Dataset Information

Meta-Analysis Comparing Potent Oral P2Y₁₂ Inhibitors versus Clopidogrel in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

ABSTRACT:

Background

In patients with atrial fibrillation (AF) receiving percutaneous coronary intervention (PCI), current guidelines recommend against combining potent oral P2Y₁₂ inhibitors (i.e. ticagrelor or prasugrel) with oral anticoagulant (OAC) therapy, but the evidence is limited.

Objective

The aim of this meta-analysis was to compare the efficacy and safety of potent oral P2Y₁₂ inhibitors with clopidogrel in patients receiving OAC therapy for AF after a recent PCI.

Methods

Electronic databases were searched for randomized controlled trials (RCT) reporting outcomes according to the P2Y₁₂ inhibitor used. Major or clinically relevant non-major bleeding were the safety endpoints, while the efficacy outcomes were major adverse cardiovascular events (MACE). The potent oral P2Y₁₂ inhibitors prasugrel and ticagrelor were compared with clopidogrel. A subgroup analysis was conducted to evaluate the differences between patients treated with dual antithrombotic therapy (DAT) versus triple antithrombotic therapy (TAT).

Results

Four RCTs that included 10,057 patients were included in this analysis. Potent oral P2Y₁₂ inhibitors were associated with a significant increase in major or clinically relevant non-major bleeding compared with clopidogrel (risk ratio [RR] 1.30, 95% confidence interval [CI] 1.06-1.59, p = 0.01; number needed to harm 18, 95% CI 12-36). This finding was consistent regardless of the concomitant antithrombotic therapy (DAT vs. TAT; p = 0.69). The risk of MACE did not differ between potent oral P2Y₁₂ inhibitors and clopidogrel (RR 1.02, 95% CI 0.57-1.82).

Conclusions

In patients receiving OAC therapy for AF after a recent PCI, potent oral P2Y₁₂ inhibitors increase the risk of clinically relevant bleeding compared with clopidogrel, with no evident benefit in terms of MACE reduction.

SUBMITTER: Casula M

PROVIDER: S-EPMC7956939 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Selatogrel is a potent and reversible P2Y12 receptor antagonist developed for subcutaneous self-administration by patients with suspected acute myocardial infarction. After single-dose emergency treatment with selatogrel, patients are switched to long-term treatment with oral P2Y12 receptor antagonists. Selatogrel shows rapid onset and offset of inhibition of platelet aggregation (IPA) to overcome the critical initial time after acute myocardial infarction. Long-term benefit is provided by oral P2Y12 receptor antagonists such as clopidogrel, prasugrel, and ticagrelor. A population pharmacokinetic (PK)/pharmacodynamic (PD) model based on data from 545 subjects in 4 phase I and 2 phase II studies well described the effect of selatogrel on IPA alone and in combination with clopidogrel, prasugrel, and ticagrelor. The PK of selatogrel were described by a three-compartment model. The PD model included a receptor-pool compartment to which all drugs can bind concurrently, reversibly or irreversibly, depending on their mode of action. Furthermore, ticagrelor and its active metabolite can bind to the selatogrel-receptor complex allosterically, releasing selatogrel from the binding site. The model provided a framework for predicting the effect on IPA of selatogrel followed by reversibly and irreversibly binding oral P2Y12 receptor antagonists for sustained effects. Determining the timepoint for switching from emergency to maintenance treatment is critical to achieve sufficient IPA at all times. Simulations based on the interaction model showed that loading doses of clopidogrel and prasugrel administered 15 h and 4.5 h after selatogrel, respectively, provide sustained IPA with clinically negligible drug interaction. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Selatogrel is a potent reversible P2Y12 receptor antagonist developed for subcutaneous self-administration by patients in case of suspected acute myocardial infarction. Transition to oral P2Y12 receptor antagonists without drug interaction and sufficient inhibition of platelet aggregation must be assured at all times. WHAT QUESTION DID THIS STUDY ADDRESS? The pharmacokinetic/pharmacodynamic model semimechanistically describes the effect of selatogrel on platelet inhibition alone and in combination with the oral P2Y12 receptor antagonists clopidogrel, prasugrel, and ticagrelor. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Model-based simulations showed that loading doses of clopidogrel and prasugrel can be administered from 15 h and 4.5 h after selatogrel, respectively. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? These results support guiding the clinical transition from selatogrel emergency treatment to oral maintenance therapy in a safe and efficacious way.

Project description:BACKGROUND:Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. METHODS:Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. RESULTS:Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger (P<0.001) and had fewer clinical risk factors for AF (P=0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; P<0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; P<0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; P=0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; P=0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; P=0.13). CONCLUSIONS:Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.

Dataset Information

Meta-Analysis Comparing Potent Oral P2Y₁₂ Inhibitors versus Clopidogrel in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

Background

Objective

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Meta-Analysis Comparing Potent Oral P2Y12 Inhibitors versus Clopidogrel in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

Background

Objective

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Meta-Analysis Comparing Potent Oral P2Y₁₂ Inhibitors versus Clopidogrel in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.