# Effect of Potent P2Y12 Inhibitors on Ventricular Arrhythmias and Cardiac Dysfunction in Coronary Artery Disease: A Systematic Review and Meta-Analysis

Authors: Chunmei Wang; Guanqi Zhao; Xiao Wang; Shaoping Nie
Journal: BioMed Research International
 (2018)

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## Abstract

Background. Previous studies have shown that P2Y12 receptor inhibitors might prevent ventricular arrhythmias and cardiac dysfunction in patients with coronary artery disease. However, few studies have focused on comparison of the efficacy of novel oral potent P2Y12 receptor inhibitors with clopidogrel on these outcomes.Methods and Results. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that were published in electronic databases of MEDLINE, EMBASE, Cochrane Central Register of Clinical Trials, and ClinicalTrials.gov before June 20, 2018. We compared the effect of prasugrel and ticagrelor with clopidogrel on outcomes of ventricular tachycardia (VT), ventricular fibrillation (VF), heart failure (HF), and cardiogenic shock (CS). Data were combined using both the fixed-effects models and the random-effects models, and the heterogeneity was assessed with the I2 statistic. Nine RCTs (6 with prasugrel and 3 with ticagrelor) with 45,227 patients were included. Patients receiving prasugrel were associated with a lower risk of combined VT and VF (rate ratio [RR]: 0.72, 95% confidence interval [CI]: 95% CI: 0.52-0.99,p=0.043), as well as combined HF and CS (RR: 0.81, 95% CI: 0.70-0.94,p=0.005), compared with clopidogrel. Patients receiving ticagrelor were also associated with a reduced risk of VT and VF (RR: 0.85, 95% CI: 0.72-1.02,p=0.077), although without statistical significance, but not of HF and CS (RR: 0.96, 95% CI: 0.81-1.13,p=0.620).Conclusions. This meta-analysis of RCTs shows that, compared with clopidogrel, novel oral P2Y12 inhibitors, especially prasugrel, might have better effect on improving ventricular rhythm and cardiac function.


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## Body

## 1. Introduction

For decades, dual antiplatelet therapy with aspirin and P2Y purinoceptor 12 (P2Y12)-receptor inhibitor of clopidogrel has remained the cornerstone of treatment for patients with acute coronary syndrome (ACS). The novel oral P2Y12 receptor inhibitors of prasugrel and ticagrelor, approved by the FDA for clinical use in 2009 and 2011, have also been recommended as the first-line therapy for patients with ACS in the guideline based on their rapid onset of action and potent effects on inhibition of platelet aggregation [1, 2], as well as a better effect on lowering risk of all-cause death and major adverse cardiovascular events (MACE) [3–8]. However, whether these two novel oral P2Y12 receptor inhibitors, compared with clopidogrel, have better effect on improving heart rhythm and heart function is unclear.Ventricular arrhythmias and cardiac dysfunction are severe complications that can significantly increase the risk of death and rehospitalization for patients with coronary artery disease (CAD), especially for those with ACS [5]. Studies have suggested that antiplatelet agents might have an effect on improving ventricular rhythm and cardiac function by reducing the frequency of coronary thrombotic occlusions [9, 10]. However, few studies have focused on comparison of the effect of these novel oral P2Y12 inhibitors with clopidogrel on these complications.This meta-analysis reviewed relevant randomized controlled trials (RCTs) to compare the effects of prasugrel and ticagrelor on ventricular tachycardia (VT), ventricular fibrillation (VF), heart failure (HF), and cardiogenic shock (CS), with those of clopidogrel. We aimed to determine whether prasugrel or ticagrelor may improve prognosis by reducing ventricular arrhythmias and cardiac dysfunction.


## 2. Materials and Methods

### 2.1. Data Sources and Search Strategy

We conducted a meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [25]. We searched the electronic databases of MEDLINE, EMBASE, Cochrane Central Register of Clinical Trials, and ClinicalTrials.gov with no language restriction to identify all published or registered RCTs. All of these searches were conducted by 2 independent researchers (C.M.W. and G.Q.Z.) before June 20, 2018. The following terms were used: “coronary artery disease” OR “coronary heart disease” OR “acute coronary syndrome” OR “acute myocardial infraction” OR “ST-elevation myocardial infraction” OR “non-ST-elevation myocardial infraction” OR “unstable angina” OR “non-ST-elevation acute coronary syndromes” OR “stable angina” OR “percutaneous coronary intervention” and “ticagrelor” OR “prasugrel” and “clopidogrel” and “heart failure” OR “cardiogenic shock” OR “ventricular tachycardia” OR “ventricular fibrillation” OR “ventricular arrhythmias” and their synonyms or variations. Reference lists of selected studies, relevant articles, and related systematic reviews were manually reviewed for potential retrieved studies.


### 2.2. Study Selection and Data Extraction

RCTs that compared the outcomes of prasugrel or ticagrelor with clopidogrel in adults (≥18 years) with all forms of CAD were included to screen whether they reported at least one of the following outcomes: VT, VF, HF, and CS. Studies not reporting the clinical outcomes of interest were excluded. Meeting abstracts and studies that only reported antiplatelet effects of these agents were also excluded. The details of the study selection are described in Figure1.Figure 1
Review process for inclusion/exclusion of studies.Data extraction was performed independently by 2 researchers (C.M.W. and G.Q.Z.) with prepared standardized data forms. Divergent assessments were resolved by discussion with a third researcher (W.X.). Study information was recorded as follows: year of the study, study intervention, number of patients, characteristics of study population, primary endpoints and follow-up duration. Detailed patients’ characteristics (age, sex, proportion of patients with ACS and PCI, medical history) and crude events of VT, VF, HF, or CS during follow-up were also reported.


### 2.3. Outcomes

The outcomes of this study included VT, VF, HF, and CS, either reported in published journal articles or posted on ClinicalTrial.gov. HF was considered present if there was any reported congestive HF, acute or chronic HF. VT was considered present if sustained or nonsustained VT was reported. Other outcomes were defined according to the definitions in the respective studies.


### 2.4. Quality Assessment

The quality of RCTs was assessed using methods recommended by the Cochrane Collaboration on the basis of the following components: random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias [26] (Supplementary Figure 1).


