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- Connolly, Stuart J, et al.
(author)
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Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial.
- 2018
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In: Lancet (London, England). - 1474-547X. ; 391:10117, s. 205-218
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Journal article (peer-reviewed)abstract
- Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.Between March 12, 2013, and May 10, 2016, 27395 patients were enrolled to the COMPASS trial, of whom 24824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78-1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37-2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23-1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65-0·90, p=0·0012).In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.Bayer AG.
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- Andersson, Jan O., et al.
(author)
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A genomic survey of the fish parasite Spironucleus salmonicida indicates genomic plasticity among diplomonads and significant lateral gene transfer in eukaryote genome evolution
- 2007
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 8, s. 51-
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Research review (peer-reviewed)abstract
- Background: Comparative genomic studies of the mitochondrion-lacking protist group Diplomonadida (diplomonads) has been lacking, although Giardia lamblia has been intensively studied. We have performed a sequence survey project resulting in 2341 expressed sequence tags (EST) corresponding to 853 unique clones, 5275 genome survey sequences (GSS), and eleven finished contigs from the diplomonad fish parasite Spironucleus salmonicida (previously described as S. barkhanus). Results: The analyses revealed a compact genome with few, if any, introns and very short 3′ untranslated regions. Strikingly different patterns of codon usage were observed in genes corresponding to frequently sampled ESTs versus genes poorly sampled, indicating that translational selection is influencing the codon usage of highly expressed genes. Rigorous phylogenomic analyses identified 84 genes - mostly encoding metabolic proteins - that have been acquired by diplomonads or their relatively close ancestors via lateral gene transfer (LGT). Although most acquisitions were from prokaryotes, more than a dozen represent likely transfers of genes between eukaryotic lineages. Many genes that provide novel insights into the genetic basis of the biology and pathogenicity of this parasitic protist were identified including 149 that putatively encode variant-surface cysteine-rich proteins which are candidate virulence factors. A number of genomic properties that distinguish S. salmonicida from its human parasitic relative G. lamblia were identified such as nineteen putative lineage-specific gene acquisitions, distinct mutational biases and codon usage and distinct polyadenylation signals. Conclusion: Our results highlight the power of comparative genomic studies to yield insights into the biology of parasitic protists and the evolution of their genomes, and suggest that genetic exchange between distantly-related protist lineages may be occurring at an appreciable rate in eukaryote genome evolution.
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- 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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- Dyal Ukabhai, K., et al.
(author)
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Formation of Ti2Cu in Ti-Cu Alloys
- 2022
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In: JOURNAL OF PHASE EQUILIBRIA AND DIFFUSION. - : Springer Nature. - 1547-7037 .- 1863-7345. ; 43:3, s. 332-344
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Journal article (peer-reviewed)abstract
- One of the major issues with dental implants is failure due to bacterial infection, and additions of copper are known to improve the antimicrobial properties of Ti alloys. There are inconsistencies in the Ti rich area of the Cu-Ti binary phase diagram, hence the need to find out if Ti2Cu or Ti3Cu is formed, and to identify the type of formation of Ti2Cu. Four alloys: 20, 33, 40 and 50 Cu (mass%) were produced by arc melting and studied using SEM, XRD and DSC. The reactions were derived, and the temperatures of the reactions were determined by DSC. The formation of Ti2Cu is congruent, and no Ti3Cu was found.
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- Yusuf, S, et al.
(author)
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Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial.
- 2008
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In: Lancet. - 1474-547X. ; 372:9644, s. 1174-83
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Journal article (peer-reviewed)abstract
- BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce major cardiovascular events, but are not tolerated by about 20% of patients. We therefore assessed whether the angiotensin-receptor blocker telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with end-organ damage. METHODS: After a 3-week run-in period, 5926 patients, many of whom were receiving concomitant proven therapies, were randomised to receive telmisartan 80 mg/day (n=2954) or placebo (n=2972) by use of a central automated randomisation system. Randomisation was stratified by hospital. The primary outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00153101. FINDINGS: The median duration of follow-up was 56 (IQR 51-64) months. All randomised patients were included in the efficacy analyses. Mean blood pressure was lower in the telmisartan group than in the placebo group throughout the study (weighted mean difference between groups 4.0/2.2 [SD 19.6/12.0] mm Hg). 465 (15.7%) patients experienced the primary outcome in the telmisartan group compared with 504 (17.0%) in the placebo group (hazard ratio 0.92, 95% CI 0.81-1.05, p=0.216). One of the secondary outcomes-a composite of cardiovascular death, myocardial infarction, or stroke-occurred in 384 (13.0%) patients on telmisartan compared with 440 (14.8%) on placebo (0.87, 0.76-1.00, p=0.048 unadjusted; p=0.068 after adjustment for multiplicity of comparisons and overlap with primary outcome). 894 (30.3%) patients receiving telmisartan were hospitalised for a cardiovascular reason, compared with 980 (33.0%) on placebo (relative risk 0.92, 95% CI 0.85-0.99; p=0.025). Fewer patients permanently discontinued study medication in the telmisartan group than in the placebo group (639 [21.6%] vs 705 [23.8%]; p=0.055); the most common reason for permanent discontinuation was hypotensive symptoms (29 [0.98%] in the telmisartan group vs 16 [0.54%] in the placebo group). INTERPRETATION: Telmisartan was well tolerated in patients unable to tolerate ACE inhibitors. Although the drug had no significant effect on the primary outcome of this study, which included hospitalisations for heart failure, it modestly reduced the risk of the composite outcome of cardiovascular death, myocardial infarction, or stroke. FUNDING: Boehringer Ingelheim.
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