| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 3. |
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| 4. |
- Hohnloser, Stefan H., et al.
(författare)
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Efficacy and Safety of Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Extremes in Body Weight : Insights From the ARISTOTLE Trial
- 2019
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 139:20, s. 2292-2300
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Guidelines caution against the use of non-vitamin K antagonist oral anticoagulants in patients with extremely high (> 120 kg) or low (= 60 kg) body weight because of a lack of data in these populations.METHODS: In a post hoc analysis of ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n= 18 201), a randomized trial comparing apixaban with warfarin for the prevention of stroke in patients with atrial fibrillation, we estimated the randomized treatment effect (apixaban versus warfarin) stratified by body weight (= 60, > 60-120, > 120 kg) using a Cox regression model and tested the interaction between body weight and randomized treatment. The primary efficacy and safety outcomes were stroke or systemic embolism and major bleeding.RESULTS: Of the 18 139 patients with available weight and outcomes data, 1985 (10.9%) were in the low-weight group (= 60 kg), 15 172 (83.6%) were in the midrange weight group (> 60-120 kg), and 982 (5.4%) were in the high-weight group (> 120 kg). The treatment effect of apixaban versus warfarin for the efficacy outcomes of stroke/systemic embolism, all-cause death, or myocardial infarction was consistent across the weight spectrum (interaction P value> 0.05). For major bleeding, apixaban had a better safety profile than warfarin in all weight categories and even showed a greater relative risk reduction in patients in the low (= 60 kg; HR, 0.55; 95% CI, 0.36-0.82) and midrange (> 60-120 kg) weight groups (HR, 0.71; 95% CI, 0.61-0.83; interaction P value= 0.016).CONCLUSIONS: Our findings provide evidence that apixaban is efficacious and safe across the spectrum of weight, including in low-(= 60 kg) and highweight patients (> 120 kg). The superiority on efficacy and safety outcomes of apixaban compared with warfarin persists across weight groups, with even greater reductions in major bleeding in patients with atrial fibrillation with low to normal weight as compared with high weight. The superiority of apixaban over warfarin in regard to efficacy and safety for stroke prevention seems to be similar in patients with atrial fibrillation across the spectrum of weight, including in low-and very high-weight patients. Thus, apixaban appears to be appropriate for patients with atrial fibrillation irrespective of body weight.
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| 5. |
- Mlecnik, B, et al.
(författare)
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Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:18
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I–III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I–III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75−30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p < 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10–4.55) p = 0.0269) of the patient’s gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27−9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35−5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21−5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39−6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population.
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| 6. |
- Mlecnik, B, et al.
(författare)
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Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4–82.6), 88.1% (95%-CI, 85.7–90.4), 93.4% (95%-CI, 91.1–95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18–0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17–0.50); p < 0.0001) of the patient’s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01–0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.
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| 7. |
- Vinereanu, Dragos, et al.
(författare)
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Heart rate and death and hospitalization for heart failure in patients with persistent or permanent atrial fibrillation : Insights from the ARISTOTLE trial
- 2023
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 265, s. 132-136
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Tidskriftsartikel (refereegranskat)abstract
- Rate control is fundamental in the treatment of patients with atrial fibrillation (AF). The independent association of heart rate with outcomes and range of heart rate associated with best outcomes remains uncertain. We assessed the relationship between heart rate and clinical outcomes in patients with persistent or permanent AF enrolled in the randomized, double-blind ARISTOTLE trial. In patients with persistent or permanent AF, a faster heart rate is associated with a modest, but statistically significant increase in death and heart failure hospitalizations.
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| 8. |
- Alexander, Karen P, et al.
(författare)
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Outcomes of apixaban versus warfarin in patients with atrial fibrillation and multi-morbidity : Insights from the ARISTOTLE trial
- 2019
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 208, s. 123-131
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with atrial fibrillation (AF) often have multi-morbidity, defined as ≥3 comorbid conditions. Multi-morbidity is associated with polypharmacy, adverse events, and frailty potentially altering response to anticoagulation. We sought to describe the prevalence of multi-morbidity among older patients with AF and determine the association between multi-morbidity, clinical outcomes, and the efficacy and safety of apixaban compared with warfarin.METHODS: In this post-hoc subgroup analysis of the ARISTOTLE trial, we studied enrolled patients age ≥ 55 years (n = 16,800). Patients were categorized by the number of comorbid conditions at baseline: no multi-morbidity (0-2 comorbid conditions), moderate multi-morbidity (3-5 comorbid conditions), and high multi-morbidity (≥6 comorbid conditions). Association between multi-morbidity and clinical outcomes were analyzed by treatment with a median follow-up of 1.8 (1.3-2.3) years.RESULTS: Multi-morbidity was present in 64% (n = 10,713) of patients; 51% (n = 8491) had moderate multi-morbidity, 13% (n = 2222) had high multi-morbidity, and 36% (n = 6087) had no multi-morbidity. Compared with the no multi-morbidity group, the high multi-morbidity group was older (74 vs 69 years), took twice as many medications (10 vs 5), and had higher CHA2DS2-VASc scores (4.9 vs 2.7) (all P < .001). Adjusted rates per 100 patient-years for stroke/systemic embolism, death, and major bleeding increased with multi-morbidity (Reference no multi-morbidity; moderate multi-morbidity 1.42 [1.24-1.64] and high multi-morbidity 1.92 [1.59-2.31]), with no interaction in relation to efficacy or safety of apixaban.CONCLUSIONS: Multi-morbidity is prevalent among the population with AF; efficacy and safety of apixaban is preserved in this subgroup supporting extension of trial results to the most complex AF patients.
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| 9. |
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| 10. |
- Bahit, M. Cecilia, et al.
(författare)
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Regional variation in clinical characteristics and outcomes in patients with atrial fibrillation : Findings from the ARISTOTLE trial
- 2020
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Ingår i: International Journal of Cardiology. - : ELSEVIER IRELAND LTD. - 0167-5273 .- 1874-1754. ; 302, s. 53-58
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Tidskriftsartikel (refereegranskat)abstract
- Background: Variation in patient characteristics and practice patterns may influence outcomes at a regional level.Methods: We assessed differences in demographics, practice patterns, outcomes, and the effect of apixaban compared with warfarin in ARISTOTLE (n = 18,201) by prespecified regions: North America, Latin America, Europe, and Asia Pacific. The primary outcomes were stroke/systemic embolism and major bleeding.Results: Compared with other regions, patients from Asia Pacific were younger, more women were enrolled in Latin America. Coronary artery disease was more prevalent in Europe and Asia Pacific had the highest rate of prior stroke and renal impairment. Over 50% of patients in North America were taking >= 9 drugs at randomization, compared with 10% in Latin America. North America had the highest rates of temporary study drug discontinuation and procedures. Time in therapeutic range (INR 2.0-3.0) on warfarin was highest in North America and lowest in Asia Pacific. After adjustment and compared with Europe, patients in Asia Pacific had 2-fold higher risk of stroke/systemic embolism and 3-fold higher risk of intracranial hemorrhage. Patients in Latin America had 2-fold increased risk of all-cause death compared with Europe. The benefits of apixaban compared with war-farin were consistent across regions; there was a pronounced reduction in major bleeding in patients from Asia Pacific compared with other regions (p-interaction = 0.03).Conclusions: Patients with AF enrolled in prespecified regions in ARISTOTLE had differences in clinical baseline characteristics and practice patterns. After adjustment, patients in Asia Pacific and Latin America had worse outcomes than patients from other regions. The relative benefits of apixaban compared with warfarin were consistent across regions with an even greater treatment effect in the reduction of bleeding in patients from Asia Pacific.