### 2.5. Statistical Analysis

The meta-analysis was performed using STATA 12.0 (StataCorp LLC, Texas, USA). Rate ratios (RRs) and 95% confidence intervals (CIs) were used as summary estimates. The pooled RRs of prasugrel and ticagrelor versus clopidogrel were calculated with both the fixed-effects model and random-effects model as heterogeneity may still exist even ifI2 <50.I2 >50% suggested that heterogeneity between trials was of statistical significance. A 2-sidedp value <0.05 was considered statistically significant. Sensitivity analysis was performed by excluding trials which were examined to be main sources of heterogeneity. Funnel diagrams of the included studies are shown in Supplementary Figure 2 to estimate the publication bias. Quality assessment was performed with Review Manager 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Denmark).


## 2.1. Data Sources and Search Strategy

We conducted a meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [25]. We searched the electronic databases of MEDLINE, EMBASE, Cochrane Central Register of Clinical Trials, and ClinicalTrials.gov with no language restriction to identify all published or registered RCTs. All of these searches were conducted by 2 independent researchers (C.M.W. and G.Q.Z.) before June 20, 2018. The following terms were used: “coronary artery disease” OR “coronary heart disease” OR “acute coronary syndrome” OR “acute myocardial infraction” OR “ST-elevation myocardial infraction” OR “non-ST-elevation myocardial infraction” OR “unstable angina” OR “non-ST-elevation acute coronary syndromes” OR “stable angina” OR “percutaneous coronary intervention” and “ticagrelor” OR “prasugrel” and “clopidogrel” and “heart failure” OR “cardiogenic shock” OR “ventricular tachycardia” OR “ventricular fibrillation” OR “ventricular arrhythmias” and their synonyms or variations. Reference lists of selected studies, relevant articles, and related systematic reviews were manually reviewed for potential retrieved studies.


## 2.2. Study Selection and Data Extraction

RCTs that compared the outcomes of prasugrel or ticagrelor with clopidogrel in adults (≥18 years) with all forms of CAD were included to screen whether they reported at least one of the following outcomes: VT, VF, HF, and CS. Studies not reporting the clinical outcomes of interest were excluded. Meeting abstracts and studies that only reported antiplatelet effects of these agents were also excluded. The details of the study selection are described in Figure1.Figure 1
Review process for inclusion/exclusion of studies.Data extraction was performed independently by 2 researchers (C.M.W. and G.Q.Z.) with prepared standardized data forms. Divergent assessments were resolved by discussion with a third researcher (W.X.). Study information was recorded as follows: year of the study, study intervention, number of patients, characteristics of study population, primary endpoints and follow-up duration. Detailed patients’ characteristics (age, sex, proportion of patients with ACS and PCI, medical history) and crude events of VT, VF, HF, or CS during follow-up were also reported.


## 2.3. Outcomes

The outcomes of this study included VT, VF, HF, and CS, either reported in published journal articles or posted on ClinicalTrial.gov. HF was considered present if there was any reported congestive HF, acute or chronic HF. VT was considered present if sustained or nonsustained VT was reported. Other outcomes were defined according to the definitions in the respective studies.


## 2.4. Quality Assessment

The quality of RCTs was assessed using methods recommended by the Cochrane Collaboration on the basis of the following components: random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias [26] (Supplementary Figure 1).


## 2.5. Statistical Analysis

The meta-analysis was performed using STATA 12.0 (StataCorp LLC, Texas, USA). Rate ratios (RRs) and 95% confidence intervals (CIs) were used as summary estimates. The pooled RRs of prasugrel and ticagrelor versus clopidogrel were calculated with both the fixed-effects model and random-effects model as heterogeneity may still exist even ifI2 <50.I2 >50% suggested that heterogeneity between trials was of statistical significance. A 2-sidedp value <0.05 was considered statistically significant. Sensitivity analysis was performed by excluding trials which were examined to be main sources of heterogeneity. Funnel diagrams of the included studies are shown in Supplementary Figure 2 to estimate the publication bias. Quality assessment was performed with Review Manager 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Denmark).


