The PLATO trial: do you believe in magic?

Serebruany, Victor L.; Atar, Dan

doi:10.1093/eurheartj/ehp545

Cited by 22 publications

(18 citation statements)

References 26 publications

(25 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…47 Finally, cilostazol also can elevate circulating adenosine levels, 20 which is suggested as a mechanism for superiority of ticagrelor to prasugrel in terms of cardiovascular mortality. 48 The clinical impact of triple antiplatelet therapy has been proven mostly for an East Asian population. Because the CYP2C19 variant is more prevalent in East Asians than whites (Ϸ60% versus Ϸ30%), 14 -17,29 the benefit of this regimen may be somewhat related with ethnic singularity.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome 2C19 Polymorphism and Response to Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention

Hwang

Jeong²,

Kim³

et al. 2010

Circ: Cardiovascular Interventions

View full text Add to dashboard Cite

Background-Among patients treated with clopidogrel, carriers of the cytochrome P450 (CYP) 2C19 loss-of-function allele have shown increased platelet reactivity and higher rates of ischemic events. Although adjunctive cilostazol to dual antiplatelet therapy (or "triple antiplatelet therapy") intensifies platelet inhibition, it remains unknown whether triple antiplatelet therapy after percutaneous coronary intervention can achieve adequate platelet inhibition in patients with the CYP2C19 mutant allele. Methods and Results-CYP2C19 genotyping for *1, *2, and *3 was performed in 134 high-risk patients undergoing elective percutaneous coronary intervention. After measurement of preprocedural platelet reactivity, patients were randomly assigned to receive either adjunctive cilostazol 100 mg twice daily (triple group; nϭ69) or high maintenance-dose (MD) clopidogrel of 150 mg daily (high-MD group; nϭ65). Using light transmittance aggregometry and the VerifyNow P2Y 12 assay, platelet reactivity was assessed before the index procedure and at 30-day follow-up. The primary end point was absolute change in maximal platelet aggregation (⌬Agg max ) according to CYP2C19 genotyping. High posttreatment platelet reactivity was defined as 5 mol/L ADP-induced maximal platelet aggregation Ͼ50%.

show abstract

Section: Discussionmentioning

confidence: 99%

Cytochrome 2C19 Polymorphism and Response to Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention

Hwang

Jeong²,

Kim³

et al. 2010

Circ: Cardiovascular Interventions

View full text Add to dashboard Cite

show abstract

“…Ticagrelor-induced inhibition of adenosine reuptake by erythrocytes may potentially improve myocardial perfusion, and such an effect could possibly be more important in patients with impaired renal function. 14 Dyspnea and ventricular pauses, which are considered adenosine mediated side effects of ticagrelor, 17 were both more frequent in patients with CKD but with little difference between the two randomized groups. In patients without CKD, however, ticagrelor almost doubled the frequency of dyspnea (13.9% versus 7.5%) and led to a 51% increase of ventricular pauses when compared to clopidogrel.…”

Section: P2y12 Antagonists In Patients With Ckdmentioning

confidence: 99%

Ticagrelor in the Renal Dysfunction Subgroup: Subjugated or Substantiated?

