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| 2. |
- Ganesh, Santhi K., et al.
(author)
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Loci influencing blood pressure identified using a cardiovascular gene-centric array
- 2013
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:8, s. 1663-1678
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Journal article (peer-reviewed)abstract
- Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped 50 000 single-nucleotide polymorphisms (SNPs) that capture variation in 2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P 2.4 10(6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
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| 3. |
- Tragante, Vinicius, et al.
(author)
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Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci.
- 2014
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:3, s. 349-360
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Journal article (peer-reviewed)abstract
- Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
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| 4. |
- Capodanno, Davide, et al.
(author)
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Defining Strategies of Modulation of Antiplatelet Therapy in Patients With Coronary Artery Disease : A Consensus Document from the Academic Research Consortium
- 2023
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In: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 147:25, s. 1933-1944
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Journal article (peer-reviewed)abstract
- Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.
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| 5. |
- Lau, Emily S., et al.
(author)
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Potent P2Y(12) Inhibitors in Men Versus Women : A Collaborative Meta-Analysis of Randomized Trials
- 2017
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 69:12, s. 1549-1559
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Journal article (peer-reviewed)abstract
- BACKGROUND: Sex-specific differences in response to antiplatelet therapies have been described. Whether women and men derive comparable benefit from intensification of antiplatelet therapy remains uncertain.OBJECTIVES: The study investigated the efficacy and safety of the potent P2Y(12) inhibitors in patients with coronary artery disease.METHODS: A collaborative sex-specific meta-analysis was conducted of phase III or IV randomized trials of potent P2Y(12) inhibitors, including prasugrel, ticagrelor, and intravenous cangrelor. Seven trials were included that enrolled a total of 24,494 women and 63,346 men. Major adverse cardiovascular events (MACE) were defined as the primary endpoint for each trial.RESULTS: Potent P2Y(12) inhibitors significantly reduced the risk of MACE by 14% in women (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.78 to 0.94) and by 15% in men (HR: 0.85; 95% CI: 0.80 to 0.90; p interaction = 0.93). Treatment reduced the risk of myocardial infarction by 13% in women (HR: 0.87; 95% CI: 0.78 to 0.96) and 16% in men (HR: 0.84; 95% CI: 0.77 to 0.91; p interaction = 0.65), and the risk of stent thrombosis by 51% in women (HR: 0.49; 95% CI: 0.37 to 0.65) and 41% in men (HR: 0.59; 95% CI: 0.42 to 0.84; p interaction = 0.85). Directional consistency was seen for cardiovascular death in women (HR: 0.87; 95% CI: 0.76 to 1.01) and men (HR: 0.85; 95% CI: 0.77 to 0.95; p interaction = 0.86). The potent P2Y(12) inhibitors increased major bleeding in women (HR: 1.28; 95% CI: 0.87 to 1.88) and men (HR: 1.52; 95% CI: 1.12 to 2.07; p interaction = 0.62).CONCLUSIONS: In randomized trials, the efficacy and safety of the potent P2Y(12) inhibitors were comparable between men and women. Given these data, sex should not influence patient selection for the administration of potent P2Y(12) inhibitors.
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| 6. |
- Alfredsson, Joakim, et al.
(author)
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Predicting the risk of bleeding during dual antiplatelet therapy after acute coronary syndromes
- 2017
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In: Heart. - : BMJ PUBLISHING GROUP. - 1355-6037 .- 1468-201X. ; 103:15, s. 1168-1176
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Journal article (peer-reviewed)abstract
- Objectives Dual antiplatelet therapy (DAPT) with aspirin + a P2Y12 inhibitor is recommended for at least 12 months for patients with acute coronary syndrome (ACS), with shorter durations considered for patients with increased bleeding risk. However, there are no decision support tools available to predict an individual patients bleeding risk during DAPT treatment in the post-ACS setting. Methods To develop a longitudinal bleeding risk prediction model, we analysed 9240 patients with unstable angina/non-ST segment elevation myocardial infarction (NSTEMI) from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, who were managed without revascularisation and treated with DAPT for a median of 14.8 months. Results We identified 10 significant baseline predictors of non-coronary artery bypass grafting (CABG)-related Global Use of Strategies to Open Occluded Arteries (GUSTO) severe/life-threatening/moderate bleeding: age, sex, weight, NSTEMI (vs unstable angina), angiography performed before randomisation, prior peptic ulcer disease, creatinine, systolic blood pressure, haemoglobin and treatment with beta-blocker. The five significant baseline predictors of Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding included age, sex, angiography performed before randomisation, creatinine and haemoglobin. The models showed good predictive accuracy with Therneaus C-indices: 0.78 (SE=0.024) for the GUSTO model and 0.67 (SE=0.023) for the TIMI model. Internal validation with bootstrapping gave similar C-indices of 0.77 and 0.65, respectively. External validation demonstrated an attenuated C-index for the GUSTO model (0.69) but not the TIMI model (0.68). Conclusions Longitudinal bleeding risks during treatment with DAPT in patients with ACS can be reliably predicted using selected baseline characteristics. The TRILOGY ACS bleeding models can inform riskbenefit considerations regarding the duration of DAPT following ACS.
