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| 2. |
- Collier, T. J., et al.
(författare)
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The impact of eplerenone at different levels of risk in patients with systolic heart failure and mild symptoms: insight from a novel risk score for prognosis derived from the EMPHASIS-HF trial
- 2013
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 34:36, s. 2823-2829
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Our objective was to create a simple prognostic risk score for patients with systolic heart failure and mild symptoms. We then assessed the efficacy of eplerenone across different categories of risk. METHODS AND RESULTS: The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure trial (EMPHASIS-HF) was an international randomized trial, comparing eplerenone with placebo in 2737 patients with systolic heart failure and mild symptoms. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure, over a median 2.1 years follow-up. Using multivariable Cox modelling age, sex, systolic blood pressure, estimated glomerular filtration rate, diabetes, BMI, haemoglobin, prior heart failure (HF) hospitalization, prior myocardial infarction/coronary artery bypass surgery (CABG), and heart rate were identified as strong independent risk factors. Estimates from the model were converted into a simple integer risk score which was categorized into three groups of low-, medium-, and high risk. In placebo patients, the rates (per 100 patient-years) for the primary outcome were 7.6, 19.0, and 39.4 in the low-, medium-, and high-risk groups, respectively. On eplerenone, these rates were reduced to 5.6, 12.2, and 24.2, respectively. Eplerenone was beneficial across all risk categories and the hazard ratios were similar. The absolute treatment benefit was greatest among those at highest risk. Similar patterns emerged for all-cause mortality and for all HF hospitalizations. CONCLUSION: This easy-to-use integer risk score should be of value in quantifying individual patient risk in patients with systolic HF and mild symptoms. The relative benefits of eplerenone appeared consistent across the whole spectrum of risk, including those at lower risk.
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| 3. |
- Garcia-Reitboeck, P., et al.
(författare)
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Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis
- 2018
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 24:9, s. 2300-2311
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Tidskriftsartikel (refereegranskat)abstract
- Dysfunction of microglia, the brain's immune cells, is linked to neurodegeneration. Homozygous missense mutations in TREM2 cause Nasu-Hakola disease (NHD), an early-onset dementia. To study the consequences of these TREM2 variants, we generated induced pluripotent stem cell-derived microglia-like cells (iPSC-MGLCs) from patients with NHD caused by homozygous T66M or W50C missense mutations. iPSC-MGLCs expressed microglial markers and secreted higher levels of TREM2 than primary macrophages. TREM2 expression and secretion were reduced in variant lines. LPS-mediated cytokine secretion was comparable between control and TREM2 variant iPSC-MGLCs, whereas survival was markedly reduced in cells harboring missense mutations when compared with controls. Furthermore, TREM2 missense mutations caused a marked impairment in the phagocytosis of apoptotic bodies, but not in Escherichia coli or zymosan substrates. Coupled with changes in apoptotic cell-induced cytokine release and migration, these data identify specific deficits in the ability of iPSC-MGLCs harboring TREM2 missense mutations to respond to specific pathogenic signals.
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| 4. |
- Sprigg, N, et al.
(författare)
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Intravenous tranexamic acid for hyperacute primary intracerebral hemorrhage: Protocol for a randomized, placebo-controlled trial
- 2016
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Ingår i: International journal of stroke : official journal of the International Stroke Society. - : SAGE Publications. - 1747-4949. ; 11:6, s. 717-723
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Tidskriftsartikel (refereegranskat)abstract
- Outcome after intracerebral hemorrhage remains poor. Tranexamic acid is easy to administer, readily available, inexpensive, and effective in other hemorrhagic conditions. Aim This randomized trial aims to test the hypothesis that intravenous tranexamic acid given within 8 h of spontaneous intracerebral hemorrhage reduces death or dependency. Design Phase III prospective double-blind randomized placebo-controlled trial. Participants within 8 h of spontaneous intracerebral hemorrhage are randomized to receive either intravenous tranexamic acid 1 g 10 min bolus followed by 1 g 8 h infusion, or placebo. Sample size estimates A trial of 2000 participants (300 from start-up phase and 1700 from main phase) will have 90% power to detect an ordinal shift of the modified Rankin Scale with odds ratio 0.79. Study outcomes The primary outcome is death or dependency measured by ordinal shift analysis of the 7 level mRS at day 90. Secondary outcomes are neurological impairment at day 7 and disability, quality of life, cognition, and mood at day 90. Safety outcomes are death, serious adverse events, thromboembolic events, and seizures. Cost outcomes are length of stay in hospital, readmission, and institutionalization. Discussion This pragmatic trial is assessing efficacy of tranexamic acid after spontaneous intracerebral hemorrhage. Recruitment started in 2013; as of 15th January 2016 1355 participants have been enrolled, from 95 centers in seven countries. Recruitment is due to end in 2017. TICH-2 Trial is registered as ISRCTN93732214.
