| 1. |
- Armstrong, Paul W, et al.
(författare)
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ST Elevation Acute Coronary Syndromes in PLATO : Insights from the ECG Substudy
- 2012
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 125:3, s. 514-521
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Ticagrelor, when compared with clopidogrel, reduced the 12-month risk of vascular death/myocardial infarction (MI) and stroke in patients with ST-elevation acute coronary syndromes (ST-E ACS) intended to undergo primary percutaneous coronary intervention (PCI) in the PLATelet inhibition and patient Outcomes (PLATO) trial. This pre-specified electrocardiogram (ECG) substudy explored whether ticagrelor's association with vascular death and MI within one year would be amplified by: 1) the extent of baseline ST shift; and 2) subsequently associated with less residual ST changes at hospital discharge. METHODS AND RESULTS: ECGs were evaluated centrally in a core laboratory in 3,122 ticagrelor- and 3,084 clopidogrel-assigned patients having at least 1mm ST-E in two contiguous leads as identified by site investigators on the qualifying ECG. Patients with greater ST-segment shift at baseline had higher rates of vascular death/MI within one year. Amongst those who also had an ECG at hospital discharge (n=4,798), patients with ≥50% ∑ST-deviation (∑ST-dev) resolution had higher event-free survival than those with incomplete resolution (6.4% vs. 8.8%, adjusted hazard ratio 0.69 (0.54-0.88), p=0.003). The extent of ∑ST-dev resolution was similar irrespective of treatment assignment. The benefit of ticagrelor versus clopidogrel on clinical events was consistent irrespective of the extent of baseline ∑ST-dev (p(interaction)=0.728). When stratified according to conventional times from symptom onset i.e. ≤3 hours, 3-6 hours, >6 hours, the extent of baseline ∑ST-dev declined progressively over time. As time from symptom onset increased beyond three hours, the benefit of ticagrelor appeared to be more pronounced; however, the interaction between time and treatment was not significant (p=0.175). CONCLUSIONS: Ticagrelor did not modify ∑ST-dev resolution at discharge nor was its benefit affected by the extent of baseline ∑ST-dev. These hypothesis-generating observations suggest that the main effects of ticagrelor may not relate to the rapidity or the completeness of acute reperfusion, but rather the prevention of recurrent vascular events by more powerful platelet inhibition or other mechanisms.
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| 2. |
- Becker, Richard C, et al.
(författare)
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Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial
- 2011
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 32:23, s. 2933-2944
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Tidskriftsartikel (refereegranskat)abstract
- AimsMore intense platelet-directed therapy for acute coronary syndrome (ACS) may increase bleeding risk. The aim of the current analysis was to determine the rate, clinical impact, and predictors of major and fatal bleeding complications in the PLATO study.Methods and resultsPLATO was a randomized, double-blind, active control international, phase 3 clinical trial in patients with acute ST elevation and non-ST-segment elevation ACS. A total of 18 624 patients were randomized to either ticagrelor, a non-thienopyridine, reversibly binding platelet P2Y(12) receptor antagonist, or clopidogrel in addition to aspirin. Patients randomized to ticagrelor and clopidogrel had similar rates of PLATO major bleeding (11.6 vs. 11.2%; P = 0.43), TIMI major bleeding (7.9 vs. 7.7%, P = 0.56) and GUSTO severe bleeding (2.9 vs. 3.1%, P = 0.22). Procedure-related bleeding rates were also similar. Non-CABG major bleeding (4.5 vs. 3.8%, P = 0.02) and non-procedure-related major bleeding (3.1 vs. 2.3%, P = 0.05) were more common in ticagrelor-treated patients, primarily after 30 days on treatment. Fatal bleeding and transfusion rates did not differ between groups. There were no significant interactions for major bleeding or combined minor plus major bleeding between treatment groups and age ≥75 years, weight <60 kg, region, chronic kidney disease, creatinine clearance <60 mL/min, aspirin dose >325 mg on the day of randomization, pre-randomization clopidogrel administration, or clopidogrel loading dose.Conclusion Ticagrelor compared with clopidogrel was associated with similar total major bleeding but increased non-CABG and non-procedure-related major bleeding, primarily after 30 days on study drug treatment. Fatal bleeding was low and did not differ between groups.