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| 11. |
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| 12. |
- Hijazi, Ziad, et al.
(författare)
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Apixaban or Vitamin K Antagonists and Aspirin or Placebo According to Kidney Function in Patients With Atrial Fibrillation After Acute Coronary Syndrome or Percutaneous Coronary Intervention : Insights From the AUGUSTUS Trial
- 2021
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 143:12, s. 1215-1223
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the AUGUSTUS trial (An Open-Label, 2x2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban Versus Vitamin K Antagonist and Aspirin Versus Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention), apixaban resulted in less bleeding and fewer hospitalizations than vitamin K antagonists, and aspirin caused more bleeding than placebo in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention treated with a P2Y(12) inhibitor. We evaluated the risk-benefit balance of antithrombotic therapy according to kidney function.Methods: In 4456 patients, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was used to calculate baseline estimated glomerular filtration rate (eGFR). The effect of apixaban versus vitamin K antagonists and aspirin versus placebo was assessed across kidney function categories by using Cox models. The primary outcome was International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and ischemic events (death, stroke, myocardial infarction, stent thrombosis [definite or probable], or urgent revascularization). Creatinine clearanceResults: Overall, 30%, 52%, and 19% had an eGFR of >80, >50 to 80, and 30 to 50 mL.min(-1).1.73 m(-2), respectively. At the 6-month follow-up, a total of 543 primary outcomes of bleeding, 1125 death or hospitalizations, and 282 ischemic events occurred. Compared with vitamin K antagonists, patients assigned apixaban had lower rates for all 3 outcomes across most eGFR categories without significant interaction. The absolute risk reduction with apixaban was most pronounced in those with an eGFR of 30 to 50 mL.min(-1).1.73 m(-2) for bleeding events with rates of 13.1% versus 21.3% (hazard ratio, 0.59; 95% CI, 0.41-0.84). Patients assigned aspirin had a higher risk of bleeding in all eGFR categories with an even greater increase among those with eGFR >80 mL.min(-1).1.73 m(-2): 16.6% versus 5.6% (hazard ratio, 3.22; 95% CI, 2.19-4.74; P for interaction=0.007). The risk of death or hospitalization and ischemic events were comparable to aspirin and placebo across eGFR categories with hazard ratios ranging from 0.97 (95% CI, 0.76-1.23) to 1.28 (95% CI, 1.02-1.59) and from 0.75 (95% CI, 0.48-1.17) to 1.34 (95% CI, 0.81-2.22), respectively.Conclusions: The safety and efficacy of apixaban was consistent irrespective of kidney function, compared with warfarin, and in accordance with the overall trial results. The risk of bleeding with aspirin was consistently higher across all kidney function categories.
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| 13. |
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| 14. |
- Pol, Tymon, et al.
(författare)
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Evaluation of the prognostic value of GDF-15, ABC-AF-bleeding score and ABC-AF-death score in patients with atrial fibrillation across different geographical areas
- 2021
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Ingår i: Open heart. - : BMJ Publishing Group Ltd. - 2053-3624. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Growth differentiation factor 15 (GDF-15) is a biomarker independently associated with bleeding and death in anticoagulated patients with atrial fibrillation (AF). GDF-15 is also used as one component in the more precise biomarker-based ABC (age, biomarkers, clinical history)-AF-bleeding and ABC-AF-death risk scores. Data from large trials indicate a geographic variability in regard to overall outcomes, including bleeding and mortality risk. Our aim was to assess the consistency of the association between GDF-15, ABC-AF-bleeding score and ABC-AF-death score, with major bleeding and death, across world geographic regions. Methods Data were available from 14 767 patients with AF from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial and 8651 patients with AF from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial in this cohort study. GDF-15 was analysed from plasma samples obtained at randomisation. The geographical consistency of the associations between outcomes and GDF-15, ABC-AF-bleeding score and ABC-AF-death scores were assessed by Cox-regression models including interactions with predefined geographical region. Results GDF-15 and the ABC-AF-bleeding score were associated with major bleeding in both trials across regions (p<0.0001). Similarly, GDF-15 and the ABC-AFdeath score were associated with all-cause mortality in both trials across regions (p<0.0001). Overall, the association between GDF-15, the ABC-AF-bleeding score and ABC-AF-death risk score with major bleeding and death was consistent across regions in both ARISTOTLE and the RE-LY trial cohorts. The ABC-AF-bleeding and ABC-AF-death risk scores were consistent regarding discriminative ability when comparing geographic regions in both trial cohorts. The C-indices ranged from 0.649 to 0.760 for the ABC-AF-bleeding and from 0.677 to 0.806 for the ABC-AF-death score by different geographic regions. Conclusions In patients with AF on anticoagulation, GDF-15 and the biomarker-based ABC-AF-bleeding and ABC-AF-death risk scores are consistently associated with respectively increased risk of major bleeding and death and have similar prognostic value across world geographic regions.
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| 15. |
- Proietti, M., et al.
(författare)
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Comparison of bleeding risk scores in patients with atrial fibrillation : insights from the RE-LY trial
- 2018
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Ingår i: Journal of Internal Medicine. - : WILEY. - 0954-6820 .- 1365-2796. ; 283:3, s. 282-292
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Tidskriftsartikel (refereegranskat)abstract
- Background: Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF.Objectives: To compare the performance of contemporary clinical bleeding risk scores in 18113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE-LY trial.Methods: HAS-BLED, ORBIT, ATRIA and HEMORR(2)HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated.Results: There were 1182 (6.5%) major bleeding events during a median follow-up of 2.0 years. For all the four schemes, high-risk subgroups had higher risk of major bleeding (all P<0.001). The ORBIT score showed the best discrimination with c-indices of 0.66, 0.66 and 0.62, respectively, for major, life-threatening and intracranial bleeding, which were significantly better than for the HAS-BLED score (difference in c-indices: 0.050, 0.053 and 0.048, respectively, all P<0.05). The ORBIT score also showed the best calibration compared with previous data. Significant treatment interactions between the bleeding scores and the risk of major bleeding with dabigatran 150 mg BD versus warfarin were found for the ORBIT (P=0.0019), ATRIA (P<0.001) and HEMORR(2)HAGES (P<0.001) scores. HAS-BLED score showed a nonsignificant trend for interaction (P=0.0607).Conclusions: Amongst the current clinical bleeding risk scores, the ORBIT score demonstrated the best discrimination and calibration. All the scores demonstrated, to a variable extent, an interaction with bleeding risk associated with dabigatran or warfarin.
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| 16. |
- Rosjo, H., et al.