Montalescot¹,

Silvain²

2010

Circulation

View full text Add to dashboard Cite

C hronic kidney disease (CKD) is a serious condition associated with premature mortality, decreased quality of life, and increased health-care expenditures. The most recent data from the National Health and Nutrition Examination Survey estimated that the prevalence of CKD in the US population was 16.8% and had increased by 15.9% in comparison with that of the previous decade. 1 These numbers are expected to rapidly increase with the aging of the population and furthermore with the epidemic of diabetes mellitus, a condition associated with a three-fold increase of the prevalence of CKD. 2,3 Article see p 1056CKD prevalence is twice as high in patients with cardiovascular disease, and recent registry data using the contemporary Modification of Diet in Renal Disease equation have reported a prevalence of moderate or severe CKD of 30.5% in ST elevation myocardial infarction 4 and 42.9% in non-ST elevation myocardial infarction. This figure is much higher than what is usually reported in controlled trials where patients with CKD are often excluded, but similar to what has been observed in other registries. 5 Renal dysfunction is a powerful independent predictor of thrombotic and bleeding complications and, subsequently, of mortality. Worse clinical outcomes of patients with CKD are possibly explained by more frequent preexisting cardiovascular disease, more extended atherothrombosis, more serious presentation of Acute Coronary Syndrome (ACS), lower revascularization rates, and underutilization of evidencebased therapies with potential overdosing of medication which metabolism and excretion depend on renal function. 6,7,8 This challenging group of patients represents a clearly unmet medical need. New Oral P2Y12 AntagonistsBoth prasugrel and ticagrelor, as opposed to clopidogrel, have shown that stronger P2Y12 inhibition led to significant 19% and 16% respective relative risk reduction of a similar primary end point combining cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. 9,10 Ticagrelor also showed a 1.1% absolute reduction of cardiovascular death, and both drugs showed a significant 0.6% absolute excess of thrombolysis in myocardial infarction (TIMI) major bleeding not related to coronary artery bypass graft (CABG) surgery (25% relative excess with prasugrel and 27% with ticagrelor). These two drugs clearly have the potential to change experts' recommendations, physicians practices, and patients' prognoses. They will not, however, replace clopidogrel in all patients with ACS, as the excess of bleeding makes the risk/benefit ratio questionable in some situations, particularly when translating the results from highly selected patients to real-life patients. While waiting for more information while these drugs are tested in new trials, additional analyses of the first two pivotal trials are flourishing. These landmark analyses, multivariate or risk-model analyses, subgroup analyses, and analyses of secondary or tertiary endpoints, may help identify preferential targets for these drugs, while t...

show abstract

“…Since ticagrelor does not require hepatic metabolic activation [19], the adenosine pathway appeared to be a reasonable explanation. Moreover, some of the benefits as well as side effects of ticagrelor are similar to those of adenosine [20]. …”

Section: Ticagrelormentioning

confidence: 99%

Dyspnea and Reversibility of Antiplatelet Agents: Ticagrelor, Elinogrel, Cangrelor, and Beyond

2013

View full text Add to dashboard Cite

Context: Oral reversible platelet P2Y12 receptor inhibitors (ticagrelor and elinogrel) cause double-digit rates of dyspnea, while irreversible oral antiplatelet drugs (aspirin, ticlopidoine, clopidogrel, and prasugrel) or intravenous glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, or tirofiban) do not increase the incidence of dyspnea in randomized trials. Dyspnea after oral reversible antiplatelet agents remains unexplained. A transfusion-related acute lung injury (TRALI) hypothesis has been proposed. The dyspnea risks after cangrelor, an intravenous reversible antiplatelet agent, are not well defined but may offer a universal mechanism linking TRALI, dyspnea, and reversible platelet inhibition. Objective: We analyzed safety data from recent head-to-head randomized trials with reversible antiplatelet agents (ticagrelor, elinogrel, and cangrelor) compared to irreversible (clopidogrel/placebo) comparators. Results: All three reversible antiplatelet agents cause excess dyspnea. In contrast to the high double-digit rates after oral ticagrelor or elinogrel, the dyspnea risks after intravenous cangrelor were smaller (<2%) but still consistently and significantly higher than in the corresponding control arms. Conclusions: The clinical utility of reversible antiplatelet strategies has been challenged. Despite a potential advantage of fewer bleeding events during heart surgery, reversible antiplatelet agents carry the risk of potential autoimmune reactions manifesting as dyspnea. Repeated binding and unbinding cycles, impaired platelet turnover, and lung sequestration or apoptosis of overloaded destructive platelets are among the potential mechanism(s) responsible for dyspnea after reversible antiplatelet agents.

show abstract

The PLATO trial: do you believe in magic?

Cited by 22 publications

References 26 publications

Cytochrome 2C19 Polymorphism and Response to Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention

Cytochrome 2C19 Polymorphism and Response to Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention

Ticagrelor in the Renal Dysfunction Subgroup: Subjugated or Substantiated?

Dyspnea and Reversibility of Antiplatelet Agents: Ticagrelor, Elinogrel, Cangrelor, and Beyond

Contact Info

Product

Resources

About