PLATO Trial Research Articles

Abstract 18749: Avoidance of a Reload During the Therapeutic Shift From Clopidogrel to Ticagrelor in Patients With Acs Has No Influence on Residual Platelet Reactivity

Background: Ticagrelor (TICA) was more efficient than clopidogrel (CLO) in preventing cardiovascular events after Acute Coronary Syndrome (ACS) in the PLATO trial. However, it was associated with a higher incidence of non-procedure related bleedings. Despite TICA therapy was always started with the administration of a loading dose in the PLATO trial, the loading dose could be unnecessary in patients with ongoing CLO therapy. Aim of the present study was to verify whether the administration of a loading dose is necessary to mantain the level of inhibition of aggregation during the switch from ongoing CLO to TICA therapy. Methods and Results: Fifty patients with ACS and on CLO treatment were randomly assigned to a starting dose of TICA of 90mg (Group 1) or 180mg (Group 2), on top of aspirin treatment. Platelet aggregation was measured using multiple electrode aggregometry (MEA) at 0, 2, 6, 24 and 72h after the switch, and verified through standard LTA aggregometry. No relevant difference in platelet aggregation between the two study arms was observed at baseline (p=0.256). Residual platelet aggregation measured using MEA was significantly reduced in both arms 2h after the first administration of TICA (both p<0.001). Interestingly, no difference in aggregation was found 2 hours after the switch to TICA (176 72 vs 181 60 AUmin, p=0.281). Similar findings were confirmed with LTA. Conclusions: Therapeutic switch from ongoing clopidogrel therapy to ticagrelor without administration of a loading dose is clinically safe and is not associated to a lower degree of inhibition in patients with ACS. Avoiding the loading dose could be associated to a lower bleeding risk while mantaining the same level of aggregation. Larger trials are needed to confirm data from our proof-of-concept study.

Review of the accumulated PLATO documentation supports reliable and consistent superiority of ticagrelor over clopidogrel in patients with acute coronary syndrome: Commentary on: DiNicolantonio JJ, Tomek A, Inactivations, deletions, non-adjudications, and downgrades of clinical endpoints on ticagrelor: Serious concerns over the reliability of the PLATO trial, International Journal of Cardiology, 2013

Review of the accumulated PLATO documentation supports reliable and consistent superiority of ticagrelor over clopidogrel in patients with acute coronary syndrome Commentary on : DiNicolantonio JJ, Tomek A, Inactivations, deletions, non-adjudications, and downgrades of clinical endpoints on ticagrelor: Serious concerns over the reliability of the PLATO trial, International Journal of Cardiology, 2013

Economic Evaluation of Ticagrelor Versus Clopidogrel in Canadian Patients With Acute Coronary Syndromes Based on the Platelet Inhibition and Patient Outcomes (Plato) Trial

Economic Evaluation of Ticagrelor Versus Clopidogrel in Canadian Patients With Acute Coronary Syndromes Based on the Platelet Inhibition and Patient Outcomes (Plato) Trial

Misrepresentation of vital status follow-up: Challenging the integrity of the PLATO trial and the claimed mortality benefit of ticagrelor versus clopidogrel

ContextTicagrelor, a novel, reversible, and oral P2Y12 receptor antagonist, was claimed to reduce all-cause mortality compared to clopidogrel in the PLATO trial. ObjectiveWe sought to ascertain vital status follow-up for clopidogrel and ticagrelor to determine if any discrepancy existed by reviewing data from the FDA Complete Response Review. ResultsThe FDA Complete Response Review indicated misrepresentation of vital status follow-up by the sponsor's presenter at the Cardiovascular and Renal Drugs Advisory Committee. Instead of five patients with missing vital status follow-up, the FDA primary efficacy reviewer indicated that there was a minimum of 106 patients. Additionally and more concerning was the fact that significantly more patients on ticagrelor (3.1%, n=289 patients) had incomplete vital status follow-up versus clopidogrel (2.6%, n=242 patients, p=0.04 for the difference). ConclusionsThe Advisory Committee that voted in favor to approve ticagrelor was given misrepresented data, which may have affected the approval of ticagrelor. The fact that significantly more patients on ticagrelor had incomplete vital status follow-up versus clopidogrel challenges the claimed mortality benefit of ticagrelor and the approval of the PLATO trial.