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| 5. |
- Cannon, J. A., et al.
(författare)
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Clinical outcomes according to QRS duration and morphology in the Eplerenone in Mild Patients: Hospitalization and SurvIval Study in Heart Failure (EMPHASIS-HF)
- 2015
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842. ; 17:7, s. 707-716
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Tidskriftsartikel (refereegranskat)abstract
- AimsWe examined the relationship between different degrees of QRS prolongation and different QRS morphologies and clinical outcomes in patients with heart failure, reduced ejection fraction (HF-REF), and mild symptoms in the Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure trial (EMPHASIS-HF). We also evaluated the effect of eplerenone in these patients according to QRS duration/morphology. Methods and resultsPatients were categorized as: QRS duration (ms) (i) <120 (n = 1375); (ii) 120-149 (n = 517); and (iii) 150 (n = 383), and QRS morphology (i) normal (n = 1252); (ii) left bundle branch block (BBB) (n = 608); and (iii) right BBB/intraventricular conduction defect (IVCD) (n = 415). The outcomes examined were the composite of cardiovascular death or heart failure hospitalization and all-cause mortality. Both abnormal QRS duration and QRS morphology were associated with higher risk, e.g. the rates of the composite outcome were: 10.2, 17.6, and 15.5 per 100 patient-years in the <120, 120-149, and 150ms groups, respectively. Eplerenone reduced the risk of the primary outcome and mortality, compared with placebo, consistently across the QRS duration/morphology subgroups. ConclusionWe found that even moderate prolongation of QRS duration and right BBB/IVCD were associated with a high risk of adverse outcomes in HF-REF. Eplerenone was similarly effective, irrespective of QRS duration/morphology.
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| 6. |
- Chin, K. L., et al.
(författare)
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Aspirin does not reduce the clinical benefits of the mineralocorticoid receptor antagonist eplerenone in patients with systolic heart failure and mild symptoms: an analysis of the EMPHASIS-HF study
- 2016
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 18:9, s. 1175-1181
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: It is not known whether concomitant use of aspirin might attenuate the beneficial effects of mineralocorticoid receptor antagonists (MRAs). The purpose of this subgroup analysis was to explore the interaction between baseline aspirin treatment and the effect of eplerenone on the primary efficacy outcomes (composite of hospitalization for heart failure or cardiovascular mortality), its components, and safety markers [estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP), and serum potassium >5.5 mmol/L] in the Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure trial (EMPHASIS-HF). METHODS AND RESULTS: Patients with chronic heart failure, reduced ejection fraction (HFREF), and mild symptoms were enrolled in EMPHASIS-HF. We evaluated baseline characteristics according to aspirin use. We explored the interaction between aspirin and eplerenone, using Cox proportional hazards models providing adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) and P-values for interaction. Of the 2737 patients randomized, 1605 patients (58.6%) were taking aspirin. The beneficial effects of eplerenone on the primary endpoint were similar in patients not treated (adjusted HR 0.59, 95% CI 0.46-0.75) or treated (adjusted HR 0.71, 95% CI 0.59-0.87) with aspirin at baseline (interaction P-value = 0.19). We did not observe any significant modification of the safety markers by aspirin that was clinically meaningful. CONCLUSION: Aspirin use in patients with chronic systolic heart failure and mild symptoms did not substantially reduce the overall beneficial effects of the MRA eplerenone contrary to what has been described in some studies with ACE inhibitors.
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| 7. |
- Girerd, N., et al.
(författare)
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Clinical benefits of eplerenone in patients with systolic heart failure and mild symptoms when initiated shortly after hospital discharge: analysis from the EMPHASIS-HF trial
- 2015
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 36:34, s. 2310-2317
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Tidskriftsartikel (refereegranskat)abstract
- Aims Cardiovascular hospitalization (CVH) in patients with heart failure (HF) is associated with a high post-discharge rate of early re-admission and CV death. Eplerenone might be effective in reducing the incidence of these adverse clinical outcomes during this period. Methods and results The EMPHASIS-HF trial compared eplerenone with placebo added to standard therapy in 2737 patients with New York Heart Association class II HF and left ventricular ejection fraction <= 35%. We conducted a post hoc analysis in the 2338 patients randomized within 180 days of a CVH. The interaction between the time from the qualifying CVH to randomization and the primary outcome of CV death or hospitalization for HF (HHF), as well as other secondary outcomes, was assessed in Cox survival models. Most of the qualifying CVHs were HHF (N = 1496, 64.0%), acute coronary syndromes (N = 390, 16.7%), and arrhythmias (N = 197, 7.2%). The median time of study drug initiation from qualifying CVH was 42 days. The relative rate reductions in CV death/HHF, HHF, and all-cause mortality were similar (P for interaction = 0.65, 0.44, and 0.40, respectively) whether the treatment was initiated <42 or 42+ days after qualifying CVH. Absolute rate reductions were -5.61 [-8.67, -2.55] events per 100 patient x years in the <42 days group and -3.58 [-6.37, -0.79] in the 42+ days group. The adverse effects of eplerenone were also unaffected by the time from the qualifying CVH. Conclusion Eplerenone is safe, improves survival, and may prevent re-admission when initiated soon after a hospitalization for HF or acute coronary syndromes in patients with systolic HF and mild symptoms.