(författare)
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Cardiac troponin is associated with cardiac outcomes in men and women with atrial fibrillation, insights from the ARISTOTLE trial
- 2020
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Ingår i: Journal of Internal Medicine. - : WILEY. - 0954-6820 .- 1365-2796. ; 288:2, s. 248-259
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Tidskriftsartikel (refereegranskat)abstract
- Background Cardiac troponin T (cTnT) and I (cTnI) concentrations provide strong prognostic information in anticoagulated patients with atrial fibrillation (AF). Whether the associations between cardiac troponin concentrations and mortality and morbidity differ by sex is not known. Objectives To assess whether men and women have different concentrations and prognostic value of cTnT and cTnI measurements in anticoagulated patients with AF. Methods cTnT and cTnI concentrations were measured with high-sensitivity (hs) assays in EDTA plasma samples obtained from the multicentre ARISTOTLE trial, which randomized patients with AF and at least one risk factor for stroke or systemic embolic event to warfarin or apixaban. Patients were stratified according to sex and the associations between hs-troponin concentrations, and all-cause death, cardiac death, myocardial infarction, stroke or systemic embolic event and major bleeding were assessed in multivariable regression models. Results We found higher cardiac troponin concentrations in men (n = 9649) compared to women (n = 5331), both for hs-cTnT (median 11.8 [Q1-3 8.1-18.0] vs. 9.6 [6.7-14.3] ng L-1, P < 0.001) and hs-cTnI (5.8 [3.4-10.8] vs. 4.9 [3.1-8.8] ng L-1, P < 0.001). Adjusting for baseline demographics, comorbidities and medications, men still had significantly higher hs-troponin concentrations than women. C-reactive protein and N-terminal pro-B-type natriuretic peptide concentrations were higher in female patients. Both hs-cTnT and hs-cTnI concentrations were associated with all clinical outcomes similarly in men and women (p-value for interaction >0.05 for all end-points). Conclusion Men have higher hs-troponin concentrations than women in AF. Regardless of sex, hs-troponin concentrations remain similarly associated with adverse clinical outcomes in anticoagulated patients with AF.
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| 17. |
- Sharma, Abhinav, et al.
(författare)
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Use of Biomarkers to Predict Specific Causes of Death in Patients With Atrial Fibrillation : Insights From the ARISTOTLE Trial
- 2018
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 138:16, s. 1666-1676
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Tidskriftsartikel (refereegranskat)abstract
- Background: Atrial fibrillation is associated with an increased risk of death. High-sensitivity troponin T, growth differentiation factor-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and interleukin-6 levels are predictive of cardiovascular events and total cardiovascular death in anticoagulated patients with atrial fibrillation. The prognostic utility of these biomarkers for cause-specific death is unknown. Methods: The ARISTOTLE trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) randomized 18201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14798 patients (1.9 years median follow-up). Cox models were used to identify clinical variables and biomarkers independently associated with each specific cause of death. Results: In total, 1272 patients died: 652 (51%) cardiovascular, 32 (3%) bleeding, and 588 (46%) noncardiovascular/nonbleeding deaths. Among cardiovascular deaths, 255 (39%) were sudden cardiac deaths, 168 (26%) heart failure deaths, and 106 (16%) stroke/systemic embolism deaths. Biomarkers were the strongest predictors of cause-specific death: a doubling of troponin T was most strongly associated with sudden death (hazard ratio [HR], 1.48; P<0.001), NT-proBNP with heart failure death (HR, 1.62; P<0.001), and growth differentiation factor-15 with bleeding death (HR, 1.72; P=0.028). Prior stroke/systemic embolism (HR, 2.58; P>0.001) followed by troponin T (HR, 1.45; P<0.0029) were the most predictive for stroke/ systemic embolism death. Adding all biomarkers to clinical variables improved discrimination for each cause-specific death. Conclusions: Biomarkers were some of the strongest predictors of cause-specific death and may improve the ability to discriminate among patients' risks for different causes of death. These data suggest a potential role of biomarkers for the identification of patients at risk for different causes of death in patients anticoagulated for atrial fibrillation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00412984.
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| 18. |
- Stanifer, John W., et al.
(författare)
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Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease
- 2020
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 141:17, s. 1384-1392
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Tidskriftsartikel (refereegranskat)abstract
- Background: Compared with the general population, patients with advanced chronic kidney disease have a >10-fold higher burden of atrial fibrillation. Limited data are available guiding the use of nonvitamin K antagonist oral anticoagulants in this population.Methods: We compared the safety of apixaban with warfarin in 269 patients with atrial fibrillation and advanced chronic kidney disease (defined as creatinine clearance [CrCl] 25 to 30 mL/min) enrolled in the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). Cox proportional models were used to estimate hazard ratios for major bleeding and major or clinically relevant nonmajor bleeding. We characterized the pharmacokinetic profile of apixaban by assessing differences in exposure using nonlinear mixed effects models.Results: Among patients with CrCl 25 to 30 mL/min, apixaban caused less major bleeding (hazard ratio, 0.34 [95% CI, 0.14-0.80]) and major or clinically relevant nonmajor bleeding (hazard ratio, 0.35 [95% CI, 0.17-0.72]) compared with warfarin. Patients with CrCl 25 to 30 mL/min randomized to apixaban demonstrated a trend toward lower rates of major bleeding when compared with those with CrCl >30 mL/min (P interaction=0.08) and major or clinically relevant nonmajor bleeding (P interaction=0.05). Median daily steady-state areas under the curve for apixaban 5 mg twice daily were 5512 ng/(mL center dot h) and 3406 ng/(mL center dot h) for patients with CrCl 25 to 30 mL/min or >30 mL/min, respectively. For apixaban 2.5 mg twice daily, the median exposure was 2780 ng/(mL center dot h) for patients with CrCl 25 to 30 mL/min. The area under the curve values for patients with CrCl 25 to 30 mL/min fell within the ranges demonstrated for patients with CrCl >30 mL/min.Conclusions: Among patients with atrial fibrillation and CrCl 25 to 30 mL/min, apixaban caused less bleeding than warfarin, with even greater reductions in bleeding than in patients with CrCl >30 mL/min. We observed substantial overlap in the range of exposure to apixaban 5 mg twice daily for patients with or without advanced chronic kidney disease, supporting conventional dosing in patients with CrCl 25 to 30 mL/min. Randomized, controlled studies evaluating the safety and efficacy of apixaban are urgently needed in patients with advanced chronic kidney disease, including those receiving dialysis.
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| 19. |
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| 20. |
- Alexander, John H, et al.