## 3. Results and Discussion

### 3.1. Included Studies

Based on initial research criteria, 793 publications from MEDLINE, EMBASE, Cochrane Central Register of Clinical Trials, and ClinicalTrials.gov were identified. After duplicates and non-RCTs were excluded, 261 potentially relevant publications were included for further screening and 19 publications that fulfilled the eligibility criteria were included for full text review. Nine of these publications with interesting outcomes for this study were eventually included in the present meta-analysis [1, 2, 11–17].The characteristics of each study and detailed characteristics of patients in each study are shown in Tables1 and 2. There were some differences among the included studies regarding the study designs and patients’ characteristics. Because there were differences between ticagrelor and prasugrel, we compared the efficacy of ticagrelor and prasugrel with clopidogrel, respectively. Because not all studies provided all outcomes of interest, we summarized the outcomes of each study (Table 3). There was a total of 45,227 patients (23,102 in the potent P2Y12 inhibitor arm and 22,125 in the clopidogrel arm). In the nine included studies, six studies compared prasugrel with clopidogrel in 24,846 patients and three studies compared ticagrelor with clopidogrel in 20,381 patients.Table 1
Characteristics, designs, and follow-up durations of the included studies.
Name Year Intervention PotentP2Y12 inhibitors, n Clopidogrel, n Characteristics of Study Population Primary Endpoint Follow-up DISPERSE-2 [11] 2007 Ticagrelor vs Clopidogrel 663 327 Patients were hospitalized for NSTE-ACS within the preceding 48 hours. Major adverse cardiac event;Major bleeding (fatal/life-threatening) 12 weeks(primary endpoint) PLATO [1] 2009 Ticagrelor vs Clopidogrel 9333 9291 Hospitalized patients with ACS. CV death, MI, or stroke;Major bleeding, study criteria 12 months(primary endpoint) PHILO [12] 2015 Ticagrelor vs Clopidogrel 387 380 Patients with non-ST or ST segment elevation ACS Major adverse cardiac event;Major bleeding 12 months(primary endpoint) JUMBO-TIMI26 [13] 2005 Prasugrel vs Clopidogrel 651 254 Patients candidate for elective or urgent PCI with intended coronary stenting. Major adverse cardiac event;Non-CABG TIMI Major or Minor Bleeding Events 30 days(primary endpoint) TRITON-TIMI 38 [2] 2007 Prasugrel vs Clopidogrel 6741 6716 Patients with ACS and scheduled for PCI CV death, nonfatal MI, or nonfatal stroke;TIMI non-CABG major bleeding 14.5 months(median) Ge et al. [14] 2010 Prasugrel vs Clopidogrel 463 299 East or southeast Asian patients with ACS and scheduled for PCI. ADP-InducedP2Y12 PRU at 4 hours and 30 days 30 days(primary endpoint) TRILOGY ACS [15] 2012 Prasugrel vs Clopidogrel 4623 4617 Patients with ACS who were medically managed. CV death, nonfatal MI, or nonfatal stroke;TIMI non-CABG major bleeding 17.1 months(median) TRIGGER PCI [16] 2012 Prasugrel vs Clopidogrel 210 210 Coronary artery disease patients underwent PCI with at least one drug-eluting stent implantation. Composite endpoint of CV death or MI 6 months(primary endpoint) ETAMI [17] 2015 Prasugrel vs Clopidogrel 31 31 Patients with acute STEMI ≤ 12 hours and scheduled for PCI Platelet reactivity index (PRI) 2 hours after the initiation of the therapy 30 days(clinical events) DISPERSE-2: dose confirmation study assessing anti-platelet effects of AZD6140 vs. clopidogrel in non-ST-segment elevation myocardial infarction-2, PLATO: platelet inhibition and patient outcomes, PHILO: ticagrelor vs. clopidogrel in Japanese, Korean, and Taiwanese patients with acute coronary syndrome, JUMBO-TIMI26: joint utilization of medications to block platelets optimally-thrombolysis in myocardial infarction 26, TRITON-TIMI 38: trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel–thrombolysis in myocardial infarction, TRILOGY ACS: the targeted platelet inhibition to clarify the optimal strategy to medically manage acute coronary syndromes, TRIGGER PCI: testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel, ETAMI: early thienopyridine treatment to improve primary PCI in patients with acute myocardial infarction, PCI: percutaneous coronary intervention, NSTE-ACS: non-ST-segment elevation acute coronary syndrome, ACS: acute coronary syndrome, CABG: coronary artery bypass grafting, CV: cardiovascular, TIMI: thrombolysis in myocardial infarction, MI: myocardial infarction, NSTEMI: non-ST-segment elevation myocardial infarction, STEMI: ST-segment elevation myocardial infarction, GUSTO: Global use of strategies to open occluded coronary arteries, ADP: adenosine diphosphate, PRU:P2Y12 reaction units.Table 2
Patients’ characteristics of included RCTs.
Study Age (years)∗ Male (%) ACS (%) PCI (%) Smoker (%) Diabetes mellitus (%) Hypertension (%) Prior MI (%) DISPERSE-2 [11] 63.0±11.6 63.7 100.0 42.0 N/A 24.8 N/A 26.0 PLATO [1] 62.2 (53.0, 70.0) 74.8 99.8 76.8 35.9 23.2 65.4 17.0 PHILO [12] 67.0±11.0 76.4 100.0 84.6 38.5 34.7 74.3 8.0 JUMBO-TIMI26 [13] 59.2±9.03 77.0 40.0 100.0 28.4 25.0 N/A N/A TRITON-TIMI 38 [2] 60.9±11.3 74.1 100.0 100.0 38.0 23.0 64.0 18.0 Ge et al. [14] 60.8±11.1 74.8 100.0 100.0 N/A N/A N/A N/A TRILOGY ACS [15] 65.7±11.0 60.9 100.0 0 39.9 37.9 82.0 42.8 TRIGGER PCI [16] 66.1±8.4 72.6 0 100.0 14.4 41.8 88.9 27.4 ETAMI [17] N/A 72.6 100.0 87.1 74.2 19.4 54.8 8.1 N/A: not available, DISPERSE-2: dose confirmation study assessing anti-platelet effects of AZD6140 vs. clopidogrel in non-ST-segment elevation myocardial infarction-2, PLATO: platelet inhibition and patient outcomes, PHILO: ticagrelor vs. clopidogrel in Japanese, Korean, and Taiwanese patients with acute coronary syndrome, JUMBO-TIMI26: joint utilization of medications to block platelets optimally-thrombolysis in myocardial infarction 26, TRITON-TIMI 38: trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel–thrombolysis in myocardial infarction, TRILOGY ACS: the targeted platelet inhibition to clarify the optimal strategy to medically manage acute coronary syndromes, TRIGGER PCI: testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel, ETAMI: early thienopyridine treatment to improve primary PCI in patients with acute myocardial infarction ACS: acute coronary syndrome, PCI: percutaneous coronary intervention, MI: myocardial infarction. ∗Age is presented as either mean ± standard deviation or median (interquartile range) when available.Table 3
Outcomes of the potentP2Y12 inhibitors.
Study Heart failure Cardiogenic Shock Ventricular tachycardia Ventricular fibrillation PotentP2Y12 inhibitors Clopidogrel PotentP2Y12 inhibitors Clopidogrel PotentP2Y12 inhibitors Clopidogrel PotentP2Y12 inhibitors Clopidogrel DISPERSE-2 [11]∗ N/A N/A N/A N/A 166/663 93/327 N/A N/A PLATO [1, 18] 196/9333 198/9291 60/9333 66/9291 29/9333 33/9291 48/9333 64/9291 PHILO [12, 19] 11/387 13/380 N/A N/A 8/387 8/380 3/387 1/380 JUMBO-TIMI26 [13, 20] 1/651 0/254 N/A N/A N/A N/A N/A N/A TRITON-TIMI 38 [2, 21] 71/6741 92/6716 13/6741 8/6716 24/6741 25/6716 18/6741 25/6716 Ge et al. [14, 22] 2/463 4/229 4/463 2/229 3/463 1/229 1/463 0/229 TRILOGY ACS [15, 23] 199/4623 238/4617 15/4623 23/4617 15/4623 20/4617 3/4623 15/4617 TRIGGER PCI [16, 24] 1/210 5/210 N/A N/A 0/210 1/210 0/210 0/210 ETAMI [17] N/A N/A 1/31 2/31 N/A N/A N/A N/A Values are n/N N/A: not available, DISPERSE-2: dose confirmation study assessing anti-platelet effects of AZD6140 vs. clopidogrel in non-ST-segment elevation myocardial infarction-2, PLATO: platelet inhibition and patient outcomes, PHILO: ticagrelor vs. clopidogrel in Japanese, Korean, and Taiwanese patients with acute coronary syndrome, JUMBO-TIMI26: joint utilization of medications to block platelets optimally-thrombolysis in myocardial infarction 26, TRITON-TIMI 38: trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel–thrombolysis in myocardial infarction, TRILOGY ACS: the targeted platelet inhibition to clarify the optimal strategy to medically manage acute coronary syndromes, TRIGGER PCI: testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel, ETAMI: early thienopyridine treatment to improve primary PCI in patients with acute myocardial infarction. ∗Heart failure was defined as any reported congestive heart failure, acute and chronic heart failure. †Ventricular tachycardia (VT) was categorized into sustained VT (lasting >30 s), non-sustained ventricular tachycardia (NSVT) (≥4 beats and <30 s in length), and triplets (3 ventricular beats).


