Novel P2Y12 Inhibitors Versus Clopidogrel in Patients With STEMI Undergoing PCI in the L-DAPT Subgroup
This analysis included 5 RCTs6,10,23,24,31 with a total of 16, 296 patients (n = 8243 in the novel oral P2Y12 inhibitor group vs. n = 8053 in the clopidogrel group). Novel oral P2Y12 inhibitors could significantly decrease death by 32% from 4.18% to 2.82% (pooled RR: 0.65, 95% CI, 0.47–0.89, P = 0.007) than clopidogrel. Similarly, a significant 44% reduction in ST from 1.86% to 1.04% (pooled RR: 0.61, 95% CI, 0.45–0.84, P = 0.002) was observed. Furthermore, the novel oral P2Y12 inhibitors reduced MI (3.20% vs. 4.00%, pooled RR: 0.84, 95% CI, 0.72–0.99, P = 0.04) and MACE (6.49% vs. 8.33%, pooled RR: 0.76, 95% CI, 0.60–0.95, P = 0.02). There was no difference in stroke (P = 0.84), major bleeding (P = 0.63), and major/minor bleeding (P = 0.40) between the 2 groups.
Heterogeneity was observed in the magnitude of the effect across the trials (I2 = 61%, P = 0.04 for MACE; I2 = 49%, P = 0.10 for death; I2 = 59%, P = 0.05 for stroke). According to sensitivity analysis, when we excluded the INFUSE-AMI Trial,23 the heterogeneity decreased significantly (I2 = 0%, P = 0.53 for MACE; I2 = 4%, P = 0.37 for death; I2 = 2%, P = 0.38 for stroke). It might indicate that there was a large heterogeneity between the INFUSE-AMI Trial and other RCTs. In the INFUSE-AMI trial, all patients were treated with bivalirudin and then randomized to intralesional abciximab or placebo. Bivalirudin is an anticoagulant, and abciximab is an antiplatelet drug. These might have contributed to affect the ischemic events, leading to the generation of heterogeneity. After this exclusion, we could conclude that novel oral P2Y12 inhibitors significantly decreased MACE (pooled RR: 0.84, 95% CI, 0.76–0.94, P = 0.003), stent thrombosis (pooled RR: 0.63, 95% CI, 0.46–0.86, P = 0.003), and death (pooled RR: 0.74, 95% CI, 0.62–0.88, P = 0.0008) than clopidogrel. The results of stroke (pooled RR: 1.31, 95% CI, 0.95–1.81, P = 0.10), major bleeding (pooled RR: 1.02, 95% CI, 0.78–1.35, P = 0.86), and major/minor bleeding (pooled RR: 1.08, 95% CI, 0.87–1.34, P = 0.47) were not affected. The result of MI did not change.
Novel P2Y12 Inhibitors Versus Clopidogrel in Patients With STEMI Undergoing PCI in the S-DAPT Subgroup
In this analysis, 4874 patients with STEMI undergoing PCI were included from 8 studies.25–32 The results showed that novel P2Y12 inhibitors had a greater anti-ischemic effect than that of clopidogrel, with a significant reduction of 51% in death (1.44% vs. 2.94%, pooled RR: 0.49, 95% CI, 0.33–0.74, P = 0.0006), 63% in ST (0.86% vs. 2.38%, pooled RR: 0.40, 95% CI, 0.21–0.75, P = 0.004), and 37% in MACE (4.47% vs. 7.16%, pooled RR: 0.56, 95% CI, 0.40–0.79, P = 0.0009). However, novel P2Y12 inhibitors increased the major/minor bleeding by 11% (from 1.69% to 2.19%), although it was not statistically significant (P = 0.37). There was no difference in MI (P = 0.10), stroke (P = 0.25), and major bleeding (P = 0.96) between the 2 groups. All results were confirmed by a fixed-effects model. No heterogeneity was observed in the analysis of each endpoint (P > 0.28 in all cases). Moreover, when we sequentially excluded each study from all the pooled analyses, the results were not affected.
