| 1. |
- Bhatt, Deepak L., et al.
(författare)
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Rationale, design and baseline characteristics of the effect of ticagrelor on health outcomes in diabetes mellitus patients Intervention study
- 2019
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Ingår i: Clinical Cardiology. - : Wiley. - 0160-9289 .- 1932-8737. ; 42:5, s. 498-505
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Tidskriftsartikel (refereegranskat)abstract
- In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double-blinded, placebo-controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients >= 50 years with type 2 diabetes receiving anti-diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of >= 50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19 220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow-up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice daily dose, as the dose was lowered from 90 mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention.
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| 2. |
- Bui, An H., et al.
(författare)
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Relationship Between Early and Late Nonsustained Ventricular Tachycardia and Cardiovascular Death in Patients With Acute Coronary Syndrome in the Platelet Inhibition and Patient Outcomes (PLATO) Trial
- 2016
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Ingår i: Circulation. - 1941-3149 .- 1941-3084. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- Background- Nonsustained ventricular tachycardia (NSVT) is common after acute coronary syndrome (ACS) and a marker of increased risk of arrhythmogenic death. However, the prognostic significance of NSVT when evaluated with other contemporary risk markers and at later time points after ACS remains uncertain. Methods and Results- In the Platelet Inhibition and Patient Outcomes (PLATO) trial, continuous ECGs were performed during the first 7 days after ACS (n=2866) and repeated for another 7 days at day 30 (n=1991). Median follow-up was 1 year. There was a time-varying interaction between NSVT and cardiovascular death such that NSVT was significantly associated with increased risk within the first 30 days after randomization (22/999 [2.2%] versus 16/1825 [0.9%]; adjusted hazard ratio, 2.84; 95% confidence interval, 1.39-5.79; P=0.004) but not after 30 days (28/929 [3.0%] versus 42/1734 [2.4%]; P=0.71). Detection of NSVT during the convalescent phase (n=428/1991; 21.5%) was also associated with an increased risk of cardiovascular death, and was most marked within the first 2 months after detection (1.9% versus 0.3%; adjusted hazard ratio, 5.48; 95% confidence interval, 1.07-28.20; P=0.01), and then decreasing over time such that the relationship was no longer significant by approximate to 5 months after ACS. Conclusions- NSVT occurred frequently during the acute and convalescent phases of ACS. The risk of cardiovascular death associated with NSVT was the greatest during the first 30 days after presentation; however, patients with NSVT detected during the convalescent phase were also at a significantly increased risk of cardiovascular death that persisted for an additional several months after the index event.
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| 3. |
- Costa, Francesco, et al.
(författare)
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Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score : a pooled analysis of individual-patient datasets from clinical trials
- 2017
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 389:10073, s. 1025-1034
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Tidskriftsartikel (refereegranskat)abstract
- Background: Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y(12) inhibitor prevents ischaemic events after coronary stenting, but increases bleeding. Guidelines support weighting bleeding risk before the selection of treatment duration, but no standardised tool exists for this purpose.Methods: A total of 14 963 patients treated with DAPT after coronary stenting-largely consisting of aspirin and clopidogrel and without indication to oral anticoagulation-were pooled at a single-patient level from eight multicentre randomised clinical trials with independent adjudication of events. Using Cox proportional hazards regression, we identified predictors of out-of-hospital Thrombosis in Myocardial Infarction (TIMI) major or minor bleeding stratified by trial, and developed a numerical bleeding risk score. The predictive performance of the novel score was assessed in the derivation cohort and validated in patients treated with percutaneous coronary intervention from the PLATelet inhibition and patient Outcomes (PLATO) trial (n=8595) and BernPCI registry (n=6172). The novel score was assessed within patients randomised to different DAPT durations (n=10 081) to identify the effect on bleeding and ischaemia of a long (12-24 months) or short (3-6 months) treatment in relation to baseline bleeding risk.Findings: The PRECISE-DAPT score (age, creatinine clearance, haemoglobin, white-blood-cell count, and previous spontaneous bleeding) showed a c-index for out-of-hospital TIMI major or minor bleeding of 0.73 (95% CI 0.61-0.85) in the derivation cohort, and 0.70 (0.65-0.74) in the PLATO trial validation cohort and 0.66 (0.61-0.71) in the BernPCI registry validation cohort. A longer DAPT duration significantly increased bleeding in patients at high risk (score >= 25), but not in those with lower risk profiles (p(interaction)=0.007), and exerted a significant ischaemic benefit only in this latter group.Interpretation: The PRECISE-DAPT score is a simple five-item risk score, which provides a standardised tool for the prediction of out-of-hospital bleeding during DAPT. In the context of a comprehensive clinical evaluation process, this tool can support clinical decision making for treatment duration.
