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Platelet Inhibition, Revascularization, and Risk Prediction in Non-ST-elevation Acute Coronary Syndromes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cardiovascular disease is the leading cause of death worldwide and ischemic heart disease is the most common manifestation. Despite improved outcomes during the last decades, patients with acute coronary syndromes (ACS) are still at substantial risk of recurrent ischemic events and mortality.

The aims of this thesis were to investigate the effect of the novel antiplatelet agent ticagrelor versus clopidogrel in patients with non-ST-elevation ACS (NSTE-ACS), overall and in relation to initial revascularization, and to explore this effect in relation to cardiac biomarkers. The impact of timing of revascularization in non-ST-elevation myocardial infarction (NSTEMI) was also studied, by assessing risk of mortality and recurrent myocardial infarction in relation to delay of percutaneous coronary intervention (PCI) in a nation-wide cohort. Finally, a novel clinical prediction model based on angiographic findings, biomarkers, and clinical characteristics was developed to estimate risk of ischemic events after performed revascularization.

Ticagrelor treatment compared with clopidogrel was associated with a reduction in the composite endpoint of cardiovascular death/myocardial infarction/stroke and mortality alone, without any increase in overall major bleeding, but increased non-CABG-related major bleeding. The effect of ticagrelor over clopidogrel was consistent independent of initial revascularization. Elevated high-sensitivity cardiac troponin-T predicted benefit of ticagrelor over clopidogrel, while no difference between treatments was detected at normal levels. In patients with NSTEMI, PCI treatment within two days after hospital admission was associated with lower risk of all-cause death and recurrent myocardial infarction compared with delayed PCI. The new clinical prediction model included the following variables: prior vascular disease, extent of coronary artery disease, level of N-terminal pro-B-type natriuretic peptide and estimated glomerular filtration rate; and showed good discriminatory ability for the risk prediction of cardiovascular death/myocardial infarction/stroke and cardiovascular death alone.

In conclusion, these results show that ticagrelor reduces the risk of recurrent ischemic events and mortality in patients with NSTE-ACS when compared with clopidogrel, and this effect seems independent of performed revascularization. The results also indicate that biomarkers could be used to select patients who would benefit most from more intense platelet inhibition. Furthermore, early PCI in NSTEMI seems to be associated with improved outcome. Finally, the novel clinical prediction model based only on four variables showed good discriminatory ability, which makes it a potentially effective and simple tool for tailored treatment based on individual risk of recurrent events.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 85 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1151
Keyword [en]
coronary artery disease, myocardial infarction, acute coronary syndrome, non-ST-elevation acute coronary syndrome, P2Y12 inhibitors, ticagrelor, biomarkers, revascularization, percutaneous coronary intervention, risk prediction
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
URN: urn:nbn:se:uu:diva-265083ISBN: 978-91-554-9384-4 (print)OAI: oai:DiVA.org:uu-265083DiVA: diva2:862377
Public defence
2015-12-11, Enghoffsalen, Akademiska sjukhuset, ing. 50, Uppsala, 08:30 (English)
Opponent
Supervisors
Available from: 2015-11-17 Created: 2015-10-21 Last updated: 2016-10-07Bibliographically approved
List of papers
1. Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial
Open this publication in new window or tab >>Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial
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2014 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 35, no 31, 2083-2093 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
Platelet inhibition, Acute coronary syndrome
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-235190 (URN)10.1093/eurheartj/ehu160 (DOI)000342232600013 ()24727884 (PubMedID)
Available from: 2014-10-30 Created: 2014-10-29 Last updated: 2017-12-05Bibliographically approved
2. Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization A Substudy From the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial
Open this publication in new window or tab >>Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization A Substudy From the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial
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2014 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 129, no 3, 293-303 p.Article in journal (Refereed) Published
Abstract [en]

