ticagrelor and Renal-Insufficiency

The optimal utilization of antiplatelet therapy in patients with renal impairment (RI) following acute coronary syndromes (ACS) represents an urgent, unmet and yet unsolved need with regards to the choice of agents, duration of treatment and potential dose/regimen adjustment. The lack of any large randomized trials designed and powered specifically in such high-risk patients, absence of the uniformed efficacy and safety data reporting policy to the FDA and endless overoptimistic publications based on post hoc analyses of primary trials sometimes exaggerating benefits and hiding risks, clouds reality. In addition, triaging RI patients is problematic due to ongoing kidney deterioration and the fact that such patients are prone to both vascular occlusions and bleeding. The authors summarize available FDA-confirmed evidence from the latest trials with approved antiplatelet agents, namely clopidogrel (CAPRIE, CURE, CREDO, CLARITY, CHARISMA); prasugrel (TRITON, TRILOGY); ticagrelor (PLATO, and PEGASUS); and vorapaxar (TRACER and TRA2P) in RI patient cohorts on top of aspirin as part of dual antiplatelet therapy (DAPT). We deliberately avoided any results unless they were verified by the FDA, with the exception of the recent PEGASUS, since Agency reviews are not yet available. Despite differences among the trials and DAPT choices, RI patients universally experience much higher (HR = 1.3-3.1) rates of primary endpoint events, and bleeding risks (HR = 1.7-3.6). However, only ticagrelor increases creatinine and uric acid levels above that of clopidogrel; has the worst incidence of serious adverse events, more adverse events, and inferior outcomes in patients with severe (eGFR <30 ml/min), especially in the lowest (eGFR <15 ml/min) RI subsets. Clopidogrel, prasugrel and vorapaxar appear safer. Moreover, less aggressive half dose (5 mg/daily) prasugrel and strict DAPT, are well justified in RI, but not predominantly triple strategies with vorapaxar as tested in TRA2P and especially in TRACER. In conclusion, data from clinical trials, their sub-studies and affiliated FDA reviews indicate that RI cause more vascular occlusions and bleeding in ACS patients treated with DAPT. Among the novel antiplatelet agents, prasugrel and vorapaxar, but probably not ticagrelor, offer advantage in RI patients.

Topics: Acute Coronary Syndrome; Adenosine; Clinical Trials as Topic; Clopidogrel; Comparative Effectiveness Research; Glomerular Filtration Rate; Hemorrhage; Humans; Lactones; Patient Selection; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Renal Insufficiency; Ticagrelor; Ticlopidine

Effective antagonism of the P2Y12 platelet receptor is central to the treatment of acute coronary syndrome (ACS) patients, especially in the setting of percutaneous coronary intervention and stenting. According to consensus guidelines, early revascularization and intensive antiplatelet therapy are key to reducing the complications that arise from myocardial ischaemia and the recurrence of cardiovascular events. Until recently, clopidogrel was the key P2Y12 antagonist advocated, but due to several limitations as an antiplatelet agent, newer drugs with more predictable, rapid and potent effects have been developed. Prasugrel and ticagrelor are now the recommended first-line agents in patients presenting with non-ST-segment elevation ACS and ST-segment elevation ACS, due to large-scale randomized trials that demonstrated net clinical benefit of these agents over clopidogrel, as stated in the European guidelines. Although no study has directly compared the two agents, analysis of the data to date suggests that certain patient types, such as diabetics, those with ST-segment elevation myocardial infarction or renal failure and the elderly may have a better outcome with one agent over the other. Further studies are needed to confirm these differences and answer pending questions regarding the use of these drugs to optimize efficacy while minimizing adverse events, such as bleeding. The aim of this review is to provide an overview of the current P2Y12 receptor antagonists in the treatment of ACS, with a focus on issues of appropriate agent selection, timing of treatment, bleeding risk and the future role of personalized treatment using platelet function and genetic testing.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Clinical Trials as Topic; Clopidogrel; Combined Modality Therapy; Coronary Artery Bypass; Coronary Thrombosis; Diabetes Complications; Hemorrhage; Humans; Multicenter Studies as Topic; Piperazines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prasugrel Hydrochloride; Precision Medicine; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Receptors, Purinergic P2Y12; Renal Insufficiency; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Impaired renal function (IRF) is associated with increased risks of both ischemic and bleeding events. Ticagrelor has been shown to provide greater absolute reduction in ischemic risk following acute coronary syndrome (ACS) in those with versus without IRF.. A pre-specified sub-analysis of the randomized GLOBAL LEADERS trial (n = 15,991) comparing the experimental strategy of 23-month ticagrelor monotherapy (after 1-month ticagrelor and aspirin dual anti-platelet therapy [DAPT]) with 12-month DAPT followed by 12-month aspirin after percutaneous coronary intervention (PCI) in ACS and stable coronary artery disease (CAD) patients stratified according to IRF (glomerular filtration rate < 60 ml/min/1.73 m. At 2 years, patients with IRF (n = 2171) had a higher rate of the primary endpoint (all-cause mortality or centrally adjudicated, new Q-wave myocardial infarction [MI](hazard ratio [HR] 1.64, 95% confidence interval [CI] 1.35-1.98, p. IRF negatively impacted long-term prognosis after PCI. There were no differential treatment effects found with regard to all-cause death or new Q-wave MI after PCI in patients with IRF treated with ticagrelor monotherapy.. The trial has been registered with ClinicalTrials.gov, number NCT01813435.

