| 1. |
- Batra, Gorav, et al.
(författare)
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Interleukin 6 and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Chronic Coronary Syndrome
- 2021
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Ingår i: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 6:12, s. 1440-1445
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Inflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. It is unclear how inflammation mediated by interleukin 6 (IL-6) in patients with CKD is linked to cardiovascular disease.Objective: To investigate associations between IL-6 and cardiovascular outcomes in patients with chronic coronary syndrome in association with kidney function.Design, Setting, and Participants: This multicenter cohort study included patients enrolled at 663 centers in 39 countries with chronic coronary syndrome who were included in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial. Patients were enrolled between December 2008 and April 2010 and were followed up for a median length of 3.7 years. Analysis in this substudy began September 2020.Exposures: Exposures were IL-6 and creatinine estimated glomerular filtration rates (eGFR), which were collected at baseline. Associations between continuous and categorical levels (<2.0 ng/L vs ≥2.0 ng/L) of IL-6 and cardiovascular outcomes were tested in association with eGFR cutoffs (normal eGFR level [≥90 mL/min/1.73 m2], mildly decreased eGFR level [60-90 mL/min/1.73 m2], and moderately to severely decreased eGFR level [<60 mL/min/1.73 m2]).Main Outcomes and Measures: Main outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke.Results: This substudy of the STABILITY trial included 14 611 patients with available IL-6 levels at baseline. The median (interquartile range) age was 65 (59-71) years, and 2700 (18.5%) were female. During follow-up, MACE occurred in 1459 individuals (10.0%). Higher levels of IL-6 were in continuous models independently associated with risk of MACE (P < .001) in all CKD strata. Using predefined strata, elevated IL-6 level (≥2.0 vs <2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio, 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [hazard ratio, 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [hazard ratio, 1.60; 95% CI, 1.28-1.99]).Conclusions and Relevance: In patients with chronic coronary syndrome, elevated levels of IL-6 were associated with risk of MACE in all CKD strata. Thus, IL-6 and CKD stage may help when identifying patients with chronic coronary syndrome for anti-inflammatory treatment.
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| 2. |
- Giannitsis, Evangelos, et al.
(författare)
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Outcomes after planned invasive or conservative treatment strategy in patients with non-ST-elevation acute coronary syndrome and a normal value of high sensitivity troponin at randomisation : A Platelet Inhibition and Patient Outcomes (PLATO) trial biomarker substudy.
- 2017
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 6:6, s. 500-510
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Current guidelines for patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) recommend early invasive treatment in intermediate-to-high risk patients based on medical history, electrocardiogram (ECG) and elevated troponin. Patients with normal levels of cardiac troponin measured with a high-sensitivity method (cTnT-hs) might not benefit from early invasive procedures.METHODS AND RESULTS: In this Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) blood-core substudy, 1232 patients presented with NSTE-ACS had a high sensitivity cardiac troponin T (cTnT-hs) level <99(th) percentile (<14 ng/l) at randomisation. The outcomes in relation to a planned invasive (n=473) vs planned conservative treatment (n=759), were evaluated by adjusted Cox proportional hazard analyses. In patients with a normal cTnT-hs at randomisation, regardless of randomised treatment, a planned invasive vs conservative treatment was associated with a 2.3-fold higher risk (7.3% vs 3.4%, p=0.0028) for cardiovascular (CV) death or myocardial infarction (MI), driven by higher rates of procedure-related MI (3.4% vs 0.1%), while there were no differences in rates of CV death (1.3% vs 1.3%, p=0.72) or spontaneous MI (3.0% vs 2.1%, p=0.28). There were significantly more major bleeds (hazard ratio (HR) 2.98, p<0.0001), mainly due to coronary artery bypass graft (CABG)-related (HR 4.05, p<0.0001) and non-CABG procedural-related major bleeding events (HR 5.31, p=0.0175), however there were no differences in non-procedure-related major bleeding (1.5% vs 1.9%, p=0.45). Findings were consistent for patients with a normal cTnI-hs at randomisation.CONCLUSIONS: In patients with NSTE-ACS and normal cTnT-hs, a planned early invasive treatment strategy was associated with increased rates of procedure-related MI and bleeding but no differences in long-term spontaneous MI, non-procedure-related bleeding or mortality.