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| 4. |
- Ducrocq, Gregory, et al.
(författare)
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Balancing the risk of spontaneous ischemic and major bleeding events in acute coronary syndromes
- 2017
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Ingår i: American Heart Journal. - : MOSBY-ELSEVIER. - 0002-8703 .- 1097-6744. ; 186, s. 91-99
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Tidskriftsartikel (refereegranskat)abstract
- Background: Evaluation of antithrombotic treatments for acute coronary syndromes (ACS) requires balancing ischemic and bleeding risks to assess net benefit. We sought to compare the relative effects of ischemic and bleeding events on mortality.Methods: In the PLATelet inhibition and patient Outcomes (PLATO) trial, we compared spontaneous ischemic events (myocardial infarction or stroke) with spontaneous major bleeding events (PLATO major, Thrombolysis In Myocardial Infarction [TIMI] major, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO] severe) with respect to risk of mortality using time-dependent Cox proportional hazards models. The comparison was performed using ratio of hazard ratios for mortality increase after ischemic vs bleeding events.Results: A total of 822 patients (4.4%) had >= 1 spontaneous ischemic event; 485 patients (2.6%), >= 1 spontaneous PLATO major bleed, 282 (1.5%), >= 1 spontaneous TIMI major bleed; and 207 (1.1%), >= 1 spontaneous severe GUSTO bleed. In patients who had both events, bleeding occurred first in most patients. Regardless of classification, major bleeding events were associated with increased short- and long-term mortality that were not significantly different from the increase associated with spontaneous ischemic events: ratio of hazard ratios (95% Cls) for short- and long-term mortality after spontaneous ischemic vs bleeding events: 1.46 (0.98-2.19) and 0.92 (0.52-1.62) (PLATO major); 1.26 (0.80-1.96) and 1.19 (0.58-2.24) (TIMI major), 0.72 (0.47-1.10) and 0.83 (0.38-1.79) (GUSTO severe) (all P > 0.05)Conclusions: In patients with ACS on dual antiplatelet therapy, spontaneous major bleeding events seem "prognostically equivalent" to spontaneous ischemic complications. This result allows quantitative comparisons between both actual and predicted bleeding and ischemic risks. Our findings help to better define net clinical benefit of antithrombotic treatments and more accurately estimate mortality after ischemic and bleeding events in patients with ACS.
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| 5. |
- 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. ; 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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| 6. |
- Hagström, Emil, et al.
(författare)
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Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes : results from the PLATO study
- 2016
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 37:16, s. 1325-1333
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Tidskriftsartikel (refereegranskat)abstract
- Aims Growth differentiation factor-15 (GDF-15) predicts death and composite cardiovascular (CV) events in patients with acute coronary syndrome (ACS). We investigated the independent associations between GDF-15 levels and major bleeding, the extent of coronary lesions and individual CV events in patients with ACS. Methods and results Growth differentiation factor-15 was analysed at baseline (n = 16 876) in patients with ACS randomized to ticagrelor or clopidogrel in the PLATO (PLATelet inhibition and patient Outcomes) trial. Growth differentiation factor-15 levels were related to extent of coronary artery disease (CAD) and to all types of non-coronary artery bypass grafting (CABG)-related major bleeding, spontaneous myocardial infarction (MI), stroke, and death during 12-month follow-up. In Cox proportional hazards models adjusting for established risk factors for CV disease and prognostic biomarkers (N-terminal pro B-type natriuretic peptide, cystatin C, high-sensitive C-reactive protein, and high-sensitive troponin T), 1 SD increase in ln GDF-15 was associated with increased risk of major bleeding with a hazard ratio (HR) 1.37 (95% confidence interval: 1.25-1.51) and with a similar increase in risk across different bleeding locations. For the same increase in ln GDF-15, the HR for the composite of CV death, spontaneous MI, and stroke was 1.29 (1.21-1.37), CV death 1.41 (1.30-1.53), all-cause death 1.41 (1.31-1.53), spontaneous MI 1.15 (1.05-1.26), and stroke 1.19 (1.01-1.42). The C-statistic improved for the prediction of CV death and non-CABG-related major bleeding when adding GDF-15 to established risk factors. Conclusions In patients with ACS, higher levels of GDF-15 are associated with raised risks of all types of major non-CABG-related bleeding, spontaneous MI, and stroke as well as CV and total mortality and seem to improve risk stratification for CV-mortality and major bleeding beyond established risk factors.
