Studies have linked on-treatment platelet reactivity (PR) to adverse clinical outcomes. Because new P2Y 12 inhibitors (prasugrel and ticagrelor) have been predominantly tested against clopidogrel, data on pharmacodynamic comparisons between these 2 drugs are scarce. We compared ticagrelor with prasugrel in a network meta-analysis. PubMed, Cochrane, and EMBASE were searched for studies assessing PR in patients with coronary artery disease treated with ticagrelor or prasugrel. All studies using prasugrel and/or ticagrelor providing platelet function measurement data using VerifyNow P2Y12 reaction units (PRUs), platelet reactivity index (PRI) vasodilator-stimulated phosphoprotein phosphorylation, or maximal platelet aggregation (MPA) by light transmission aggregometry were considered eligible. Mixed treatment comparison models directly compared ticagrelor and prasugrel and indirectly compared them using clopidogrel as a comparator with data presented as mean difference (95% confidence interval). Data were extracted from 29 studies, including 5,395 patients. Compared with clopidogrel 75 mg, both prasugrel 10 mg and ticagrelor 90 mg twice daily were associated with lower PRU (mean difference −117 [−134.1, −100.5] and −159.7 [−182.6, −136.6], respectively), a lower PRI (−24.2 [−28.2, −20.3] and −33.6 [−39.9, −27.6], respectively), and lower MPA (−11.8 [−17, −6.3] and −20.7 [−28.5, −12.8], respectively). Similar results were obtained with clopidogrel 150 mg. Ticagrelor 90 mg twice daily was associated with lower PRU (−42.5 [−62.9, −21.9]), lower PRI (−9.3 [−15.6, −3.5]), and lower MPA (−8.9 [−16.4, −1.2]) compared with prasugrel 10 mg. In conclusion, our meta-analysis suggests that ticagrelor achieved significantly lower on-treatment PR compared with prasugrel, with both being superior to clopidogrel standard or high dose.
Landmark clinical trials and subsequent supportive data have established clopidogrel in combination with aspirin as the cornerstone of antithrombotic therapy after acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). The P2Y 12 receptor has, thus, become an established target in the setting of atherothrombosis and PCI. Because of the pharmacodynamic limitations that were associated with adverse clinical events, efforts were focused to develop novel P2Y 12 inhibitors with improved pharmacodynamic/pharmacokinetic properties. After promising phase II results, prasugrel and ticagrelor have clearly demonstrated in their respective phase III studies, “Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction” (TRITON-TIMI 38) and the “Platelet Inhibition and Patient Outcomes” (PLATO), their superiority over clopidogrel to prevent long-term ischemic end point recurrence after ACS. Thus, they are recommended as first-line agents in the treatment of patients with ACS by the European guidelines. However, it is noteworthy that these 2 trials had different results. In PLATO, ticagrelor decreased cardiovascular mortality and did not increase the rate of overall major bleeding according to the study criteria, whereas in TRITON-TIMI 38, prasugrel did not significantly improve overall mortality and was associated with an increase in TIMI major bleeding and fatal bleeding. These differences in efficacy and safety outcomes were mainly attributed to discrepancies in study design, populations, and end point definitions. A relation between platelet reactivity (PR) and ischemic or bleeding events has been established. Prasugrel and ticagrelor demonstrated greater platelet inhibition than clopidogrel, but data regarding head-to-head pharmacodynamic comparison between them are available in studies with a limited number of patients. In the following network meta-analysis, we aimed to directly and indirectly compare pharmacodynamic effects of prasugrel with ticagrelor.
Methods
The primary objective of this meta-analysis was to compare the pharmacodynamic effect of ticagrelor and prasugrel. We included all studies providing PR data assessed in patients on prasugrel or ticagrelor maintenance dose. We selected studies including patients with coronary artery disease with or without PCI and excluded the ones performed in healthy volunteers. We limited our analysis to publications providing PR data according to the 3 most widely used platelet function tests: the VerifyNow P2Y12 assay (VN-P2Y12; Accumetrics Corporation, San Diego, California), the vasodilator-stimulated phosphoprotein phosphorylation (VASP; Biocytex, Marseille, France), and light transmission aggregometry (LTA). We included original publications or abstracts published with adequate data providing results expressed as mean platelet reactivity unit (PRU), mean platelet reactivity index (PRI), or mean maximal platelet aggregation (MPA) obtained with adenosine diphosphate (ADP) 20 μM with corresponding SD or SE for the respective tests.
