| 1. |
- White, Harvey D, et al.
(författare)
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Darapladib for preventing ischemic events in stable coronary heart disease
- 2014
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 370:18, s. 1702-1711
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2.METHODS:In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization).RESULTS:During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02).CONCLUSIONS:In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).
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| 2. |
- White, Harvey D., et al.
(författare)
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Survival with Cardiac-Resynchronization Therapy in Mild Heart Failure
- 2014
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 370:18, s. 1702-1711
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Tidskriftsartikel (refereegranskat)abstract
- Background: Elevated lipoprotein-associated phospholipase A(2) activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A(2). Methods: In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization). Results: During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02). ConclusionsIn patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.)
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| 3. |
- Jander, Nikolaus, et al.
(författare)
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Outcome of Patients With Low-Gradient "Severe" Aortic Stenosis and Preserved Ejection Fraction
- 2011
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Ingår i: Circulation. - 1524-4539 .- 0009-7322. ; 123:8, s. 887-895
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Tidskriftsartikel (refereegranskat)abstract
- Background-Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area <1.0 cm(2) and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient "severe" stenosis (defined as aortic valve area < 1.0 cm(2) and mean gradient <= 40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Methods and Results-Outcome in patients with low-gradient "severe" aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm(2); mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67 +/- 10 years; ejection fraction, >= 55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182 +/- 64 versus 212 +/- 68 g; P < 0.01). During 46 months of follow-up, aortic valve events occurred in 48.5% versus 44.6%, respectively (P=0.37; major cardiovascular events, 50.9% versus 48.5%, P=0.58; cardiovascular death, 7.8% versus 4.9%, P=0.19). Low-gradient severe stenosis patients with reduced stroke volume index (<= 35 mL/m(2); n=223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P=0.53). Conclusions-Patients with low-gradient "severe" aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis. (Circulation. 2011;123:887-895.)
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| 4. |
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| 5. |
- Green, Anders, et al.
(författare)
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Incidence of Cancer and Mortality in Patients from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) Trial.
- 2014
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Ingår i: American Journal of Cardiology. - : Elsevier BV. - 1879-1913 .- 0002-9149. ; 114:10, s. 1518-1522
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Tidskriftsartikel (refereegranskat)abstract
- The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) clinical trial, including 1,873 patients found an increased risk for cancer with lipid-lowering therapy with ezetimibe/simvastatin 10/40 mg/day, relative to placebo. In a registry-based follow-up study over 21 months from the conclusion of the SEAS trial, new incident cancer and total mortality were investigated in the SEAS study cohort from Denmark, Finland, Norway, Sweden, and the United Kingdom. Among 1,359 subjects eligible for follow-up (73% of the original total cohort), 1,194 had no history of cancer (primary follow-up cohort). New cancers and deaths were identified in the national cancer and mortality registries and classified by an Expert Review Committee. Data were analyzed using Cox proportional-hazards models of new cancers and mortality during follow-up according to treatment group assigned in the SEAS base study and with age, gender, smoking history, and previous cancers as covariates. The primary follow-up cohort had 12 patients with new cancers in the ezetimibe/simvastatin group and 22 in the placebo group (hazard ratio 0.55, 95% confidence interval 0.27 to 1.11), indicating no significant difference between the treatment groups. During follow-up, 43 patients assigned to ezetimibe/simvastatin and 33 assigned to placebo died (hazard ratio 1.29, 95% confidence interval 0.82 to 2.03). In conclusion, in this registry-based observational follow-up study of the original SEAS study patient population, treatment with ezetimibe/simvastatin was not associated with an increased risk for cancer or mortality in the 21-month period after the completion of the original SEAS study.
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| 6. |
- Greve, Anders M., et al.
