The important point: Our meta-analysis represents the first systemic analysis comparing the efficacy and safety of newer P2Y12 inhibitors (oral preparation or intravenous) with clopidogrel in patients with ACS.
The reasons are as follows: (1) The ways of administration are different, but the pharmacological mechanism is same basically. (2) The indications for 3 drugs are consistent basically. (3) Both of these drugs are available clinically. (4) There was no significant relationship between the end point and the route of administration.
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the mainstay of treatment for acute coronary syndrome (ACS), whether these patients undergo a percutaneous coronary intervention (PCI) or are managed medically. In recent years, the incidence of bleeding and the degree of inhibition of platelet aggregation caused by P2Y12 receptor inhibition have been of great concern.1–3 Clopidogrel is usually the antiplatelet drug of choice in patients with ACS; however, its lower bioavailability, slower onset of platelet inhibition, uncertainty of patient response, and drug resistance3 have led to the development of newer P2Y12 inhibitors such as cangrelor, prasugrel, and ticagrelor. Recently, these 3 drugs have been deemed acceptable for use in more and more patients who need antiplatelet therapy. Cangrelor, a nonthienopyridine adenosine triphosphate analog, is classified as an intravenous inhibitor of the adenosine diphosphate (ADP) receptor P2Y12 and could have a role in the treatment of patients who require rapid, predictable, profound, and reversible platelet inhibition,4–6 whereas 2 newer ADP inhibitors, prasugrel and ticagrelor, have been associated with less interpatient variability and more potent antiplatelet-aggregation response.7–11 Several meta-analyses have been conducted to explore the efficacy and safety of cangrelor, prasugrel, and ticagrelor in comparison with those of clopidogrel in patients with ACS.12–14 However, none of the meta-analyses involving the newer P2Y12 inhibitors (oral or intravenous preparations) have comprehensively assessed for a difference in cardiovascular events compared with clopidogrel in patients with ACS. Therefore, in this study, we performed a systematic evaluation and meta-analysis to compare the available evidence from large clinical trials on the efficacy of cangrelor, prasugrel, and ticagrelor relative to clopidogrel in decreasing the incidence of cardiovascular events in patients with ACS.
Based on this meta-analysis, newer P2Y12 inhibitors were significantly more effective than clopidogrel in the events of myocardial infarction (MI) and cardiovascular death in patients with ACS, although the incidence of thrombosis in MI (TIMI)-defined bleeding was higher compared with clopidogrel.
Our meta-analysis represents the first systemic analysis comparing the efficacy and safety of the newer P2Y12 inhibitors with clopidogrel in patients with ACS. This meta-analysis provides evidence for the efficacy of clopidogrel relative to that of cangrelor, prasugrel, and ticagrelor in reducing the incidence of MI and death from cardiovascular causes. However, newer P2Y12 inhibitors were associated with a higher risk of TIMI-defined bleeding compared with clopidogrel group.
This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement15 and the Cochrane Collaboration guidelines.16
Search Strategy and Study Selection
Systematic searches of the PubMed and Embase databases were conducted using the following keywords and subject terms: acute coronary syndromes, clopidogrel, cangrelor, prasugrel, and ticagrelor. Searches were also conducted for evaluations of clopidogrel. The materials in this analysis were only derived from journal articles, and the publication language was limited to English. All references in the determined research were also inspected as part of the evaluation of supplementary interrelated work. The literature search was last updated on August 20, 2016.
Studies were included if they met the following criteria1: clinical trial comparing clopidogrel versus cangrelor, prasugrel, or ticagrelor2; inclusion of patients with ACS, of whom 83,586 (95%) were treated after angiography and 4399 (5%) were treated without angiography or were undergoing PCI. The exclusion criteria consisted of the following1: ongoing studies,2 duplicate reports,3 unpublished studies (with data unavailable from the principal investigators),3 studies with incomplete follow-up.
The primary efficacy end point was the incidence of major adverse cardiovascular and vascular effects, and was defined as the composite events of MI and stroke. TIMI-defined bleeding was chosen as a primary safety end point.