Topics: Acute Coronary Syndrome; Aged; Coronary Artery Disease; Drug-Eluting Stents; Dual Anti-Platelet Therapy; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Renal Insufficiency; Ticagrelor; Treatment Outcome

Ticagrelor, a P2Y(12) receptor antagonist, is approved in the European Union and the US for the prevention of thrombotic events in patients with acute coronary syndromes. Renal dysfunction potentially affects drug disposition. Ticagrelor pharmacokinetics, pharmacodynamics, and safety in renal impairment were assessed. A single 180-mg ticagrelor dose was administered to volunteers with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) and normal renal function (CrCL ≥ 80 mL/min; n = 10/group). Severe renal impairment did not significantly affect ticagrelor's pharmacokinetics, pharmacodynamics, or safety. Ticagrelor absorption and AR-C124910XX (active metabolite) formation were rapid. In renally impaired volunteers, ticagrelor mean maximum concentration (C(max)) and area under the plasma concentration-time curve from zero to infinity were 20% lower and for AR-C124910XX was 17% higher versus normal volunteers. Ticagrelor systemic exposure was low in 3 volunteers (CrCL < 20 mL/min), but data were variable. Onset and offset of final-extent inhibition of platelet aggregation were comparable in both groups. Inhibition of platelet aggregation parameters and profiles were similar between groups, indicating that platelet sensitivity to ticagrelor was not affected by severe renal impairment. Ticagrelor was well tolerated in both groups with few adverse events. No ticagrelor dose adjustment is required for renally impaired patients.

Topics: Adenosine; Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Renal Insufficiency; Ticagrelor

No study has so far evaluated the impact of chronic kidney disease (CKD) on high-on treatment platelet reactivity (HRPR) with ticagrelor and their prognostic consequences, that were therefore the aim of the present study.. Patients on dual antiplatelet therapy with ASA+ticagrelor (90mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30-90 days post-discharge. The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome (MI), target vessel revascularization) at the longest available follow-up.. We included 396 patients, that were divided according to CKD (eGFR

Topics: Acute Coronary Syndrome; Adenosine; Aftercare; Clopidogrel; Humans; Patient Discharge; Percutaneous Coronary Intervention; Platelet Aggregation; Platelet Aggregation Inhibitors; Renal Insufficiency; Renal Insufficiency, Chronic; Ticagrelor; Ticlopidine

Current guidelines recommend the use of potent antiplatelet agents in patients undergoing percutaneous coronary intervention (PCI) following an acute coronary syndrome (ACS). However, data about optimal platelet inhibition in severe renal insufficiency patients are scarce. The purpose of this study is to determine if ticagrelor is more effective than clopidogrel in patients with ACS and severe renal insufficiency treated with PCI.. We retrospectively enrolled patients with ACS and severe renal insufficiency (eGFR ≤ 30 ml/min·1.73 m. A total of 276 patients with ACS and severe renal insufficiency who were treated with PCI with ticagrelor (. Ticagrelor did not improve the major adverse cardiovascular events and all-cause mortality when compared to clopidogrel, but significantly increased the risk of bleeding in Chinese patients with ACS and severe renal insufficiency undergoing PCI.

Topics: Acute Coronary Syndrome; Clopidogrel; Hemorrhage; Humans; Percutaneous Coronary Intervention; Renal Insufficiency; Retrospective Studies; Ticagrelor; Treatment Outcome

Prasugrel and ticagrelor have superior efficacy compared with clopidogrel in moderate CKD but have not been studied in kidney failure. The study objective is to determine the effectiveness and safety of prasugrel and ticagrelor in kidney failure.. This retrospective cohort study used United States Renal Data System data from 2012 to 2015. We identified all patients on dialysis who received a drug-eluting stent and were alive at 90 days after stent implantation. Inverse probability-weighted Cox proportional hazard models were used. Weights were estimated with propensity scores for multiple treatments.. This cohort included 6648 patients on clopidogrel, 621 on prasugrel, and 449 on ticagrelor. A total of 3279 primary composite (cardiovascular death, myocardial infarction, or stroke) and 2120 clinically relevant bleeding events were observed. The incidence of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke at 12 months was similar across the three treatment groups. The absolute event rate in the unweighted cohort was 144 events per 100 patient-years for clopidogrel, 126 for prasugrel, and 161 for ticagrelor. For prasugrel versus clopidogrel, the weighted hazard ratio was 0.96 (95% confidence interval, 0.82 to 1.11;. Prasugrel or ticagrelor does not seem to be associated with significant benefits compared with clopidogrel in patients with kidney failure treated with drug-eluting stents.. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_04_02_CJN12120720.mp3.

Topics: Aged; Clopidogrel; Cohort Studies; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Renal Insufficiency; Retrospective Studies; Ticagrelor; Treatment Outcome

Background Peripheral artery disease (PAD) is a known risk factor for adverse outcomes in patients undergoing percutaneous coronary intervention. However, in some studies PAD is not an independent risk factor. We sought to examine the independent impact of PAD on a large prospective percutaneous coronary intervention registry. Methods and Results From our single-center prospective percutaneous coronary intervention registry, we have retrospectively analyzed 25 690 patients (years 2004-2018). We examined the influence of PAD on short- and long-term outcomes using both regression and propensity-matched analyses. Patients with documented PAD (n=1610, 6.3% of total) were older (66.7±10.8 versus 65.4±12.1,

Topics: Aged; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus; Female; Humans; Hypertension; Male; Middle Aged; Percutaneous Coronary Intervention; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Registries; Renal Insufficiency; Retrospective Studies; Risk Factors; Ticagrelor; Treatment Outcome