(författare)
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Apixaban 5 mg Twice Daily and Clinical Outcomes in Patients With Atrial Fibrillation and Advanced Age, Low Body Weight, or High Creatinine : A Secondary Analysis of a Randomized Clinical Trial
- 2016
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Ingår i: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 1:6, s. 673-681
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: In the Apixaban for Reduction of Stroke and Other Thromboembolic Complications in Atrial Fibrillation (ARISTOTLE) trial, the standard dose of apixaban was 5 mg twice daily; patients with at least 2 dose-reduction criteria-80 years or older, weight 60 kg or less, and creatinine level 1.5 mg/dL or higher-received a reduced dose of apixaban of 2.5 mg twice daily. Little is known about patients with 1 dose-reduction criterion who received the 5 mg twice daily dose of apixaban.OBJECTIVE: To determine the frequency of 1 dose-reduction criterion and whether the effects of the 5 mg twice daily dose of apixaban on stroke or systemic embolism and bleeding varied among patients with 1 or no dose-reduction criteria.DESIGN, SETTING, AND PARTICIPANTS: Among 18 201 patients in the ARISTOTLE trial, 17 322 were included in this analysis. Annualized event rates of stroke or systemic embolism and major bleeding and hazard ratios (HRs) and 95% CIs were evaluated. Interactions between the effects of apixaban vs warfarin and the presence of 1 or no dose-reduction criteria were assessed. The first patient was enrolled in the ARISTOTLE trial on December 19, 2006, and follow-up was completed on January 30, 2011. Data were analyzed from January 2015 to May 30, 2016.MAIN OUTCOMES AND MEASURES: Analysis of major bleeding included events during study drug treatment. Analysis of stroke or systemic embolism was based on intention to treat.RESULTS: Of the patients with 1 or no dose-reduction criteria assigned to receive the 5 mg twice daily dose of apixaban or warfarin, 3966 had 1 dose-reduction criterion; these patients had higher rates of stroke or systemic embolism (HR, 1.47; 95% CI, 1.20-1.81) and major bleeding (HR, 1.89; 95% CI, 1.62-2.20) compared with those with no dose-reduction criteria (n = 13 356). The benefit of the 5 mg twice daily dose of apixaban (n = 8665) compared with warfarin (n = 8657) on stroke or systemic embolism in patients with 1 dose-reduction criterion (HR, 0.94; 95% CI, 0.66-1.32) and no dose-reduction criterion (HR, 0.77; 95% CI, 0.62-0.97) were similar (P for interaction = .36). Similarly, the benefit of 5 mg twice daily dose of apixaban compared with warfarin on major bleeding in patients with 1 dose-reduction criterion (HR, 0.68; 95% CI, 0.53-0.87) and no dose-reduction criterion (HR, 0.72; 95% CI, 0.60-0.86) were similar (P for interaction = .71). Similar patterns were seen for each dose-reduction criterion and across the spectrum of age, body weight, creatinine level, and creatinine clearance.CONCLUSIONS AND RELEVANCE: Patients with atrial fibrillation and isolated advanced age, low body weight, or renal dysfunction have a higher risk of stroke or systemic embolism and major bleeding but show consistent benefits with the 5 mg twice daily dose of apixaban vs warfarin compared with patients without these characteristics. The 5 mg twice daily dose of apixaban is safe, efficacious, and appropriate for patients with only 1 dose-reduction criterion.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00412984.
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| 21. |
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| 22. |
- Aulin, Julia, et al.
(författare)
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Serial measurement of interleukin-6 and risk of mortality in anticoagulated patients with atrial fibrillation : Insights from ARISTOTLE and RE-LY trials.
- 2020
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 18:9, s. 2287-2295
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The inflammatory biomarker interleukin-6 (IL-6) is associated with mortality in atrial fibrillation (AF).OBJECTIVE: To investigate if repeated IL-6 measurements improve the prognostication for stroke or systemic embolism, major bleeding, and mortality in anticoagulated patients with AF.METHODS: IL-6 levels by ELISA were measured at study entry and at 2 months in 4830 patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial with 1.8 years median follow-up. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, IL-6 was measured at study entry, 3, 6, and 12 months in 2559 patients with 2.0 years median follow-up. Associations between a second IL-6 measurement and outcomes, adjusted for baseline IL-6, clinical variables, and other cardiovascular biomarkers, were analyzed by Cox regression.RESULTS: Median IL-6 levels were 2.0 ng/L (interquartile range [IQR] 1.30-3.20) and 2.10 ng/L (IQR 1.40-3.40) at the two time-points in ARISTOTLE, and, in RE-LY, 2.5 ng/L (IQR 1.6-4.3), 2.5 ng/L (IQR 1.6-4.2), 2.4 ng/L (IQR 1.6, 3.9), and 2.4 ng/L (IQR 1.5, 3.9), respectively. IL-6 was associated with mortality; hazard ratios per 50% higher IL-6 at 2 or 3 months, respectively, were 1.32 (95% confidence interval, 1.23-1.41; P < .0001) in ARISTOTLE, and 1.11 (1.01-1.22, P = .0290) in RE-LY; with improved C index from 0.74 to 0.76 in ARISTOTLE, but not in the smaller RE-LY cohort. There were no consistent associations with second IL-6 and stroke or systemic embolism, or major bleeding.CONCLUSIONS: Persistent systemic inflammatory activity, assessed by repeated IL-6 measurements, is associated with mortality independent of established clinical risk factors and other strong cardiovascular biomarkers in anticoagulated patients with AF.
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| 23. |
- Carnicelli, Anthony P., et al.
(författare)
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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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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 145:4, s. 242-255
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Tidskriftsartikel (refereegranskat)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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| 24. |
- Ghazal, Ahmad, et al.
(författare)
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Venomous gland transcriptome and venom proteomic analysis of the scorpion Androctonus amoreuxi reveal new peptides with anti-SARS-CoV-2 activity
- 2024
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Ingår i: Peptides. - : Elsevier. - 0196-9781 .- 1873-5169. ; 173
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Tidskriftsartikel (refereegranskat)abstract
- The recent COVID-19 pandemic shows the critical need for novel broad spectrum antiviral agents. Scorpion venoms are known to contain highly bioactive peptides, several of which have demonstrated strong antiviral activity against a range of viruses. We have generated the first annotated reference transcriptome for the Androctonus amoreuxi venom gland and used high performance liquid chromatography, transcriptome mining, circular dichroism and mass spectrometric analysis to purify and characterize twelve previously undescribed venom peptides. Selected peptides were tested for binding to the receptor-binding domain (RBD) of the SARSCoV-2 spike protein and inhibition of the spike RBD - human angiotensin-converting enzyme 2 (hACE2) interaction using surface plasmon resonance-based assays. Seven peptides showed dose-dependent inhibitory effects, albeit with IC50 in the high micromolar range (117-1202 mu M). The most active peptide was synthesized using solid phase peptide synthesis and tested for its antiviral activity against SARS-CoV-2 (Lineage B.1.1.7). On exposure to the synthetic peptide of a human lung cell line infected with replication-competent SARS-CoV-2, we observed an IC50 of 200 nM, which was nearly 600-fold lower than that observed in the RBD - hACE2 binding inhibition assay. Our results show that scorpion venom peptides can inhibit the SARS-CoV-2 replication although unlikely through inhibition of spike RBD - hACE2 interaction as the primary mode of action. Scorpion venom peptides represent excellent scaffolds for design of novel anti-SARS-CoV-2 constrained peptides. Future studies should fully explore their antiviral mode of action as well as the structural dynamics of inhibition of target virushost interactions.
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| 25. |
- Guimaraes, Patricia O., et al.
