| 1. |
- De Caterina, Raffaele, et al.
(author)
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New Oral Anticoagulants in Atrial Fibrillation and Acute Coronary Syndromes : ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease Position Paper
- 2012
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 59:16, s. 1413-1425
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Research review (peer-reviewed)abstract
- Until recently, vitamin K antagonists were the only available oral anticoagulants, but with numerous limitations that prompted the introduction of new oral anticoagulants targeting the single coagulation enzymes thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, and edoxaban) and given in fixed doses without coagulation monitoring. Here we review the pharmacology and the results of clinical trials with these new agents in stroke prevention in atrial fibrillation and secondary prevention after acute coronary syndromes, providing perspectives on their future incorporation into clinical practice. In phase III trials in atrial fibrillation, compared with warfarin, dabigatran etexilate 150 mg B.I.D. reduced the rates of stroke/systemic embolism without any difference in major bleeding; dabigatran etexilate 110 mg B.I.D. had similar efficacy with decreased bleeding; apixaban 5 mg B.I.D. reduced stroke, systemic embolism, and mortality as well as major bleeding; and rivaroxaban 20 mg Q.D. was noninferior to warfarin for stroke and systemic embolism without a difference in major bleeding. All these agents reduced intracranial hemorrhage. Edoxaban is currently being evaluated in a further large phase III trial. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischemia in patients with acute coronary syndromes who were mostly receiving dual antiplatelet therapy, with conflicting results on efficacy but consistent results for increased major bleeding. Overall, the new oral anticoagulants are poised to replace vitamin K antagonists for many patients with atrial fibrillation and may have a role after acute coronary syndromes. Although convenient to administer and manage, they present challenges that need to be addressed.
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| 2. |
- Eggers, Kai M, et al.
(author)
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Relations of growth-differentiation factor-15 to biomarkers reflecting vascular pathologies in a population-based sample of elderly subjects
- 2012
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In: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 72:1, s. 45-51
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Journal article (peer-reviewed)abstract
- Background. Growth-differentiation factor-15 (GDF-15) has recently emerged as a risk predictor in patients with cardiac diseases. GDF-15 is commonly related to cardiovascular risk factors, inflammatory activity and cardiac abnormalities. However, it is not clear whether it might be an indicator of vascular pathologies as well.Methods.Circulating levels of GDF-15 were measured in 1004 elderly community dwellers participating in the PIVUS study. The relations of GDF-15 to biomarkers of endothelial activation (E-selectin, P-selectin, ICAM-1, VCAM-1), extracellular matrix degradation (MMP-9, TIMP-1), coagulatory activity (D-dimer, von Willebrand factor, prothrombin fragment 1 + 2, factor VIIa), and fibrinolytic activity (PAI-1 activity, tPA-antigen) were assessed by multiple linear regressions.Results. The median GDF-15 level was 1135 ng/L. By linear correlation analysis, GDF-15 exhibited a moderate relation to von Willebrand factor (r = 0.30), and weak, albeit significant relations (r = 0.13-0.29) to E-selectin, P-selectin, ICAM-1, VCAM-1, MMP-9, TIMP-1, D-dimer, PAI-1 activity and tPA-antigen. The relations to the assessed biomarkers of endothelial activation, TIMP-1, D-dimer and von Willebrand factor remained significant applying multiple linear regression models adjusted for clinical covariates and echocardiographic data. There were no significant relations between GDF-15 and biomarkers solely reflecting coagulatory activity.Conclusions.In the elderly, GDF-15 reflects endothelial activation and vascular inflammation and thus, multiple pathways involved in the development and progression of atherosclerosis.
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| 3. |
- Armstrong, Paul W, et al.