In addition, we performed a subgroup analysis for ticagrelor versus clopidogrel in Chinese patients with STEMI undergoing PCI. The analysis included 5 studies,25–29 accounting for 554 Chinese patients (ticagrelor for 279 patients and clopidogrel for 275 patients). The ticagrelor group had a moderate reduction in MACE (3.94% vs. 11.6%, pooled RR: 0.35, 95% CI, 0.18–0.68, P = 0.002), and a modest reduction in MI (1.35% vs. 5.88%, pooled RR: 0.26, 95% CI, 0.08–0.84, P = 0.02) than that of the clopidogrel group. Moreover, ticagrelor resulted in numerically improved ST (P = 0.08) and mortality (P = 0.10), but had a greater risk of bleeding (P = 0.08) than clopidogrel, although the difference was statistically insignificant. The risk of dyspnea in the ticagrelor group (33/225, 14.6%) was significantly higher than in the clopidogrel group (13/220, 5.9%) (P = 0.004). There were no differences regarding the risk of stroke (P = 0.66) and bradycardia (P = 0.44) between the 2 groups. All results were confirmed by a fixed-effects model. No heterogeneity was observed in evaluated endpoints (P > 0.70, I2 = 0% in all case). Moreover, when we sequentially excluded each study from all the pooled analyses, the results were not affected. The results are shown in Table 4.
Relative RR (RRR) of Endpoints Compared L-DAPT With S-DAPT for Novel P2Y12 Inhibitors
The Relative RR (RRR) of endpoint for the novel oral P2Y12 inhibitors was calculated between L-DAPT and S-DAPT (Table 5). The pooled RRR showed no significant difference (P > 0.05) in each endpoint, including death (P = 0.408), MACE (P = 0.233), MI (P = 0.633), stroke (P = 0.327), stent thrombosis (P = 0.245), and bleeding (P = 0.810).
Review of the funnel plots could not rule out potential publication bias for events such as death, MACE, MI, stroke, ST, and bleeding. Egger's and Begg's tests showed no evidence of publication bias for events such as death (P value for Egger's test: 0.229; P value for Begg's test: 0.210), MACE (P value for Egger's test: 0.071; P value for Begg's test: 0.100), MI (P value for Egger's test: 0.208; P value for Begg's test: 0.251), ST (P value for Egger's test: 0.299; P value for Begg's test: 1.000), and bleeding (P value for Egger's test: 0.329; P value for Begg's test: 0.304). Although Egger's test showed no evidence of publication bias for stroke (P = 0.164), Begg's test did (P = 0.048) (Fig. 10). The conclusions were not changed after an adjustment for publication bias was made using the trim and fill method.
This study was based on RCTs and explored the efficacy and safety of DAPT with novel oral P2Y12 inhibitors against the outcomes of major cardiovascular outcomes. This comprehensive meta-analysis included 18,732 patients from 12 trials. The findings from this study indicated that novel oral P2Y12 inhibitors were associated with significant reductions in the incidence of MACE, stent thrombosis, and all-cause death than clopidogrel in patients with STEMI undergoing PCI. Furthermore, subgroup analyses suggested that the administration of novel oral P2Y12 inhibitors provided significant reductions in all-cause death, MACE, and stent thrombosis than did clopidogrel without increasing the risk of bleeding in both the S-DAPT and the L-DAPT subgroups; however, a benefit for MI in the L-DAPT group was observed. Identical results were observed in the Chinese patients under ticagrelor treatment, except a slight increase in bleeding. However, when we compared the incidence of endpoints for the novel oral P2Y12 inhibitors between S-DAPT and L-DAPT, we observed that L-DAPT might not be associated with a difference in the risk of ischemic events and bleeding compared with S-DAPT.