Data Collection and Quality Assessment
Two investigators were all alone data evaluated using a standardized data-extraction protocol. Differing conclusions were resolved by discussion with a third investigator. The following data were extracted from each reference: author's name, year of publication, patient's age, sex, type of ACS, previous PCI, dose and method of drugs, number of patients, number of patients with cardiovascular events, follow-up time, and efficacy and safety of treatment. The quality of the included studies was assessed by evaluating the risk of bias in accordance with the Cochrane Collaboration methods.16 Subsequently, the following data were evaluated in detail: sequence generation, incomplete data, and allocation of different group ratios for concealment, double-blindness, selective reporting, and other biases. The scoring system used was not formal. The selection of journal, author, and institution was fair.
Analyses were performed using Review Manager 5.3. Statistics were used to assess agreement between reviewers for study selection. The treatment effect was evaluated using the odds ratio (OR) and 95% confidence interval (CI). All the results of the study were assessed using pooled ORs and 95% CIs by a fixed-effect or a random-effect model. The I2 test was used to assess the heterogeneity of the results, with I2 values greater than 75% indicating that the 2 groups had a high heterogeneity, independence, and no significance of meta-analysis.17–20 I2 values <50% and >50% were analyzed using fixed-effect and random-effect models, respectively. Sensitivity analysis was used to take into account the influence of study quality. The cutoff for statistical significance for each test was set at P < 0.05. If the I2 exceeded 50%, we considered heterogeneity to be substantial. Sensitivity analysis was performed, when possible, by removing one study at a time. Potential publication bias was evaluated using funnel plots.
A schematic of the study selection process is presented in Figure 1. The database and manual searches yielded 1376 citations, of which 786 were duplicates and thus excluded after either title or abstract evaluation, and 8 were excluded after full-text screening because they did not fulfill the inclusion criteria. Ultimately, 13 studies involving 87,985 patients were included in this systematic review.21–33
Methodological Quality of Studies Included
The detailed characteristics of the included 13 studies are shown in Tables 1 and 2. The methodological quality of the studies was determined by assessing the risk of biases (Fig. 2). Disagreements concerning data evaluation were resolved by consensus. All studies reported random sequence generation and selective reporting by lottery,21–33 whereas the methods used in the remaining studies to randomly categorize patients were insufficiently described. The random allocation concealment of all the studies was briefly mentioned.21–33 In addition, all the studies, except one, describe the blinding of participants and personnel in detail.32 On the basis of this information, it was easy to discover detection bias in 3 studies21,26,32 in the secondary outcomes of side effects. Nine of the studies reported missing data.21–23,25–30 Owing to the incompleteness of some primary outcome indicators (eg, bleeding), selection bias was found to exist in 2 studies.24,30
Quantitative Data Synthesis
Primary Efficacy End Point
The rates of MI events in patients with ACS were identified in 9 of the included studies.21–23,25–27,30,31 As shown in Figure 3, the risk of MI was significantly lower for newer P2Y12 inhibitors than that for clopidogrel (OR = 0.86, 95% CI, 0.77–0.96, I2 = 54%, and P < 0.05). No obvious heterogeneity among studies was observed.
Nine of the research groups investigated the incidence of stroke events in patients with ACS.21,23,25–27,29–32 The rates of stroke events in patients with ACS did not differ statistically between the clopidogrel group and the group of newer P2Y12 inhibitors (OR = 0.95, 95% CI, 0.79–1.14, I2 = 0%, and P = 0.57) (Fig. 4). The heterogeneity among studies was low.
Death From Cardiovascular Causes/Vascular Causes
The rates of death from cardiovascular causes in patients with ACS were identified in 12 of the 13 studies included in this review.21–32 Newer P2Y12 inhibitors had a significantly decreased incidence of death from cardiovascular causes than the clopidogrel group (OR = 0.85, 95% CI, 0.77–0.93, I2 = 42%, and P < 0.001) (Fig. 5). There was low heterogeneity among the 9 studies.
Primary Safety End Point
TIMI-Defined Bleeding (Major and Minor)
The incidences of bleeding events in patients with ACS were identified in 11 articles.21–23,25–27,29–33 Newer P2Y12 inhibitors significantly increased the risk of TIMI-defined bleeding compared with clopidogrel (OR = 1.21, 95% CI, 1.03–1.42, I2 = 56%, and P = 0.02) (Fig. 6). Although high heterogeneity between 2 studies was found (I2 = 60%), no outliers were identified after sensitivity analysis.