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| 3. |
- 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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| 4. |
- Lindholm, Daniel, 1982-, et al.
(författare)
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Biomarker-Based Risk Model to Predict Cardiovascular Mortality in Patients With Stable Coronary Disease
- 2017
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 70:7, s. 813-826
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Tidskriftsartikel (refereegranskat)abstract
- Background Currently, there is no generally accepted model to predict outcomes in stable coronary heart disease (CHD).Objectives This study evaluated and compared the prognostic value of biomarkers and clinical variables to develop a biomarker-based prediction model in patients with stable CHD.Methods In a prospective, randomized trial cohort of 13,164 patients with stable CHD, we analyzed several candidate biomarkers and clinical variables and used multivariable Cox regression to develop a clinical prediction model based on the most important markers. The primary outcome was cardiovascular (CV) death, but model performance was also explored for other key outcomes. It was internally bootstrap validated, and externally validated in 1,547 patients in another study.Results During a median follow-up of 3.7 years, there were 591 cases of CV death. The 3 most important biomarkers were N-terminal pro–B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and low-density lipoprotein cholesterol, where NT-proBNP and hs-cTnT had greater prognostic value than any other biomarker or clinical variable. The final prediction model included age (A), biomarkers (B) (NT-proBNP, hs-cTnT, and low-density lipoprotein cholesterol), and clinical variables (C) (smoking, diabetes mellitus, and peripheral arterial disease). This “ABC-CHD” model had high discriminatory ability for CV death (c-index 0.81 in derivation cohort, 0.78 in validation cohort), with adequate calibration in both cohorts.Conclusions This model provided a robust tool for the prediction of CV death in patients with stable CHD. As it is based on a small number of readily available biomarkers and clinical factors, it can be widely employed to complement clinical assessment and guide management based on CV risk. (The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial [STABILITY]; NCT00799903)
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| 5. |
- Lindholm, Daniel P, 1982-, et al.
(författare)
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Association of Multiple Biomarkers With Risk of All-Cause and Cause-Specific Mortality After Acute Coronary Syndromes : A Secondary Analysis of the PLATO Biomarker Study
- 2018
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Ingår i: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 3:12, s. 1160-1166
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Mortality remains at about 5% within a year after an acute coronary syndrome event. Prior studies have assessed biomarkers in relation to all-cause or cardiovascular deaths but not across multiple causes.Objective: To assess if different biomarkers provide information about the risk for all-cause and cause-specific mortality.Design, Setting, and Participants: The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18 624 patients with acute coronary syndrome to ticagrelor or clopidogrel from October 2006 through July 2008. In this secondary analysis biomarker substudy, 17 095 patients participated.Main Outcomes and Measures: Death due to myocardial infarction, heart failure, sudden cardiac death/arrhythmia, bleeding, procedures, other vascular causes, and nonvascular causes, as well as all-cause death.Exposures: At baseline, levels of cystatin-C, growth differentiation factor-15 (GDF-15), high-sensitivity C-reactive protein, high-sensitivity troponin I and T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were determined.Results: The median (interquartile range) age of patients was 62.0 (54.0-71.0) years. Of 17 095 patients, 782 (4.6%) died during follow-up. The continuous associations between biomarkers and all-cause and cause-specific mortality were modeled using Cox models and presented as hazard ratio (HR) comparing the upper vs lower quartile. For all-cause mortality, NT-proBNP and GDF-15 were the strongest markers with adjusted HRs of 2.96 (95% CI, 2.33-3.76) and 2.65 (95% CI, 2.17-3.24), respectively. Concerning death due to heart failure, NT-proBNP was associated with an 8-fold and C-reactive protein, GDF-15, and cystatin-C, with a 3-fold increase in risk. Regarding sudden cardiac death/arrhythmia, NT-proBNP was associated with a 4-fold increased risk and GDF-15 with a doubling in risk. Growth differentiation factor-15 had the strongest associations with other vascular and nonvascular deaths and was possibly associated with death due to major bleeding (HR, 4.91; 95% CI, 1.39-17.43).Conclusions and Relevance: In patients with acute coronary syndrome, baseline levels of NT-proBNP and GDF-15 were strong markers associated with all-cause death based on their associations with death due to heart failure as well as due to arrhythmia and sudden cardiac death. Growth differentiation factor-15 had the strongest associations with death due to other vascular or nonvascular causes and possibly with death due to bleeding.Trial Registration: ClinicalTrials.gov Identifier: NCT00391872.