### 3.2. Analysis of Ventricular Arrhythmias

Four and three studies compared the effects of prasugrel [2, 14–16, 21–23] and ticagrelor [1, 11, 12, 18, 19] with clopidogrel on VT, respectively. Compared with clopidogrel, prasugrel (RR: 0.86, 95% CI: 0.57-1.31,p=0.494; I2=0) and ticagrelor (RR: 0.88, 95% CI: 0.73-1.08,p=0.220; I2=0) were not significantly associated with reduced risk of VT (Figure 2).Figure 2
Forest plot for ventricular tachycardia, ventricular fibrillation, and pooled data of ventricular arrhythmias. A, ventricular tachycardia; B, ventricular fibrillation; C, ventricular tachycardia or ventricular fibrillation. CI: confidence interval.Three studies compared the effects of prasugrel and clopidogrel on VF [2, 14, 15, 21–23]. Prasugrel was associated with a 46% reduced risk of VF compared with clopidogrel (RR: 0.54, 95% CI: 0.32-0.91,p=0.020; I2=46.1%) (Figure 2). Two studies compared the effect of ticagrelor and clopidogrel on VF [1, 12, 18, 19], but we did not observe a significantly reduced risk of VF in ticagrelor (RR: 0.78, 95% CI: 0.54-1.13,p=0.184; I2=27.7%) (Figure 2).When we pooled VT and VF, both being manifestation of ventricular arrhythmias, a 28% reduced risk was observed in prasugrel (RR: 0.72, 95% CI: 0.52-0.99,p=0.043; I2=0) and a 15% reduced risk with ticagrelor (RR: 0.85, 95% CI: 0.72-1.02,p=0.077; I2=0) although without statistical significance, compared with clopidogrel (Figure 2).


### 3.3. Analysis of Cardiac Dysfunction

Five studies compared the effects of prasugrel and clopidogrel on HF [2, 13–16, 20–24]. Prasugrel was associated with a 20% reduced risk of HF compared with clopidogrel (RR: 0.80, 95% CI: 0.68-0.93,p=0.005; I2=0) (Figure 3). Two studies compared the effects of ticagrelor and clopidogrel on HF [1, 12, 18, 19]. We did not observe a reduced risk of HF in ticagrelor compared with clopidogrel (RR: 0.98, 95% CI: 0.81-1.18,p=0.801; I2=0) (Figure 3).Figure 3
Forest plot for heart failure, cardiogenic shock, and pooled data of cardiac dysfunction. A, heart failure; B, cardiogenic shock; C, heart failure or cardiogenic shock. CI: confidence interval.Four studies compared the effects of prasugrel and clopidogrel on CS [2, 14, 15, 17, 21–23]. Only the Platelet Inhibition and Patient Outcomes (PLATO) trial [1, 18] reported the incidence of CS in patients who took ticagrelor and clopidogrel. However, a reduced risk of CS was not observed with both prasugrel (RR: 0.98, 95% CI: 0.68-1.19,p=0.617; I2=0) and ticagrelor (RR: 0.90, 95% CI: 0.64-1.28,p=0.574) compared with clopidogrel (Figure 3).When we pooled HF and CS, both being manifestation of cardiac dysfunction, patients with prasugrel had 19% lower risk (RR: 0.81, 95% CI: 0.70-0.94,p=0.005; I2=0), but not with ticagrelor (RR: 0.96, 95% CI: 0.81-1.13,p=0.620; I2=0), compared with clopidogrel (Figure 3).


### 3.4. Sensitivity Analysis

Among the studies, the proportions of patients with ACS in the testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel (TRIGGER PCI) study [16] and joint utilization of medications to block platelets optimally thrombolysis in myocardial infarction 26 (JUMBO-TIMI 26) study [13] were significantly lower than those in other studies. Therefore, we performed sensitivity analyses of patients with ACS by excluding studies that showed similar rates of all the outcomes tested. We found that the RR of VT was 0.89 (95% CI: 0.66-1.21,p=0.967; I2=0%) and the RR of VF was 0.69 (95% CI: 0.51-0.93, p=0.014; I2=31.6%), that of VT and VF was 0.78 (95% CI: 0.63-0.96,p=0.022; I2=0%), the RR of HF was 0.87 (95% CI: 0.77-0.98,p=0.027; I2=11.3%) and the RR of CS was 0.90 (95% CI: 0.68-1.19,p=0.454; I2=0%), and that of HF and CS was 0.88 (95% CI: 0.78-0.98,p=0.020; I2=0%). The incidence of VT in the dose confirmation study assessing antiplatelet effects of AZD6140 versus clopidogrel in non-ST-segment elevation myocardial infarction-2 (DISPERSE-2) [11] was much higher than that in the other studies because of the definition of VT in this study. Therefore, sensitivity analysis that excluded this study showed that the RR of VT was 0.88 (95% CI: 0.65-1.19,p=0.405; I2=0%) and that of VT and VF was 0.78 (0.63-1.96,p=0.019; I2=0%). We also preformed sensitivity analysis by including studies with relatively large sample size (>5000) or with relatively long follow-up (>6 months). Similar results to the main result were observed (Supplementary Figures 3, 4, 5, and 6).