In a previous meta-analysis that compared novel P2Y12 receptor inhibitors with clopidogrel, including oral and intravenous drugs,33–35 the major limitation could be due to the difference in drug characteristics that resulted in heterogeneity. Others compared novel oral P2Y12 inhibitors with clopidogrel in ACS or PCI,35–39 wherein a meta-analysis of patients without STEMI undergoing PCI40 was conducted. At present, specific meta-analyses on novel oral P2Y12 inhibitors in patients with STEMI undergoing PCI are limited. However, there are 2 articles that focused on the duration of DAPT11,12 and included trials that assessed clopidogrel without evaluating the novel oral P2Y12 inhibitors. In addition, the results of previous meta-analyses were somewhat controversial. The meta-analysis33 showed that novel P2Y12 inhibitors decreased all-cause mortality and major ischemic events, without significant increases in major bleeding in PCI patients. However, a recent meta-analysis40 indicated that newer oral P2Y12 inhibitors decreased MACE and MI at the expense of a significant increase in the risk of bleeding. Therefore, we strictly restricted our analysis to trials that met the inclusion criteria, leading to minimum heterogeneity. The efficacy and safety of novel oral P2Y12 inhibitors and clopidogrel in patients with STEMI undergoing PCI were compared, and the Relative RR of endpoints for novel oral P2Y12 inhibitors was compared among different durations.
Clopidogrel, combined with aspirin, has proved effective in reducing the risk of thrombotic events.41,42 However, clopidogrel has its own limitations such as delayed onset of action, high individual variability, and moderate platelet inhibition.43 Therefore, novel oral P2Y12 receptor antagonists such as prasugrel and ticagrelor, which compensate for the shortcomings of clopidogrel, were verified by large, double-blind, randomized trials. Our results show that the novel oral antiplatelet agents had more benefits in ischemic events than clopidogrel, particularly in the incidence of MACE, stent thrombosis, and all-cause death, regardless of the overall group, the prasugrel versus clopidogrel subgroup, the ticagrelor versus clopidogrel subgroup, the S-DAPT group, and L-DAPT group, without increasing the risk of bleeding. This benefit might be due to the contribution of novel oral P2Y12 inhibitors to the establishment of a better antithrombotic environment within the blood vessels and their ability to effect a more rapid, stronger inhibition of platelet aggregation. Ticagrelor and prasugrel had a rapid onset and offset of antiplatelet action,44 and marked and consistent inhibitory action on platelet aggregation.45 In the ONSET/OFFSET trial,46 the maximum platelet inhibition (∼80%) was achieved within 1 hour of ticagrelor administration; the time to peak inhibition of platelet aggregation was 2 hours with ticagrelor compared with 7.8 hours with clopidogrel. Another trial with ticagrelor6 showed an effective reduction in the incidence of CV death, MI, and stent thrombosis without increasing the risk of bleeding in patients with STEMI undergoing PCI and during a 12-month follow-up after PCI. Furthermore, prasugrel was shown to be effective in the TRITON-TIMI 38 study9 in reducing the incidence of ischemic events. Our finding further confirmed that the novel P2Y12 receptor antagonist significantly reduced ischemic events compared with clopidogrel in patients with STEMI undergoing PCI and theoretically achieved more survival benefits, particularly with regard to MACE, stent thrombosis, and all-cause death. Two large studies6,31 are included in our global analysis, and their outcomes supported our findings.
Administration of novel oral P2Y12 receptor antagonists combined with aspirin is recommended by the current guidelines.47,48 Clopidogrel is used only as an alternative in case of contraindications in the above-mentioned drugs. However, in Chinese guidelines, novel oral P2Y12 oral antiplatelet drugs (ticagrelor and prasugrel) are not recommended as a priority, mainly because clinical evidence of efficacy of ticagrelor is less substantial in Chinese patients with STEMI undergoing PCI. Therefore, our study conducted subgroup analyses for ticagrelor in Chinese patients. The results showed that ticagrelor could significantly reduce the incidence of MI and MACE, reduce stent thrombosis and mortality, and increase the risk of bleeding and dyspnea compared with clopidogrel. Currently, most studies on the pharmacokinetics of ticagrelor are based on white populations. A study showed that East Asian patients with ACS who underwent PCI and received ticagrelor had higher event rates of primary safety and efficacy endpoints than those who received clopidogrel, albeit not significantly.49 The average bioavailability of ticagrelor is 1.3-fold higher in Asian populations than in white populations, but dose adjustments based on the basis of race were not sufficient for Asian populations. Therefore, when ticagrelor prevents ischemic events, care should be taken regarding the risk of bleeding.