Health economic evaluation of ticagrelor compared to generic clopidogrel in patients with acute coronary syndromes intended for non-invasive management based on the PLATO trial

Health economic evaluation of ticagrelor compared to generic clopidogrel in patients with acute coronary syndromes intended for non-invasive management based on the PLATO trial

Comparison of baseline characteristics between a contemporary >real world< STEMI cohort and the PLATO and TRITON trial populations

Purpose: Broader non-trial populations might differ from populations of randomized controlled trials (RCT) due to selected inclusion and exclusion criteria. Knowledge of these potential differences is crucial to generalize from trial results Methods: We used prospective registry data of 1289 patients of one interventional center participating in a metropolitan network established for obligatory treatment of acute ST-elevation myocardial infarction (STEMI) by primary PCI assessed from November 2006 to December 2011 to compare 17 characteristics of demography, co-morbidity and disease severity with published data of the STEMI subpopulations of the Inhibition and Patient (PLATO) and the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON) trial. Results: Compared to PLATO our population showed significant differences with higher age, higher prevalence of hyperlipidaemia, renal dysfunction, Killip class 3-4, history of PCI, CABG and heart failure, a higher heart rate, lower diastolic blood pressure, and a lower prevalence of smokers and left-bundle branch block. Compared to TRITON our population showed significant differences with higher age, higher prevalence of women, hypertension, hyperlipidaemia, renal dysfunction, history of CABG and myocardial infarction and a lower prevalence of smokers. Conclusions: Patients enrolled in recent RCTs of STEMI differed significantly from our contemporaneous patients participating in a registry, with real-world patients being overall more morbid. Thus more pragmatic trials are required to evaluate the generalizability of results from recent RCTs.

TRIOLOGY ACS: No benefit/No harm

[first paragraph of article] Potent and consistent P2Y12 receptor inhibition is associated with reduced risk of atherothrombotic events in patients presenting with acute coronary syndromes (ACS), but with inevitable increased risk of bleeding as demonstrated in TRITON and PLATO trials – a finding that is especially pertinent to the treatment of medically managed NSTE ACS patients, who typical have a greater burden of comorbidities that predispose to bleeding. Given the significant proportion of non-ST elevation myocardial infarction (NSTE) ACS patients managed medically worldwide and the need to mitigate both ischemic and bleeding risks in this vulnerable, high-risk population, novel clinical trials are needed.

Lifetime cost-effectiveness analysis of ticagrelor in patients with acute coronary syndromes based on the PLATO trial: a Singapore healthcare perspective

Ticagrelor is a novel antiplatelet drug developed to reduce atherothrombosis. The PLATO trial compared ticagrelor and aspirin to clopidogrel and aspirin in patients with acute coronary syndromes (ACS). Ticagrelor was found to be superior in the primary composite endpoint of cardiovascular death, myocardial infarction or stroke, without increasing major bleeding events. The current study estimates the lifetime cost-effectiveness of ticagrelor relative to generic clopidogrel from a Singapore public healthcare perspective. This study used a two-part cost-effectiveness model. The first part was a 12-month decision tree (using PLATO trial data) to estimate the rates of major cardiovascular events, healthcare costs and health-related quality of life. The second part was a Markov model estimating lifetime quality-adjusted survival and costs conditional on events during the initial 12 months. Daily drug costs applied were SGD 1.05 (generic clopidogrel) and SGD 6.00 (ticagrelor). Cost per quality-adjusted life years (QALY) was estimated from a Singapore public healthcare perspective using life tables and short-term costs from Singapore, and long-term costs from South Korea. Deterministic and probabilistic sensitivity analyses were performed. Ticagrelor was associated with a lifetime QALY gain of 0.13, primarily driven by lower mortality. The resulting incremental cost per QALY gained was SGD 10,136.00. Probabilistic sensitivity analysis indicated that ticagrelor had a > 99% probability of being cost-effective, given the lower recommended WHO willingness-to-pay threshold of one GDP/capita per QALY. Based on PLATO trial data, one-year treatment with ticagrelor versus generic clopidogrel in patients with ACS, relative to WHO reference standards, is cost-effective from a Singapore public healthcare perspective.