(författare)
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International normalized ratio control and subsequent clinical outcomes in patients with atrial fibrillation using warfarin
- 2019
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 48:1, s. 27-34
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Tidskriftsartikel (refereegranskat)abstract
- We explored associations between INR measures and clinical outcomes in patients with AF using warfarin, and whether INR history predicted future INR measurements. We included patients in ARISTOTLE who were randomized to and received warfarin. Among patients who had events, we included those with ≥ 3 INR values in the 180 days prior to the event, with the most recent ≤ 60 days prior to the event, who were on warfarin at the time of event (n = 545). Non-event patients were included in the control group if they had ≥ 180 days of warfarin exposure with ≥ 3 INR measurements (n = 7259). The median (25th, 75th) number of INR values per patient was 29 (21, 38) over a median follow-up of 1.8 years. A total of 87% had at least one INR value < 1.5; 49% had at least one value > 4.0. The last INRs before events (median 14 [24, 7] days) were < 3.0 for at least 75% of patients with major bleeding and > 2.0 for half of patients with ischemic stroke. Historic time in therapeutic range (TTR) was weakly associated with future TTR (R2 = 0.212). Historic TTR ≥ 80% had limited predictive ability to discriminate future TTR ≥ 80% (C index 0.61). In patients with AF receiving warfarin, most bleeding events may not have been preventable despite careful INR control. Our findings suggest that INRs collected through routine management are not sufficiently predictive to provide reassurance about future time in therapeutic range or to prevent subsequent outcomes, and might be over-interpreted in clinical practice.
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| 26. |
- Hijazi, Ziad, et al.
(författare)
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A biomarker-based risk score to predict death in patients with atrial fibrillation : the ABC (age, biomarkers, clinical history) death risk score
- 2018
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Ingår i: European Heart Journal. - : OXFORD UNIV PRESS. - 0195-668X .- 1522-9645. ; 39:6, s. 477-485
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Tidskriftsartikel (refereegranskat)abstract
- Aims: In atrial fibrillation (AF), mortality remains high despite effective anticoagulation. A model predicting the risk of death in these patients is currently not available. We developed and validated a risk score for death in anticoagulated patients with AF including both clinical information and biomarkers.Methods and results: The new risk score was developed and internally validated in 14 611 patients with AF randomized to apixaban vs. warfarin for a median of 1.9 years. External validation was performed in 8548 patients with AF randomized to dabigatran vs. warfarin for 2.0 years. Biomarker samples were obtained at study entry. Variables significantly contributing to the prediction of all-cause mortality were assessed by Cox-regression. Each variable obtained a weight proportional to the model coefficients. There were 1047 all-cause deaths in the derivation and 594 in the validation cohort. The most important predictors of death were N-terminal pro B-type natriuretic peptide, troponin-T, growth differentiation factor-15, age, and heart failure, and these were included in the ABC (Age, Biomarkers, Clinical history)-death risk score. The score was well-calibrated and yielded higher c-indices than a model based on all clinical variables in both the derivation (0.74 vs. 0.68) and validation cohorts (0.74 vs. 0.67). The reduction in mortality with apixaban was most pronounced in patients with a high ABC-death score.Conclusion: A new biomarker-based score for predicting risk of death in anticoagulated AF patients was developed, internally and externally validated, and well-calibrated in two large cohorts. The ABC-death risk score performed well and may contribute to overall risk assessment in AF.
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| 27. |
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| 28. |
- Hijazi, Ziad, et al.
(författare)
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Biomarkers of inflammation and risk of cardiovascular events in anticoagulated patients with atrial fibrillation
- 2016
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 102:7, s. 508-517
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Atrial fibrillation (AF) is a risk factor for stroke and mortality and the prothrombotic state has been linked to inflammation. In this study we evaluated the relationship between inflammatory biomarkers at baseline and future risk of cardiovascular events in the Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.Methods: The ARISTOTLE trial randomised 18 201 patients with AF to apixaban or warfarin. Interleukin 6 (IL-6) and C reactive protein (CRP) were analysed in plasma obtained at randomisation from 14 954 participants, and median follow-up was 1.9 years. Association between quartile groups of IL-6 and CRP and outcomes were analysed by Cox regression adjusted for clinical risk factors and other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C).Results: The IL-6 median level was 2.3 ng/L (IQR 1.5-3.9), median CRP level was 2.2 mg/L (1.0-4.8). IL-6 and CRP were significantly associated with all-cause mortality independent of clinical risk factors and other biomarkers (HR (95% CI) 1.93 (1.57 to 2.37) and 1.49 (1.24 to 1.79), respectively, Q4 vs Q1). IL-6 was associated with myocardial infarction, cardiovascular mortality, and major bleeding beyond clinical risk factors but not in the presence of cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Neither inflammatory biomarker was associated with stroke/systemic embolism. Risk prediction for stroke, death and major bleeding was not improved by IL-6 or CRP when added to clinical risk factors and the other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C).Conclusions: In patients with AF on anticoagulation, after accounting for clinical risk factors and other biomarkers, biomarkers of inflammation were significantly associated with an increased risk of mortality. However, there were no associations with the risk of stroke or major bleeding.
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| 29. |
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| 30. |
- Hijazi, Ziad, et al.
(författare)
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Comparison of Cardiac Troponins I and T Measured with High-Sensitivity Methods for Evaluation of Prognosis in Atrial Fibrillation : An ARISTOTLE Substudy
- 2015
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 61:2, s. 368-378
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Although cardiac troponin is associated with outcomes in atrial fibrillation (AF), the complementary prognostic information provided by cardiac troponin I (cTnI) and cTnT is unknown. This study investigated the distribution, determinants, and prognostic value of cTnI and cTnT concentrations in patients with AF.METHODS:At the time of randomization, we analyzed cTnI and cTnT concentrations of 14 806 AF patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial using high-sensitivity assays. Correlations (Spearman), determinants (multiple analysis of variance), and outcomes (adjusted Cox models and c-statistics) were investigated.RESULTS:Concentrations of cTnI and cTnT were correlated (r = 0.70) and measurable in most participants [cTnI 98.5% (median 5.4 ng/L, ≥99th percentile in 9.2%) and cTnT 93.5% (median 10.9 ng/L, ≥99th percentile in 34.4%)]. Renal impairment was the most important factor affecting the concentrations of both troponins. cTnI increase was more associated with heart failure, vascular disease, and persistent/permanent AF, and cTnT with age, male sex, and diabetes. Over a median 1.9 years of follow-up, patients with both troponins above the median had significantly higher risk for stroke/systemic embolism [hazard ratio (HR) 1.72 (95% CI 1.31-2.27)], cardiac death [3.14 (2.35-4.20)], and myocardial infarction [2.99 (1.78-5.03)] than those with both troponins below median (all P < 0.005). Intermediate risks were observed when only 1 troponin was above the median. When combined with clinical information, each marker provided similar prognostication and had comparable c-statistics.CONCLUSIONS:cTnI and cTnT concentrations are moderately correlated and measurable in plasma of most AF patients. The risk of stroke and cardiovascular events is highest when both troponins are above median concentrations. Each troponin provides comparable prognostic information when combined with clinical risk factors.
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| 31. |
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| 32. |
- Hijazi, Ziad, et al.