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| 6. |
- Lindholm, Daniel P, et al.
(författare)
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Biomarkers and Coronary Lesions Predict Outcomes after Revascularization in Non-ST-Elevation Acute Coronary Syndrome
- 2017
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 63:2, s. 573-584
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Risk stratification in non-ST-elevation acute coronary syndrome (NSTE-ACS) is currently mainly based on clinical characteristics. With routine invasive management, angiography findings and biomarkers are available and may improve prognostication. We aimed to assess if adding biomarkers [high-sensitivity cardiac troponin T (cTnT-hs), N-terminal probrain-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15)] and extent of coronary artery disease (CAD) might improve prognostication in revascularized patients with NSTE-ACS.METHODS: In the PLATO (Platelet Inhibition and Patient Outcomes) trial, 5174 NSTE-ACS patients underwent initial angiography and revascularization and had cTnT-hs, NT-proBNP, and GDF-15 measured. Cox models were developed adding extent of CAD and biomarker levels to established clinical risk variables for the composite of cardiovascular death (CVD)/spontaneous myocardial infarction (MI), and CVD alone. Models were compared using c-statistic and net reclassification improvement (NRI).RESULTS: For the composite end point and CVD, prognostication improved when adding extent of CAD, NT-proBNP, and GDF-15 to clinical variables (c-statistic 0.685 and 0.805, respectively, for full model vs 0.649 and 0.760 for clinical model). cTnT-hs did not contribute to prognostication. In the full model (clinical variables, extent of CAD, all biomarkers), hazard ratios (95% CI) per standard deviation increase were for cTnT-hs 0.93(0.81-1.05), NT-proBNP 1.32(1.13-1.53), GDF-15 1.20(1.07-1.36) for the composite end point, driven by prediction of CVD by NT-proBNP and GDF-15. For spontaneous MI, there was an association with NT-proBNP or GDF-15, but not with cTnT-hs.CONCLUSIONS: In revascularized patients with NSTE-ACS, the extent of CAD and concentrations of NT-proBNP and GDF-15 independently improve prognostication of CVD/spontaneous MI and CVD alone. This information may be useful for selection of patients who might benefit from more intense and/or prolonged antithrombotic treatment.
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| 7. |
- Lindholm, Daniel P, 1982-, et al.
(författare)
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Growth Differentiation Factor 15 at 1 Month After an Acute Coronary Syndrome Is Associated With Increased Risk of Major Bleeding.