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| 7. |
- Hagström, Emil, et al.
(författare)
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Growth Differentiation Factor 15 Predicts All-Cause Morbidity and Mortality in Stable Coronary Heart Disease
- 2017
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 63:1, s. 325-333
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Higher growth differentiation factor 15 (GDF-15) concentrations are associated with cardiovascular (CV) and non-CV morbidity and mortality. However, information on associations between GDF-15 and the risk of specific CV and non-CV events in stable coronary heart disease (CHD) patients is limited.METHODS: In 14 577 patients with stable CHD participating in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial (STABILITY), GDF-15 and other prognostic biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity troponin T, cystatin C, and high-sensitivity C-reactive protein) were measured. In adjusted Cox regression models, the associations between GDF-15 and the composite CV end point [CV death, myocardial infarction (MI), and stroke], as well as other CV and non-CV events, were assessed.RESULTS: The median concentration (interquartile range) of GDF-15 at baseline was 1253 (915-1827) ng/L. The hazard ratio for the composite end point for the highest compared to the lowest quartile of GDF-15 was 1.8 (95% CI, 1.5-2.2); for CV death, 2.63 (1.9-3.6); for sudden death, 3.06 (1.9-4.8); for heart failure (HF) death, 4.3 (1.3-14); for cancer death, 2.5 (1.3-4.7); for hospitalization for HF, 5.8 (3.2-10); for MI 1.4 (95% CI, 1.1-1.9); and for stroke, 1.8 (95% CI, 1.1-2.8). After adjustment for other prognostic biomarkers, GDF-15 remained significantly associated with all outcomes except for MI.CONCLUSIONS: In stable CHD, GDF-15 was independently associated with CV, non-CV, and cancer mortality, as well as with MI and stroke. When also adjusting for other prognostic biomarkers, the associations to all fatal and nonfatal events were maintained except for MI. Information on GDF-15, therefore, might be helpful when assessing the risk of adverse outcomes in patients with stable CHD. ClinicalTrials.gov Identifier: NCT00799903.
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| 8. |
- Held, Claes, 1956-, et al.
(författare)
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Inflammatory Biomarkers Interleukin-6 and C-Reactive Protein and Outcomes in Stable Coronary Heart Disease : Experiences From the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial
- 2017
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 6:10
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundEvaluation of cardiovascular prognosis in patients with stable coronary heart disease is based on clinical characteristics and biomarkers indicating dysglycemia, dyslipidemia, renal dysfunction, and possibly cardiac dysfunction. Inflammation plays a key role in atherosclerosis, but the association between inflammatory biomarkers and clinical outcomes is less studied in this population.Methods and ResultsOverall, 15 828 patients with coronary heart disease in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial werer and randomized to treatment with darapladib or placebo and observed for a median of 3.7 years. In 14 611 patients, levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein were measured in plasma samples: median levels were2.1 (interquartile range, 1.4-3.2) ng/Land1.3 (interquartile range, 0.6-3.1) mg/L, respectively. Associations between continuous levels or quartile groups and adjudicated outcomes were evaluated by spline graphs and Cox regression adjusted for clinical factors and cardiovascular biomarkers. IL-6 was associated with increased risk of major adverse cardiovascular events (quartile 4 versus quartile 1 hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.30-1.97; P< 0.0001); cardiovascular death (HR, 2.15; 95% CI, 1.53-3.04; P< 0.0001); myocardial infarction (HR, 1.53; 95% CI, 1.14-2.04; P< 0.05); all-cause mortality (HR, 2.11; 95% CI, 1.62-2.76; P< 0.0001); and risk of hospitalization for heart failure (HR, 2.28; 95% CI, 1.34-3.89; P< 0.001). Cancer death was doubled in the highest IL-6 quartile group (HR, 2.34; 95% CI, 1.20-4.53; P< 0.05). High-sensitivity C-reactive protein was associated with both cardiovascular and non-cardiovascular events in the unadjusted model, but these did not remain after multivariable adjustments.ConclusionsIL-6, an upstream inflammatory marker, was independently associated with the risk of major adverse cardiovascular events, cardiovascular and all-cause mortality, myocardial infarction, heart failure, and cancer mortality in patients with stable coronary heart disease. IL-6 might reflect a pathophysiological process involved in the development of these events.