Symmetry in the funnel plot was observed (Fig. 7).
Our meta-analysis represents the first systemic analysis comparing the efficacy and safety of newer P2Y12 inhibitors with clopidogrel in patients with ACS. This meta-analysis provides evidence for the efficacy of clopidogrel relative to that of cangrelor, prasugrel, and ticagrelor in reducing the incidence of cardiovascular events in patients with ACS. Thirteen studies were included in this analysis: 3 compared clopidogrel and cangrelor, 6 compared clopidogrel and prasugrel, and 4 compared clopidogrel and ticagrelor. The main findings of this review can be summarized as follows:
1. There were no differences in the primary efficacy end points of stroke between patients with ACS taking clopidogrel and newer P2Y12 inhibitors.
2. The incidences of MI and death from cardiovascular causes significantly decreased in the newer P2Y12 inhibitor group than in the clopidogrel group.
3. However, newer P2Y12 inhibitors were associated with a higher risk of TIMI-defined bleeding compared with the clopidogrel group.
Of the studies evaluated, the average age of patients ranged from 52–77 years, and the course of disease ranged from 2–15 years. The specific intervention strategies used in the newer P2Y12 inhibitors group included cangrelor, prasugrel, or ticagrelor. Moreover, 3 studies administered cangrelor through intravenous (IV) drip, whereas the others involved orally administered prasugrel or ticagrelor. In addition, the disparity in age, treatment duration, the “unclear risk of bias” involved in patient allocation, concealment, and blinding, and the lack of description of details associated with patient characteristics were likely important sources of heterogeneity associated with this meta-analysis. Although the heterogeneity between studies allows us to make only preliminary conclusions, future larger clinical trials should enhance our ability to draw more definite conclusions regarding the use of the newer P2Y12 inhibitors as an adjuvant treatment for ACS. Sensitivity analysis failed to show any outliers, confirming the robustness of our results.
Clinical Significance of the Findings
Clopidogrel is an orally administered, irreversible P2Y12 receptor inhibitor. Because clopidogrel is a prodrug, it needs to undergo in vivo activation to exert antiplatelet action. Clopidogrel's antiplatelet potency is closely related to the patient's CYP2C19 genotype, in vivo absorption, and drug metabolism. Genotypes with fast or moderate drug metabolism are required to have a good therapeutic effect with oral clopidogrel. For patients with slow metabolism, cardiovascular events such as death or early stent thrombosis may occur even if a preoperative dose of clopidogrel is administered before PCI, and the risk of such events is high.34 Furthermore, because clopidogrel is a prodrug, its onset of action is slow. A meta-analysis of studies with 3960 patients suggested that 25% of patients possess clopidogrel resistance and that their risk of recurrent ischemic events was 3 times greater than in other patients.35 The presence of clopidogrel resistance has driven the development and marketing of a new generation of antiplatelet agents, such as cangrelor, prasugrel, and ticagrelor. Compared with clopidogrel, the greatest advantage of cangrelor, ticagrelor, and prasugrel is that they have more effective antiplatelet action, faster inhibition of platelet aggregation, higher potency, more resistance to genotype variability, and fewer individual differences. Ticagrelor in particular has an advantage in that it acts directly and is reversible. For ACS patients with high thrombotic risk, these 3 drugs are more suitable for antiplatelet therapy after PCI.
