| 11. |
- Bueno, Hector, et al.
(author)
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Report of the European Society of Cardiology Cardiovascular Round Table regulatory workshop update of the evaluation of new agents for the treatment of acute coronary syndrome : Executive summary
- 2019
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In: European Heart Journal. - : SAGE PUBLICATIONS LTD. - 2048-8726 .- 2048-8734. ; 8:8, s. 745-754
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Journal article (peer-reviewed)abstract
- Regulatory authorities interpret the results of randomized controlled trials according to published principles. The European Medicines Agency (EMA) is planning a revision of the 2000 and 2003 guidance documents on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (ACS) to achieve consistency with current knowledge in the field. This manuscript summarizes the key output from a collaborative workshop, organized by the Cardiovascular Round Table and the European Affairs Committee of the European Society of Cardiology, involving clinicians, academic researchers, trialists, European and US regulators, and pharmaceutical industry researchers. Specific questions in four key areas were selected as priorities for changes in regulatory guidance: patient selection, endpoints, methodologic issues and issues related to the research for novel agents. Patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) should be studied separately for therapies aimed at the specific pathophysiology of either condition, particularly for treatment of the acute phase, but can be studied together for other treatments, especially long-term therapy. Unstable angina patients should be excluded from acute phase ACS trials. In general, cardiovascular death and reinfarction are recommended for primary efficacy endpoints; other endpoints may be considered if specifically relevant for the therapy under study. New agents or interventions should be tested against a background of evidence-based therapy with expanded follow-up for safety assessment. In conclusion, new guidance documents for randomized controlled trials in ACS should consider changes regarding patient and endpoint selection and definitions, and trial designs. Specific requirements for the evaluation of novel pharmacological therapies need further clarification.
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| 12. |
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| 13. |
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| 14. |
- Carnicelli, Anthony P., et al.
(author)
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Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation : Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex
- 2022
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In: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 145:4, s. 242-255
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Journal article (peer-reviewed)abstract
- Background: Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation. Meta-analyses using individual patient data offer substantial advantages over study-level data.Methods: We used individual patient data from the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database, which includes all patients randomized in the 4 pivotal trials of DOACs versus warfarin in atrial fibrillation (RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48]), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (HRs [95% CIs]) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex.Results: A total of 71 683 patients were included (29 362 on standard-dose DOAC, 13 049 on lower-dose DOAC, and 29 272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke or systemic embolism (883/29 312 [3.01%] versus 1080/29 229 [3.69%]; HR, 0.81 [95% CI, 0.74-0.89]), death (2276/29 312 [7.76%] versus 2460/29 229 [8.42%]; HR, 0.92 [95% CI, 0.87-0.97]), and intracranial bleeding (184/29 270 [0.63%] versus 409/29 187 [1.40%]; HR, 0.45 [95% CI, 0.37-0.56]), but no statistically different hazard of major bleeding (1479/29 270 [5.05%] versus 1733/29 187 [5.94%]; HR, 0.86 [95% CI, 0.74-1.01]), whereas lower-dose DOACs were associated with no statistically different hazard of stroke or systemic embolism (531/13 049 [3.96%] versus 1080/29 229 [3.69%]; HR, 1.06 [95% CI, 0.95-1.19]) but a lower hazard of intracranial bleeding (55/12 985 [0.42%] versus 409/29 187 [1.40%]; HR, 0.28 [95% CI, 0.21-0.37]), death (1082/13 049 [8.29%] versus 2460/29 229 [8.42%]; HR, 0.90 [95% CI, 0.83-0.97]), and major bleeding (564/12 985 [4.34%] versus 1733/29 187 [5.94%]; HR, 0.63 [95% CI, 0.45-0.88]). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke or systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use (P=0.01) and lower creatinine clearance (P=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (P=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction P=0.02) and lower-dose DOACs (interaction P=0.01) versus warfarin.Conclusions: Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with atrial fibrillation.
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| 15. |
- Cornel, Jan H., et al.