(författare)
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Prognostic importance of atrial fibrillation in asymptomatic aortic stenosis: The Simvastatin and Ezetimibe in Aortic Stenosis study
- 2013
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 166:1, s. 72-76
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Tidskriftsartikel (refereegranskat)abstract
- Background: The frequency and prognostic importance of atrial fibrillation (AF) in asymptomatic mild-to-moderate aortic stenosis (AS) has not been well described. Methods: Clinical examination, electrocardiography and echocardiography were obtained in asymptomatic patients with mild-to-moderate AS and preserved left ventricular (LV) systolic function, randomized to simvastatin/ezetimibe combination vs. placebo in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. At inclusion, AF was categorized as episodic or longstanding. Rhythm change was assessed on annual in-study electrocardiograms. Impact of AF on cardiovascular morbidity and mortality was determined by adjusting for biomarkers, clinical- and echocardiographic covariates. Results: Mean follow-up was 4.3 +/- 0.8 years (6,721 patient-years of follow-up). At baseline, episodic AF was present in 87 patients (5.6%), longstanding AF in 55 (3.5%) and no AF in 1,421 (90.9%). Incidence of new-onset AF was 1.2%/year; highest in those with impaired LV function. In multivariable analysis, longstanding AF was compared to no AF at baseline, associated with a 4.1-fold higher risk of heart failure (CI 1.2 to 13.8, p = 0.02) and a 4.8-fold higher risk of non-hemorrhagic stroke (CI 1.7 to 13.6, p = 0.003). Conclusion: Rate of AF is moderate in asymptomatic AS. Longstanding but not episodic AF was, independently predictive of increased risk of heart failure and non-hemorrhagic stroke. New-onset AF was associated with cardiac decompensation. (c) 2011 Elsevier Ireland Ltd. All rights reserved.
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| 7. |
- Holme, Ingar, et al.
(författare)
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A risk score for predicting mortality in patients with asymptomatic mild to moderate aortic stenosis
- 2012
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Ingår i: Heart. - : BMJ Publishing Group Ltd & British Cardiovascular Society. - 1355-6037 .- 1468-201X. ; 98:5, s. 377-383
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Tidskriftsartikel (refereegranskat)abstract
- Background Prognostic information for asymptomatic patients with aortic stenosis (AS) from prospective studies is scarce and there is no risk score available to assess mortality. Objectives To develop an easily calculable score, from which clinicians could stratify patients into high and lower risk of mortality, using data from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Method A search for significant prognostic factors (p < 0.01) among SEAS patients was made by a combined judgemental and statistical elimination procedure to derive a set of three factors (age, gender and smoking) that were forced into the model, and four additional factors captured by the data: left-ventricular mass index, bilirubin, heart rate and natural logarithm of C reactive protein. Calibration was done by comparing observed with calculated number of deaths by tenths of calculated risk using coefficients from the simvastatin + ezetimibe group on placebo group patients. Results Discrimination was good with ROC area of 0.76 for all patients. Estimated probabilities of death were categorised into thirds. An optimised split point of estimated 5-year risk was about 15% (close to the upper 14% tertile split point), with risk 4 times as high in the upper compared to the two lower thirds. The SEAS score performed better than another established high risk score developed for other purposes. Conclusion A new seven factor model for risk stratification of patients with mild to moderate asymptomatic AS identified a high risk group for total mortality with good discrimination properties. Trial registration number ClinicalTrials.gov, NCT 00092677.
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| 8. |
- Holme, Ingar, et al.
(författare)
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Observed and predicted reduction of ischemic cardiovascular events in the Simvastatin and Ezetimibe in Aortic Stenosis trial.
- 2010
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Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149 .- 1879-1913. ; 105:12, s. 1802-1808
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Tidskriftsartikel (refereegranskat)abstract
- In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, combined ezetimibe (10 mg) and simvastatin (40 mg) decreased low-density lipoprotein cholesterol levels by 50% and ischemic cardiovascular event (ICE) risk by 22% compared to placebo. A larger decrease in ICE risk might have been expected for the degree of lipid-lowering observed. This analysis investigated relations between changes in lipoprotein components (LCs), and ICE risk decrease in the SEAS trial in all patients, by severity of aortic stenosis (AS), and compared to results of other clinical trials. A total of 1,570 patients with baseline aortic jet velocity (JV) data, baseline and 1-year low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B, and no ICEs during the first year were included in the analysis. Relations between on-treatment measurements of 1-year LCs and time-to-ICE occurrence were assessed in all patients and in JV tertiles (<2.8, 2.8 to 3.3, and >3.3 m/s). Observed and predicted ICE risk decreases were compared by Cox model. Decreases in LCs after 1 year of ezetimibe plus simvastatin were associated with decreased ICE risk in all patients and in the 2 lower JV tertiles (p <0.05 to <0.001) but not in tertile 3. In JV tertiles 1 and 2, ICE risk decreased by 47% and 36%, respectively, was reasonably well predicted by all LCs, and was consistent with findings from meta-regression analyses in other populations. In conclusion, the degree of lipid lowering by ezetimibe plus simvastatin may predict the extent of ICE risk decrease in patients with mild AS, but ICE risk prediction in patients with more severe AS is confounded by AS-associated cardiovascular events and a shorter interval of exposure to lipid lowering.