Relevant publications to include in this meta-analysis were searched through MEDLINE/Pubmed, the Cochrane Collaboration database, and EMBASE with the following key words: “platelet reactivity” and (“prasugrel” or “ticagrelor”). Two physicians independently reviewed the titles, abstracts, and studies to determine whether they met inclusion criteria. No language, publications date, or publication status restrictions were imposed. In the case of duplication of data, the most inclusive data were chosen. Inclusion criteria were controlled comparison of clopidogrel, prasugrel, or ticagrelor in patients with coronary artery disease treated for at least 6 days to determine maintenance PR. The primary efficacy end point was PR expressed appropriately according to 1 of 3 platelet function as previously mentioned.
Continuous variables are presented as mean ± SD, and categorical variables are presented as percentages. Mixed treatment comparison model generation was performed to directly and indirectly compare maintenance therapy platelet function expressed as PRU, VASP, and MPA for different doses of clopidogrel, prasugrel, and ticagrelor using GeMTC 0.14.3 software (GeMTC; http://drugis.org/mtc ). Bayesian hierarchical random-effects model with directed acyclic graph model for general-purpose Markov chain Monte Carlo analysis was performed with 50,000 tuning iterations and 100,000 simulation iterations for PRU and PRI and 200,000 simulation iterations for MPA. Data are presented as mean difference (95% confidence intervals). Statistical significance was defined as a p value <0.05.
Results
From a total of 268 initial hits, 7 publications ( Supplementary Data A ) for direct comparison and 22 for indirect comparison ( Supplementary Data B ; 18 studies for clopidogrel-prasugrel comparison and 3 studies for clopidogrel-ticagrelor comparison) were found. The flow diagram of the study analysis and the design of the included studies are shown in Figure 1 and listed in Table 1 , respectively. The clinical characteristics of patients enrolled in the studies included in the meta-analysis are reported in Table 2 . The PR results of each study are presented in Table 3 .
| First author | Year | Patients | Timing of dosage ∗ | Arms | Specific population | Platelet function test |
|---|---|---|---|---|---|---|
| Prasugrel vs. clopidogrel | ||||||
| Alexopoulos AHJ | 2011 | 28 | 14 | Clopidogrel 150 mg Prasugrel 10 mg | HTPR | VN |
| Alexopoulos JACC Interv | 2011 | 64 | 30 | Clopidogrel 75 mg Clopidogrel 150 mg Prasugrel 10 mg | HTPR | VN |
| Alexopoulos JTH | 2011 | 21 | 15 | Clopidogrel 150 mg Prasugrel 10 mg | HTPR | VN |
| Alexopoulos AHJ | 2013 | 27 | 15 | Clopidogrel 150 mg Prasugrel 5 mg | HTPR | VN |
| Angiolillo | 2011 | 35 | 7 | Clopidogrel 150 mg Prasugrel 10 mg | – | LTA |
| Capranzano | 2011 | 20 | 15 | Clopidogrel 75 mg Prasugrel 5 mg | HTPR | VN LTA |
| Collet | 2014 | 82 | 14 | Clopidogrel 75 mg Clopidogrel 150 mg Prasugrel 10 mg | HTPR | VN VASP |
| Cuisset | 2013 | 1542 | 30 | Clopidogrel 75 mg Clopidogrel 150 mg Prasugrel 10 mg | – | VASP |
| Darlington | 2013 | 42 | 7 | Clopidogrel 150 mg Prasugrel 10 mg | – | VN VASP LTA |
| Erlinge | 2013 | 155 | 12 | Clopidogrel 75 mg Prasugrel 5 mg Prasugrel 10 mg | – | VN VASP |
| Gurbel | 2013 | 102 | 10 | Clopidogrel 75 mg Prasugrel 10 mg | – | VN VASP |
| Jin | 2014 | 63 | 30 | Clopidogrel 75 mg Prasugrel 5 mg Prasugrel 10 mg | – | VN |
| Kerneis | 2013 | 31 | 15 | Clopidogrel 75 mg Prasugrel 10 mg | – | VN VASP |
| Michelson | 2009 | 125 | 30 | Clopidogrel 75 mg Prasugrel 10 mg | – | VASP LTA |
| Price | 2012 | 54 | 7 | Clopidogrel 75 mg Prasugrel 10 mg | – | VN |
| Roberts | 2012 | 46 | 7 | Clopidogrel 75 mg Prasugrel 10 mg | CYP2C19 ∗ carreers | VN |
| Silvain | 2012 | 1331 | 14 | Clopidogrel 75 mg Clopidogrel 150 mg Prasugrel 10 mg | – | VN LTA |
| Wallentin | 2008 | 110 | 29 | Clopidogrel 75 mg Prasugrel 10 mg | – | VASP LTA |
| Wiviott | 2007 | 201 | 14 | Clopidogrel 150 mg Prasugrel 10 mg | – | VASP LTA |
| Ticagrelor vs. clopidogrel | ||||||
| Gurbel combined † | 2009 2010 | 174 | 14 | Prasugrel 10 mg Ticagrelor 90 mg bid | – | VN VASP LTA |
| Storey | 2010 | 69 | 28 | Clopidogrel 75 mg Ticagrelor 90 mg bid | – | VN VASP |
| Ticagrelor vs. prasugrel | ||||||
| Alexopoulos Circ Interv | 2012 | 55 | 5 | Prasugrel 10 mg Ticagrelor 90 mg bid | – | VN |
| Alexopoulos JACC | 2012 | 44 | 15 | Prasugrel 10 mg Ticagrelor 90 mg bid | HTPR | VN |
| Alexopoulos Thromb Haemost | 2014 | 512 | 30 | Prasugrel 10 mg Ticagrelor 90 mg bid | – | VN |
| Angiolillo | 2013 | 98 | 7 | Prasugrel 10 mg Ticagrelor 90 mg bid | – | VN VASP |
| Deharo | 2013 | 96 | 30 | Prasugrel 10 mg Ticagrelor 90 mg bid | – | VASP LTA |
| Lee | 2014 | 95 | 30 | Clopidogrel 75 mg Prasugrel 10 mg Ticagrelor 90 mg bid | – | PRU |
| Perl | 2014 | 86 | 30 | Prasugrel 10 mg Ticagrelor 90 mg bid | VN |
∗ Interval between initiation of the maintenance dose and platelet reactivity assessment.