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| 7. |
- Benza, Raymond L., et al.
(author)
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CS1, a controlled-release formulation of valproic acid, for the treatment of patients with pulmonary arterial hypertension: Rationale and design of a Phase 2 clinical trial
- 2024
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In: PULMONARY CIRCULATION. - 2045-8932 .- 2045-8940. ; 14:1
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Journal article (peer-reviewed)abstract
- Although rare, pulmonary arterial hypertension (PAH) is associated with substantial morbidity and a median survival of approximately 7 years, even with treatment. Current medical therapies have a primarily vasodilatory effect and do not modify the underlying pathology of the disease. CS1 is a novel oral, controlled-release formulation of valproic acid, which exhibits a multi-targeted mode of action (pulmonary pressure reduction, reversal of vascular remodeling, anti-inflammatory, anti-fibrotic, and anti-thrombotic) and therefore potential for disease modification and right ventricular modeling in patients with PAH. A Phase 1 study conducted in healthy volunteers indicated favorable safety and tolerability, with no increased risk of bleeding and significant reduction of plasminogen activator inhibitor 1. In an ongoing randomized Phase 2 clinical trial, three doses of open-label CS1 administered for 12 weeks is evaluating the use of multiple outcome measures. The primary endpoint is safety and tolerability, as measured by the occurrence of adverse events. Secondary outcome measures include the use of the CardioMEMS (TM) HF System, which provides a noninvasive method of monitoring pulmonary artery pressure, as well as cardiac magnetic resonance imaging and echocardiography. Other outcomes include changes in risk stratification (using the REVEAL 2.0 and REVEAL Lite 2 tools), patient reported outcomes, functional capacity, 6-min walk distance, actigraphy, and biomarkers. The pharmacokinetic profile of CS1 will also be evaluated. Overall, the novel design and unique, extensive clinical phenotyping of participants in this trial will provide ample evidence to inform the design of any future Phase 3 studies with CS1.
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| 8. |
- Bhatt, Deepak L., et al.
(author)
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Rationale, design and baseline characteristics of the effect of ticagrelor on health outcomes in diabetes mellitus patients Intervention study
- 2019
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In: Clinical Cardiology. - : Wiley. - 0160-9289 .- 1932-8737. ; 42:5, s. 498-505
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Journal article (peer-reviewed)abstract
- In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double-blinded, placebo-controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients >= 50 years with type 2 diabetes receiving anti-diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of >= 50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19 220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow-up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice daily dose, as the dose was lowered from 90 mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention.
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| 9. |
- Cannon, Christopher P., et al.
(author)
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Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation.
- 2017
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In: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 377:16, s. 1513-1524
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Journal article (peer-reviewed)abstract
- BACKGROUND: Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the standard of care after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, but this therapy is associated with a high risk of bleeding.METHODS: inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg and 150-mg dual-therapy groups). Outside the United States, elderly patients (≥80 years of age; ≥70 years of age in Japan) were randomly assigned to the 110-mg dual-therapy group or the triple-therapy group. The primary end point was a major or clinically relevant nonmajor bleeding event during follow-up (mean follow-up, 14 months). The trial also tested for the noninferiority of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin with respect to the incidence of a composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization.RESULTS: The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group as compared with 26.9% in the triple-therapy group (hazard ratio, 0.52; 95% confidence interval [CI], 0.42 to 0.63; P<0.001 for noninferiority; P<0.001 for superiority) and 20.2% in the 150-mg dual-therapy group as compared with 25.7% in the corresponding triple-therapy group, which did not include elderly patients outside the United States (hazard ratio, 0.72; 95% CI, 0.58 to 0.88; P<0.001 for noninferiority). The incidence of the composite efficacy end point was 13.7% in the two dual-therapy groups combined as compared with 13.4% in the triple-therapy group (hazard ratio, 1.04; 95% CI, 0.84 to 1.29; P=0.005 for noninferiority). The rate of serious adverse events did not differ significantly among the groups.CONCLUSIONS: inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events. (Funded by Boehringer Ingelheim; RE-DUAL PCI ClinicalTrials.gov number, NCT02164864)
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| 10. |
- 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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| 11. |
- Gaudino, Mario, et al.