(author)
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Relationship of Platelet Reactivity With Bleeding Outcomes During Long-Term Treatment With Dual Antiplatelet Therapy For Medically Managed Patients With Non-St-Segment Elevation Acute Coronary Syndromes
- 2016
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In: Journal of the American Heart Association. - 2047-9980. ; 5:11
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Journal article (peer-reviewed)abstract
- Background--The relationship between "on-treatment" low platelet reactivity and longitudinal risks of major bleeding dual antiplatelet therapy following acute coronary syndromes remains uncertain, especially for patients who do not undergo percutaneous coronary intervention. Methods and Results--We analyzed 2428medicallymanaged acute coronary syndromes patients fromthe Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial who had serial platelet reactivity measurements (P2Y12 reaction units; PRUs) and were randomized to aspirin+prasugrel versus aspirin+clopidogrel for up to 30 months. Contal's method was used to determine whether a cut point for steady-state PRU values could distinguish high versus low bleeding risk using 2-level composites: Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe/life-threatening or moderate bleeding unrelated to coronary artery bypass grafting (CABG) and non-CABG Thrombolysis In Myocardial Infarction (TIMI) major orminor bleeding. Exploratory analyses used 3-level composites that incorporatedmild andminimalGUSTOand TIMI events.Continuousmeasures of PRUs (per 10-unit decrease)were not independently associatedwith the 2-levelGUSTO (adjusted hazard ratio [HR], 1.01; 95% CI, 0.96-1.06) or TIMI composites (1.02; 0.98-1.07). Furthermore, no PRU cut point could significantly distinguish bleeding risk using the 2-level composites.However, the PRUcut point of 75 differentiated bleeding riskwith the 3-level composites ofGUSTO(26.5% vs 12.6%; adjusted HR, 2.28; 95% CI, 1.77-2.94; P<0.001) and TIMI bleeding events (25.9% vs 12.2%; adjusted HR, 2.30; 95% CI, 1.78-2.97; P<0.001). Conclusions--Among medically managed non-ST-segment elevation acute coronary syndromes patients receiving prolonged dual antiplatelet therapy, PRU values were not significantly associated with the long-term risk of major bleeding events, suggesting that low on-treatment platelet reactivity does not independently predict serious bleeding risk.
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| 16. |
- Gurbel, Paul A., et al.
(author)
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Platelet Function During Extended Prasugrel and Clopidogrel Therapy for Patients With ACS Treated Without Revascularization The TRILOGY ACS Platelet Function Substudy
- 2012
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In: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598. ; 308:17, s. 1785-1794
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Journal article (peer-reviewed)abstract
- Context The relationship of platelet function testing measurements with outcomes in patients with acute coronary syndromes (ACS) initially managed medically without revascularization is unknown. Objective To characterize the differences and evaluate clinical outcomes associated with platelet reactivity among patients with ACS treated with clopidogrel or prasugrel. Design, Setting, and Patients Patients with medically managed unstable angina or non-ST-segment elevation myocardial infarction were enrolled in the TRILOGY ACS trial (2008 to 2011) comparing clopidogrel vs prasugrel. Of 9326 participants, 27.5% were included in a platelet function substudy: 1286 treated with prasugrel and 1278 treated with clopidogrel. Interventions Aspirin with either prasugrel (10 or 5 mg/d) or clopidogrel (75 mg/d); those 75 years or older and younger than 75 years but who weighed less than 60 kg received a 5-mg prasugrel maintenance dose. Main Outcome Measures Platelet reactivity, measured in P2Y(12) reaction units (PRUs), was performed at baseline, at 2 hours, and at 1, 3, 6, 12, 18, 24, and 30 months after randomization. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke through 30 months. Results Among participants younger than 75 years and weighing 60 kg or more, the median PRU values at 30 days were 64 (interquartile range [IQR], 33-128) in the prasugrel group vs 200 (IQR, 141-260) in the clopidogrel group (P<.001), a difference that persisted through all subsequent time points. For participants younger than 75 years and weighing less than 60 kg, the median 30-day PRU values were 139 (IQR, 86-203) for the prasugrel group vs 209 (IQR, 148-283) for the clopidogrel group (P<.001), and for participants 75 years or older, the median PRU values were 164 (IQR, 105-216) for the prasugrel group vs 222 (IQR, 148-268) for the clopidogrel group (P<.001). At 30 months the rate of the primary efficacy end point was 17.2% (160 events) in the prasugrel group vs 18.9% (180 events) in the clopidogrel group (P=.29). There were no significant differences in the continuous distributions of 30-day PRU values for participants with a primary efficacy end point event after 30 days (n=214) compared with participants without an event (n=1794; P=.07) and no significant relationship between the occurence of the primary efficacy end point and continuous PRU values (adjusted hazard ratio [HR] for increase of 60 PRUs, 1.03; 95% CI, 0.96-1.11; P=.44). Similar findings were observed with 30-day PRU cut points used to define high on-treatment platelet reactivity-PRU more than 208 (adjusted HR, 1.16; 95% CI, 0.89-1.52, P=.28) and PRU more than 230 (adjusted HR, 1.20; 95% CI, 0.90-1.61; P=.21). Conclusions Among patients with ACS without ST-segment elevation and initially managed without revascularization, prasugrel was associated with lower platelet reactivity than clopidogrel, irrespective of age, weight, and dose. Among those in the platelet substudy, no significant differences existed between prasugrel vs clopidogrel in the occurence of the primary efficacy end point through 30 months and no significant association existed between platelet reactivity and occurrence of ischemic outcomes.
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| 17. |
- Katus, Hugo, et al.
(author)
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Early diagnosis of acute coronary syndrome
- 2017
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 38:41, s. 3049-3055
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Research review (peer-reviewed)abstract
- The diagnostic evaluation of acute chest pain has been augmented in recent years by advances in the sensitivity and precision of cardiac troponin assays, new biomarkers, improvements in imaging modalities, and release of new clinical decision algorithms. This progress has enabled physicians to diagnose or rule-out acute myocardial infarction earlier after the initial patient presentation, usually in emergency department settings, which may facilitate prompt initiation of evidence-based treatments, investigation of alternative diagnoses for chest pain, or discharge, and permit better utilization of healthcare resources. A non-trivial proportion of patients fall in an indeterminate category according to rule-out algorithms, and minimal evidence-based guidance exists for the optimal evaluation, monitoring, and treatment of these patients. The Cardiovascular Round Table of the ESC proposes approaches for the optimal application of early strategies in clinical practice to improve patient care following the review of recent advances in the early diagnosis of acute coronary syndrome. The following specific 'indeterminate' patient categories were considered: (i) patients with symptoms and high-sensitivity cardiac troponin <99th percentile; (ii) patients with symptoms and high-sensitivity troponin <99th percentile but above the limit of detection; (iii) patients with symptoms and high-sensitivity troponin >99th percentile but without dynamic change; and (iv) patients with symptoms and high-sensitivity troponin >99th percentile and dynamic change but without coronary plaque rupture/erosion/dissection. Definitive evidence is currently lacking to manage these patients whose early diagnosis is 'indeterminate' and these areas of uncertainty should be assigned a high priority for research.
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| 18. |
- O'Donoghue, Michelle, et al.
