| 1. |
- Chiang, Chern-En, et al.
(author)
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Alirocumab and Cardiovascular Outcomes in Patients With Previous Myocardial Infarction : Prespecified Subanalysis From ODYSSEY OUTCOMES
- 2022
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In: Canadian Journal of Cardiology. - : Elsevier. - 0828-282X .- 1916-7075. ; 38:10, s. 1542-1549
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Journal article (peer-reviewed)abstract
- BACKGROUND: After acute coronary syndrome (ACS), patients with a previous myocardial infarction (MI) may be at particularly high risk for major adverse cardiovascular events (MACE) and death. We studied the effects of the PCSK9 inhibitor alirocumab in patients with recent ACS according to previous history of MI.METHODS: The ODYSSEY OUTCOMES trial compared alirocumab with placebo, beginning 1 to 12 months after ACS with median 2.8-year follow-up. The primary MACE outcome comprised death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, and hospitalization for unstable angina. Of 18,924 patients, 3633 (19.2%) had previous MI.RESULTS: Patients with previous MI were older, more likely male, with more cardiovascular risk factors and previous events. With placebo, 4-year risks of MACE and death were higher among those with vs without previous MI (20.5% vs 8.9%, P < 0.001; 7.4% vs 3.4%, P < 0.001, respectively). Alirocumab reduced the risk of events regardless of the presence or absence of a history of MI (MACE, adjusted hazard ratio [aHR] 0.90, 95% confidence interval [CI], 0.78-1.05 vs 0.82, 0.73-0.92; Pinteraction = 0.34; death, aHR 0.84; 95% CI, 0.64-1.08 vs 0.87, 0.72-1.05; Pinteraction = 0.81). Estimated absolute risk reductions with alirocumab were numerically greater with vs without previous MI (MACE, 1.91% vs 1.42%; death, 1.35% vs 0.41%).CONCLUSIONS: A previous history of MI places patients with recent ACS at high risk for recurrent MACE and death. Alirocumab reduced the relative risks of these events consistently in patients with or without previous MI but with numerically greater absolute benefit in the former subgroup. (ODYSSEY OUTCOMES: NCT01663402).
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| 2. |
- Hagström, Emil, et al.
(author)
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Growth Differentiation Factor 15 Predicts All-Cause Morbidity and Mortality in Stable Coronary Heart Disease
- 2017
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In: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 63:1, s. 325-333
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Journal article (peer-reviewed)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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| 3. |
- Held, Claes, 1956-, et al.
(author)
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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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In: Journal of the American Heart Association. - 2047-9980 .- 2047-9980. ; 6:10
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Journal article (peer-reviewed)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.
(author)
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Biomarker-Based Risk Model to Predict Cardiovascular Mortality in Patients With Stable Coronary Disease
- 2017
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In: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 70:7, s. 813-826
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Journal article (peer-reviewed)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. |
- Marquis-Gravel, Guillaume, et al.
(author)
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Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI
- 2020
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 76:2, s. 162-171
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Journal article (peer-reviewed)abstract
- BACKGROUND The long-term prognostic impact of post-discharge bleeding in the unique population of patients with acute coronary syndrome (ACS) treated without percutaneous coronary intervention (PCI) remains unexplored.OBJECTIVES The aim of this study was to assess the association between post-discharge bleeding and subsequent mortality after ACS according to index strategy (PCI or no PCI) and to contrast with the association between post-discharge myocardial infarction (MI) and subsequent mortality.METHODS In a harmonized dataset of 4 multicenter randomized trials (APPRAISE-2 [Apixaban for Prevention of Acute Ischemic Events-2], PLATO [Study of Platelet Inhibition and Patient Outcomes], TRACER [Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome], and TRILOGY ACS [Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes]), the association between post-discharge noncoronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate, severe, or life-threatening bleeding (landmark 7 days post-ACS) and subsequent all-cause mortality was evaluated in a time-updated Cox proportional hazards analysis. Interaction with index treatment strategy was assessed. Results were contrasted with risk for mortality following post-discharge MI.RESULTS Among 45,011 participants, 1,133 experienced post-discharge bleeding events (2.6 per 100 patient-years), and 2,149 died during follow-up. The risk for mortality was significantly higher <30 days (adjusted hazard ratio: 15.7; 95% confidence interval: 12.3 to 20.0) and 30 days to 12 months (adjusted hazard ratio: 2.7; 95% confidence interval: 2.1 to 3.4) after bleeding, and this association was consistent in participants treated with or without PCI for their index ACS (p for interaction = 0.240). The time-related association between post-discharge bleeding and mortality was similar to the association between MI and subsequent mortality in participants treated with and without PCI (p for interaction = 0.696).CONCLUSIONS Post-discharge bleeding after ACS is associated with a similar increase in subsequent all-cause mortality in participants treated with or without PCI and has an equivalent prognostic impact as post-discharge MI.