TICAGRELOR VERSUS CLOPIDOGREL IN PATIENTS WITH NON-ST-ELEVATION ACUTE CORONARY SYNDROME: RESULTS FROM THE PLATO TRIAL

Ticagrelor versus clopidogrel in patients with non-st-elevation acute coronary syndrome : results from the PLATO trial

Dual Antiplatelet Therapy with Prasugrel or Ticagrelor Versus Clopidogrel in Interventional Cardiology

For several years, clopidogrel plus aspirin has been the dual antiplatelet therapy (DAPT) of choice for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation. More recently, prasugrel and ticagrelor have demonstrated greater efficacy than clopidogrel. In TRITON-TIMI 38, the risk of TIMI major bleeding unrelated to coronary artery bypass graft (CABG) surgery was similar for prasugrel and clopidogrel after excluding subgroups with increased bleeding risk (previous stroke or transient ischemic event; age ≥75 years; weight <60 kg). In the PLATO trial, rates of TIMI major bleeding were similar for ticagrelor and clopidogrel, but ticagrelor was associated with a significantly higher rate of non-CABG-related TIMI major bleeding. Current evidence suggests that prasugrel or ticagrelor plus aspirin should be the DAPT of choice in patients with ACS undergoing PCI unless they are at particularly high risk of bleeding. No studies have yet compared prasugrel and ticagrelor in ACS patients, however prasugrel and ticagrelor have different side effect profiles, and the choice of agent should be made either as a default choice and/or on an individual patient basis. Ongoing trials in ACS patients will increase the evidence base for new P2Y(12) receptor inhibitors and help to establish the most effective DAPT regimens.

‘FREEDOM’ trial: Have the interventional cardiologists lost their freedom?

‘FREEDOM’ trial: Have the interventional cardiologists lost their freedom?

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Introduction: A recent post-hoc analysis of the PLATO trial suggests that the antiplatelet agent ticagrelor provided a significant reduction in sepsis and pulmonary adverse events compared to clopidogrel. It is unknown if clopidogrel also provides benefit in patients with sepsis. Knowing this information may help focus future research on determining the mechanism of ticagrelor’s benefit. Hypothesis: Patients with sepsis exposed to clopidogrel have lower mortality and fewer days on mechanical ventilation compared to patients not exposed to clopidogrel Methods: This retrospective cohort study included all patients over the age of 40 with a confirmed diagnosis of sepsis and an ICU stay at our academic medical center from 1/1/2007 to 3/31/2011. Clopidogrel use, patient demographics, and APACHE II score at the time of sepsis were collected from patient charts. Outcomes of interest were in hospital mortality, development of acute respiratory distress syndrome (ARDS), and days on mechanical ventilation. Results: We identified 561 patients who met the inclusion criteria for this study. Of these patients, 57 (10.2%) had been exposed to clopidogrel. Patients exposed to clopidogrel had a similar rate of in hospital mortality (28.1% vs 30.6%; p=0.763) and ARDS (53.5% vs 50.7%; p=0.782). These results were consistent for patients with a low APACHE II score (<25) or a high score (? 25). Patients exposed to clopidogrel did not have a higher incidence of blood product use compared to patients not exposed (70.7% vs 66.1%; p=0.558). Patients exposed to clopidogrel did have significantly more days on mechanical ventilation (5.6 days vs 4.0 days; p=0.015). This difference was seen despite the fact that the patients severity of illness (mean APACHE II score) was similar for patients receiving clopidogrel and those who did not (22.5 vs 21.7; p=0.561). Hospital costs and length of stay did not differ between the groups. Conclusions: While clopidogrel may not increase the risk of bleeding in these patients, these data suggest that clopidogrel does not reduce adverse outcomes in patients with sepsis. Future research into the mechanism of ticagrelor’s benefit reported in the PLATO trial may be directed at non-P2Y12 receptor mechanism.