† Data represent a combination of patients from the ONSET/OFFSET study and the RESPOND study.
| Variable | Overall population (N = 5395) |
|---|---|
| Age (years) | 62.4 ± 9 |
| Men | 75.3% |
| Current smoker | 33.1% |
| Diabetes mellitus | 30.8% |
| Hypertension | 69.7% |
| Hyperlipidemia ∗ | 72.27% |
| Prior percutaneous coronary intervention | 55.5% |
| Time of maintenance dose mean (min-max) | 18.4 (5-30) |
| Treatment | |
| Statins | 87.1% |
| B blockers | 76.9% |
| ACE inhibitors or ARB | 61.4% |
| Aspirin | 95.9% |
| Study | Therapy | PRU patients | PRU | PRI patients | PRI | MPA patients | MPA |
|---|---|---|---|---|---|---|---|
| Alexopoulos 2011 AHJ | Prasugrel 10 | 27 | 148.1 ± 54.7 | ||||
| Clopidogrel 150 | 27 | 219.8 ± 55.1 | |||||
| Alexopoulos 2011 JACC Int | Prasugrel 10 | 59 | 129.4 ± 73.2 | ||||
| Clopidogrel 75 | 64 | 291.0 ± 46.8 | |||||
| Clopidogrel 150 | 58 | 201.7 ± 70.5 | |||||
| Alexopoulos 2011 JTH | Prasugrel 10 | 21 | 156.7 ± 56.3 | ||||
| Clopidogrel 150 | 21 | 279.9 ± 55.9 | |||||
| Alexopoulos 2012 Circ Int | Ticagrelor | 27 | 25.6 ± 34.6 | ||||
| Prasugrel 10 | 27 | 50.3 ± 33.9 | |||||
| Alexopoulos 2012 JACC | Ticagrelor | 43 | 32.9 ± 46.7 | ||||
| Prasugrel 10 | 42 | 101.3 ± 46.8 | |||||
| Alexopoulos 2013 AHJ | Prasugrel 5 | 26 | 190.8 ± 74.7 | ||||
| Clopidogrel 150 | 27 | 240.8 ± 77 | |||||
| Alexopoulos 2014 Thromb and Haemostasis | Prasugrel 10 | 234 | 84.6 ± 84.2 | ||||
| Ticagrelor | 278 | 33.3 ± 33.4 | |||||
| Angiolillo 2011 | Prasugrel 10 | 35 | 38.3 ± 15.7 | ||||
| Clopidogrel 150 | 35 | 50.7 ± 15.7 | |||||
| Angiolillo 2013 | Ticagrelor | 33 | 47.9 ± 47.5 | 33 | 20.1 ± 17.8 | ||
| Prasugrel 10 | 65 | 95.6 ± 54.1 | 65 | 32.4 ± 18.5 | |||
| Capranzano 2011 | Prasugrel 5 | 20 | 171.7 ± 65.2 | 20 | 45.8 ± 13.4 | ||
| Clopidogrel 75 | 20 | 279.8 ± 45.1 | 20 | 62.6 ± 10.7 | |||
| Collet 2014 | Clopidogrel 75 | 82 | 143.3 ± 105 | 82 | 41 ± 30 | ||
| Clopidogrel 150 | 41 | 122.7 ± 60.5 | 41 | 32.9 ± 19.1 | |||
| Prasugrel 10 | 41 | 57.7 ± 67.1 | 41 | 20.1 ± 15.8 | |||
| Cuisset 2013 | Prasugrel 10 | 387 | 29.3 ± 13.0 | ||||
| Clopidogrel 150 | 868 | 42.1 ± 17.9 | |||||
| Clopidogrel 75 | 287 | 48.1 ± 19.1 | |||||
| Darlington 2013 | Prasugrel 10 | 22 | 104.2 ± 73.2 | 22 | 34.7 ± 27.2 | 22 | 34.2 ± 14.1 |