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| 3. |
- Cornel, Jan H., et al.
(författare)
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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
- 2012
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 164:3, s. 334-342
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Tidskriftsartikel (refereegranskat)abstract
- Background 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 composite end point of vascular death, myocardial infarction and stroke, without increasing overall rates of major bleeding. We evaluated the results in relation to smoking habits.Methods Interactions between habitual smokers (n = 6678) and in ex/nonsmokers (n = 11,932) and the effects of randomized treatments on ischemic and bleeding outcomes were evaluated by Cox regression analyses.Results Habitual smokers had an overall lower risk profile and more often ST-elevation ACS. After adjustment for baseline imbalances, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 [95% CI, 1.07-1.94]); there were no significant associations with other ischemic or bleeding end points. The effects of ticagrelor compared to clopidogrel were consistent for all outcomes regardless of smoking status. Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 [95% CI, 0.68-1.00]) and ex/nonsmokers (adjusted HR, 0.89 [95% CI, 0.79-1.00]) (interaction P = .50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 [0.39-0.91]) and ex/nonsmokers (adjusted HR, 0.69 [95% CI, 0.45-1.07]) (interaction P = .61).Conclusions In patients hospitalized with ACS, habitual smoking is associated with a greater risk of subsequent stent thrombosis. The reduction of vascular death, myocardial infarction, stroke, and stent thrombosis by ticagrelor compared to clopidogrel is consistent regardless of smoking habits.
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| 4. |
- Franchi, Francesco, et al.
(författare)
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Impact of Diabetes Mellitus and Chronic Kidney Disease on Cardiovascular Outcomes and Platelet P2Y12 Receptor Antagonist Effects in Patients With Acute Coronary Syndromes : Insights From the PLATO Trial
- 2019
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Ingår i: Journal of the American Heart Association. - 2047-9980 .- 2047-9980. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- Background-There are limited data on how the combination of diabetes mellitus (DM) and chronic kidney disease (CKD) affects cardiovascular outcomes as well as response to different P2Y(12) receptor antagonists, which represented the aim of the present investigation. Methods and Results-In this post hoc analysis of the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized acute coronary syndrome patients to ticagrelor versus clopidogrel, patients (n=15 108) with available DM and CKD status were classified into 4 groups: DM+/CKD+ (n=1058), DM+/CKD- (n=2748), DM-/CKD+ (n=2160), and DM-/CKD- (n=9142). The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke at 12 months. The primary safety end point was PLATO major bleeding. DM+/CKD+ patients had a higher incidence of the primary end point compared with DM-/CKD- patients (23.3% versus 7.1%; adjusted hazard ratio 2.22; 95% CI 1.88-2.63; P<0.001). Patients with DM+/CKD- and DM-/CKD+ had an intermediate risk profile. The same trend was shown for the individual components of the primary end point and for major bleeding. Compared with clopidogrel, ticagrelor reduced the incidence of the primary end point consistently across subgroups (P-interaction=0.264), but with an increased absolute risk reduction in DM+/CKD+. The effects on major bleeding were also consistent across subgroups (P-interaction=0.288). Conclusions-In acute coronary syndrome patients, a gradient of risk was observed according to the presence or absence of DM and CKD, with patients having both risk factors at the highest risk. Although the ischemic benefit of ticagrelor over clopidogrel was consistent in all subgroups, the absolute risk reduction was greatest in patients with both DM and CKD.
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| 5. |
- Held, Claes, 1956-, et al.