Background Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). We investigated the prognostic importance of high-sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) in relation to randomized treatment (ticagrelor versus clopidogrel) and management strategy (with or without revascularization) in the NSTE-ACS subgroup of the Platelet Inhibition and Patient Outcomes (PLATO) trial. Methods and Results Of 18 624 patients in the PLATO trial, 9946 had an entry diagnosis of NSTE-ACS and baseline blood samples available. During index hospitalization, 5357 were revascularized, and 4589 were managed without revascularization. Hs-TnT, NT-proBNP, and GDF-15 were determined and assessed according to predefined cutoff levels. Median follow-up was 9.1 months. Increasing levels of hs-TnT were associated with increasing risk of cardiovascular death, myocardial infarction, and stroke in medically managed patients (P<0.001), but not in those managed invasively. NT-proBNP and GDF-15 levels were associated with the same events independent of management strategy. Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS and hs-TnT 14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs-TnT <14.0 ng/L, there was no difference between ticagrelor and clopidogrel in the noninvasive group Conclusions Hs-TnT, NT-proBNP, and GDF-15 are predictors of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS managed noninvasively, and NT-proBNP and GDF-15 also in those managed invasively. Elevated hs-TnT predicts substantial benefit of ticagrelor over clopidogrel both in invasively and noninvasively managed patients, but no apparent benefit was seen at normal hs-TnT. Clinical Trial Registration URL:http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Keyword
acute coronary syndrome, biological markers, blood platelets, myocardial infarction, troponin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-219196 (URN)10.1161/CIRCULATIONAHA.113.004420 (DOI)000329880700006 ()
Available from: 2014-02-25 Created: 2014-02-24 Last updated: 2017-12-05Bibliographically approved
3. Timing of percutaneous coronary intervention in patients with non-ST-elevation myocardial infarction: a SWEDEHEART study
Open this publication in new window or tab >>Timing of percutaneous coronary intervention in patients with non-ST-elevation myocardial infarction: a SWEDEHEART study
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2017 (English)In: European Heart Journal - Quality of Care and Clinical Outcomes, E-ISSN 2058-1742, Vol. 3, no 1, 53-60 p.Article in journal (Refereed) Published
Abstract [en]

Aims

Although routine invasive management is recommended in NSTEMI patients, the optimal timing of the procedure is not defined. The aim of this study was to assess outcomes in relation to timing of PCI in NSTEMI patients.

Methods and results

This was an observational, prospective, multicentre cohort study from the SWEDEHEART registry including all Swedish PCI centres. We included 40 494 consecutive PCI-treated patients who were admitted to any coronary care unit from 2006 to 2013. The primary outcome was all-cause death, and secondary outcomes were recurrent myocardial infarction (MI), stent thrombosis, and severe in-hospital bleeding. Outcomes were assessed within 1 year from admission in relation to pre-specified cut-offs to define early PCI: within 1, 2, or 3 days. Patients who received delayed PCI, compared with those who did not, were older, and had a higher prevalence of comorbidities (hypertension, hyperlipidaemia, diabetes, and prior stroke) but showed similar angiographic findings. Cox mixed-effects models showed a lower risk of all-cause death with early PCI across all three cut-offs: HR (95% CI) of 0.88 (0.80–0.98), 0.78 (0.71–0.86), and 0.75 (0.68–0.84), for the 1-, 2-, and 3-day cut-offs, respectively. Early PCI was associated with lower risk of recurrent MI for the 2- and 3-day cut-offs, but not for the 1-day cut-off. The reported rates of severe in-hospital bleeding were low, but tended to be higher in patients receiving delayed PCI.

Conclusion

In patients undergoing PCI for NSTEMI, early invasive treatment is associated with lower risk of ischaemic outcomes.

Keyword
cardiology, acute coronary syndromes, non-st-elevation myocardial infarction, percutaneous coronary intervention, timing
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-265012 (URN)10.1093/ehjqcco/qcw044 (DOI)
Available from: 2015-10-20 Created: 2015-10-20 Last updated: 2017-03-02Bibliographically approved
4. Development of a novel biomarker-based clinical prediction model for major adverse cardiovascular events in revascularized patients with acute coronary syndromes
Open this publication in new window or tab >>Development of a novel biomarker-based clinical prediction model for major adverse cardiovascular events in revascularized patients with acute coronary syndromes
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(English)Manuscript (preprint) (Other academic)
Keyword
acute coronary syndromes, risk prediction, biomarkers
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:uu:diva-265014 (URN)
Available from: 2015-10-20 Created: 2015-10-20 Last updated: 2016-01-13

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