Subgroup analyses according to the duration of treatment with novel oral P2Y12 inhibitors indicated no significant difference between L-DAPT and S-DAPT. The previous REal Safety and Efficacy of a 3-month DAPT after E-ZES implantation (RESET) trial50 and the OPTIMIZE randomized trial51 showed that 3 months of DAPT treatment after stent implantation was not inferior to 12 months of DAPT treatment after implantation, in terms of MACE, MI, all-cause death, ST, and major or minor bleeding. Another randomized multicenter trial52 found that 24 months of clopidogrel therapy was not significantly more effective than 6 months of clopidogrel in reducing the incidence of all-cause death, MI, or cerebrovascular events. Meanwhile, a previously reported meta-analysis of randomized trials53,54 demonstrated that extending DAPT treatment duration after PCI did not reduce the risk of all-cause death, MI, and MACE, but did increase the risk of major bleeding. In accordance with this meta-analysis and previous trials, our study suggests no difference in adverse cardiovascular events between S-DAPT and L-DAPT treatment with novel oral P2Y12 inhibitors, and the risk of bleeding was not increased. However, the meta-analysis and trials described above assessed clopidogrel without evaluating the novel oral P2Y12 inhibitors. The difference in bleeding risk might be related to the characteristics of the drugs, in that the novel oral P2Y12 inhibitors might contribute to faster, greater, and more consistent therapeutic action than clopidogrel. The results suggest that long-term DAPT with novel oral P2Y12 inhibitors might retain a powerful benefit for ischemia, a theory supported by European and US guidelines that recommend a duration of at least 12 months for prasugrel or ticagrelor DAPT.4,55 The optimal duration of DAPT remains uncertain, however, and a longer duration of treatment may be required. To date, one randomized control trial56 has compared 12-month DAPT with 30-month DAPT for novel oral P2Y12 inhibitors and showed that continuing DAPT with prasugrel and aspirin for 30 months was associated with lower rates of MACE, driven largely by fewer spontaneous and ST-related MI with no apparent increase in severe bleeding. Therefore, assessment of the optimum duration for DAPT using novel oral P2Y12 inhibitors in patients with STEMI undergoing PCI has been mainly concerned with balancing the incidence of ischemic complications (such as MI, stent thrombosis, and stroke) with bleeding complications.
Two strengths of our study should be highlighted. First, only prospective studies were included, which avoids selection and recall bias. Second, we strictly limited the condition of the disease, and divided the group according to the follow-up time, which can effectively reduce the heterogeneity between studies.
There are several limitations of our study that should be considered. The main limitation of the study is the inclusion of some small-scale original studies. Although medium and large-scale studies were included and the number of patients increased, the small-scale studies could still introduce bias. Therefore, larger and higher-quality RCTs are required to confirm our findings in the future. The second is a lack of patient-level data. Patient-level data can be used as a basis for identifying ischemic benefits and the risk of bleeding during different durations of DAPT. In particular, not all studies reported on the use of stent type; different stent types have been related to the safety and efficacy of endpoints in patients undergoing PCI.57 Third, the bias may be introduced by the different follow-up times. Most of the clinical effects focused on short-term studies such that the lower incidence of endpoints might be accounted for by the lower exposure and shorter follow-up time. Furthermore, all the studies were not conducted with genotypes of clopidogrel for hepatic cytochrome Cyp2C19 gene polymorphism, which is about 25%–30% of the patients taking clopidogrel, reducing protection from clopidogrel in preventing cardiovascular events after PCI.58 Therefore, it will increase the incidence of endpoint events that can affect the results of our study by introducing bias. Finally, there was heterogeneity between the studies. Although we tried to strictly limit the inclusion and exclusion criteria to ensure a more homogenous population in our meta-analysis, there was a large difference in protocols, endpoint definitions, and follow-up periods between trials. Each trial might have reported and adjudicated the endpoints with a slight difference.