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| 9. |
- Jander, Nikolaus, et al.
(författare)
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Indexing aortic valve area by body surface area increases the prevalence of severe aortic stenosis
- 2014
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 100:1, s. 28-33
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Tidskriftsartikel (refereegranskat)abstract
- Background To account for differences in body size in patients with aortic stenosis, aortic valve area (AVA) is divided by body surface area (BSA) to calculate indexed AVA (AVA(index)). Cut-off values for severe stenosis are <1.0cm(2) for AVA and <0.6cm(2)/m(2) for AVA(index). Objective To investigate the influence of indexation on the prevalence of severe aortic stenosis and on the predictive accuracy regarding clinical outcome. Methods Echocardiographic and anthropometric data from a retrospective cohort of 2843 patients with aortic stenosis (jet velocity >2.5m/s) and from 1525 patients prospectively followed in the simvastatin and ezetimibe in aortic stenosis (SEAS) trial were analysed. Results The prevalence of severe stenosis increased with the AVA(index) criterion compared to AVA from 71% to 80% in the retrospective cohort, and from 29% to 44% in SEAS (both p<0.001). Overall, the predictive accuracy for aortic valve events was virtually identical for AVA and AVA(index) in the SEAS population (mean follow-up of 46months; area under the receiver operating characteristic curve: 0.67 (95% CI 0.64 to 0.70) vs 0.68 (CI 0.65 to 0.71) (NS). However, 213 patients additionally categorised as severe by AVA(index) experienced significantly less valve related events than those fulfilling only the AVA criterion (p<0.001). Conclusions Indexing AVA by BSA (AVA(index)) significantly increases the prevalence of patients with criteria for severe stenosis by including patients with a milder degree of the disease without improving the predictive accuracy for aortic valve related events.
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| 10. |
- Jander, Nikolaus, et al.
(författare)
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Velocity ratio predicts outcomes in patients with low gradient severe aortic stenosis and preserved EF
- 2014
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 100:24, s. 1946-1953
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate the usefulness of velocity ratio (VR) in patients with low gradient severe aortic stenosis (LGSAS) and preserved EF.Background LGSAS despite preserved EF represents a clinically challenging entity. Reliance on mean pressure gradient (MPG) may underestimate stenosis severity as has been reported in the context of paradoxical low flow, LGSAS. On the other hand, grading of stenosis severity by aortic valve area (AVA) may overrate stenosis severity due to erroneous underestimation of LV outflow tract (LVOT) diameter, small body size or inconsistencies in cut-off values for severe stenosis. We hypothesised that VR may have conceptual advantages over MPG and AVA, predict clinical outcomes and thereby be useful in the management of patients with LGSAS.Methods Patients from the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study with an AVA<1.0 cm(2), MPG <= 40 mm Hg and EF >= 55% and asymptomatic at baseline were stratified according to VR with a cut-off value of 0.25. Outcomes were evaluated according to aortic valve-related events and cardiovascular death.Results Of 435 patients with LGSAS, 197 (45%) had VR<0.25 suggesting severe and 238 (55%) had VR >= 0.25 suggesting non-severe stenosis. Aortic valve-related events (mean follow-up 42 +/- 14 months) were more frequent in patients with VR<0.25 (57% vs 41%; p<0.001) as was cardiovascular death within the first 24 months (p<0.05). In multivariable Cox regression analysis, MPG was the strongest independent predictor of aortic valve events (p<0.001) followed by VR (p<0.02). Adjusting AVA by VR increased predictive accuracy for aortic valve events (area under the receiver operating curve 0.62 (95% CI 0.57 to 0.67) vs 0.56 (95% CI 0.51 to 0.61) for AVA, p=0.02) with net reclassification improvement calculated at 0.36 (95% CI 0.17 to 0.54, p<0.001). VR did not improve the prediction of clinical events by MPG.Conclusions In the difficult setting of LGSAS, VR shows a strong association with valve-related events and - although not outperforming MPG-may be particularly useful in guiding clinical management.
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