Prof. Felicita Andreotti,
Prof. Freek Verheugt,
Since ESC 2014 six interesting studies have been published or presented during TCT 2014 and AHA 2014on the efficacy and safety of novel antithrombotic strategies.
Patients undergoing primary PCI for STEMI often are triaged by ambulance personnel or in non-PCI capable hospitals. A time gain in the initiation of reperfusion therapy of nearly 1 hour has been achieved with prehospital fibrinolytic therapy resulting in a 15% reduction in hospital mortality in comparison to in-hospital fibrinolysis (1). The early administration of clopidogrel in STEMI has been shown to be superior to placebo pre-PCI in the setting after fibrinolysis (2). Aspirin and clopidogrel are the antiplatelet drugs that are usually given prehospital, but clopidogrel has been shown to be inferior to the new P2Y12 blockers in STEMI. There were limited data on the new P2Y12 blockers administered prehospital.In the ATLANTIC trial 1,862 patients presenting with signs and symptoms of STEMI were randomized in the prehospital setting to prehospital ticagrelor loading (180 mg) followed by placebo in the cath lab, or to prehospital placebo followed by ticagrelor loading in the cath lab (3). The time difference between prehospital and in-hospital ticagrelor was 31 minutes. The first co-secondary endpoint of post PCI < 70 ST-resolution ST was seen in 42.5% in the prehospital group and 47.5% in the in-hospital group (p = 0.05). The second co-secondary primary endpoint of post-PCI TIMI flow < 3 occurred in 17.8% in the prehospital group and 19.6% in the in-hospital group (p = 0.34). The rate of early stent thrombosis, however was significantly reduced (fig. 1). There were no significant differences in ischemic or bleeding outcome at 24 h or 30 days.
Thus, when compared to in-hospital administration of ticagrelor in STEMI, prehospital ticagrelor was not associated with improved early reperfusion or better outcomes. But early stent thrombosis was less with prehospital ticagrelor.
An interesting antidote study was done in a placebo-controlled trial with 3 doses of intravenous antidote PER977 (aripazine, or ciraparantag) in 80 healthy individuals 3 hours after a single oral dose of edoxaban 60 mg (4). Whole-blood clotting time was reduced to baseline already by 100 mg within one hour (fig. 2).
Thus, PER977 seems to be a promising antidote for reversal of anticoagulation with full dose edoxaban. --------------------The use of aspirin in primary prevention remains controversial. Until recently prospective studies focused on the elderly were not available. Such studies are necessary since myocardial infarction risk increases with age, as is the risk of bleeding with aspirin.The Japanese Primary Prevention Project (JPPP) randomized 14,464 Japanese men and women between 60 and 85 years (mean 71 years) without coronary disease, but with hypertension, dyslipidemia and/or diabetes to open label enteric-coated aspirin 100 mg daily, or no aspirin (5). They were followed for a mean of 5 years. The trial was stopped because of lack of efficacy in the light of increased harm with aspirin. The 5 year primary endpoint cardiovascular death, non-fatal MI or stroke occurred in 2.8% on aspirin versus 3.0% without (RR 0.94, 95% CI 0.77 - 1.15, p = 0.54, fig 3). MI was seen in 0.3% on aspirin versus 0.6% without (RR 0.53, 95% CI 0.31 - 0.91, p = 0.02) and TIA in 0.3% on aspirin versus 0.5% without (RR 0.49, 95% CI 0.32 - 0.99, p = 0.04).
Major extracranial bleeding needing transfusion or hospitalization nearly doubled with aspirin: 0.9% versus 0.5% without (RR 1.85, 95% CI 1.22 - 2.81, p = 0.004). Intracranial bleeding (ICH) was rare, but also higher on aspirin: 28 patients versus 15 without aspirin.Thus, despite age and risk factors the yearly overall CV risk in this population was very low (0.6%) and was not significantly reduced by low-dose aspirin. Although both MI and TIA were significantly lower, major bleeding including ICH nearly doubled. These results underscore the CV event threshold of at least 2% per year for routine primary prevention with aspirin (6). ------------------------------The optimal duration of dual antiplatelet therapy (DAPT) after coronary stenting is still not fully established. Several studies with modern drug eluting stents (DES) showed that 6 months would be sufficient in elective patients with a low-risk of bleeding and even shorter in those with a high bleeding risk. This is now also supported by the ESC guideline on revascularization (7). At AHA 2014 three trials on a shorter and longer duration of DAPT were presented.In the ISAR-SAFE study 4,005 patients were randomized 6 months after DES to continuation of clopidogrel or placebo, and followed for 9 months thereafter. Around 60% had stable coronary disease and most patients had modern DES. The study was planned to have 6,000 patients, but was stopped because of a low event rate and a slow recruitment. The primary endpoint death, MI, stent thrombosis, stroke or TIMI major bleeding occurred in 1.5% of the patients on 6 months clopidogrel versus 1.6% in those on 12 months (p non-inferiroriy < 0.001, fig 4).