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| 6. |
- Schwartz, Gregory G, et al.
(author)
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Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment.
- 2021
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In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 44:5, s. 1219-1227
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Journal article (peer-reviewed)abstract
- OBJECTIVE: In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor.RESEARCH DESIGN AND METHODS: In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data.RESULTS: Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02-1.06, P < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85-1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment-baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03-1.12; P = 0.0002) for incident type 2 diabetes.CONCLUSIONS: In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.
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| 7. |
- Stewart, Ralph A. H., et al.
(author)
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Physical Activity and Mortality in Patients With Stable Coronary Heart Disease
- 2017
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In: Journal of the American College of Cardiology. - : ELSEVIER SCIENCE INC. - 0735-1097 .- 1558-3597. ; 70:14, s. 1689-1700
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Journal article (peer-reviewed)abstract
- BACKGROUND Recommendations for physical activity in patients with stable coronary heart disease (CHD) are based on modest evidence.OBJECTIVES The authors analyzed the association between self-reported exercise and mortality in patients with stable CHD.METHODS A total of 15,486 patients from 39 countries with stable CHD who participated in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) study completed questions at baseline on hours spent each week taking mild, moderate, and vigorous exercise. Associations between the volume of habitual exercise in metabolic equivalents of task hours/week and adverse outcomes during a median follow-up of 3.7 years were evaluated.RESULTS A graded decrease in mortality occurred with increased habitual exercise that was steeper at lower compared with higher exercise levels. Doubling exercise volume was associated with lower all-cause mortality (unadjusted hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.79 to 0.85; adjusting for covariates, HR: 0.90; 95% CI: 0.87 to 0.93). These associations were similar for cardiovascular mortality (unadjusted HR: 0.83; 95% CI: 0.80 to 0.87; adjusted HR: 0.92; 95% CI: 0.88 to 0.96), but myocardial infarction and stroke were not associated with exercise volume after adjusting for covariates. The association between decrease in mortality and greater physical activity was stronger in the subgroup of patients at higher risk estimated by the ABC-CHD (Age, Biomarkers, Clinical-Coronary Heart Disease) risk score (p for interaction = 0.0007).CONCLUSIONS In patients with stable CHD, more physical activity was associated with lower mortality. The largest benefits occurred between sedentary patient groups and between those with the highest mortality risk.
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| 8. |
- Stewart, Ralph A H, et al.
(author)
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Self-Reported Health and Outcomes in Patients With Stable Coronary Heart Disease
- 2017
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In: Journal of the American Heart Association. - 2047-9980 .- 2047-9980. ; 6:8
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Journal article (peer-reviewed)abstract
- Background-—The major determinants and prognostic importance of self-reported health in patients with stable coronary heartdisease are uncertain.Methods and Results-—The STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trialrandomized 15 828 patients with stable coronary heart disease to treatment with darapladib or placebo. At baseline, 98% ofparticipants completed a questionnaire that included the question, “Overall, how do you feel your general health is now?”Possible responses were excellent, very good, good, average, and poor. Adjudicated major adverse cardiac events, whichincluded cardiovascular death, myocardial infarction, and stroke, were evaluated by Cox regression during 3.7 years of follow-upfor participants who reported excellent or very good health (n=2304), good health (n=6863), and average or poor health(n=6361), before and after adjusting for 38 covariates. Self-reported health was most strongly associated with geographicregion, depressive symptoms, and low physical activity (P<0.0001 for all). Poor/average compared with very good/excellentself-reported health was independently associated with major adverse cardiac events (hazard ratio [HR]: 2.30 [95% confidenceinterval (CI), 1.92–2.76]; adjusted HR: 1.83 [95% CI, 1.51–2.22]), cardiovascular mortality (HR: 4.36 [95% CI, 3.09–6.16];adjusted HR: 2.15 [95% CI, 1.45–3.19]), and myocardial infarction (HR: 1.87 [95% CI, 1.46–2.39]; adjusted HR: 1.68 [95% CI,1.25–2.27]; P<0.0002 for all).Conclusions-—Self-reported health is strongly associated with geographical region, mood, and physical activity. In a globalcoronary heart disease population, self-reported health was independently associated with major cardiovascular events andmortality beyond what is measurable by established risk indicators.