(author)
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Graft Failure After Coronary Artery Bypass Grafting and Its Association With Patient Characteristics and Clinical Events: A Pooled Individual Patient Data Analysis of Clinical Trials With Imaging Follow-Up.
- 2023
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In: Circulation. - 1524-4539.
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Journal article (peer-reviewed)abstract
- Graft patency is the postulated mechanism for the benefits of coronary artery bypass grafting (CABG). However, systematic graft imaging assessment after CABG is rare, and there is a lack of contemporary data on the factors associated with graft failure and on the association between graft failure and clinical events after CABG.We pooled individual patient data from randomized clinical trials with systematic CABG graft imaging to assess the incidence of graft failure and its association with clinical risk factors. The primary outcome was the composite of myocardial infarction or repeat revascularization occurring after CABG and before imaging. A 2-stage meta-analytic approach was used to evaluate the association between graft failure and the primary outcome. We also assessed the association between graft failure and myocardial infarction, repeat revascularization, or all-cause death occurring after imaging.Seven trials were included comprising 4413 patients (mean age, 64.4±9.1 years; 777 [17.6%] women; 3636 [82.4%] men) and 13163 grafts (8740 saphenous vein grafts and 4423 arterial grafts). The median time to imaging was 1.02 years (Q1;Q3: 1.00;1.03). Graft failure occurred in 1487 (33.7%) patients and in 2190 (16.6%) grafts. Age (adjusted odds ratio [aOR], 1.08 [per 10-year increment] [95% CI, 1.01-1.15]; P=0.03), female sex (aOR, 1.27 [95% CI, 1.08-1.50]; P=0.004), and smoking (aOR, 1.20 [95% CI, 1.04-1.38]; P=0.01) were independently associated with graft failure, whereas statins were associated with a protective effect (aOR, 0.74 [95% CI, 0.63-0.88]; P<0.001). Graft failure was associated with an increased risk of myocardial infarction or repeat revascularization occurring between CABG and imaging assessment (8.0% in patients with graft failure versus 1.7% in patients without graft failure; aOR, 3.98 [95% CI, 3.54-4.47]; P<0.001). Graft failure was also associated with an increased risk of myocardial infarction or repeat revascularization occurring after imaging (7.8% versus 2.0%; aOR, 2.59 [95% CI, 1.86-3.62]; P<0.001). All-cause death after imaging occurred more frequently in patients with graft failure compared with patients without graft failure (11.0% versus 2.1%; aOR, 2.79 [95% CI, 2.01-3.89]; P<0.001).In contemporary practice, graft failure remains common among patients undergoing CABG and is strongly associated with adverse cardiac events.
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| 12. |
- Hageman, Steven H. J., et al.
(author)
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Estimation of recurrent atherosclerotic cardiovascular event risk in patients with established cardiovascular disease : the updated SMART2 algorithm
- 2022
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In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 43:18, s. 1715-1727
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Journal article (peer-reviewed)abstract
- Aims The 10-year risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events in patients with established ASCVD can be estimated with the Secondary Manifestations of ARTerial disease (SMART) risk score, and may help refine clinical management. To broaden generalizability across regions, we updated the existing tool (SMART2 risk score) and recalibrated it with regional incidence rates and assessed its performance in external populations.Methods and results Individuals with coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysms were included from the Utrecht Cardiovascular Cohort-SMART cohort [n = 8355; 1706 ASCVD events during a median follow-up of 8.2 years (interquartile range 4.2-12.5)] to derive a 10-year risk prediction model for recurrent ASCVD events (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular mortality) using a Fine and Gray competing risk-adjusted model. The model was recalibrated to four regions across Europe, and to Asia (excluding Japan), Japan, Australia, North America, and Latin America using contemporary cohort data from each target region. External validation used data from seven cohorts [Clinical Practice Research Datalink, SWEDEHEART, the international REduction of Atherothrombosis for Continued Health (REACH) Registry, Estonian Biobank, Spanish Biomarkers in Acute Coronary Syndrome and Biomarkers in Acute Myocardial Infarction (BACS/BAMI), the Norwegian COgnitive Impairment After STroke, and Bialystok PLUS/Polaspire] and included 369 044 individuals with established ASCVD of whom 62 807 experienced an ASCVD event. C-statistics ranged from 0.605 [95% confidence interval (CI) 0.547-0.664] in BACS/BAMI to 0.772 (95% CI 0.659-0.886) in REACH Europe high-risk region. The clinical utility of the model was demonstrated across a range of clinically relevant treatment thresholds for intensified treatment options.Conclusion The SMART2 risk score provides an updated, validated tool for the prediction of recurrent ASCVD events in patients with established ASCVD across European and non-European populations. The use of this tool could allow for a more personalized approach to secondary prevention based upon quantitative rather than qualitative estimates of residual risk.
