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Efficacy and safety of newer P2Y12 inhibitors for acute coronary syndrome: a network meta-analysis.

ABSTRACT: Whether newer P2Y12 inhibitors are more efficacious and safer than clopidogrel and whether there is a superior one remain uncertain. We compared the effect of P2Y12 inhibitors on clinical outcomes in patients with acute coronary syndrome (ACS). Randomized controlled trials comparing clopidogrel, prasugrel, ticagrelor, or cangrelor, in combination with aspirin were searched. Sixteen trials with altogether 77,896 patients were included. Compared to clopidogrel, cardiovascular mortality was reduced with prasugrel (OR 0.85, 95% CI 0.75-0.97) and ticagrelor (0.82, 0.73-0.93). Myocardial infarction (0.75, 0.63-0.89) and major adverse cardiovascular events (0.80, 0.69-0.94) were reduced by prasugrel. Stent thrombosis was reduced by prasugrel (0.49, 0.38-0.63), ticagrelor (0.72, 0.57-0.90), and cangrelor (0.59, 0.43-0.81). It was reduced more by prasugrel than ticagrelor (0.69, 0.51-0.93). There were more major bleeds with prasugrel (1.24, 1.05-1.48). Thrombolysis in Myocardial Infarction (TIMI) major bleeding was increased with prasugrel compared to clopidogrel (1.36, 1.11-1.66) and ticagrelor (1.33, 1.06-1.67). TIMI minor bleeding was increased with prasugrel (1.44, 1.16-1.77) and cangrelor (1.47, 1.01-2.16) compared to clopidogrel while it was increased with prasugrel compared to ticagrelor (1.32, 1.01-1.72). Prasugrel is preferable to those ACS patients at low bleeding risk to reduce cardiovascular events whereas ticagrelor is a relatively safe antiplatelet drug of choice for most patients.

SUBMITTER: Fei Y

PROVIDER: S-EPMC7545197 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Efficacy and safety of newer P2Y12 inhibitors for acute coronary syndrome: a network meta-analysis.

Fei Yue Y Lam Cheuk Kiu CK Cheung Bernard Man Yung BMY

Scientific reports 20201008 1

Whether newer P2Y12 inhibitors are more efficacious and safer than clopidogrel and whether there is a superior one remain uncertain. We compared the effect of P2Y12 inhibitors on clinical outcomes in patients with acute coronary syndrome (ACS). Randomized controlled trials comparing clopidogrel, prasugrel, ticagrelor, or cangrelor, in combination with aspirin were searched. Sixteen trials with altogether 77,896 patients were included. Compared to clopidogrel, cardiovascular ...[more]

PMID: 33033323

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Project description:BackgroundNew randomized, controlled trials have become available on oral P2Y12 inhibitors in acute coronary syndrome. We aimed to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor, and clopidogrel in acute coronary syndrome by a meta-analysis of randomized controlled trials.MethodsWe performed a network meta-analysis and direct pairwise comparison analysis of efficacy and safety outcomes from 12 randomized controlled trials including a total of 52 816 patients with acute coronary syndrome.ResultsIn comparison with clopidogrel, ticagrelor significantly reduced cardiovascular mortality (hazard ratio [HR], 0.82 [95% CI, 0.72-0.92]) and all-cause mortality (HR, 0.83 [95% CI, 0.75-0.92]), whereas there was no statistically significant mortality reduction with prasugrel (HR, 0.90 [95% CI, 0.80-1.01] and HR, 0.92 [95% CI, 0.84-1.02], respectively). In comparison with each other, there were no significant differences in mortality (HR prasugrel versus ticagrelor, 1.10 [95% CI, 0.94-1.29] and 1.12 [95% CI, 0.98-1.28]). In comparison with clopidogrel, prasugrel reduced myocardial infarction (HR, 0.81 [95% CI, 0.67-0.98]), whereas ticagrelor showed no risk reduction (HR, 0.97 [95% CI, 0.78-1.22]). Differences between prasugrel and ticagrelor were not statistically significant. Stent thrombosis risk was significantly reduced by both ticagrelor and prasugrel versus clopidogrel (28%-50% range of reduction). In comparison with clopidogrel, both prasugrel (HR, 1.26 [95% CI, 1.01-1.56]) and ticagrelor (HR, 1.27 [95% CI, 1.04-1.55]) significantly increased major bleeding. There were no significant differences between prasugrel and ticagrelor for all outcomes explored.ConclusionsPrasugrel and ticagrelor reduced ischemic events and increased bleeding in comparison with clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019155648.

Project description:Introduction: The most common side effect of ticagrelor is dyspnea, which leads to premature withdrawal of this life-saving medication in 6.5% of patients. Increased chemoreceptors' sensitivity was suggested as a possible pathophysiological explanation of this phenomenon; however, the link between oversensitization of peripheral and/or central chemosensory areas and ticagrelor intake has not been conclusively proved. Methods: We measured peripheral chemoreceptors' sensitivity using hypoxic ventilatory response (HVR), central chemoreceptors' sensitivity using hypercapnic hyperoxic ventilatory response (HCVR), and dyspnea severity before and 4 ± 1 weeks following ticagrelor initiation in 11 subjects with chronic coronary syndrome undergoing percutaneous coronary intervention (PCI). The same tests were performed in 11 age-, sex-, and BMI-matched patients treated with clopidogrel. The study is registered at ClinicalTrials.com at NCT05080478. Results: Ticagrelor significantly increased both HVR (0.52 ± 0.46 vs. 0.84 ± 0.69 L min-1 %-1; p < 0.01) and HCVR (1.05 ± 0.64 vs. 1.75 ± 1.04 L min-1 mmHg-1; p < 0.01). The absolute change in HVR correlated with the change in HCVR. Clopidogrel administration did not significantly influence HVR (0.63 ± 0.32 vs. 0.58 ± 0.33 L min-1%-1; p = 0.53) and HCVR (1.22 ± 0.67 vs. 1.2 ± 0.64 L min-1 mmHg-1; p = 0.79). Drug-related dyspnea was reported by three subjects in the ticagrelor group and by none in the clopidogrel group. These patients were characterized by either high baseline HVR and HCVR or excessive increase in HVR following ticagrelor initiation. Discussion: Ticagrelor, contrary to clopidogrel, sensitizes both peripheral and central facets of chemodetection. Two potential mechanisms of ticagrelor-induced dyspnea have been identified: 1) high baseline HVR and HCVR or 2) excessive increase in HVR or HVR and HCVR. Whether other patterns of changes in chemosensitivities play a role in the pathogenesis of this phenomenon needs to be further investigated.

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.

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Efficacy and safety of newer P2Y12 inhibitors for acute coronary syndrome: a network meta-analysis.

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Efficacy and safety of newer P2Y<sub>12</sub> inhibitors for acute coronary syndrome: a network meta-analysis.

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