### 3.5. Discussion

To the best of our knowledge, this is the first meta-analysis that performs a comparison between novel oralP2Y12 inhibitors and clopidogrel on outcomes of cardiac dysfunction and ventricular arrhythmias in patients with CAD.Our meta-analysis showed that potentP2Y12 inhibitors, including prasugrel and ticagrelor, were associated with a lower risk of ventricular arrhythmias (although there was no significance with ticagrelor compared with clopidogrel). A lowered risk of HF and CS was observed in patients taking prasugrel. In summary, compared with clopidogrel, use of prasugrel or ticagrelor could further improve ventricular rhythm and cardiac function to some extent.Prompt and adequate dual antiplatelet therapy is essential for patients with ACS. Myocardial ischemia caused by acute thrombosis leads to severe metabolic, electrophysiological, and structural changes in the ventricular myocardium that induce life-threatening arrhythmias and heart failure [6, 27]. These directly lead to sudden cardiac death in some situations. Acute myocardial ischemia leads to ionic imbalance, less contractile force by events that culminate in mishandling of intracellular calcium, and a reduced conduction velocity because of less functional gap junctions [28]. Additionally, currents flowing from the ischemic/reperfused zones to the nonischemic zones are also important mechanisms of ventricular arrhythmias [29]. In patients with ACS, ventricular myocardium may be ischemic, stunned, hibernating, or irrevocably injured. Ventricular remodeling after onset of ACS may cause CS by mechanical complications and HF by contractile dysfunction and derangement of cardiac structure [30]. Platelet activation by the time or after myocardial infarction also plays an important role in cardiac remodeling by its proinflammatory effects apart from prothrombotic effects [31, 32].The trend of oral antiplatelet agents reducing the incidence of ventricular arrhythmias and dysfunction has been observed in previous studies. In the landmark second international study of infarct survival (ISIS-2), antiplatelet therapy with aspirin in patients with myocardial infarction significantly reduced the incidence of VF compared with placebo (4.3% versus 5.1%,p=0.022) [33]. The clopidogrel in unstable angina to prevent recurrent events (CURE) trial also showed that, compared with aspirin alone, the benefits of cardiac function were observed in aspirin in addition to clopidogrel. Clopidogrel significantly reduced the risk of heart failure (3.6% versus 4.5%,p=0.017) in the CURE trial [34].As a prodrug, clopidogrel has several limitations, such as requiring hepatic conversion, low bioavailability, relatively slow onset of action, and variability in responsiveness in patients [35]. Pharmacodynamics and pharmacokinetics studies have shown that prasugrel and ticagrelor have a greater and more rapid inhibition of platelet aggregation [36, 37]. A meta-analysis of phase III/IV RCTs showed better efficacy on MACE and all-cause death of these 2 potent P2Y12 inhibitors compared with clopidogrel [38]. The real-world outcomes were consistent with RCTs. In the SWEDEHEART registry, post-ACS use of ticagrelor was associated with a lower risk of death and ischemic events compared with clopidogrel [39]. These new drugs could induce earlier and more complete inhibition of platelets, leading to a lower thrombus burden and platelet-induced ventricular remodeling. In the CvLPRIT study, the novel P2Y12 inhibitors were associated with smaller infarct size and lower microvascular obstruction incidence versus the clopidogrel for ST-segment elevation myocardial infarction [40]. This would result in a lower rate of cardiac dysfunction and ventricular arrhythmias [41]. This may partially explain why novel P2Y12 inhibitors have a significantly protective effect on mortality in patients with CAD. Further studies on the exact mechanisms of these inhibitors are required.Furthermore, ticagrelor was proved to provide extra effects on myocardial protection beyond the inhibition ofP2Y12 receptor. In vitro studies indicated that, compared with clopidogrel, ticagrelor could limit myocardial infarct size and reduce myocardial edema and reperfusion injury by adenosine-mediated effects, improving endothelial function and dampening release of inflammatory mediators [42–46]. However, limited studies were conducted to explore cardioprotective mechanism of prasugrel [47]. In a recent meta-analysis of observational and randomized studies, prasugrel seems to be equivalent or superior to ticagrelor in ACS patients undergoing PCI on the 30-day outcomes [48]. But future randomized trials are still needed to evaluate the superiority of these drugs.


### 3.6. Limitations

This meta-analysis has several limitations. First, trials included in our study had different sample sizes, hypotheses, inclusion and exclusion criteria, and duration of follow-up and varied drug doses of potentP2Y12 inhibitors. Therefore, there must be potential heterogeneity between studies although tests for heterogeneity were of no statistical significance. Second, this analysis was not based on the results of the main outcomes from each trial, which may not be adjudicated by clinical end point committee. In addition, the definitions of cardiac function (CS/HF) and rhythm (VT/VF) outcomes varied among trials, which resulted in a varied incidence of outcomes in each study. Especially for ventricular arrhythmias, it is unknown whether events that occurred in the index event phase were included. DISPERSE-2, which had a relatively higher incidence of VT compared with other studies, was excluded in a sensitivity analysis. The results remained almost unchanged in this sensitivity analysis. Third, as the incidences of VT and VF were very low, the net benefit of prasugrel still needs to be considered. Finally, limited original clinical studies reporting the effects of novel P2Y12 receptor inhibitors on cardiac rhythm and cardiac function limited the reliability of the results, especially for ticagrelor, clinical evidence of which was mostly based on PLATO studies. Therefore, more studies are still needed to explore the effect of these novel P2Y12 inhibitors.