Death, MI, stent thrombosis or stroke was seen in 1.3% of the 6 months patients and 1.6% in the 12 months patients (HR 0.87, 95% CI 0.51 - 1.47, p = 0.59), whereas TIMI major and minor bleeding was 0.3% in the 6 months patients and 0.7% in the 12 months patients (HR 0.46, 95% CI 0.18 - 1.21, p = 0.12).A more or less similar trial was the ITALIC study, in which 1,850 aspirin-responsive patients were randomized to 6 months or 24 months of clopidogrel after DES. Around 60% had stable coronary disease and all patients had Xience-V DES. The follow-up at 1 year was presented and published (8). The primary endpoint death, MI, stroke, urgent target vessel revascularization, or TIMI major bleeding occurred in 1.6% of the patients planned for 24 months and 1.5% in those who stopped clopidogrel at 6 months (HR 1.07, 95% CI 0.52 – 2.22, p = 0.85, p non-inferiroriy = 0.0002, fig 5).
Both ISAR-SAFE and ITALIC are in the long list of trials showing that a shorter duration of 6 months of DAPT after DES is not inferior to 12 months.Finally, the DAPT study, the larger trial on DAPT duration after DES, was presented and published at AHA 2014(9). In that trial 9,961 patients who had not experienced stent thrombosis or major bleeding in the first 12 months after DES, were randomized 12 months after DES to continuation of a P2Y12 blocker for another 18 months or placebo, and followed for 3 months after study drug withdrawal. Around 60% had stable coronary disease and only 47% patients had everolimus eluting stents. The P2Y12 blocker use was 65% clopidogrel and 35% prasugrel (almost exclusively with paclitaxel stents). The first co-primary endpoint definite or probable stent thrombosis occurred in 0.4% of the patients on 30 months DAPT versus 1.4% in those on 12 months (HR 0.29, 95% CI 0.17 – 0.49, p < 0.001, fig 6). The second co-primary endpoint death, MI or stroke was seen in 4.3% of the patients on 30 months DAPT versus 5.9% in those on 12 months (HR 0.71, 95% CI 0.59 – 0.85, p < 0.001, fig 7). This difference was mainly driven by lower rates of MI with 30 months DAPT. Most MIs occurred in the non-stented areas, the rate of which increased after stopping study medication within 3 months.
Major bleeding (GUSTO moderate to severe) was increased from 1.6% for 12 months to 2.5% for 30 months (absolute increase 1.0%, 95% CI 0.4 - 1.5, p < 0.001) and major and minor bleeding (BARC 2,3 or 5) was increased from 2.9% for 12 months to 5.6% for 30 months (absolute increase 2.6%, 95% CI 1.8 - 3.5), p < 0.001). Also mortality was increased: 2.0% for 30 months versus 1.5% for 12 months (HR 1.36, 95% CI 1.00 - 1.85, p = 0.05)DAPT is the first study on DAPT beyond 12 months showing a benefit on ischemic endpoints for longer treatment. These data are at odds with the smaller studies LATE (10) and ARCTIC interruption (11), where the former also saw a mortality increase. In DAPT three out of five patients had stable disease, where dual therapy usually is shorter than 12 months. Moreover, the majority of patients had older DES than currently used. The MACCE benefit observed was significantly less with the everolimus stents and in patients on clopidogrel. The question is whether these results apply to current practice in Europe. Probably, only for patients on DAPT 12 months after implantation of an older DES type, who have a low-bleeding risk, physicians should consider to prolong treatment. But they must also realize that this almost doubles the risk of bleeding and may increase mortality too.
(1) Morrison LJ, Verbeek PR, McDonald AC, Sawadsky BV, Cook DJ. Mortality and prehospital thrombolysis for acute myocardial infarction. JAMA 2000;283:2686-2692 (2) Sabatine MS, Cannon CP, Gibson CM, et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study JAMA 2005;294:1224-1232 (3) Montalescot G, van ’t Hof AW, Lapostolle F, et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 2014;371:1016-1027 (4) Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014;371:2141-2142(5) Ikeda Y, Shimada K, Teramoto T, et al. Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Japanese Patients 60 Years or Older With Atherosclerotic Risk Factors: A Randomized Clinical Trial. JAMA 2014; Nov 17. doi: 10.1001/jama.2014.15690 (6) Halvorsen S, Andreotti F, Ten Berg J, et al. Aspirin therapy in cardiovascular disease prevention: a position paper of the European Society of Cardiology Working Group on Thrombosis. J Am Coll Cardiol 2014;64:319-327 (7) Windecker S, Khol P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2014;35:2541-2619 (8) Gilard M, Barragan P, Noryani AA, et al. Six-month versus 24-month dual antiplatelet therapy after implantation of drug eluting stents in patients non-resistant to aspirin: ITALIC, a randomized multicenter trial. J Am Coll Cardiol 2014 Nov 16. pii: S0735-1097(14)06970-8. doi: 10.1016/j.jacc.2014.11.008 (9) Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med.2014;371:2155-2166 (10) Lee WC, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized controlled trial. Circulation 2014;129:304-312 (11) Collet JP, Silvain J, Barthélémy O, et al. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet 2014;384:1577-1585
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