| 1. |
- Goodman, Shaun G., et al.
(författare)
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Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes With Clopidogrel and Ticagrelor : Outcomes With Clopidogrel and Ticagrelor
- 2012
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 125:8, s. 978-986
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Tidskriftsartikel (refereegranskat)abstract
- Background-The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear. Methods and Results-We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (n = 6539) compared with those not on a PPI (n = 12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04 -1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07-1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79-1.23; ticagrelor, HR, 0.89; 95% CI, 0.73-1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12-1.49; ticagrelor, HR, 1.30; 95% CI, 1.14-1.49). Conclusions-The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events.
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| 2. |
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| 3. |
- 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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| 4. |
- Cannon, Christopher P., et al.
(författare)
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Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO) : a randomised double-blind study
- 2010
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 375:9711, s. 283-293
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients. METHODS: At randomisation, an invasive strategy was planned for 13 408 (72.0%) of 18 624 patients hospitalised for acute coronary syndromes (with or without ST elevation). In a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300-600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6-12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00391872. FINDINGS: 6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopidogrel group (569 [event rate at 360 days 9.0%] vs 668 [10.7%], hazard ratio 0.84, 95% CI 0.75-0.94; p=0.0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (691 [11.6%] vs 689 [11.5%], 0.99 [0.89-1.10]; p=0.8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 [3.2%] vs 185 [2.9%], 0.91 [0.74-1.12]; p=0.3785). INTERPRETATION: Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned.
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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
- Lindholm, Daniel, et al.
(författare)
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Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization : results from the PLATO trial
- 2014
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 35:31, s. 2083-2093
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Tidskriftsartikel (refereegranskat)abstract
- Aims The optimal platelet inhibition strategy for ACS patients managed without revascularization is unknown. We aimed to evaluate efficacy and safety of ticagrelor vs. clopidogrel in the non-ST-elevation acute coronary syndrome (NSTE-ACS) subgroup of the PLATO trial, in the total cohort, and in the subgroups managed with and without revascularization within 10 days of randomization. Methods and results We performed a retrospective analysis of the primary endpoint of cardiovascular death/myocardial infarction/stroke. Among 18 624 PLATO patients, 11 080 (59%) were categorized as NSTE-ACS at randomization. During the initial 10 days, 74% had angiography, 46% PCI, and 5% CABG. In NSTE-ACS patients, the primary endpoint was reduced with ticagrelor vs. clopidogrel [10.0 vs. 12.3%; hazard ratio (HR) 0.83; 95% confidence interval (CI) = 0.74-0.93], as was myocardial infarction (6.6 vs. 7.7%; HR 0.86; 95% CI = 0.74-0.99), cardiovascular death (3.7 vs. 4.9%; HR 0.77; 95% CI = 0.64-0.93), and all-cause death (4.3 vs. 5.8%; HR 0.76; 95% CI = 0.64-0.90). Major bleeding rate was similar between treatment groups (13.4 vs. 12.6%; HR 1.07; 95% CI = 0.95-1.19), but ticagrelor was associated with an increase in non-CABG major bleeding (4.8 vs. 3.8%; HR 1.28; 95% CI = 1.05-1.56). Within the first 10 days, 5366 (48.4%) patients were managed without revascularization. Regardless of revascularization or not, ticagrelor consistently reduced the primary outcome (HR 0.86 vs. 0.85, interaction P = 0.93), and all-cause death (HR 0.75 vs. 0.73, interaction P = 0.89) with no significant increase in overall major bleeding. Conclusion In patients with NSTE-ACS, benefit of ticagrelor over clopidogrel in reducing ischaemic events and total mortality was consistent with the overall PLATO trial, independent of actually performed revascularization during the initial 10 days.
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| 9. |
- Mahaffey, Kenneth W., et al.