(författare)
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Evaluation of the Age, Biomarkers, and Clinical History-Bleeding Risk Score in Patients With Atrial Fibrillation With Combined Aspirin and Anticoagulation Therapy Enrolled in the ARISTOTLE and RE-LY Trials
- 2020
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Ingår i: JAMA Network Open. - : AMER MEDICAL ASSOC. - 2574-3805. ; 3:9
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Most patients with atrial fibrillation (AF) and coronary artery disease have indications for preventing stroke with oral anticoagulation therapy and preventingmyocardial infarction and stent thrombosis with platelet inhibition. OBJECTIVE To evaluate whether the recently developed ABC (age, biomarkers, and clinical history)bleeding risk score might be useful to identify patients with AF with different risks of bleeding during concomitant aspirin and anticoagulation therapy. DESIGN, SETTING, AND PARTICIPANTS The biomarkers in the ABC-bleeding risk score (growth differentiation factor 15, hemoglobin, and troponin) were measured in blood samples collected at randomization between 2006 and 2010 in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial and between 2005 and 2009 in the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial, both of which were multinational randomized clinical trials. The trials were reported 2011 and 2009, respectively. A total of 24 349 patients with AF (14 980 patients from the ARISTOTLE trial and 9369 patients from the RE-LY trial) were analyzed in the present cohort study. The median (interquartile range) length of follow-up was 1.8 (1.3-2.3) years in the ARISTOTLE cohort and 2.0 (1.6-2.3) years in the RE-LY cohort. Data analysis was performed from February 2018 to June 2019. EXPOSURES Concomitant aspirin treatment during study follow-up. MAIN OUTCOMES AND MEASURES Time to first occurrence of a major bleeding was determined according to International Society on Thrombosis and Hemostasis definition. Hazard ratios were estimated with Cox models adjusted for ABC-bleeding risk score and randomized treatment. RESULTS The median (interquartile range) age was 70 (63-76) years in the ARISTOTLE cohort and 72 (67-77) years in the RE-LY cohort (5238 patients [35.6%] in the ARISTOTLE cohort and 3086 patients [36.4%] in the RE-LY cohort were women). The total number of patients with a first major bleeding event was 651 (207 with aspirin and 444 without) in ARISTOTLE and 463 (238 with aspirin and 225 without) in RE-LY. For both cohorts, in those with a lowABC-bleeding risk score, the absolute bleeding rate was low even with concomitant aspirin treatment, whereas in those with a higher ABC-bleeding risk score, the rate of bleedingwas higher with concomitant aspirin compared with oral anticoagulation alone (ARISTOTLE, hazard ratio, 1.65; 95% CI, 1.40-1.95; P <.001; RE-LY, hazard ratio, 1.70; 95% CI, 1.42-2.04; P <.001). Thus, a low annual ABC-bleeding risk (eg, 0.5% without aspirin use) would with concomitant aspirin result in an annual rate of 0.8%, and a high estimated ABC-bleeding risk (eg, 3.0%) would result in a substantially higher rate of 5.0%. CONCLUSIONS AND RELEVANCE These findings suggest that the ABC-bleeding risk score identifies patients with different risks of bleeding when combining aspirin and oral anticoagulation. The ABC-bleeding risk score may, therefore, be a useful tool for decision support concerning intensity and duration of combination antithrombotic treatment in patients with AF and coronary artery disease.
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| 33. |
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| 34. |
- Hijazi, Ziad, et al.
(författare)
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High-Sensitivity Troponin I for Risk Assessment in Patients With Atrial Fibrillation Insights From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial
- 2014
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 129:6, s. 625-634
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Tidskriftsartikel (refereegranskat)abstract
- Background High-sensitivity troponin-I (hs-TnI) measurement improves risk assessment for cardiovascular events in many clinical settings, but the added value in atrial fibrillation patients has not been described. Methods and Results At randomization, hs-TnI was analyzed in 14 821 atrial fibrillation patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban with warfarin. The associations between hs-TnI concentrations and clinical outcomes were evaluated by using adjusted Cox analysis. The hs-TnI assay detected troponin (1.3 ng/L) in 98.5% patients, 50% had levels >5.4, 25% had levels >10.1, and 9.2% had levels 23 ng/L (the 99th percentile in healthy individuals). During a median of 1.9 years follow-up, annual rates of stroke or systemic embolism ranged from 0.76% in the lowest hs-TnI quartile to 2.26% in the highest quartile (>10.1 ng/L). In multivariable analysis, hs-TnI was significantly associated with stroke or systemic embolism, adjusted hazard ratio 1.98 (1.42-2.78), P=0.0007. hs-TnI was also significantly associated with cardiac death; annual rates ranged from 0.40% to 4.24%, hazard ratio 4.52 (3.05-6.70), P<0.0001, in the corresponding groups, and for major bleeding hazard ratio 1.44 (1.11-1.86), P=0.0250. Adding hs-TnI levels to the CHA(2)DS(2)VASc score improved c-statistics from 0.629 to 0.653 for stroke or systemic embolism, and from 0.591 to 0.731 for cardiac death. There were no significant interactions with study treatment. Conclusions Troponin-I is detected in 98.5% and elevated in 9.2% of atrial fibrillation patients. The hs-TnI level is independently associated with a raised risk of stroke, cardiac death, and major bleeding and improves risk stratification beyond the CHA(2)DS(2)VASc score. The benefits of apixaban in comparison with warfarin are consistent regardless of hs-TnI levels.
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| 35. |
- Hijazi, Ziad, et al.
(författare)
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High Sensitivity Troponin T and Risk Stratification in Patients with Atrial Fibrillation during Treatment with Apixaban or Warfarin
- 2014
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 63:1, s. 52-61
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesThe aim of this study was to evaluate the prognostic value of high-sensitivity troponin T (hs-TnT) in addition to clinical risk factors and the CHA2DS2VASc (congestive heart failure, hypertension, 75 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, 65 to 74 years of age, female) risk score in patients with atrial fibrillation (AF).BackgroundThe level of troponin is a powerful predictor of cardiovascular events and mortality.MethodsA total of 14,897 patients with AF were randomized to treatment with apixaban or warfarin in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial. The associations between baseline hs-TnT levels and outcomes were evaluated using adjusted Cox regression models.ResultsLevels of hs-TnT were measurable in 93.5% of patients; 75% had levels >7.5 ng/l, 50% had levels >11.0 ng/l, and 25% had levels >16.7 ng/l. During a median 1.9-year period, the annual rates of stroke or systemic embolism ranged from 0.87% in the lowest hs-TnT quartile to 2.13% in the highest hs-TnT quartile (adjusted hazard ratio [HR]: 1.94; 95% confidence interval [CI]: 1.35 to 2.78; p = 0.0010). The annual rates in the corresponding groups ranged from 0.46% to 4.24% (adjusted HR: 4.31; 95% CI: 2.91 to 6.37; p < 0.0001) for cardiac death and from 1.26% to 4.21% (adjusted HR: 1.91; 95% CI: 1.43 to 2.56; p = 0.0001) for major bleeding. Adding hs-TnT levels to the CHA2DS2VASc score improved the C statistic from 0.620 to 0.635 for stroke or systemic embolism (p = 0.0226), from 0.592 to 0.711 for cardiac death (p < 0.0001), and from 0.591 to 0.629 for major bleeding (p < 0.0001). Apixaban reduced rates of stroke, mortality, and bleeding regardless of the hs-TnT level.ConclusionsLevels of hs-TnT are often elevated in patients with AF. The hs-TnT level is independently associated with an increased risk of stroke, cardiac death, and major bleeding and improves risk stratification beyond the CHA2DS2VASc risk score. The benefits of apixaban as compared with warfarin are consistent regardless of the hs-TnT level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE];
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| 36. |
- Hijazi, Ziad, et al.