(author)
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ST Elevation Acute Coronary Syndromes in PLATO : Insights from the ECG Substudy
- 2012
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In: Circulation. - 0009-7322 .- 1524-4539. ; 125:3, s. 514-521
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Journal article (peer-reviewed)abstract
- BACKGROUND: Ticagrelor, when compared with clopidogrel, reduced the 12-month risk of vascular death/myocardial infarction (MI) and stroke in patients with ST-elevation acute coronary syndromes (ST-E ACS) intended to undergo primary percutaneous coronary intervention (PCI) in the PLATelet inhibition and patient Outcomes (PLATO) trial. This pre-specified electrocardiogram (ECG) substudy explored whether ticagrelor's association with vascular death and MI within one year would be amplified by: 1) the extent of baseline ST shift; and 2) subsequently associated with less residual ST changes at hospital discharge. METHODS AND RESULTS: ECGs were evaluated centrally in a core laboratory in 3,122 ticagrelor- and 3,084 clopidogrel-assigned patients having at least 1mm ST-E in two contiguous leads as identified by site investigators on the qualifying ECG. Patients with greater ST-segment shift at baseline had higher rates of vascular death/MI within one year. Amongst those who also had an ECG at hospital discharge (n=4,798), patients with ≥50% ∑ST-deviation (∑ST-dev) resolution had higher event-free survival than those with incomplete resolution (6.4% vs. 8.8%, adjusted hazard ratio 0.69 (0.54-0.88), p=0.003). The extent of ∑ST-dev resolution was similar irrespective of treatment assignment. The benefit of ticagrelor versus clopidogrel on clinical events was consistent irrespective of the extent of baseline ∑ST-dev (p(interaction)=0.728). When stratified according to conventional times from symptom onset i.e. ≤3 hours, 3-6 hours, >6 hours, the extent of baseline ∑ST-dev declined progressively over time. As time from symptom onset increased beyond three hours, the benefit of ticagrelor appeared to be more pronounced; however, the interaction between time and treatment was not significant (p=0.175). CONCLUSIONS: Ticagrelor did not modify ∑ST-dev resolution at discharge nor was its benefit affected by the extent of baseline ∑ST-dev. These hypothesis-generating observations suggest that the main effects of ticagrelor may not relate to the rapidity or the completeness of acute reperfusion, but rather the prevention of recurrent vascular events by more powerful platelet inhibition or other mechanisms.
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| 4. |
- Cornel, Jan H., et al.
(author)
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Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes-Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial
- 2012
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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 164:3, s. 334-342
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Journal article (peer-reviewed)abstract
- Background Habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo. In the PLATO trial, ticagrelor compared to clopidogrel in patients with acute coronary syndromes (ACS) reduced the primary composite end point of vascular death, myocardial infarction and stroke, without increasing overall rates of major bleeding. We evaluated the results in relation to smoking habits.Methods Interactions between habitual smokers (n = 6678) and in ex/nonsmokers (n = 11,932) and the effects of randomized treatments on ischemic and bleeding outcomes were evaluated by Cox regression analyses.Results Habitual smokers had an overall lower risk profile and more often ST-elevation ACS. After adjustment for baseline imbalances, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 [95% CI, 1.07-1.94]); there were no significant associations with other ischemic or bleeding end points. The effects of ticagrelor compared to clopidogrel were consistent for all outcomes regardless of smoking status. Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 [95% CI, 0.68-1.00]) and ex/nonsmokers (adjusted HR, 0.89 [95% CI, 0.79-1.00]) (interaction P = .50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 [0.39-0.91]) and ex/nonsmokers (adjusted HR, 0.69 [95% CI, 0.45-1.07]) (interaction P = .61).Conclusions In patients hospitalized with ACS, habitual smoking is associated with a greater risk of subsequent stent thrombosis. The reduction of vascular death, myocardial infarction, stroke, and stent thrombosis by ticagrelor compared to clopidogrel is consistent regardless of smoking habits.
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| 5. |
- Damman, P., et al.