(author)
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Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction : a meta-analysis
- 2008
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In: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 300:1, s. 71-80
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Research review (peer-reviewed)abstract
- CONTEXT: Although an invasive strategy is frequently used in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), data from some trials suggest that this strategy may not benefit women. OBJECTIVE: To conduct a meta-analysis of randomized trials to compare the effects of an invasive vs conservative strategy in women and men with NSTE ACS. DATA SOURCES: Trials were identified through a computerized literature search of the MEDLINE and Cochrane databases (1970-April 2008) using the search terms invasive strategy, conservative strategy, selective invasive strategy, acute coronary syndromes, non-ST-elevation myocardial infarction, and unstable angina. STUDY SELECTION: Randomized clinical trials comparing an invasive vs conservative treatment strategy in patients with NSTE ACS. DATA EXTRACTION: The principal investigators for each trial provided the sex-specific incidences of death, myocardial infarction (MI), and rehospitalization with ACS through 12 months of follow-up. DATA SYNTHESIS: Data were combined across 8 trials (3075 women and 7075 men). The odds ratio (OR) for the composite of death, MI, or ACS for invasive vs conservative strategy in women was 0.81 (95% confidence interval [CI], 0.65-1.01; 21.1% vs 25.0%) and in men was 0.73 (95% CI, 0.55-0.98; 21.2% vs 26.3%) without significant heterogeneity between sexes (P for interaction = .26). Among biomarker-positive women, an invasive strategy was associated with a 33% lower odds of death, MI, or ACS (OR, 0.67; 95% CI, 0.50-0.88) and a nonsignificant 23% lower odds of death or MI (OR, 0.77; 95% CI, 0.47-1.25). In contrast, an invasive strategy was not associated with a significant reduction in the triple composite end point in biomarker-negative women (OR, 0.94; 95% CI, 0.61-1.44; P for interaction = .36) and was associated with a nonsignificant 35% higher odds of death or MI (OR, 1.35; 95% CI, 0.78-2.35; P for interaction = .08). Among men, the OR for death, MI, or ACS was 0.56 (95% CI, 0.46-0.67) if biomarker-positive and 0.72 (95% CI, 0.51-1.01) if biomarker-negative (P for interaction = .09). CONCLUSIONS: In NSTE ACS, an invasive strategy has a comparable benefit in men and high-risk women for reducing the composite end point of death, MI, or rehospitalization with ACS. In contrast, our data provide evidence supporting the new guideline recommendation for a conservative strategy in low-risk women.
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| 19. |
- O'Donoghue, Michelle L., et al.
(author)
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An Invasive or Conservative Strategy in Patients With Diabetes Mellitus and Non-ST-Segment Elevation Acute Coronary Syndromes A Collaborative Meta-Analysis of Randomized Trials
- 2012
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 60:2, s. 106-111
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Journal article (peer-reviewed)abstract
- Objectives The purpose of this study was to conduct a meta-analysis to examine an invasive or conservative strategy in diabetic versus nondiabetic patients. Background Diabetic patients are at increased risk of cardiovascular events after an acute coronary syndrome, yet it remains unknown whether they derive enhanced benefit from an invasive strategy.Methods Randomized trials comparing an invasive versus conservative treatment strategy were identified. The prevalence of cardiovascular events through 12 months was reported for each trial, stratified by diabetes mellitus status and randomized treatment strategy. Relative risk (RR) ratios and absolute risk reductions were combined using random-effects models.Results Data were combined across 9 trials comprising 9,904 subjects of whom 1,789 (18.1%) had diabetes mellitus. The RRs for death, nonfatal myocardial infarction (MI), or rehospitalization with an acute coronary syndrome for an invasive versus conservative strategy were similar between diabetic patients (RR: 0.87; 95% confidence interval [CI]: 0.73 to 1.03) and nondiabetic patients (RR: 0.86; 95% CI: 0.70 to 1.06; p interaction = 0.83). An invasive strategy reduced nonfatal MI in diabetic patients (RR: 0.71; 95% CI: 0.55 to 0.92), but not in nondiabetic patients (RR: 0.98; 95% CI: 0.74 to 1.29; p interaction = 0.09). The absolute risk reduction in MI with an invasive strategy was greater in diabetic than nondiabetic patients (absolute risk reduction: 3.7% vs. 0.1%; p interaction = 0.02). There were no differences in death or stroke between groups (p interactions 0.68 and 0.20, respectively).Conclusions An early invasive strategy yielded similar RR reductions in overall cardiovascular events in diabetic and nondiabetic patients. However, an invasive strategy appeared to reduce recurrent nonfatal MI to a greater extent in diabetic patients. These data support the updated guidelines that recommend an invasive strategy for patients with diabetes mellitus and non-ST-segment elevation acute coronary syndromes.
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| 20. |
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