## 3.1. Included Studies

Based on initial research criteria, 793 publications from MEDLINE, EMBASE, Cochrane Central Register of Clinical Trials, and ClinicalTrials.gov were identified. After duplicates and non-RCTs were excluded, 261 potentially relevant publications were included for further screening and 19 publications that fulfilled the eligibility criteria were included for full text review. Nine of these publications with interesting outcomes for this study were eventually included in the present meta-analysis [1, 2, 11–17].The characteristics of each study and detailed characteristics of patients in each study are shown in Tables1 and 2. There were some differences among the included studies regarding the study designs and patients’ characteristics. Because there were differences between ticagrelor and prasugrel, we compared the efficacy of ticagrelor and prasugrel with clopidogrel, respectively. Because not all studies provided all outcomes of interest, we summarized the outcomes of each study (Table 3). There was a total of 45,227 patients (23,102 in the potent P2Y12 inhibitor arm and 22,125 in the clopidogrel arm). In the nine included studies, six studies compared prasugrel with clopidogrel in 24,846 patients and three studies compared ticagrelor with clopidogrel in 20,381 patients.Table 1
Characteristics, designs, and follow-up durations of the included studies.
Name Year Intervention PotentP2Y12 inhibitors, n Clopidogrel, n Characteristics of Study Population Primary Endpoint Follow-up DISPERSE-2 [11] 2007 Ticagrelor vs Clopidogrel 663 327 Patients were hospitalized for NSTE-ACS within the preceding 48 hours. Major adverse cardiac event;Major bleeding (fatal/life-threatening) 12 weeks(primary endpoint) PLATO [1] 2009 Ticagrelor vs Clopidogrel 9333 9291 Hospitalized patients with ACS. CV death, MI, or stroke;Major bleeding, study criteria 12 months(primary endpoint) PHILO [12] 2015 Ticagrelor vs Clopidogrel 387 380 Patients with non-ST or ST segment elevation ACS Major adverse cardiac event;Major bleeding 12 months(primary endpoint) JUMBO-TIMI26 [13] 2005 Prasugrel vs Clopidogrel 651 254 Patients candidate for elective or urgent PCI with intended coronary stenting. Major adverse cardiac event;Non-CABG TIMI Major or Minor Bleeding Events 30 days(primary endpoint) TRITON-TIMI 38 [2] 2007 Prasugrel vs Clopidogrel 6741 6716 Patients with ACS and scheduled for PCI CV death, nonfatal MI, or nonfatal stroke;TIMI non-CABG major bleeding 14.5 months(median) Ge et al. [14] 2010 Prasugrel vs Clopidogrel 463 299 East or southeast Asian patients with ACS and scheduled for PCI. ADP-InducedP2Y12 PRU at 4 hours and 30 days 30 days(primary endpoint) TRILOGY ACS [15] 2012 Prasugrel vs Clopidogrel 4623 4617 Patients with ACS who were medically managed. CV death, nonfatal MI, or nonfatal stroke;TIMI non-CABG major bleeding 17.1 months(median) TRIGGER PCI [16] 2012 Prasugrel vs Clopidogrel 210 210 Coronary artery disease patients underwent PCI with at least one drug-eluting stent implantation. Composite endpoint of CV death or MI 6 months(primary endpoint) ETAMI [17] 2015 Prasugrel vs Clopidogrel 31 31 Patients with acute STEMI ≤ 12 hours and scheduled for PCI Platelet reactivity index (PRI) 2 hours after the initiation of the therapy 30 days(clinical events) DISPERSE-2: dose confirmation study assessing anti-platelet effects of AZD6140 vs. clopidogrel in non-ST-segment elevation myocardial infarction-2, PLATO: platelet inhibition and patient outcomes, PHILO: ticagrelor vs. clopidogrel in Japanese, Korean, and Taiwanese patients with acute coronary syndrome, JUMBO-TIMI26: joint utilization of medications to block platelets optimally-thrombolysis in myocardial infarction 26, TRITON-TIMI 38: trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel–thrombolysis in myocardial infarction, TRILOGY ACS: the targeted platelet inhibition to clarify the optimal strategy to medically manage acute coronary syndromes, TRIGGER PCI: testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel, ETAMI: early thienopyridine treatment to improve primary PCI in patients with acute myocardial infarction, PCI: percutaneous coronary intervention, NSTE-ACS: non-ST-segment elevation acute coronary syndrome, ACS: acute coronary syndrome, CABG: coronary artery bypass grafting, CV: cardiovascular, TIMI: thrombolysis in myocardial infarction, MI: myocardial infarction, NSTEMI: non-ST-segment elevation myocardial infarction, STEMI: ST-segment elevation myocardial infarction, GUSTO: Global use of strategies to open occluded coronary arteries, ADP: adenosine diphosphate, PRU:P2Y12 reaction units.Table 2
Patients’ characteristics of included RCTs.
Study Age (years)∗ Male (%) ACS (%) PCI (%) Smoker (%) Diabetes mellitus (%) Hypertension (%) Prior MI (%) DISPERSE-2 [11] 63.0±11.6 63.7 100.0 42.0 N/A 24.8 N/A 26.0 PLATO [1] 62.2 (53.0, 70.0) 74.8 99.8 76.8 35.9 23.2 65.4 17.0 PHILO [12] 67.0±11.0 76.4 100.0 84.6 38.5 34.7 74.3 8.0 JUMBO-TIMI26 [13] 59.2±9.03 77.0 40.0 100.0 28.4 25.0 N/A N/A TRITON-TIMI 38 [2] 60.9±11.3 74.1 100.0 100.0 38.0 23.0 64.0 18.0 Ge et al. [14] 60.8±11.1 74.8 100.0 100.0 N/A N/A N/A N/A TRILOGY ACS [15] 65.7±11.0 60.9 100.0 0 39.9 37.9 82.0 42.8 TRIGGER PCI [16] 66.1±8.4 72.6 0 100.0 14.4 41.8 88.9 27.4 ETAMI [17] N/A 72.6 100.0 87.1 74.2 19.4 54.8 8.1 N/A: not available, DISPERSE-2: dose confirmation study assessing anti-platelet effects of AZD6140 vs. clopidogrel in non-ST-segment elevation myocardial infarction-2, PLATO: platelet inhibition and patient outcomes, PHILO: ticagrelor vs. clopidogrel in Japanese, Korean, and Taiwanese patients with acute coronary syndrome, JUMBO-TIMI26: joint utilization of medications to block platelets optimally-thrombolysis in myocardial infarction 26, TRITON-TIMI 38: trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel–thrombolysis in myocardial infarction, TRILOGY ACS: the targeted platelet inhibition to clarify the optimal strategy to medically manage acute coronary syndromes, TRIGGER PCI: testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel, ETAMI: early thienopyridine treatment to improve primary PCI in patients with acute myocardial infarction ACS: acute coronary syndrome, PCI: percutaneous coronary intervention, MI: myocardial infarction. ∗Age is presented as either mean ± standard deviation or median (interquartile range) when available.Table 3
Outcomes of the potentP2Y12 inhibitors.
Study Heart failure Cardiogenic Shock Ventricular tachycardia Ventricular fibrillation PotentP2Y12 inhibitors Clopidogrel PotentP2Y12 inhibitors Clopidogrel PotentP2Y12 inhibitors Clopidogrel PotentP2Y12 inhibitors Clopidogrel DISPERSE-2 [11]∗ N/A N/A N/A N/A 166/663 93/327 N/A N/A PLATO [1, 18] 196/9333 198/9291 60/9333 66/9291 29/9333 33/9291 48/9333 64/9291 PHILO [12, 19] 11/387 13/380 N/A N/A 8/387 8/380 3/387 1/380 JUMBO-TIMI26 [13, 20] 1/651 0/254 N/A N/A N/A N/A N/A N/A TRITON-TIMI 38 [2, 21] 71/6741 92/6716 13/6741 8/6716 24/6741 25/6716 18/6741 25/6716 Ge et al. [14, 22] 2/463 4/229 4/463 2/229 3/463 1/229 1/463 0/229 TRILOGY ACS [15, 23] 199/4623 238/4617 15/4623 23/4617 15/4623 20/4617 3/4623 15/4617 TRIGGER PCI [16, 24] 1/210 5/210 N/A N/A 0/210 1/210 0/210 0/210 ETAMI [17] N/A N/A 1/31 2/31 N/A N/A N/A N/A Values are n/N N/A: not available, DISPERSE-2: dose confirmation study assessing anti-platelet effects of AZD6140 vs. clopidogrel in non-ST-segment elevation myocardial infarction-2, PLATO: platelet inhibition and patient outcomes, PHILO: ticagrelor vs. clopidogrel in Japanese, Korean, and Taiwanese patients with acute coronary syndrome, JUMBO-TIMI26: joint utilization of medications to block platelets optimally-thrombolysis in myocardial infarction 26, TRITON-TIMI 38: trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel–thrombolysis in myocardial infarction, TRILOGY ACS: the targeted platelet inhibition to clarify the optimal strategy to medically manage acute coronary syndromes, TRIGGER PCI: testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel, ETAMI: early thienopyridine treatment to improve primary PCI in patients with acute myocardial infarction. ∗Heart failure was defined as any reported congestive heart failure, acute and chronic heart failure. †Ventricular tachycardia (VT) was categorized into sustained VT (lasting >30 s), non-sustained ventricular tachycardia (NSVT) (≥4 beats and <30 s in length), and triplets (3 ventricular beats).