Cangrelor was the first intravenous and competitive P2Y12 inhibitor developed, with a reversible mode of action and a very short half-life of 5 minutes. Cangrelor belongs to a new family of drugs: ADP analogs. Its rapid onset of action is possible because it acts directly on the P2Y12 receptor, without the need for in vivo bioactivation.21 It has a high inhibitory effect on ADP-induced platelet aggregation, with immediate onset on intravenous administration and rapid recovery of platelet function 1–2 hours after discontinuation in patients with ACS without persistent ST-segment elevation (NSTE-ACS).21 The 2015 European Society of Cardiology (ESC) guidelines for the management of NSTE-ACS report that selected patients who require noncardiac surgery after recently implanted stents may benefit from bridging therapy with small-molecule GPIIb/IIIa inhibitors (ie, tirofiban or eptifibatide) after discontinuation of the P2Y12 inhibitor; in contrast, cangrelor has so far been tested as a bridging therapy to coronary artery bypass grafting (IIb). Prasugrel, similar to clopidogrel, is also a prodrug, and needs to be converted into its active metabolites in vivo to bind to the platelet P2Y12 receptor and produce an antiplatelet effect.36 The normal dose of prasugrel in healthy volunteers and patients with ACS, including those undergoing PCI, inhibits ADP-induced platelet aggregation faster, stronger, and more consistently than the standard or higher doses of clopidogrel.25 However, in patients with ACS with scheduled PCI, prasugrel treatment was associated with an additional risk of major bleeding that could be fatal.25 Ticagrelor is a new ADP receptor inhibitor that was recently recommended as a substitute for clopidogrel for first-line treatment. Unlike other P2Y12 receptor inhibitors, ticagrelor does not require in vivo activation, and its metabolites are also pharmacologically active, resulting in more rapid platelet inhibition. Ticagrelor also has a reversible mode of action. The 2016 American College of Cardiology/American Health Association (ACC/AHA) Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With ACS suggests: “In patients with ACS (NSTE-ACS or STEMI) treated with DAPT after coronary stent implantation and in patients with NSTE-ACS treated with medical therapy alone (without revascularization), it is reasonable to use ticagrelor in preference to clopidogrel for maintenance P2Y12 inhibitor therapy (I).37 Compared to clopidogrel, the new generation of P2Y12 receptor inhibitors (ticagrelor or prasugrel) reduces the risk of ischemia and increases the risk of hemorrhagic shock.37”
The findings suggest that the newer P2Y12 inhibitors could replace clopidogrel in clinical practice. However, 3 major problems cannot be ignored, with the first being hemorrhagic risk. The risk of bleeding when taking the new generation of antiplatelet drugs still requires assessment. The 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with ACS recommendations state that the assessment of bleeding risk should consider the possibility of hemorrhage. Patients with severe bleeding reactions should stop using P2Y12 receptor inhibitors. Second, breathing difficulties are a possible adverse effect; for breathing difficulties that last longer than 30 days, remission may be considered as an alternative to clopidogrel. Lastly, prasugrel and cangrelor are listed in the Health Insurance Directory in China, but ticagrelor is not. The national per capita medical expenditure was 1165 yuan in 2015, no more than 3.2 yuan per day. However, the daily cost of ticagrelor treatment is 25.7 yuan, far more than the per capita health insurance consumption. Therefore, from a cost-effectiveness standpoint, it is better to take clopidogrel.38
In summary, based on our meta-analysis, newer P2Y12 inhibitors are significantly more effective than clopidogrel in preventing MI and cardiovascular death in patients with ACS. However, our meta-analysis suggests that the new generation of P2Y12 inhibitors can also increase the risk of bleeding in patients. Therefore, application of these new inhibitors should only be considered after evaluating the individual's bleeding risk. The use of these drugs can be guided by a hierarchical comparison of the ischemic and hemorrhagic risks of the patients. In the future, data from more design-perfect, large-scale, multi-center randomized controlled trials would greatly aid in the decision-making process of providing safe and convenient anticoagulant therapy for patients with ACS.
This systematic review had one major limitation: all of the information in previously published articles was already screened for refinement, resulting in the exclusion of highly heterogeneous results. The heterogeneity of the clinical outcomes in this article was not significant and did not affect the overall study conclusion. Of course, more large clinical trials are needed to achieve more accurate results.
Our meta-analysis represents the first systemic analysis comparing the efficacy and safety of cangrelor, prasugrel, and ticagrelor with clopidogrel in patients with ACS. This meta-analysis provides evidence for the efficacy of cangrelor, prasugrel, and ticagrelor relative to clopidogrel relative in reducing the incidence of MI and death from cardiovascular causes. However, these newer P2Y12 inhibitors were also associated with a higher risk of TIMI-defined bleeding compared with clopidogrel.
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