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| 9. |
- Vedin, Ola, et al.
(author)
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Associations between tooth loss and prognostic biomarkers and the risk for cardiovascular events in patients with stable coronary heart disease
- 2017
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In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 245, s. 271-276
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Journal article (peer-reviewed)abstract
- Background:Underlying mechanisms behind the hypothesized relationship between periodontal disease (PD) and coronary heart disease (CHD) have been insufficiently explored. We evaluated associations between self-reported tooth loss-a marker of PD- and prognostic biomarkers in 15,456 (97%) patients with stable CHD in the global STABILITY trial.Methods and results:Baseline blood samples were obtained and patients reported their number of teeth according to the following tooth loss levels: "26-32 (All)" [lowest level], "20-25", "15-19", "1-14", and "No Teeth" [highest level]. Linear and Cox regression models assessed associations between tooth loss levels and biomarker levels, and the relationship between tooth loss levels and outcomes, respectively.After multivariable adjustment, the relative biomarker increase between the highest and the lowest tooth loss level was: high-sensitivity C-reactive protein 1.21 (95% confidence interval, 1.14-1.29), interleukin 6 1.14 (1.10-1.18), lipoprotein-associated phospholipase A(2) activity 1.05 (1.03-1.06), growth differentiation factor 15 1.11 (1.08-1.14), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) 1.18 (1.11-1.25). No association was detected for high-sensitivity troponin T 1.02 (0.98-1.05). Some attenuation of the relationship between tooth loss and outcomes resulted from the addition of biomarkers to the multivariable analysis, of which NT-proBNP had the biggest impact.Conclusions:A graded and independent association between tooth loss and several prognostic biomarkers was observed, suggesting that tooth loss and its underlying mechanisms may be involved in multiple pathophysiological pathways also implicated in the development and prognosis of CHD. The association between tooth loss and cardiovascular death and stroke persisted despite comprehensive adjustment including prognostic biomarkers.
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| 10. |
- Vidal-Petiot, Emmanuelle, et al.
(author)
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Visit-to-visit variability of blood pressure and cardiovascular outcomes in patients with stable coronary heart disease. Insights from the STABILITY trial
- 2017
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In: European Heart Journal. - : OXFORD UNIV PRESS. - 0195-668X .- 1522-9645. ; 38:37, s. 2813-2822
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Journal article (peer-reviewed)abstract
- Aims To study the relation between visit-to-visit variability of blood pressure (BP) and cardiovascular risk in patients with stable coronary heart disease. Methods and results In 15 828 patients from the STABILITY trial (darapladib vs. placebo in patients with established coronary heart disease), BP variability was assessed by the standard deviation (SD) of systolic BP, the SD of diastolic BP, maximum BP, and minimum BP, from 5 measurements (baseline and months 1, 3, 6, and 12) during the first year after randomisation. Mean (SD) average BP during the first year of study was 131.0 (13.7) mmHg over 78.3 (8.3) mmHg. Mean (SD) of the visit-to-visit SD was 9.8 (4.8) mmHg for systolic and 6.3 (3.0) mmHg for diastolic BP. During the subsequent median follow-up of 2.6 years, 1010 patients met the primary endpoint, a composite of time to cardiovascular death, myocardial infarction, or stroke. In Cox regression models adjusted for average BP during first year of study, baseline vascular disease, treatment, renal function and cardiovascular risk factors, the primary endpoint was associated with SD of systolic BP (hazard ratio for highest vs. lowest tertile, 1.30, 95% CI 1.10-1.53, P = 0.007), and with SD of diastolic BP (hazard ratio for highest vs. lowest tertile, 1.38, 95% CI 1.18-1.62, P < 0.001). Peaks and troughs in BP were also independently associated with adverse events. Conclusion In patients with stable coronary heart disease, higher visit-to-visit variabilities of both systolic and diastolic BP are strong predictors of increased risk of cardiovascular events, independently of mean BP.
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