(författare)
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N-Terminal Pro-B-Type Natriuretic Peptide for Risk Assessment in Patients With Atrial Fibrillation : Insights from the ARISTOTLE trial
- 2013
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 61:22, s. 2274-2284
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:This study sought to assess the prognostic value of N-terminal pro–B-type natriuretic peptide (NT-proBNP) in patients with atrial fibrillation (AF) enrolled in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial, and the treatment effect of apixaban according to NT-proBNP levels.BACKGROUND:Natriuretic peptides are associated with mortality and cardiovascular events in several cardiac diseases.METHODS:In the ARISTOTLE trial, 18,201 patients with AF were randomized to apixaban or warfarin. Plasma samples at randomization were available from 14,892 patients. The association between NT-proBNP concentrations and clinical outcomes was evaluated using Cox proportional hazard models, after adjusting for established cardiovascular risk factors.RESULTS:Quartiles of NT-proBNP were Q1:≤363, Q2:364-713, Q3:714-1250 and Q4:>1250 ng/L. During 1.8 years the annual rates of stroke or systemic embolism ranged from 0.74% in the bottom NT-proBNP quartile to 2.21% in the top quartile, adjusted hazard ratio (HR) 2.35 (95% CI 1.62-3.40, p<0.0001. Annual rates of cardiac death ranged from 0.86% in Q1 to 4.14% in Q4, adjusted HR 2.50 (1.81-3.45), p<0.0001. Adding NT-proBNP levels to the CHA2DS2VASc score improved C-statistics from 0.62 to 0.65 (p=0.0009) for stroke or systemic embolism and from 0.59 to 0.69 for cardiac death (p<0.0001). Apixaban reduced stroke, mortality, and bleeding regardless of the NT-proBNP level.CONCLUSIONS:NT-proBNP levels are often elevated in AF and independently associated with an increased risk of stroke and mortality. NT-proBNP improves risk stratification beyond the CHA2DS2VASc score and might be a novel tool for improved stroke prediction in AF. The efficacy of apixaban compared with warfarin is independent of the NT-proBNP level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE].
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| 37. |
- Hijazi, Ziad, et al.
(författare)
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Repeated Measurements of Cardiac Biomarkers in Atrial Fibrillation and Validation of the ABC Stroke Score Over Time
- 2017
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Ingår i: Journal of the American Heart Association. - : WILEY. - 2047-9980. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cardiac biomarkers are independent risk markers in atrial fibrillation, and the novel biomarker-based ABC stroke score (age, biomarkers, and clinical history of prior stroke) was recently shown to improve the prediction of stroke risk in patients with atrial fibrillation. Our aim was to investigate the short-term variability of the cardiac biomarkers and evaluate whether the ABC stroke risk score provides a stable short- term risk estimate.Methods and Results: According to the study protocol, samples were obtained at entry and also at 2 months in 4796 patients with atrial fibrillation followed for a median of 1.8 years in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Cardiac troponin I, cardiac troponin T, and N-terminal pro-B-type natriuretic peptide were measured with high-sensitivity immunoassays. Associations with outcomes were evaluated by Cox regression. C indices and calibration plots were used to evaluate the ABC stroke score at 2 months. The average changes in biomarker levels during 2 months were small ( median change cardiac troponin T +2.8%, troponin I +2.0%, and N-terminal pro-B-type natriuretic peptide +13.5%) and within-subject correlation was high ( all >= 0.82). Repeated measurement of cardiac biomarkers provided some incremental prognostic value for mortality but not for stroke when combined with clinical risk factors and baseline levels of the biomarkers. Based on 8702 person-years of follow-up and 96 stroke/systemic embolic events, the ABC stroke score at 2 months achieved a similar C index of 0.70 (95% CI, 0.65-0.76) as compared with 0.70 (95% CI, 0.65-0.75) at baseline. The ABC stroke score remained well calibrated using predefined risk classes.Conclusions: In patients with stable atrial fibrillation, the variability of the cardiac biomarkers and the biomarker- based ABC stroke score during 2 months are small. The prognostic information by the ABC stroke score remains consistent and well calibrated with similar good predictive performance if patients are retested after 2 months.Clinical Trial Registration --URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.
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| 38. |
- Hijazi, Ziad, et al.
(författare)
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The ABC (age, biomarkers, clinical history) stroke risk score : a biomarker-based risk score for predicting stroke in atrial fibrillation
- 2016
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 37:20, s. 1582-1590
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Atrial fibrillation (AF) is associated with an increased risk of stroke, which is currently estimated by clinical characteristics. The cardiac biomarkers N-terminal fragment B-type natriuretic peptide (NT-proBNP) and cardiac troponin high-sensitivity (cTn-hs) are independently associated with risk of stroke in AF. Our objective was to develop and validate a new biomarker-based risk score to improve prognostication of stroke in patients with AF.Methods: and results A new risk score was developed and internally validated in 14 701 patients with AF and biomarkers levels determined at baseline, median follow-up of 1.9 years. Biomarkers and clinical variables significantly contributing to predicting stroke or systemic embolism were assessed by Cox-regression and each variable obtained a weight proportional to the model coefficients. External validation was performed in 1400 patients with AF, median follow-up of 3.4 years. The most important predictors were prior stroke/transient ischaemic attack, NT-proBNP, cTn-hs, and age, which were included in the ABC (Age, Biomarkers, Clinical history) stroke risk score. The ABC-stroke score was well calibrated and yielded higher c-indices than the widely used CHA2DS2-VASc score in both the derivation cohort (0.68 vs. 0.62, P < 0.001) and the external validation cohort (0.66 vs. 0.58, P < 0.001). Moreover, the ABC-stroke score consistently provided higher c-indices in several important subgroups.Conclusion: A novel biomarker-based risk score for predicting stroke in AF was successfully developed and internally validated in a large cohort of patients with AF and further externally validated in an independent AF cohort. The ABC-stroke score performed better than the presently used clinically based risk score and may provide improved decision support in AF.
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| 39. |
- Hijazi, Ziad, et al.