## 3.2. Analysis of Ventricular Arrhythmias

Four and three studies compared the effects of prasugrel [2, 14–16, 21–23] and ticagrelor [1, 11, 12, 18, 19] with clopidogrel on VT, respectively. Compared with clopidogrel, prasugrel (RR: 0.86, 95% CI: 0.57-1.31,p=0.494; I2=0) and ticagrelor (RR: 0.88, 95% CI: 0.73-1.08,p=0.220; I2=0) were not significantly associated with reduced risk of VT (Figure 2).Figure 2
Forest plot for ventricular tachycardia, ventricular fibrillation, and pooled data of ventricular arrhythmias. A, ventricular tachycardia; B, ventricular fibrillation; C, ventricular tachycardia or ventricular fibrillation. CI: confidence interval.Three studies compared the effects of prasugrel and clopidogrel on VF [2, 14, 15, 21–23]. Prasugrel was associated with a 46% reduced risk of VF compared with clopidogrel (RR: 0.54, 95% CI: 0.32-0.91,p=0.020; I2=46.1%) (Figure 2). Two studies compared the effect of ticagrelor and clopidogrel on VF [1, 12, 18, 19], but we did not observe a significantly reduced risk of VF in ticagrelor (RR: 0.78, 95% CI: 0.54-1.13,p=0.184; I2=27.7%) (Figure 2).When we pooled VT and VF, both being manifestation of ventricular arrhythmias, a 28% reduced risk was observed in prasugrel (RR: 0.72, 95% CI: 0.52-0.99,p=0.043; I2=0) and a 15% reduced risk with ticagrelor (RR: 0.85, 95% CI: 0.72-1.02,p=0.077; I2=0) although without statistical significance, compared with clopidogrel (Figure 2).


## 3.3. Analysis of Cardiac Dysfunction

Five studies compared the effects of prasugrel and clopidogrel on HF [2, 13–16, 20–24]. Prasugrel was associated with a 20% reduced risk of HF compared with clopidogrel (RR: 0.80, 95% CI: 0.68-0.93,p=0.005; I2=0) (Figure 3). Two studies compared the effects of ticagrelor and clopidogrel on HF [1, 12, 18, 19]. We did not observe a reduced risk of HF in ticagrelor compared with clopidogrel (RR: 0.98, 95% CI: 0.81-1.18,p=0.801; I2=0) (Figure 3).Figure 3
Forest plot for heart failure, cardiogenic shock, and pooled data of cardiac dysfunction. A, heart failure; B, cardiogenic shock; C, heart failure or cardiogenic shock. CI: confidence interval.Four studies compared the effects of prasugrel and clopidogrel on CS [2, 14, 15, 17, 21–23]. Only the Platelet Inhibition and Patient Outcomes (PLATO) trial [1, 18] reported the incidence of CS in patients who took ticagrelor and clopidogrel. However, a reduced risk of CS was not observed with both prasugrel (RR: 0.98, 95% CI: 0.68-1.19,p=0.617; I2=0) and ticagrelor (RR: 0.90, 95% CI: 0.64-1.28,p=0.574) compared with clopidogrel (Figure 3).When we pooled HF and CS, both being manifestation of cardiac dysfunction, patients with prasugrel had 19% lower risk (RR: 0.81, 95% CI: 0.70-0.94,p=0.005; I2=0), but not with ticagrelor (RR: 0.96, 95% CI: 0.81-1.13,p=0.620; I2=0), compared with clopidogrel (Figure 3).


## 3.4. Sensitivity Analysis

Among the studies, the proportions of patients with ACS in the testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel (TRIGGER PCI) study [16] and joint utilization of medications to block platelets optimally thrombolysis in myocardial infarction 26 (JUMBO-TIMI 26) study [13] were significantly lower than those in other studies. Therefore, we performed sensitivity analyses of patients with ACS by excluding studies that showed similar rates of all the outcomes tested. We found that the RR of VT was 0.89 (95% CI: 0.66-1.21,p=0.967; I2=0%) and the RR of VF was 0.69 (95% CI: 0.51-0.93, p=0.014; I2=31.6%), that of VT and VF was 0.78 (95% CI: 0.63-0.96,p=0.022; I2=0%), the RR of HF was 0.87 (95% CI: 0.77-0.98,p=0.027; I2=11.3%) and the RR of CS was 0.90 (95% CI: 0.68-1.19,p=0.454; I2=0%), and that of HF and CS was 0.88 (95% CI: 0.78-0.98,p=0.020; I2=0%). The incidence of VT in the dose confirmation study assessing antiplatelet effects of AZD6140 versus clopidogrel in non-ST-segment elevation myocardial infarction-2 (DISPERSE-2) [11] was much higher than that in the other studies because of the definition of VT in this study. Therefore, sensitivity analysis that excluded this study showed that the RR of VT was 0.88 (95% CI: 0.65-1.19,p=0.405; I2=0%) and that of VT and VF was 0.78 (0.63-1.96,p=0.019; I2=0%). We also preformed sensitivity analysis by including studies with relatively large sample size (>5000) or with relatively long follow-up (>6 months). Similar results to the main result were observed (Supplementary Figures 3, 4, 5, and 6).