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| 9. |
- Horowitz, John D., et al.
(författare)
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Asymmetric and Symmetric Dimethylarginine Predict Outcomes in Patients With Atrial Fibrillation : An ARISTOTLE Substudy
- 2018
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 72:7, s. 721-733
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND There is little mechanistic information on factors predisposing atrial fibrillation (AF) patients to thromboembolism or bleeding, but generation of nitric oxide (NO) might theoretically contribute to both. OBJECTIVES The authors tested the hypothesis that plasma levels of the methylated arginine derivatives asymmetric and symmetric dimethylarginine (ADMA/SDMA), which inhibit NO generation, might be associated with outcomes in AF. METHODS Plasma samples were obtained from 5,004 patients with AF at randomization to warfarin or apixaban in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. ADMA and SDMA concentrations were measured by high-performance liquid chromatography. Relationships to clinical characteristics were evaluated by multivariable analyses. Associations with major outcomes, during a median of 1.9 years follow-up, were evaluated by adjusted Cox proportional hazards models. RESULTS Both ADMA and SDMA plasma concentrations at study entry increased significantly with patients' age, female sex, renal impairment, permanent AF, or congestive heart failure. ADMA and SDMA increased (p < 0.001) with both increased CHA2DS2-VASc and HAS-BLED scores, but decreased in the presence of diabetes. On multivariable analysis adjusting for established risk factors and treatment, tertile groups of ADMA concentrations were significantly associated with stroke/systemic embolism (p = 0.034), and death (p < 0.0001), whereas tertile groups of SDMA were associated with major bleeding and death (p < 0.001 for both). Incorporating ADMA and SDMA into CHA2DS2-VASc or HAS-BLED predictive models improved C-indices for those outcomes. Neither ADMA nor SDMA predicted differential responses to warfarin or apixaban. CONCLUSIONS In anticoagulated patients with AF, elevated ADMA levels are weakly associated with thromboembolic events, elevated SDMA levels with bleeding events and both are strongly associated with increased mortality. These findings suggest that disturbances of NO function modulate both thrombotic and hemorrhagic risk in anticoagulated patients with AF. (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]; NCT00412984)
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| 10. |
- Johansson, Åsa, et al.
(författare)
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Genome-wide association and Mendelian randomization study of NT-proBNP in patients with acute coronary syndrome
- 2016
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 25:7, s. 1447-1456
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Tidskriftsartikel (refereegranskat)abstract
- N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a strong predictor of mortality in coronary artery disease and is widely employed as a prognostic biomarker. However, a causal relationship between NT-proBNP and clinical endpoints has not been established. We have performed a genome-wide association and Mendelian randomization study of NT-proBNP. We used a discovery set of 3740 patients from the PLATelet inhibition and patient Outcomes (PLATO) trial, which enrolled 18 624 patients with acute coronary syndrome (ACS). A further set of 5492 patients, from the same trial, was used for replication. Genetic variants at two novel loci (SLC39A8 and POC1B/GALNT4) were associated with NT-proBNP levels and replicated together with the previously known NPPB locus. The most significant SNP (rs198389, pooled P = 1.07 x 10(-15)) in NPPB interrupts an E-box consensus motif in the gene promoter. The association in SLC39A8 is driven by a deleterious variant (rs13107325, pooled P = 5.99 x 10(-10)), whereas the most significant SNP in POC1B/GALNT4 (rs11105306, pooled P = 1.02 x 10(-16)) is intronic. The SLC39A8 SNP was associated with higher risk of cardiovascular (CV) death (HR = 1.39, 95% CI: 1.08-1.79, P = 0.0095), but the other loci were not associated with clinical endpoints. We have identified two novel loci to be associated with NT-proBNP in patients with ACS. Only the SLC39A8 variant, but not the NPPB variant, was associated with a clinical endpoint. Due to pleotropic effects of SLC39A8, these results do not suggest that NT-proBNP levels have a direct effect on mortality in ACS patients. PLATO Clinical Trial Registration: ; NCT00391872.
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