| Clopidogrel 150 | 20 | 144.4 ± 71.6 | 20 | 42.9 ± 25.9 | 20 | 40.1 ± 13.9 | |
| Deharo 2013 | Ticagrelor | 48 | 37.9 ± 10.3 | ||||
| Prasugrel 10 | 48 | 48.9 ± 10.8 | |||||
| Erlinge 2013 | Prasugrel 10 | 149 | 84.8 ± 54.5 | 139 | 25.3 ± 14.1 | ||
| Prasugrel 5 | 148 | 176.0 ± 62.7 | 140 | 49.7 ± 18.8 | |||
| Clopidogrel 75 | 148 | 195.7 ± 70.8 | 140 | 54.7 ± 20.4 | |||
| Gurbel 2013 | Prasugrel 10 | 102 | 107.5 ± 57.2 | 102 | 28.7 ± 17.6 | ||
| Clopidogrel 75 | 101 | 197.7 ± 71.8 | 101 | 55.6 ± 19.5 | |||
| Gurbel Combined ∗ | Ticagrelor | 82 | 44.7 ± 45.8 | 82 | 21.2 ± 15.5 | 82 | 29.3 ± 13.6 |
| Clopidogrel 75 | 92 | 201 ± 98.5 | 92 | 54.5 ± 22.7 | 92 | 47.9 ± 14 | |
| Jin 2014 | Prasugrel 10 | 20 | 71.9 ± 34.4 | ||||
| Prasugrel 5 | 20 | 174.6 ± 60.2 | |||||
| Clopidogrel 75 | 23 | 223.4 ± 72.9 | |||||
| Kozinski | Clopidogrel 75 | ||||||
| Prasugrel 10 | |||||||
| Lee 2014 | Prasugrel 10 | 34 | 86 ± 59 | ||||
| Ticagrelor | 25 | 49 ± 30 | |||||
| Clopidogrel 75 | 36 | 179 ± 77 | |||||
| Kerneis 2013 | Prasugrel 10 | 31 | 14.2 ± 21.9 | 28 | 12.5 ± 11.9 | ||
| Clopidogrel 75 | 31 | 155.0 ± 87.2 | 22 | 43.6 ± 21.8 | |||
| Michelson 2009 | Prasugrel 10 | 51 | 33.6 ± 20.7 | 11 | 39.9 ± 10.6 | ||
| Clopidogrel 75 | 51 | 47.9 ± 19.3 | 11 | 55.2 ± 10.6 | |||
| Perl 2014 | Prasugrel 10 | 46 | 67.3 ± 62.5 | ||||
| Ticagrelor | 40 | 21.1 ± 26.1 | |||||
| Price 2012 | Prasugrel 10 | 29 | 78.0 ± 36.0 | ||||
| Clopidogrel 75 | 27 | 196.0 ± 81.0 | |||||
| Roberts 2012 | Prasugrel 10 | 23 | 75.6 ± 57.3 | ||||
| Clopidogrel 75 | 23 | 207.3 ± 55.8 | |||||
| Silvain 2012 | Prasugrel 10 | 165 | 69.0 ± 75.0 | 165 | 32.2 ± 15.0 | ||
| Clopidogrel 150 | 139 | 161.0 ± 97.0 | 139 | 50.4 ± 17.0 | |||
| Clopidogrel 75 | 1027 | 160.0 ± 86.0 | 1027 | 47.2 ± 18.0 | |||
| Storey 2010 | Ticagrelor | 37 | 31.3 ± 32.5 | 37 | 14.6 ± 12.4 | 37 | 27.6 ± 10.0 |
| Clopidogrel 75 | 32 | 190.0 ± 82.8 | 32 | 51.5 ± 22.5 | 32 | 45.5 ± 15.0 | |
| Wallentin 2008 | Prasugrel 10 | 54 | 25.0 ± 11.8 | 54 | 42.6 ± 10.1 | ||
| Clopidogrel 75 | 52 | 51.2 ± 18.2 | 52 | 53.5 ± 11.0 | |||
| Wiviott 2007 | Prasugrel 10 | 101 | 23.4 ± 16.0 | 173 | 29.2 ± 13.2 | ||
| Clopidogrel 150 | 102 | 43.8 ± 22.5 | 153 | 40.9 ± 15.9 |
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