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| 13. |
- Hess, Connie N., et al.
(author)
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Apixaban Plus Mono Versus Dual Antiplatelet Therapy in Acute Coronary Syndromes Insights From the APPRAISE-2 Trial
- 2015
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 66:7, s. 777-787
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Journal article (peer-reviewed)abstract
- BACKGROUND Bleeding limits anticoagulant treatment in patients with acute coronary syndromes (ACS). OBJECTIVES We investigated whether background concomitant antiplatelet therapy influences the effects of apixaban after ACS. METHODS This study examined high-risk ACS patients who were treated with aspirin or aspirin plus clopidogrel and who were randomized to apixaban 5 mg twice daily or placebo. In a post-hoc analysis, we assessed whether the effect of apixaban on efficacy and safety outcomes varied by the concomitant antiplatelet regimen by using simple Cox modeling and marginal structural models with propensity scores and antiplatelet therapy as a time-dependent covariate. RESULTS At baseline, of 7,364 patients, 16.3% (n = 1,202) were on aspirin alone, and 79.0% (n = 5,814) were on aspirin plus clopidogrel. A total of 19.2% (n = 1,415) switched antiplatelet therapy during follow-up. No differential effect of apixaban versus placebo was observed for the composite endpoint of cardiovascular death, myocardial infarction, and ischemic stroke in patients taking aspirin (12.21 per 100 patient-years vs. 13.21 per 100 patient-years; adjusted hazard ratio [HR]: 0.91; 95% confidence interval [CI]: 0.62 to 1.32) or aspirin plus clopidogrel (13.22 vs. 14.24; adjusted HR: 0.95; 95% CI: 0.78 to 1.14; p(interaction) = 0.84). Compared with placebo, apixaban increased Thrombolysis In Myocardial Infarction major bleeding in patients taking aspirin (1.48 vs. 0.25; adjusted HR: 6.62; 95% CI: 0.75 to 51.73) and in patients taking aspirin plus clopidogrel (2.58 vs. 1.02; adjusted HR: 2.44; 95% CI: 1.34 to 4.45; p(interaction) = 0.41). Similar results were obtained with marginal structural models and in patients treated with and without percutaneous coronary intervention. CONCLUSIONS Post-ACS treatment with apixaban versus placebo showed no efficacy, but it increased bleeding regardless of concomitant therapy with aspirin alone or aspirin plus clopidogrel. (Apixaban for Prevention of Acute Ischemic Events 2 [APPRAISE-2]; NCT00831441) (J Am Coll Cardiol 2015; 66: 777-87)
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| 14. |
- Hohnloser, Stefan H., et al.
(author)
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Renal Function and Outcomes With Dabigatran Dual Antithrombotic Therapy in Atrial Fibrillation Patients After PCI
- 2019
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In: JACC. - : ELSEVIER SCIENCE INC. - 1936-8798 .- 1876-7605. ; 12:16, s. 1553-1561
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Journal article (peer-reviewed)abstract
- OBJECTIVES: The study sought to evaluate the effect of dabigatran dual therapy versus warfarin triple therapy across categories of renal function in the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial.BACKGROUND: The RE-DUAL PCI (NCT02164864) trial of patients with atrial fibrillation undergoing percutaneous coronary intervention reported that dabigatran dual therapy (110 or 150 mg twice daily, plus clopidogrel or ticagrelor) reduced the primary endpoint of major bleeding events (MBE) or clinically relevant nonmajor bleeding events (CRNMBE) compared with warfarin triple therapy, with noninferiority in overall thromboembolic events.METHODS: Risk of a first MBE or CRNMBE and the composite of death or thromboembolic event (DTE) or unplanned revascularization were evaluated in 2,725 patients according to baseline creatinine clearance (CrCl) categories: 30 to <50, 50 to <80, and >= 80 ml/min.RESULTS: Compared with warfarin, dabigatran 110 mg dual therapy reduced risk of MBE or CRNMBE across all categories of CrCl (p for interaction = 0.19). Dabigatran 150 mg dual therapy reduced risk of MBE or CRNMBE regardless of the CrCl category (p for interaction = 0.31). Risk of DTE or unplanned revascularization was similar to warfarin triple therapy for dabigatran 110 mg dual therapy across all CrCl categories. Dabigatran 150 mg dual therapy versus warfarin triple therapy had similar risk for DTE or unplanned revascularization in patients with CrCl 30 to <80 ml/min and lower risk at CrCl >= 80 ml/min (p for interaction = 0.02).CONCLUSIONS: In the RE-DUAL PCI trial, dabigatran dual therapy reduced bleeding events versus warfarin triple therapy irrespective of renal function, with overall similar risks of thromboembolic events but lower risks with dabigatran 150 mg in patients with normal CrCl.