(author)
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Effects of age on long-term outcomes after a routine invasive or selective invasive strategy in patients presenting with non-ST segment elevation acute coronary syndromes : A collaborative analysis of individual data from the FRISC II - ICTUS - RITA-3 (FIR) trials
- 2012
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In: Heart. - : BMJ Publishing Group. - 1355-6037 .- 1468-201X. ; 98:3, s. 207-213
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Journal article (peer-reviewed)abstract
- Objective: To perform a patient-pooled analysis of a routine invasive versus a selective invasive strategy in elderly patients with non-ST segment elevation acute coronary syndrome. Methods: A meta-analysis was performed of patientpooled data from the FRISC IIeICTUSeRITA-3 (FIR) studies. (Un)adjusted HRs were calculated by Cox regression, with adjustments for variables associated with age and outcomes. The main outcome was 5-year cardiovascular death or myocardial infarction (MI) following routine invasive versus selective invasive management. Results: Regarding the 5-year composite of cardiovascular death or MI, the routine invasive strategy was associated with a lower hazard in patients aged 65-74 years (HR 0.72, 95% CI 0.58 to 0.90) and those aged ≥75 years (HR 0.71, 95% CI 0.55 to 0.91), but not in those aged less than65 years (HR 1.11, 95% CI 0.90 to 1.38), p=0.001 for interaction between treatment strategy and age. The interaction was driven by an excess of early MIs in patients less than65 years of age; there was no heterogeneity between age groups concerning cardiovascular death. The benefits were smaller for women than for men (p=0.009 for interaction). After adjustment for other clinical risk factors the HRs remained similar. Conclusion: The current analysis of the FIR dataset shows that the long-term benefit of the routine invasive strategy over the selective invasive strategy is attenuated in younger patients aged less than65 years and in women by the increased risk of early events which seem to have no consequences for long-term cardiovascular mortality. No other clinical risk factors were able to identify patients with differential responses to a routine invasive strategy. Trial registration: http://www.controlled-trials.com/ISRCTN82153174 (ICTUS), http://www.controlled-trials.com/ISRCTN07752711 (RITA-3).
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| 6. |
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| 7. |
- Damman, Peter, et al.
(author)
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Long-Term Cardiovascular Mortality after Procedure-Related or Spontaneous Myocardial Infarction in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome : A Collaborative Analysis of Individual Patient Data from the FRISC II, ICTUS, and RITA-3 Trials (FIR)
- 2012
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In: Circulation. - 0009-7322 .- 1524-4539. ; 125:4, s. 568-576
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Journal article (peer-reviewed)abstract
- BACKGROUND: To investigate the long-term prognostic impact of procedure-related and spontaneous myocardial infarction (MI) on cardiovascular mortality in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS AND RESULTS: Five-year follow-up after procedure-related or spontaneous MI was investigated in the individual patient-pooled dataset of the FRISC-II, ICTUS and RITA-3 (FIR) NSTE-ACS trials. The principal outcome was cardiovascular death up to 5 years of follow-up. Cumulative event rates were estimated with the Kaplan-Meier method, hazard ratios (HR) were calculated with time-dependent Cox proportional-hazards models. Adjustments were made for the variables associated with long-term outcomes. Of the 5467 patients, 212 endured a procedure-related MI within 6 months after enrolment. A spontaneous MI occurred in 236 patients within 6 months. The cumulative cardiovascular death rate was 5.2% in patients who endured a procedure-related MI and comparable to patients without a procedure-related MI (HR 0.66, 95%CI: 0.36-1.20, P=0.17). In patients who endured a spontaneous MI within 6 months, the cumulative cardiovascular death rate was 22.2% and higher than patients without a spontaneous MI (HR 4.52, 95%CI: 3.37-6.06, P<0.001). These HRs did not materially alter after risk adjustments. CONCLUSIONS: Five-year follow-up of NSTE-ACS patients from the three FIR trials showed no association between a procedure-related MI and long-term cardiovascular mortality. In contrast there was a substantially raised long-term mortality after a spontaneous MI.
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| 8. |
- Damman, Peter, et al.