(författare)
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Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes Undergoing Coronary Artery Bypass Surgery Results From the PLATO (Platelet Inhibition and Patient Outcomes) Trial
- 2011
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 57:6, s. 672-684
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The purpose of this study is to evaluate the efficacy and safety of ticagrelor and clopidogrel in patients with acute coronary syndrome undergoing coronary artery bypass graft surgery (CABG), as a post-randomization strategy. Background Ticagrelor is a novel, reversibly binding, oral, direct-acting P2Y(12)-receptor antagonist. In the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized 18,624 patients with acute coronary syndromes, ticagrelor compared with clopidogrel significantly reduced the risk of the primary composite end point of cardiovascular (CV) death, myocardial infarction, or stroke (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.77 to 0.92; p < 0.001). This report investigated the outcomes of patients treated with CABG during the trial. Methods In total, 1,899 patients underwent CABG post-randomization. The protocol recommended ticagrelor/placebo to be withheld for 24 to 72 h and clopidogrel/placebo for 5 days preoperatively. In all, 1,261 patients underwent CABG and were receiving study drug treatment <7 days before surgery. The statistical analysis was based on events occurring from the CABG procedure until the end of the study, excluding 3 patients with CABG after study end. Results In the 1,261 patient cohort, the relative reduction of primary composite end point at 12 months (10.6% [66 of 629] with ticagrelor versus 13.1% [79 of 629] with clopidogrel; HR: 0.84; 95% CI: 0.60 to 1.16; p = 0.29) was consistent with the results of the whole trial. Total mortality was reduced from 9.7% (58 of 629) to 4.7% (29 of 629; HR: 0.49; 95% CI: 0.32 to 0.77; p < 0.01), CV death from 7.9% (47 of 629) to 4.1% (25 of 629; HR: 0.52; 95% CI: 0.32 to 0.85; p < 0.01), and non-CV death numerically from 2.0% to 0.7% (p = 0.07). There was no significant difference in CABG-related major bleeding between the randomized treatments. Conclusions In the subgroup of patients undergoing CABG within 7 days after the last study drug intake, ticagrelor compared with clopidogrel was associated with a substantial reduction in total and CV mortality without excess risk of CABG-related bleeding.
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| 6. |
- James, Stefan K., et al.
(författare)
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Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management : substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial
- 2011
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Ingår i: The BMJ. - : BMJ. - 1756-1833. ; 342, s. d3527-
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy. Design Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial. Setting 862 centres in 43 countries. Participants 5216 (28%) of 18 624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management. Interventions Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615). Main outcome measurements Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year. Results 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel. Conclusions In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy.
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| 7. |
- James, Stefan, et al.
(författare)
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Ticagrelor Versus Clopidogrel in Acute Coronary Syndromes in Relation to Renal Function Results From the Platelet Inhibition and Patient Outcomes (PLATO) Trial
- 2010
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 122:11, s. 1056-1067
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Tidskriftsartikel (refereegranskat)abstract
- Background-Reduced renal function is associated with a poorer prognosis and increased bleeding risk in patients with acute coronary syndromes and may therefore alter the risk-benefit ratio with antiplatelet therapies. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor compared with clopidogrel reduced the primary composite end point of cardiovascular death, myocardial infarction, and stroke at 12 months but with similar major bleeding rates. Methods and Results-Central laboratory serum creatinine levels were available in 15 202 (81.9%) acute coronary syndrome patients at baseline, and creatinine clearance, estimated by the Cockcroft Gault equation, was calculated. In patients with chronic kidney disease (creatinine clearance <60 mL/min; n = 3237), ticagrelor versus clopidogrel significantly reduced the primary end point to 17.3% from 22.0% (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.65 to 0.90) with an absolute risk reduction greater than that of patients with normal renal function (n = 11 965): 7.9% versus 8.9% (HR, 0.90; 95% CI, 0.79 to 1.02). In patients with chronic kidney disease, ticagrelor reduced total mortality (10.0% versus 14.0%; HR, 0.72; 95% CI, 0.58 to 0.89). Major bleeding rates, fatal bleedings, and non-coronary bypass-related major bleedings were not significantly different between the 2 randomized groups (15.1% versus 14.3%; HR, 1.07; 95% CI, 0.88 to 1.30; 0.34% versus 0.77%; HR, 0.48; 95% CI, 0.15 to 1.54; and 8.5% versus 7.3%; HR, 1.28; 95% CI, 0.97 to 1.68). The interactions between creatinine clearance and randomized treatment on any of the outcome variables were nonsignificant. Conclusions-In acute coronary syndrome patients with chronic kidney disease, ticagrelor compared with clopidogrel significantly reduces ischemic end points and mortality without a significant increase in major bleeding but with numerically more non-procedure-related bleeding.
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| 8. |
- Kunadian, Vijay, et al.