## 3.5. Discussion

To the best of our knowledge, this is the first meta-analysis that performs a comparison between novel oralP2Y12 inhibitors and clopidogrel on outcomes of cardiac dysfunction and ventricular arrhythmias in patients with CAD.Our meta-analysis showed that potentP2Y12 inhibitors, including prasugrel and ticagrelor, were associated with a lower risk of ventricular arrhythmias (although there was no significance with ticagrelor compared with clopidogrel). A lowered risk of HF and CS was observed in patients taking prasugrel. In summary, compared with clopidogrel, use of prasugrel or ticagrelor could further improve ventricular rhythm and cardiac function to some extent.Prompt and adequate dual antiplatelet therapy is essential for patients with ACS. Myocardial ischemia caused by acute thrombosis leads to severe metabolic, electrophysiological, and structural changes in the ventricular myocardium that induce life-threatening arrhythmias and heart failure [6, 27]. These directly lead to sudden cardiac death in some situations. Acute myocardial ischemia leads to ionic imbalance, less contractile force by events that culminate in mishandling of intracellular calcium, and a reduced conduction velocity because of less functional gap junctions [28]. Additionally, currents flowing from the ischemic/reperfused zones to the nonischemic zones are also important mechanisms of ventricular arrhythmias [29]. In patients with ACS, ventricular myocardium may be ischemic, stunned, hibernating, or irrevocably injured. Ventricular remodeling after onset of ACS may cause CS by mechanical complications and HF by contractile dysfunction and derangement of cardiac structure [30]. Platelet activation by the time or after myocardial infarction also plays an important role in cardiac remodeling by its proinflammatory effects apart from prothrombotic effects [31, 32].The trend of oral antiplatelet agents reducing the incidence of ventricular arrhythmias and dysfunction has been observed in previous studies. In the landmark second international study of infarct survival (ISIS-2), antiplatelet therapy with aspirin in patients with myocardial infarction significantly reduced the incidence of VF compared with placebo (4.3% versus 5.1%,p=0.022) [33]. The clopidogrel in unstable angina to prevent recurrent events (CURE) trial also showed that, compared with aspirin alone, the benefits of cardiac function were observed in aspirin in addition to clopidogrel. Clopidogrel significantly reduced the risk of heart failure (3.6% versus 4.5%,p=0.017) in the CURE trial [34].As a prodrug, clopidogrel has several limitations, such as requiring hepatic conversion, low bioavailability, relatively slow onset of action, and variability in responsiveness in patients [35]. Pharmacodynamics and pharmacokinetics studies have shown that prasugrel and ticagrelor have a greater and more rapid inhibition of platelet aggregation [36, 37]. A meta-analysis of phase III/IV RCTs showed better efficacy on MACE and all-cause death of these 2 potent P2Y12 inhibitors compared with clopidogrel [38]. The real-world outcomes were consistent with RCTs. In the SWEDEHEART registry, post-ACS use of ticagrelor was associated with a lower risk of death and ischemic events compared with clopidogrel [39]. These new drugs could induce earlier and more complete inhibition of platelets, leading to a lower thrombus burden and platelet-induced ventricular remodeling. In the CvLPRIT study, the novel P2Y12 inhibitors were associated with smaller infarct size and lower microvascular obstruction incidence versus the clopidogrel for ST-segment elevation myocardial infarction [40]. This would result in a lower rate of cardiac dysfunction and ventricular arrhythmias [41]. This may partially explain why novel P2Y12 inhibitors have a significantly protective effect on mortality in patients with CAD. Further studies on the exact mechanisms of these inhibitors are required.Furthermore, ticagrelor was proved to provide extra effects on myocardial protection beyond the inhibition ofP2Y12 receptor. In vitro studies indicated that, compared with clopidogrel, ticagrelor could limit myocardial infarct size and reduce myocardial edema and reperfusion injury by adenosine-mediated effects, improving endothelial function and dampening release of inflammatory mediators [42–46]. However, limited studies were conducted to explore cardioprotective mechanism of prasugrel [47]. In a recent meta-analysis of observational and randomized studies, prasugrel seems to be equivalent or superior to ticagrelor in ACS patients undergoing PCI on the 30-day outcomes [48]. But future randomized trials are still needed to evaluate the superiority of these drugs.


## 3.6. Limitations

This meta-analysis has several limitations. First, trials included in our study had different sample sizes, hypotheses, inclusion and exclusion criteria, and duration of follow-up and varied drug doses of potentP2Y12 inhibitors. Therefore, there must be potential heterogeneity between studies although tests for heterogeneity were of no statistical significance. Second, this analysis was not based on the results of the main outcomes from each trial, which may not be adjudicated by clinical end point committee. In addition, the definitions of cardiac function (CS/HF) and rhythm (VT/VF) outcomes varied among trials, which resulted in a varied incidence of outcomes in each study. Especially for ventricular arrhythmias, it is unknown whether events that occurred in the index event phase were included. DISPERSE-2, which had a relatively higher incidence of VT compared with other studies, was excluded in a sensitivity analysis. The results remained almost unchanged in this sensitivity analysis. Third, as the incidences of VT and VF were very low, the net benefit of prasugrel still needs to be considered. Finally, limited original clinical studies reporting the effects of novel P2Y12 receptor inhibitors on cardiac rhythm and cardiac function limited the reliability of the results, especially for ticagrelor, clinical evidence of which was mostly based on PLATO studies. Therefore, more studies are still needed to explore the effect of these novel P2Y12 inhibitors.


## 4. Conclusions

This meta-analysis of RCTs shows that novel oralP2Y12 inhibitors, especially prasugrel, might have better effect on improving ventricular rhythm and cardiac function compared with clopidogrel, which, to some extent, explained the reasons for the improved prognosis of these novel oral P2Y12 inhibitors. However, future special studies are still needed to reevaluate these results.



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