Patients with STEMI undergoing PCI who received novel oral P2Y12 inhibitors had significant reductions in the risk of MACE, all-cause death, and stent thrombosis without a significant effect on the risk of bleeding events compared with clopidogrel. However, extended duration of treatment with potential P2Y12 inhibitors might be not associated with the risk of ischemic events and bleeding compared with short-duration DAPT in patients with STEMI undergoing PCI.
This study was supported by grants from the National Key Technologies R&D Program (2016YFC0904900) the National Natural Science Foundation (No.81273592, No.81573504 and No.81673509) of PR China.
1. Falk E, Nakano M, Bentzon JF, et al. Update on acute coronary syndromes: the pathologists' view. Eur Heart J. 2013;34:719–728.
2. Santos-Gallego CG, Picatoste B, Badimon JJ. Pathophysiology of acute coronary syndrome. Curr Atheroscler Rep. 2014;16:401.
3. Holmes DR Jr, Kereiakes DJ, Garg S, et al. Stent thrombosis. J Am Coll Cardiol. 2010;56:1357–1365.
4. American College of Emergency Physicians; Society for cardiovascular Angiography and Interventions, O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart association task force on practice guidelines. Circ January. 2013;127:e362–e425.
5. Wiviott SD. Clopidogrel response variability, resistance, or both? Am J Cardiol. 2006;98:18N–24N.
6. Steg PG, James S, Harrington RA, et al. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a platelet inhibition and patient outcomes (PLATO) trial subgroup analysis. Circulation. 2010;122:2131–2141.
7. Storey RF, Angiolillo DJ, Patil SB, et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient outcomes) PLATELET substudy. J Am Coll Cardiol. 2010;56:1456–1462.
8. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29:21–30.
9. Udell JA, Braunwald E, Antman EM, et al. Prasugrel versus clopidogrel in patients with ST-segment elevation myocardial infarction according to timing of percutaneous coronary intervention: a TRITON-TIMI 38 subgroup analysis (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38). JACC Cardiovasc interv. 2014;7:604–612.
10. Kurz DJ, Radovanovic D, Seifert B, et al. Comparison of prasugrel and clopidogrel-treated patients with acute coronary syndrome undergoing percutaneous coronary intervention: a propensity score-matched analysis of the Acute Myocardial Infarction in Switzerland (AMIS)-Plus Registry. Eur Heart J Acute Cardiovasc Care. 2015;5:13–22.
11. Elmariah S, Mauri L, Doros G, et al. Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis. Lancet. 2015;385:792–798.
12. Giustino G, Baber U, Sartori S, et al. Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2015;65:1298–1310.
13. Kushner FG, Hand M, Smith SC Jr, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Catheter Cardiovasc Interv. 2009;74:E25–E68.
14. Mauri L, Hsieh WH. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med. 2007;356:1020–1029.
15. Julian PT Higgins, Sally Green. Cochrane handbook for systematic reviews of interventions (version 5.1.0). Available at: http://wwwcochrane-handbookorg
. Accessed March, 2011.
16. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634.
17. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–1101.
18. Niazi AK, Dinicolantonio JJ, Lavie CJ, et al. Triple versus dual antiplatelet therapy in acute coronary syndromes: adding cilostazol to aspirin and clopidogrel? Cardiology. 2013;126:233–243.
19. Yang TH, Jin HY, Choi KN, et al. Randomized comparison of new dual-antiplatelet therapy (aspirin, prasugrel) and triple-antiplatelet therapy (aspirin, clopidogrel, cilostazol) using P2Y12 point-of-care assay in patients with STEMI undergoing primary PCI. Int J Cardiol. 2013;168:207–211.
20. Park SD, Baek YS, Woo SI, et al. Comparing the effect of clopidogrel versus ticagrelor on coronary microvascular dysfunction in acute coronary syndrome patients (TIME trial): study protocol for a randomized controlled trial. Trials. 2014;15:151.