PCV26 Lifetime Cost-Effectiveness Analysis of Ticagrelor in Patients With Acute Coronary Syndromes Based on the Plato Trial: A Singapore Health Care Perspective

PCV26 Lifetime Cost-Effectiveness Analysis of Ticagrelor in Patients With Acute Coronary Syndromes Based on the Plato Trial: A Singapore Health Care Perspective

PCV45 Long Term Cost-Effectiveness Analysis of Ticagrelor in Patients with Acute Coronary Syndromes From a Turkish Health Care Perspective Based on Data From the Plato Trial

The PLATO trial showed that in patients with acute coronary syndromes (ACS) treatment with ticagrelor compared with clopidogrel significantly reduced the rate of myocardial infarction, stroke, or death from vascular causes without a significant increase in the rate of overall major bleeding. The aim of this analysis is to estimate long-term cost-effectiveness of treating ACS patients with ticagrelor from a Turkish health care perspective. A two-part decision-analytic model, including a one-year decision tree and a long-term Markov model, was constructed to estimate lifetime costs, LYGs and QALYs of treating patients for one year with ticagrelor plus acetylsalicylic acid (ASA) compared with clopidogrel plus ASA. Event rates, health-care costs, and QALYs were estimated for the first year by using individual-patient data from PLATO. The cost was calculated by applying Turkish unit costs. For the second year onwards, necessary assumptions and external data sources were utilized to extrapolate quality-adjusted survival conditional on whether a non-fatal MI, a non-fatal stroke or no event occurred during the first year. Probabilistic ssensitivity analyses were performed. The willingness to pay threshold per QALY considered for the cost effectiveness analysis was 3 times GDP per capita. Ticagrelor was associated with life expectancy gains of 0.116 years primarily due to reduced rate of CV mortality and 0.101 additional QALYs and an incremental cost of 1662 TL compared to clopidogrel over a life time horizon.The incremental cost per life year and QALY gained were 14 297 TL and 16 415 TL respectively compared to clopidogrel. Probabilistic sensitivity analysis indicated > 99% probability of ticagrelor being cost-effective compared with clopidogrel at a willingness to pay of 52002 TL per QALY. Treating ACS patients with ticagrelor instead of clopidogrel for one year is cost-effective from the Turkish public health care perspective.

Comparing Ticagrelor Versus Clopidogrel in Patients With a History of Cerebrovascular Disease

The PLATO trial was a phase 3, randomized, double-blind, parallel-group, multinational, clinical study comparing the efficacy of ticagrelor (formerly known as AZD6140, marketed as Brilinta) versus standard care treatment with clopidogrel. Patients (n=18624) with moderate- to high-risk acute coronary syndrome undergoing coronary intervention or medically managed were randomized to ticagrelor 180mg loading dose followed by 90mg twice daily thereafter, or clopidogrel 300 to 600mg loading dose followed by 75mg once daily for 6 to 12 months.1 The primary end point was the time of the first event of death from vascular causes, myocardial infarction or stroke, and occurred in 11.7% of patients treated with clopidogrel, versus 9.8% of patients randomized to ticagrelor, representing a highly significant benefit (hazard ratio [HR]=0.84; CI=0.77–0.92; P <0.001) for ticagrelor.1 Importantly, the benefit of ticagrelor was driven equally by the reduction of vascular death ( P <0.001), and myocardial infarction ( P <0.005) with 89 events favoring ticagrelor each, but not stroke ( P =0.22) with 19 less events in the clopidogrel arm.1 Moreover, the original PLATO data indicated a 17% increase in stroke (19 extra events; number needed to harm 491) with ticagrelor versus clopidogrel (125/9333 [1.5%] versus 106/9291 [1.3%]; HR=1.17 [0.91–1.52]; P =0.22) (Table 1).1 However, the Food and Drug Administration complete response review indicates an even greater risk of stroke (24% increase) with ticagrelor versus …

TCT-741 Impact of clinical presentation on platelet inhibition by ticagrelor compared to clopidogrel: insights from a single-center cohort of the PLATO trial