- 2017
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Growth differentiation factor-15 (GDF-15) is related to major bleeding when measured at initial presentation in patients with acute coronary syndromes (ACSs) treated with dual antiplatelet therapy. It is unknown whether follow-up measurements provide additional information. The objective of this study was to investigate whether GDF-15 measured 1 month after an ACS provides additional information beyond the baseline levels with regard to the risk of major bleeding.METHODS AND RESULTS: GDF-15 was measured at baseline and at 1 month after an ACS in 4049 patients included in the PLATelet inhibition and patient Outcomes (PLATO) trial. The association between 1-month GDF-15 level and non-coronary artery bypass grafting surgery-related major bleeding was assessed by a multivariable Cox model, adjusting for baseline GDF-15, age, anemia, impaired renal function, history of gastrointestinal bleeding, and sex. Elevated GDF-15 (>1800 ng/L) at 1 month was associated with an increased risk of non-coronary artery bypass grafting-related major bleeding (3.9% versus 1.2%; hazard ratio, 3.38; 95% CI, 1.89-6.06), independent of baseline GDF-15. Patients who had elevated GDF-15 levels at baseline and subsequent nonelevated GDF-15 at 1 month had a similar risk as patients who had nonelevated levels at both measurements.CONCLUSIONS: GDF-15 at 1 month after an ACS is related to the risk of bleeding during DAPT and provides additional information on the bleeding risk beyond baseline GDF-15 levels. GDF-15 levels may therefore be useful as part of decision support concerning long-term antithrombotic treatment in patients post-ACS.CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.
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| 8. |
- Lowenstern, Angela, et al.
(författare)
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Platelet-related biomarkers and their response to inhibition with aspirin and p2y12-receptor antagonists in patients with acute coronary syndrome
- 2017
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 44:2, s. 145-153
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Tidskriftsartikel (refereegranskat)abstract
- The PLATelet inhibition and patient Outcomes (PLATO) trial showed that treatment with ticagrelor reduced the rate of death due to vascular causes, myocardial infarction and stroke when compared to clopidogrel in patients with ST-elevation or non-ST-elevation acute coronary syndrome (ACS). While the comparative benefit of ticagrelor over clopidogrel increased over time, event rates accrued in both groups during the study period. The purpose of our biomarker-based exploratory analysis was to determine whether long-term platelet inhibition may be associated with platelet adaptation. A sample of 4000 participants from the PLATO trial also consented to participate in a prospectively designed biomarker substudy. Blood samples were procured at baseline, immediately prior to hospital discharge and at 1 and 6 months. Markers of platelet activity, including platelet count, serum CD40-ligand and soluble P-selectin were analyzed. Mean levels were compared at discharge, 1 and 6 months following study drug initiation-first for all patients and subsequently stratified by treatment group. A linear mixed model was used to estimate the short-term change rate (baseline to 1 month) and long-term change rate (1-6 months) for each biomarker. A Cox proportional hazards model was used to calculate hazard ratios for each change in biomarker over the two time periods examined: baseline to 1 month and 1 to 6 months. Prior to randomized treatment (baseline), sCD40 ligand and sP-selectin levels were elevated above the normal range of the assay (0.39 and 33.5 A μg/L, respectively). The mean level of each biomarker was significantly different at 1 month compared to baseline (p < 0.0001). When stratified by treatment group, at 1 month patients treated with ticagrelor had a larger increase in platelet count compared to those treated with clopidogrel (p < 0.0001). Similarly, when comparing biomarker levels for all patients at 6 months with those at 1 month, each differed significantly (p < 0.05). There was no significant difference between treatment groups during this time period. The rate of change for both platelet count and sP-selectin were significantly different between baseline and 1 month when compared to the 1 to 6-month time period (p < 0.0001). When comparing treatment groups, the rate of increase in platelets from baseline to 1 month was greater for patients treated with ticagrelor (p < 0.0001). This was no longer observed in the 1 to 6-month interval. Using a Cox proportional hazard model, the increase in platelet count from 1 to 6 months was associated with ischemic-thrombotic events, while sCD40 ligand decrease from 1 to 6 months was associated with hemorrhagic events. There were no differences between treatment groups for the associations with clinical endpoints. Dynamic changes in platelet count, sCD-40 ligand and sP-selectin occur over time among patients with ACS. Platelet-directed therapy with a P2Y12 receptor inhibitor in combination with aspirin modestly impacts the expression of these biomarkers. Platelet count and sCD40 ligand may offer modest overall predictive value for future ischemic-thrombotic or hemorrhagic clinical events, respectively. The existence of a platelet adaptome and its overall clinical significance among patients at risk for thrombotic events will require a more in-depth and platelet-biology specific investigation.