21. Wallentin L, James S, Giannitsis E, et al. Usefulness of biomarkers for prognostication of outcome with early invasive or noninvasive treatment in non-ST-elevation acute coronary syndromes—a substudy from the prospective randomized platelet inhibition and patient outcomes (PLATO) trial. J Am Coll Cardiol. 2012;59:E497.
22. Montalescot G, Collet JP, Ecollan P, et al. Effect of prasugrel pre-treatment strategy in patients undergoing percutaneous coronary intervention for NSTEMI: the ACCOAST-PCI study. J Am Coll Cardiol. 2014;64:2563–2571.
23. Brener SJ, Oldroyd KG, Maehara A, et al. Outcomes in patients with ST-segment elevation acute myocardial infarction treated with clopidogrel versus prasugrel (from the INFUSE-AMI trial). Am J Cardiol. 2014;113:1457–1460.
24. Clemmensen P, Grieco N, Ince H, et al. MULTInational non-interventional study of patients with ST-segment elevation myocardial infarction treated with PRimary Angioplasty and Concomitant use of upstream antiplatelet therapy with prasugrel or clopidogrel–the European MULTIPRAC Registry. Eur Heart J Acute Cardiovasc Care. 2015;4:220–229.
25. Dayi L. Application of ticagrelor in elderly patients with ST segment elevation myocardial infarction undergoing emergency PCI. Chin J Gerontol. 2014;34:2638–2641.
26. Ji X. Efficacy and safety of ticagrelor combined with primary PCI in elderly patients with ST-elevated acute myocardial infarction. J Capital Med Univ. 2015;36:73–77.
27. Qing SD, Jian WQ. The clinical effect of Ticagrelor joint the treatment by directly percutaneous coronary intervention for the patients with ST segment elevation myocardial infarction. China Med Herald. 2015;12:115–119.
28. Que L. The efficacy and safety of ticagrelor in patients with acute STEMI undergoing emergency PCI. Chin J Clin Res. 2014;27:937–939.
29. Xiaodong Q, Xujie C, Xin Z. A randomized control study of ticagrelor therapy on patient with acute ST-elevation myocardial infarction. Acta Universitatis Medicinalis Nanjing. 2014;34:1515–1521.
30. Zeymer U, Mochmann HC, Mark B, et al. Double-blind, randomized, prospective comparison of loading doses of 600 mg clopidogrel versus 60 mg prasugrel in patients with acute ST-segment elevation myocardial infarction scheduled for primary percutaneous intervention: the ETAMI trial (early thienopyridine treatment to improve primary PCI in patients with acute myocardial infarction). JACC Cardiovasc interv. 2015;8(1 pt B):147–154.
31. Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009;373:723–731.
32. Zeymer U, Hochadel M, Lauer B, et al. Use, efficacy and safety of prasugrel in patients with ST segment elevation myocardial infarction scheduled for primary percutaneous coronary intervention in clinical practice. Results of the prospective ATACS-registry. Int J Cardiol. 2015;184:122–127.
33. Bellemain-Appaix A, Brieger D, Beygui F, et al. New P2Y12 inhibitors versus clopidogrel in percutaneous coronary intervention: a meta-analysis. J Am Coll Cardiol. 2010;56:1542–1551.
34. Tang XF, Fan JY, Meng J, et al. Impact of new oral or intravenous P2Y12 inhibitors and clopidogrel on major ischemic and bleeding events in patients with coronary artery disease: a meta-analysis of randomized trials. Atherosclerosis. 2014;233:568–578.
35. Gan XD, Wei BZ, Fang D, et al. Efficacy and safety analysis of new P2Y12 inhibitors versus clopidogrel in patients with percutaneous coronary intervention: a meta-analysis. Curr Med Res Opin. 2015;31:2313–2323.
36. Aradi D, Komocsi A, Vorobcsuk A, et al. Impact of clopidogrel and potent P2Y 12 -inhibitors on mortality and stroke in patients with acute coronary syndrome or undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Thromb Haemost. 2013;109:93–101.