TCT-741 Impact of clinical presentation on platelet inhibition by ticagrelor compared to clopidogrel: insights from a single-center cohort of the PLATO trial

Baseline Q waves as a prognostic modulator in patients with ST-segment elevation: insights from the PLATO trial

Baseline Q waves may provide additional value compared with time from the onset of symptoms in predicting outcomes for patients with ST-segment elevation. We evaluated whether baseline Q waves superseded time from symptom onset as a prognostic marker of one-year mortality in patients with ST-segment elevation acute coronary syndrome. Our study was derived from data from patients undergoing primary percutaneous coronary intervention within 24 hours in the PLATelet inhibition and patient Outcomes trial Q waves on the baseline electrocardiogram were evaluated by a blinded core laboratory. We assessed the associations between baseline Q waves and time from symptom onset to percutaneous coronary intervention with peak biomarkers, ST-segment resolution on the discharge electrocardiogram, and one-year all-cause and vascular mortality. Of 4341 patients with ST-segment elevation, 46% had baseline Q waves. Compared to those without Q waves, those with baseline Q waves were older, more frequently male, had higher heart rates, more advanced Killip class and had a longer time between the onset of symptoms and percutaneous coronary intervention. They also had higher one-year all-cause mortality than patients without baseline Q waves (baseline Q waves: 4.9%; no baseline Q waves: 2.8%; hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.29-2.45, p < 0.001). Complete ST-segment resolution was greatest and all-cause mortality lowest among those with symptom onset three hours or less before percutaneous coronary intervention and no baseline Q waves. After multivariable adjustment, baseline Q waves, but not time from symptom onset, were associated with a significant increase in all-cause mortality (adjusted HR 1.42, 95% CI 1.10-2.01, p = 0.046) and vascular mortality (adjusted HR 1.58, 95% CI 1.09-2.28, p = 0.02). The presence of baseline Q waves provides useful additional prognostic insight into the clinical outcome of patients with ST-segment elevation. Clinical Trials.gov registration no. NCT00391872.

Oral antiplatelet therapy in acute coronary syndromes: update 2012

Dual antiplatelet therapy (DAPT), usually consisting of clopidogrel and acetylsalicylic acid (ASA), has come into discussion in recent years due to an increasing number of major adverse cardiac events based on insufficient ADP-mediated platelet inhibition with clopidogrel, mainly explained by drug interactions or genetic variants slowing or hindering the bioactivation of the prodrug clopidgrel into an active metabolite. Accordingly, new antiplatelet agents like prasugrel and ticagrelor were investigated in large prospective randomized clinical trials in patients with different entities of acute coronary syndromes (ACS). Based on their beneficial results in comparison to clopidogrel, these agents have found their way into the recent international guidelines for treatment of patients with acute coronary syndromes. Both antiplatelet agents demonstrated superiority with respect to the primary composite endpoint (cardiovascular death/non-lethal myocardial infarction/stroke). Ticagrelor even exhibited a mortality benefit over the comparator, but both compounds also increased the risk of spontaneous major bleedings to a significant extent. However, the efficacy/safety ratio of prasugrel and ticagrelor compared to clopidogrel is better. This article widens the insight into the recent changes in antiplatelet therapy in ACS by discussing the clinically most important data derived from the TRITON-TIMI 38 trial and the PLATO trial, including also the retrospective and pre-defined subgroup analyses. This article also gives information about the recommended duration of DAPT and the situation when patients who need permanent anticoagulation (e.g. in case of non-valvular atrial fibrillation) deserve also DAPT after coronary stenting ('triple therapy').

Peripheral Vascular Outcomes in the PLATO Trial

Peripheral Vascular Outcomes in the PLATO Trial

PRIOR SMOKING STATUS, CLINICAL OUTCOMES, AND THE COMPARISON OF TICAGRELOR WITH CLOPIDOGREL IN ACUTE CORONARY SYNDROMES – INSIGHTS FROM THE PLATELET INHIBITION AND PATIENT OUTCOMES (PLATO) TRIAL

Habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo. In the PLATO trial, ticagrelor compared to clopidogrel in patients with acute coronary syndromes (ACS) reduced the primary