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| 8. |
- Pocock, T H, et al.
(författare)
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Susceptibility to low-temperature photoinhibition and the acquisition of freezing tolerance in winter and spring wheat : The role of growth temperature and irradiance
- 2001
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Ingår i: Physiologia Plantarum. - 0031-9317 .- 1399-3054. ; 113:4, s. 499-506
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Tidskriftsartikel (refereegranskat)abstract
- Five winter and five spring wheat (Triticum aestivum L.) cultivars were grown under either control conditions (20 degreesC/250 photosynthetic photon flux density (PPFD) [mu mol m(-2) s(-1)]), high irradiance (20 degreesC/800 PPFD) or at low temperature (either 5 degreesC/250 PPFD or 5 degreesC/50 PPFD). To eliminate any potential bias, the wheat cultivars were arbitrarily chosen without any previous knowledge of their freezing tolerance or photosynthetic competence. We show that the differential susceptibilities to photoinhibition exhibited between spring and winter wheat cultivars, as assessed by chlorophyll fluorescence cannot be explained on the basis of either growth irradiance or low growth temperature per se. The role of excitation pressure is discussed. We assessed the correlation between susceptibility to low-temperature photoinhibition, maximum ribulose 1,5-bisphosphate carboxylase-oxygenase (EC 4.1.1.39) and NADP-dependent malate dehydrogenase (EC 1.1.1.82) activities, chlorophyll and protein concentrations and freezing tolerance determined by electrolyte leakage. Susceptibility to photoinhibition is the only parameter examined that is strongly and negatively correlated with freezing tolerance. We suggest that the assessment of susceptibility to photoinhibition may be a useful predictor of freezing tolerance and field survival of cereals.
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| 9. |
- Poulter, N. R., et al.
(författare)
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Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)
- 2005
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Ingår i: Lancet. - 1474-547X. ; 366:9489, s. 907-13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Results of the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) show significantly lower rates of coronary and stroke events in individuals allocated an amlodipine-based combination drug regimen than in those allocated an atenolol-based combination drug regimen (HR 0.86 and 0.77, respectively). Our aim was to assess to what extent these differences were due to significant differences in blood pressures and in other variables noted after randomisation. METHODS: We used data from ASCOT-BPLA (n=19 257) and compared differences in accumulated mean blood pressure levels at sequential times in the trial with sequential differences in coronary and stroke events. Serial mean matching for differences in systolic blood pressure was used to adjust HRs for differences in these events. We used an updated Cox-regression model to assess the effects of differences in accumulated mean levels of various measures of blood pressure, serum HDL-cholesterol, triglycerides and potassium, fasting blood glucose, heart rate, and bodyweight on differences in event rates. FINDINGS: We noted no temporal link between size of differences in blood pressure and different event rates. Serial mean matching for differences in systolic blood-pressure attenuated HRs for coronary and stroke events to a similar extent as did adjustments for systolic blood-pressure differences in Cox-regression analyses. HRs for coronary events and stroke adjusted for blood pressure rose from 0.86 (0.77-0.96) to 0.88 (0.79-0.98) and from 0.77 (0.66-0.89) to 0.83 (0.72-0.96), respectively. Multivariate adjustment gave HRs of 0.94 (0.81-1.08) for coronary events (HDL cholesterol being the largest contributor) and 0.87 (0.73-1.05) for stroke events. INTERPRETATION: Multivariate adjustment accounted for about half of the differences in coronary events and for about 40% of the differences in stroke events between the treatment regimens tested in ASCOT-BPLA, but residual differences were no longer significant. These residual differences could indicate inadequate statistical adjustment, but it remains possible that differential effects of the two treatment regimens on other variables also contributed to the different rates noted, particularly for stroke.
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| 10. |
- Zannad, F., et al.
(författare)
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Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document
- 2013
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 15:10, s. 1082-1094
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Tidskriftsartikel (refereegranskat)abstract
- Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all-cause mortality, cause-specific mortality, relevant non-fatal morbidity (e.g. all-cause and cause-specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient-reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA-ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12-13 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the group's recommendations for achieving common views on heart failure endpoints in clinical trials.
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