorial by Lars Wallentin from the Uppsala Clinical Research Center in Sweden.14 The next clinical research paper ‘Causes of late mortality with dual antiplatelet therapy after coronary stents’ by Laura Mauri and colleagues from the Brigham and Women's in Boston provides further crucial information on this issue.15 The authors noted that in the DAPT Study reported earlier,16 continued thienopyridine beyond 12 months after DES placement was associated with increased mortality. In the current study, the authors sought to evaluate factors related to mortality. Patients were enrolled after DES implantation, given thienopyridine and aspirin for 12 months, and then randomly assigned to continued thienopyridine or placebo for an additional 18 months on top of aspirin, and subsequently treated with aspirin alone for another 3 months. A blinded adjudication found among 11 648 randomized patients that rates of all-cause mortality were 1.9% and 1.5%, cardiovascular mortality 1.0% and 1.0%, and non-cardiovascular mortality 0.9% and 0.5% in the two groups. Rates of fatal bleeding were also similar, i.e. 0.2% vs. 0.1%, and deaths related to any prior bleeding were 0.3% vs. 0.2%. Similarly, cancer incidence did not differ, while cancer-related deaths occurred more often with continued DAPT, i.e. 0.6% vs. 0.3%, but were rarely related to bleeding (0.1% vs. 0%). The authors conclude that bleeding accounted for a minority of deaths among patients treated with continued thienopyridine. Cancer-related death in association with thienopyridine therapy was mainly not related to bleeding and may be a chance finding. Caution may, however, be warranted when considering extended thienopyridine in patients with advanced cancer. The manuscript is accompanied by a interesting Editorial by Robert F. Storey from the University of Sheffield in the UK.17 This topic is further discussed in another ESC FAST TRACK entitled ‘Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials’ by Jacob Allan Udell and colleagues from the Women's College Hospital in Toronto, Canada.18 A total of 33 435 patients were followed over a mean 31 months. Extended DAPT significantly decreased the risk of major adverse cardiovascular events compared with aspirin alone from 7.5% to 6.4% and reduced cardiovascular death from 2.6% to 2.3%, with no increase in non-cardiovascular death. This resulted in a risk reduction of all-cause mortality of 8%. Extended DAPT also reduced myocardial infarction by 30%, stroke by 19%, and stent thrombosis by 50%. This came at a cost of an increased risk of major bleeding from 1.09% to 1.85%, but not fatal bleeding. The authors conclude that compared with aspirin alone, DAPT beyond 1 year among stabilized high-risk patients with prior MI decreases ischaemic events, including cardiovascular death, recurrent infarction, and stroke. DAPT beyond 1 year, however, increases major bleeding, but not fatal bleeding or non-cardiovascular death. Further evidence on this topic is provided in another ESC FAST TRACK entitled ‘Efficacy and safety of ticagrelor for long-term secondary prevention of atherothrombotic events in relation to renal function: insights from the PEGASUS-TIMI 54 trial’ by Marc Bonaca and colleagues from the TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital in Boston.19 The authors evaluated the relationship of renal function and ischaemic and bleeding risk as well as the efficacy and safety of ticagrelor in stable patients with prior MI of the PEGASUS-TIMI 54 trial who were stratified based on estimated glomerular filtration rate (eGFR), with <60 mL/min/1.73 m2 pre-specified for analysis of the effect of ticagrelor on the primary efficacy composite of cardiovascular death, MI, or stroke and the primary safety endpoint of TIMI major bleeding. Of 20 898 patients, the 23% with eGFR <60 mL/min/1.73 m2 had a greater risk of major adverse cardiac events (MACE) at 3 years relative to those with normal GFR. The relative risk reduction in major events with ticagrelor was similar in those with eGFR <60 mL/min/1.73 m2 and averaged 19% and 12%, respectively. However, due to the greater absolute risk in the renal failure group, the absolute risk reduction with ticagrelor was 2.7% and only 0.6% in those with normal kidney function. Bleeding tended to occur more frequently in patients with renal dysfunction, but the absolute increase in TIMI major bleeding was similar in both groups, whereas minor bleeding tended to be more pronounced in those with renal failure. Thus, in patients with a history of infarction, renal dysfunction increases the risk of events and hence ticagrelor exerts a particulary robust absolute risk reduction. The manuscript is accompanied by a critical Editorial by Nicolas Danchin from the Hopital Europeen Georges Pompidou in Paris, France.20 A last concern related to long-term DAPT is increased cancer incidence, an issue addressed by Matthew T. Roe and the TRILOGY ACS Investigators in their manuscript ‘Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome’.21 The TRILOGY ACS trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel over 15 months. The primary outcome was detection of new, non-benign neoplasm. Among 9240 participants, 1.8% had a confirmed neoplasm. The efficacy composite of cardiovascular death, MI, or stroke occurred in 18.2% among those with a neoplasm and in 13.5% in those without it. Similarly, GUSTO severe or moderate bleeding was 11.2% and 1.5%, respectively. Screening rates were substantially higher in North America, Western Europe, and Scandinavia compared with other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current or recent smoking. Among the pre-specified 9105 patients without a history of neoplasm or previous treatment for neoplasm, the incidence of neoplasm events was similar with prasugrel and clopidogrel. The authors conclude that neoplasm events were infrequent during long-term DAPT after an ACS and were associated with differential cancer screening practices across regions. Importantly, the frequency of neoplasm detection was similar with prasugrel and clopidogrel. The editors hope that this issue of the European Heart Journal will be of interest to its readers.