(författare)
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Angiographic Outcomes in the PLATO Trial (Platelet Inhibition and Patient Outcomes)
- 2013
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Ingår i: JACC-CARDIOVASCULAR INTERVENTIONS. - : Elsevier BV. - 1936-8798. ; 6:7, s. 671-683
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The PLATO (Platelet Inhibition and Patient Outcomes) angiographic substudy sought to compare the efficacy of ticagrelor versus clopidogrel with respect to angiographic outcomes before and after PCI in the setting of acute coronary syndrome. Background Greater platelet inhibition has been associated with improved angiographic outcomes before and after percutaneous coronary intervention (PCI). Therefore, it was hypothesized that treatment with ticagrelor, which achieves more rapid, higher, and more consistent platelet inhibition, would be associated with improved angiographic outcomes when compared with those of clopidogrel treatment. Methods The angiographic cohort consists of 2,616 patients drawn from the 18,624-patient PLATO trial. Clopidogrel naive or pre-treated patients were randomized to 180 mg of ticagrelor or 300 mg of clopidogrel (75 mg for clopidogrel pre-treated patients). PCI patients were administered, as per treatment group: 1) an additional 90 mg of ticagrelor if >24 h following the initial loading dose; or 2) an optional further 300 mg of clopidogrel or placebo (total 600 mg) prior to PCI. The substudy primary endpoint was the incidence of post-PCI TIMI (Thrombolysis In Myocardial Infarction) myocardial perfusion grade 3 (TMPG 3) among patients who received a study drug prior to PCI. Results In total, 21.3% of patients were pretreated with clopidogrel prior to randomization. There was a short time interval between randomization and PCI (median: 0.68 [interquartile range (IQR): 0.30 to 2.21] h) among all patients. Post-PCI TMPG 3 was similar between the ticagrelor and clopidogrel groups (47.1% vs. 46.9%; p = 0.96). Likewise, the following pre-PCI outcomes were similar in the ticagrelor and clopidogrel groups, respectively: TMPG 3 (30.5% vs. 31.2%), TIMI flow grade 3 (37.1% vs. 39.3%), corrected TIMI frame count (median: 100 vs. 71 frames), TIMI thrombus grade 0 (24.1% vs. 27.6%), minimum lumen diameter (median: 0.3 [IQR: 0.0 to 0.6] vs. 0.3 [IQR: 0.0 to 0.6] mm) and percentage of diameter stenosis (median: 89 [IQR: 78 to 100] vs. 89 [IQR: 77 to 100]). Conclusions Neither coronary flow nor myocardial perfusion, evaluated on coronary angiograms performed before or following PCI procedures within a few hours after the start of oral antiplatelet treatment in the setting of acute coronary syndromes, demonstrated a difference with ticagrelor versus clopidogrel. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872)
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| 9. |
- Mahaffey, Kenneth W., et al.
(författare)
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Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial
- 2011
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 124:5, s. 544-554
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Tidskriftsartikel (refereegranskat)abstract
- Background-In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region (P = 0.045), with less effect of ticagrelor in North America than in the rest of the world. Methods and Results-Reasons for the interaction were explored independently by 2 statistical groups. Systematic errors in trial conduct were investigated. Statistical approaches evaluated the likelihood of play of chance. Cox regression analyses were performed to quantify how much of the regional interaction could be explained by patient characteristics and concomitant treatments, including aspirin maintenance therapy. Landmark Cox regressions at 8 time points evaluated the association of selected factors, including aspirin dose, with outcomes by treatment. Systematic errors in trial conduct were ruled out. Given the large number of subgroup analyses performed and that a result numerically favoring clopidogrel in at least 1 of the 4 prespecified regions could occur with 32% probability, chance alone cannot be ruled out. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose >= 300 mg/d. Of 37 baseline and postrandomization factors explored, only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, both Cox regression with median maintenance dose and landmark techniques showed that, in patients taking low-dose maintenance aspirin, ticagrelor was associated with better outcomes compared with clopidogrel, with statistical superiority in the rest of the world and similar outcomes in the US cohort. Conclusions-The regional interaction could arise from chance alone. Results of 2 independently performed analyses identified an underlying statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel is associated with a low maintenance dose of concomitant aspirin.
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| 10. |
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