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| 9. |
- Storey, Robert F, et al.
(författare)
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Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study
- 2014
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Ingår i: Platelets. - : Informa UK Limited. - 0953-7104 .- 1369-1635. ; 25:7, s. 517-525
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Tidskriftsartikel (refereegranskat)abstract
- In the PLATelet inhibition and patient Outcomes (PLATO) study of patients with acute coronary syndromes, ticagrelor reduced mortality compared to clopidogrel but the mechanisms for this mortality reduction remain uncertain. We analysed adverse events (AEs) consistent with either pulmonary infection or sepsis, and subsequent mortality, in 18,421 PLATO patients treated with ticagrelor or clopidogrel. AEs occurring within 7 days of last dose of study medication were defined as "on-treatment". Serial measurements of blood leukocyte counts, C-reactive protein and interleukin-6 were performed. Fewer on-treatment pulmonary AEs occurred in the ticagrelor compared to the clopidogrel group (275 vs. 331 respectively; p = 0.019), with fewer deaths following these AEs (33 vs. 71; p < 0.001), particularly in those who remained on study medication three days after AE onset (10 vs. 43; p < 0.001). There were fewer deaths attributed to sepsis in the ticagrelor group (7 vs. 23; p = 0.003). Leukocyte counts were lower in the clopidogrel group during treatment (p < 0.0001 at 1, 3 and 6 months) but not at 1 month post-discontinuation. C-reactive protein increased more at discharge in the ticagrelor group (28.0 ± 38.0 vs. 26.1 ± 36.6 mg/l; p < 0.001) and interleukin-6 remained higher during the first month of treatment with ticagrelor. We conclude that the mortality risk following pulmonary AEs and sepsis in acute coronary syndrome patients appears to be lower during ticagrelor compared to clopidogrel therapy. Further work should assess whether ticagrelor and clopidogrel have differential effects on immune signalling.
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| 10. |
- Thomas, Mark R., et al.
(författare)
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Prognostic impact of baseline inflammatory markers in patients with acute coronary syndromes treated with ticagrelor and clopidogrel.
- 2019
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 10:2, s. 153-163
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Inflammation plays a major role in the pathophysiology of coronary artery disease. We aimed to determine whether baseline inflammatory markers were associated with clinical outcomes and the observed superiority of ticagrelor compared to clopidogrel in patients with acute coronary syndromes in the PLATO study.METHODS: Blood samples were collected from 16,400 patients within 24 hours of the onset of acute coronary syndrome, at the time of random assignment to ticagrelor or clopidogrel in the PLATO study and prior to invasive procedures. The differential white blood cell count and plasma levels of C-reactive protein, interleukin-6 and interleukin-10 were determined and their relationships with clinical outcomes were assessed according to quartiles and using continuous models. The substudy primary endpoint was a composite of cardiovascular death and myocardial infarction.RESULTS: Compared to the lowest quartile, the risk of the primary endpoint was significantly elevated in patients in the highest quartile of white blood cell count (hazard ratio (HR) 1.30; P=0.01), neutrophil count (HR 1.33; P=0.007), monocyte count (HR 1.24; P=0.004), C-reactive protein (HR 1.93; P<0.001) and interleukin-6 (HR 2.29; P<0.001). This was predominantly driven by an association with cardiovascular death. Following adjustment for clinical characteristics, troponin, cystatin C and N-terminal pro-brain-type natriuretic peptide, only white blood cell count and neutrophil count maintained a significant association with the primary endpoint. Ticagrelor had a consistent relative cardiovascular benefit compared to clopidogrel in each quartile of each of the inflammatory markers.CONCLUSIONS: Acute coronary syndrome patients with elevated levels of baseline inflammatory markers are at increased risk of adverse cardiovascular events, particularly cardiovascular death. The consistent cardiovascular benefit of ticagrelor compared to clopidogrel tended to confer a greater absolute risk reduction in patients with the highest levels of inflammatory markers, as they were at highest risk.
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