(author)
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Timing of Angiography With a Routine Invasive Strategy and Long-Term Outcomes in Non-ST-Segment Elevation Acute Coronary Syndrome : A Collaborative Analysis of Individual Patient Data From the FRISC II (Fragmin and Fast Revascularization During Instability in Coronary Artery Disease), ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes), and RITA-3 (Intervention Versus Conservative Treatment Strategy in Patients With Unstable Angina or Non-ST Elevation Myocardial Infarction) Trials
- 2012
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In: JACC: Cardiovascular Interventions. - : Elsevier BV. - 1936-8798. ; 5:2, s. 191-199
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Journal article (peer-reviewed)abstract
- Objectives: This study sought to investigate long-term outcomes after early or delayed angiography in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS) undergoing a routine invasive management. Background The optimal timing of angiography in patients with nSTE-ACS is currently a topic for debate.Methods: Long-term follow-up after early (within 2 days) angiography versus delayed (within 3 to 5 days) angiography was investigated in the FRISC-II (Fragmin and Fast Revascularization During Instability in Coronary Artery Disease), ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes), and RITA-3 (Intervention Versus Conservative Treatment Strategy in Patients With Unstable Angina or Non-ST Elevation Myocardial Infarction) (FIR) nSTE-ACS patient-pooled database. The main outcome was cardiovascular death or myocardial infarction up to 5-year follow-up. Hazard ratios (HR) were calculated with Cox regression models. Adjustments were made for the FIR risk score, study, and the propensity of receiving early angiography using inverse probability weighting.Results: Of 2,721 patients originally randomized to the routine invasive arm, consisting of routine angiography and subsequent revascularization if suitable, 975 underwent early angiography and 1,141 delayed angiography. No difference was observed in 5-year cardiovascular death or myocardial infarction in unadjusted (HR: 1.06, 95% confidence interval [CI]: 0.79 to 1.42, p = 0.61) and adjusted (HR: 0.93, 95% CI: 0.75 to 1.16, p = 0.54) Cox regression models.Conclusions: In the FIR database of patients presenting with nSTE-ACS, the timing of angiography was not related to long-term cardiovascular mortality or myocardial infarction. (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes [ICTUS]; ISRCTN82153174. Intervention Versus Conservative Treatment Strategy in Patients With Unstable Angina or Non-ST Elevation Myocardial Infarction [the Third Randomised Intervention Treatment of Angina Trials (RITA-3)]; ISRCTN07752711)
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| 9. |
- Damman, Peter, et al.
(author)
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Usefulness of the Admission Electrocardiogram to Predict Long-Term Outcomes After Non-ST-Elevation Acute Coronary Syndrome (from the FRISC II, ICTUS, and RITA-3 [FIR] Trials)
- 2012
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In: American Journal of Cardiology. - : Elsevier BV. - 0002-9149 .- 1879-1913. ; 109:1, s. 6-12
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Journal article (peer-reviewed)abstract
- The aim of this study was to evaluate the independent prognostic value of qualitative and quantitative admission electrocardiographic (ECG) analysis regarding long-term outcomes after non-ST-segment elevation acute coronary syndromes (NSTE-ACS). From the Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II), Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS), and Randomized Intervention Trial of Unstable Angina 3 (RITA-3) patient-pooled database, 5,420 patients with NSTE-ACS with qualitative ECG data, of whom 2,901 had quantitative data, were included in this analysis. The main outcome was 5-year cardiovascular death or myocardial infarction. Hazard ratios (HRs) were calculated with Cox regression models, and adjustments were made for established outcome predictors. The additional discriminative value was assessed with the category-less net reclassification improvement and integrated discrimination improvement indexes. In the 5,420 patients, the presence of ST-segment depression (≥1 mm; adjusted HR 1.43, 95% confidence interval [CI] 1.25 to 1.63) and left bundle branch block (adjusted HR 1.64, 95% CI 1.18 to 2.28) were independently associated with long-term cardiovascular death or myocardial infarction. Risk increases were short and long term. On quantitative ECG analysis, cumulative ST-segment depression (≥5 mm; adjusted HR 1.34, 95% CI 1.05 to 1.70), the presence of left bundle branch block (adjusted HR 2.15, 95% CI 1.36 to 3.40) or ≥6 leads with inverse T waves (adjusted HR 1.22, 95% CI 0.97 to 1.55) was independently associated with long-term outcomes. No interaction was observed with treatment strategy. No improvements in net reclassification improvement and integrated discrimination improvement were observed after the addition of quantitative characteristics to a model including qualitative characteristics. In conclusion, in the FRISC II, ICTUS, and RITA-3 NSTE-ACS patient-pooled data set, admission ECG characteristics provided long-term prognostic value for cardiovascular death or myocardial infarction. Quantitative ECG characteristics provided no incremental discrimination compared to qualitative data.
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