(författare)
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The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation : a derivation and validation study
- 2016
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 387:10035, s. 2302-2311
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Tidskriftsartikel (refereegranskat)abstract
- Background: The benefit of oral anticoagulation in atrial fibrillation is based on a balance between reduction in ischaemic stroke and increase in major bleeding. We aimed to develop and validate a new biomarker-based risk score to improve the prognostication of major bleeding in patients with atrial fibrillation.Methods: We developed and internally validated a new biomarker-based risk score for major bleeding in 14 537 patients with atrial fibrillation randomised to apixaban versus warfarin in the ARISTOTLE trial and externally validated it in 8468 patients with atrial fibrillation randomised to dabigatran versus warfarin in the RE-LY trial. Plasma samples for determination of candidate biomarker concentrations were obtained at randomisation. Major bleeding events were centrally adjudicated. The predictive values of biomarkers and clinical variables were assessed with Cox regression models. The most important variables were included in the score with weights proportional to the model coefficients. The ARISTOTLE and RE-LY trials are registered with ClinicalTrials.gov, numbers NCT00412984 and NCT00262600, respectively.Findings: The most important predictors for major bleeding were the concentrations of the biomarkers growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (cTnT-hs) and haemoglobin, age, and previous bleeding. The ABC-bleeding score (age, biomarkers [GDF-15, cTnT-hs, and haemoglobin], and clinical history [previous bleeding]) score yielded a higher c-index than the conventional HAS-BLED and the newer ORBIT scores for major bleeding in both the derivation cohort (0.68 [95% CI 0.66-0.70] vs 0.61 [0.59-0.63] vs 0.65 [0.62-0.67], respectively; ABC-bleeding vs HAS-BLED p< 0.0001 and ABC-bleeding vs ORBIT p= 0.0008). ABC-bleeding score also yielded a higher c-index score in the the external validation cohort (0.71 [95% CI 0.68-0.73] vs 0.62 [0.59-0.64] for HAS-BLED vs 0.68 [0.65-0.70] for ORBIT; ABC-bleeding vs HAS-BLED p< 0.0001 and ABC-bleeding vs ORBIT p= 0.0016). A modified ABC-bleeding score using alternative biomarkers (haematocrit, cTnI-hs, cystatin C, or creatinine clearance) also outperformed the HAS-BLED and ORBIT scores.Interpretation: The ABC-bleeding score, using age, history of bleeding, and three biomarkers (haemoglobin, cTn-hs, and GDF-15 or cystatin C/CKD-EPI) was internally and externally validated and calibrated in large cohorts of patients with atrial fibrillation receiving anticoagulation therapy. The ABC-bleeding score performed better than HAS-BLED and ORBIT scores and should be useful as decision support on anticoagulation treatment in patients with atrial fibrillation.
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| 40. |
- Lopes, Renato D., et al.
(författare)
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Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation
- 2019
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Ingår i: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 380:16, s. 1509-1524
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Tidskriftsartikel (refereegranskat)abstract
- Background Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear. Methods In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y(12) inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events. Results Enrollment included 4614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P=0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group. Conclusions In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y(12) inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both.
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| 41. |
- Oldgren, Jonas, et al.
(författare)
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Performance and Validation of a Novel Biomarker-Based Stroke Risk Score for Atrial Fibrillation
- 2016
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 134:22, s. 1697-1707
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: -Atrial fibrillation (AF) is associated with increased but variable risk of stroke. Our aim was to validate the recently developed biomarker-based ABC-stroke risk score and compare its performance with the CHA2DS2VASc and ATRIA risk scores.METHODS: -ABC-stroke score includes Age, Biomarkers (NT-proBNP and high-sensitivity [hs] troponin [cTn]), and Clinical history (prior stroke). This validation was based on 8,356 patients, 16,137 person-years of follow-up, and 219 adjudicated stroke or systemic embolic (SE) events in anticoagulated patients with AF in the RE-LY study. Levels of NT-proBNP, hs-cTnT, and hs-cTnI were determined in plasma samples obtained at study entry.RESULTS: -The ABC-stroke score was well calibrated with 0.76 stroke/SE events per 100 person-years in the predefined low (<1%/year) risk group, 1.48 in the medium (1-2%/year) risk group, and 2.60 in the high (>2%/year) risk group for the ABC-stroke score with hs-cTnT. Hazard ratios for stroke/SE were 1.95 for medium versus low risk, and 3.44 for high versus low risk groups. ABC-stroke score achieved C indices of 0.65 with both hs-cTnT and hs-cTnI, as compared with 0.60 for CHA2DS2VASc (p=0.004 for hs-cTnT and p=0.022 hs-cTnI) and 0.61 for ATRIA scores (p=0.005 hs-cTnT and p=0.034 for hs-cTnI).CONCLUSIONS: -The biomarker-based ABC-stroke score was well calibrated and consistently performed better than both the CHA2DS2VASc and ATRIA stroke scores. The ABC score should be considered an improved decision support tool in the care of patients with AF.
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| 42. |
- Svennberg, Emma, et al.
(författare)
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NT-proBNP is a powerful predictor for incident atrial fibrillation : Validation of a multimarker approach
- 2016
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 223, s. 74-81
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Biomarkers may be of value to identify individuals at risk of developing atrial fibrillation (AF). Using a multimarker approach, this study investigated if the biomarkers; NT-proBNP, high-sensitivity cardiac troponin (hs-cTn), growth differentiation factor-15 (GDF-15), cystatin C and high-sensitivity C-reactive protein (CRP) are independent predictors for incident AF.METHODS: Blood samples were collected from 883 individuals in the Uppsala Longitudinal Study of Adult Men (ULSAM) and 978 individuals in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Participants were followed for 10-13years with n=113 incident AF cases in ULSAM and n=148 in PIVUS. The associations between biomarkers and incident AF were analysed in Cox proportional hazards regression models.RESULTS: The hazard ratio (HR) for incident AF was significant for all five biomarkers in unadjusted analyses in both cohorts. Only NT-proBNP remained significant when adjusting for cardiovascular risk factors and the other biomarkers (HR (1SD) 2.05 (1.62-2.59) (ULSAM) and 1.56 (1.30-1.86) (PIVUS), both p<0.001). The C-index improved from 0.64 to 0.69 in ULSAM and from 0.62 to 0.68 in PIVUS, by adding NT-proBNP to cardiovascular risk factors (both p<0.001). The C-index of the CHARGE-AF risk score increased from 0.62 to 0.68 (ULSAM) and 0.60 to 0.66 (PIVUS) by addition of NT-proBNP (p<0.001).CONCLUSIONS: Using a multimarker approach NT-proBNP was the strongest predictor of incident AF in two cohorts, and improved risk prediction when added to traditional risk factors. NT-proBNP significantly improved the predictive ability of the novel CHARGE-AF risk score, although the predictive value remained modest.
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| 43. |
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| 44. |
- Wallentin, Lars, et al.
(författare)
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Growth Differentiation Factor 15, a Marker of Oxidative Stress and Inflammation, for Risk Assessment in Patients With Atrial Fibrillation : Insights From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial
- 2014
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 130:21, s. 1847-1858
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Tidskriftsartikel (refereegranskat)abstract
- Background-Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation. Methods and Results-The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment, and other biomarkers. The GDF-15 level showed a median of 1383 ng/L (interquartile range, 977-2052 ng/L). Annual rates of stroke or systemic embolism ranged from 0.9% to 2.03% (P<0.001); of major bleeding, from 1.22% to 4.53% (P<0.001); and of mortality, from 1.34% to 7.19% (P<0.001) in the lowest compared with the highest GDF-15 quartile. The prognostic information provided by GDF-15 was independent of clinical characteristics and clinical risk scores. Adjustment for the other cardiac biomarkers attenuated the prognostic value for stroke, whereas the prognostic value for mortality and major bleeding remained. Apixaban consistently reduced stroke, mortality, and bleeding, regardless of GDF-15 levels. Conclusions-GDF-15 is a risk factor for major bleeding, mortality, and stroke in atrial fibrillation. The prognostic value for major bleeding and death remained even in the presence of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin I.
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| 45. |
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