37. Verdoia M, Schaffer A, Barbieri L, et al. Benefits from new ADP antagonists as compared with clopidogrel in patients with stable angina or acute coronary syndrome undergoing invasive management: a meta-analysis of randomized trials. J Cardiovasc Pharmacol. 2014;63:339–350.
38. Jia M, Li Z, Chu H, et al. Novel oral P2Y12 inhibitor prasugrel vs. clopidogrel in patients with acute coronary syndrome: evidence based on 6 studies. Med Sci monit. 2015;21:1131–1137.
39. Singh S, Singh M, Grewal N, et al. Comparative efficacy and safety of prasugrel, ticagrelor, and standard-dose and high-dose clopidogrel in patients undergoing percutaneous coronary intervention: a network meta-analysis. Am J Ther. 2015;23:e52–e62.
40. Bavishi C, Panwar S, Messerli FH, et al. Meta-analysis of comparison of the newer oral P2Y12 inhibitors (prasugrel or ticagrelor) to clopidogrel in patients with non-ST-elevation acute coronary syndrome. Am J Cardiol. 2015;116:809–817.
41. Sean M. Donahoe, Marc S. Sabatine, Donahoe SM, Sabatine MS. Adding clopidogrel to aspirin improves outcome in ST-elevation myocardial infarction patients receiving fibrinolytic therapy. Expert Rev Pharmacoecon Outcomes Res. 2005;5:751–761.
42. Yusuf SZF, Mehta SR, Chrolavicius S, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without St-segment elevation. N Engl J Med. 2001;345:494–502.
43. Serebruany VL, Steinhubl SR, Berger PB, et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol. 2005;45:246–251.
44. Husted S, van Giezen JJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27:259–274.
45. Sugidachi A, Asai F. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol. 2000;129:1439–1446.
46. Panchal HB, Shah T, Patel P, et al. Comparison of on-treatment platelet reactivity between triple antiplatelet therapy with cilostazol and standard dual antiplatelet therapy in patients undergoing coronary interventions: a meta-analysis. J Cardiovasc Pharmacol Ther. 2013, 18:533–543.
47. Dehmer GJ, Blankenship JC, Cilingiroglu M, et al. SCAI/ACC/AHA expert consensus document: 2014 update on percutaneous coronary intervention without on-site surgical backup. J Am Coll Cardiol. 2014;63:2624–2641.
48. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35:2541–2619.
49. Goto S, Huang CH, Park SJ, et al. Ticagrelor vs. clopidogrel in Japanese, Korean and Taiwanese patients with acute coronary syndrome—randomized, double-blind, phase III PHILO study. Circ J. 2015;79:2452–2460.
50. Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy. J Am Coll Cardiol. 2012;60:1340–1348.
51. Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA. 2013;310:2510–2522.
52. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation. 2012;125:2015–2026.
53. Cassese S, Byrne RA, Tada T, et al. Clinical impact of extended dual antiplatelet therapy after percutaneous coronary interventions in the drug-eluting stent era: a meta-analysis of randomized trials. Eur Heart J. 2012;33:3078–3087.
54. Palla M, Briasoulis A, Siddiqui F, et al: Long (>12 months) and short (<6 months) versus standard duration of dual antiplatelet therapy after coronary stenting: a systematic review and meta-analysis. Am J Ther. 2015;0:1–9.
55. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33:2569–2619.
56. Garratt KN, Weaver WD, Jenkins RG, et al. Prasugrel plus aspirin beyond 12 months is associated with improved outcomes after taxus liberte paclitaxel-eluting coronary stent placement. Circulation. 2014;131:62–73.
57. Saito S, Valdes-Chavarri M, Richardt G, et al. A randomized, prospective, intercontinental evaluation of a bioresorbable polymer sirolimus-eluting coronary stent system: the CENTURY ∥(Clinical Evalution of new Terumo Drug-Eluting Coronary Stent System in the Treatment of Patients with Coronary Artery Disease) trial. Eur Heart J. 2014;14:2021–2031.
58. Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302:849–857.
Keywords:Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
prasugrel; ticagrelor; ST; percutaneous coronary intervention; meta-analysis; therapy