(författare)
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Ticagrelor Effects on Myocardial Infarction and the Impact of Event Adjudication in the PLATO (Platelet Inhibition and Patient Outcomes) Trial
- 2014
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 63:15, s. 1493-1499
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study sought to report the treatment effect of ticagrelor on myocardial infarction (MI) and the strategy for and impact of event adjudication in the PLATO (Platelet Inhibition and Patient Outcomes) trial. Background In PLATO, ticagrelor reduced cardiovascular death, MI, or stroke in patients with acute coronary syndromes (ACS). Methods A CIinical events committee (CEC) prospectively defined and adjudicated all suspected MI events, on the basis of events reported by investigators and by triggers on biomarkers. Treatment comparisons used CEC-adjudicated data, and per protocol, exCIuded silent MI. Results Overall, 1,299 (610 ticagrelor, 689 CIopidogrel) MIs reported by the CEC occurred during the trial. Of these, 1,097 (504 ticagrelor, 593 CIopidogrel) contributed to the primary composite endpoint. Site investigators reported 1,198 (580 ticagrelor, 618 CIopidogrel) MIs. Ticagrelor significantly reduced overall MI rates (12-month CEC-adjudicated Kaplan-Meier rates: 5.8% ticagrelor, 6.9% CIopidogrel; hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.75 to 0.95). Nonprocedural MI (HR: 0.86; 95% CI: 0.74 to 1.01) and MI related to percutaneous coronary intervention or stent thrombosis tended to be lower with ticagrelor. MIs related to coronary artery bypass graft surgery were few, but numerical excess was observed in patients assigned ticagrelor. Analyses of overall MIs using investigator-reported data showed similar results but did not reach statistical significance (HR: 0.88; 95% CI: 0.78 to 1.00). ConCIusions In patients with ACS, ticagrelor significantly reduced the incidence of MI compared with CIopidogrel, with consistent results across most MI subtypes. CEC procedures identified more MI endpoints compared with site investigators. (A Comparison of Ticagrelor [AZD6140] and CIopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872)
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| 10. |
- Scirica, Benjamin M., et al.
(författare)
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The Incidence of Bradyarrhythmias and Clinical Bradyarrhythmic Events in Patients With Acute Coronary Syndromes Treated With Ticagrelor or Clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) Trial Results of the Continuous Electrocardiographic Assessment Substudy
- 2011
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 57:19, s. 1908-1916
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The aim of this study was to determine whether ticagrelor increased the risk of ventricular pauses compared with clopidogrel and whether these pauses were associated with any clinical bradycardic events in patients presenting with acute coronary syndromes. Background Ticagrelor, an oral reversibly binding P2Y(12) inhibitor, provides more potent and consistent inhibition of platelet aggregation than clopidogrel but in a phase II study was associated with increased risk for ventricular pauses. A prospective continuous electrocardiographic (cECG) assessment was therefore performed within the PLATO (Platelet Inhibition and Patient Outcomes) study comparing ticagrelor and clopidogrel in patients hospitalized with acute coronary syndromes. Methods Patients in the cECG assessment had planned 7-day cECG recording initiated at the time of randomization (week 1), which was within 24 h of symptom onset, and then repeated at 1 month after randomization during the convalescent phase. The principal safety endpoint was the incidence of ventricular pauses lasting at least 3 s. Investigators also reported symptomatic bradycardic adverse events during the entire study duration (median 277 days). Results A total of 2,908 patients were included in the cECG assessment, of whom 2,866 (98.5%) had week 1 recordings, 1,991 (68.4%) had 1-month recordings, and 1,949 (67.0%) had both. During the first week after randomization, ventricular pauses >= 3 s occurred more frequently in patients receiving ticagrelor than clopidogrel (84 [5.8%] vs. 51 [3.6%]; relative risk: 1.61; p = 0.006). At 1 month, pauses >= 3 s occurred overall less frequently and were similar between treatments (2.1% vs. 1.7%). Most were ventricular pauses, and the greatest excess associated with ticagrelor were asymptomatic, sinoatrial nodal in origin (66%), and nocturnal. There were no differences between ticagrelor and clopidogrel in the incidence of clinically reported bradycardic adverse events, including syncope, pacemaker placement, and cardiac arrest. Conclusions In the PLATO cECG assessment, more patients treated with ticagrelor compared with clopidogrel had ventricular pauses, which were predominantly asymptomatic, sinoatrial nodal in origin, and nocturnal and occurred most frequently in the acute phase of acute coronary syndromes. There were no apparent clinical consequences related to the excess in ventricular pauses in patients assigned to ticagrelor. (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872) (J Am Coll Cardiol 2011; 57: 1908-16) .
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