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| 15. |
- Pareek, Manan, et al.
(author)
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Enhanced predictive capability of a 1-hour oral glucose tolerance test : A prospective population-based cohort study
- 2018
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In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 41:1, s. 171-177
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Journal article (peer-reviewed)abstract
- OBJECTIVE To examine whether the 1-h blood glucose measurement would be a more suitable screening tool for assessing the risk of diabetes and its complications than the 2-h measurement. RESEARCH DESIGN AND METHODS We conducted a prospective population-based cohort study of 4,867men, randomly selected fromprespecified birth cohorts between 1921 and 1949,who underwent an oral glucose tolerance test with blood glucose measurements at 0, 1, and 2 h. Subjects were followed for up to 39 years, with registry-based recording of events. Discriminative abilities of elevated 1-h (≥8.6 mmol/L) versus 2-h (≥7.8 mmol/L) glucose for predicting incident type 2 diabetes, vascular complications, andmortality were compared using Kaplan-Meier analysis, Cox proportional hazards regression, and net reclassification improvement. RESULTS Median agewas 48 years (interquartile range [IQR] 48-49). During follow-up (median 33 years [IQR 24-37]), 636 (13%) developed type 2 diabetes. Elevated 1-h glucose was associatedwith incident diabetes (hazard ratio 3.40 [95% CI 2.90-3.98], P < 0.001) and provided better risk assessment than impaired glucose tolerance (Harrell concordance index 0.637 vs. 0.511, P < 0.001). Addition of a 1-hmeasurement in subjects stratified by fasting glucose provided greater net reclassification improvement than the addition of a 2-h measurement (0.214 vs. 0.016, respectively). Finally, the 1-h glucose was significantly associated with vascular complications and mortality. CONCLUSIONS The 1-h blood glucose level is a stronger predictor of future type 2 diabetes than the 2-h level and is associated with diabetes complications and mortality.
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| 16. |
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| 17. |
- Alexander, John H., et al.
(author)
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Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome : results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial
- 2009
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In: Circulation. - 0009-7322 .- 1524-4539. ; 119:22, s. 2877-2885
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Journal article (peer-reviewed)abstract
- BACKGROUND: After an acute coronary syndrome, patients remain at risk of recurrent events. Apixaban, an oral direct factor Xa inhibitor, is a novel anticoagulant that may reduce these events but also poses a risk of bleeding. METHODS AND RESULTS: Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) was a phase 2, double-blind, placebo-controlled, dose-ranging study. Patients (n=1715) with recent ST-elevation or non-ST-elevation acute coronary syndrome were randomized to 6 months of placebo (n=611) or 1 of 4 doses of apixaban: 2.5 mg twice daily (n=317), 10 mg once daily (n=318), 10 mg twice daily (n=248), or 20 mg once daily (n=221). Nearly all patients received aspirin; 76% received clopidogrel. The primary outcome was International Society of Thrombosis and Hemostasis major or clinically relevant nonmajor bleeding. A secondary outcome was cardiovascular death, myocardial infarction, severe recurrent ischemia, or ischemic stroke. At the recommendation of the Data Monitoring Committee, the 2 higher-dose apixaban arms were discontinued because of excess total bleeding. Compared with placebo, apixaban 2.5 mg twice daily (hazard ratio, 1.78; 95% confidence interval, 0.91 to 3.48; P=0.09) and 10 mg once daily (hazard ratio, 2.45; 95% confidence interval, 1.31 to 4.61; P=0.005) resulted in a dose-dependent increase in major or clinically relevant nonmajor bleeding. Apixaban 2.5 mg twice daily (hazard ratio, 0.73; 95% confidence interval, 0.44 to 1.19; P=0.21) and 10 mg once daily (hazard ratio, 0.61; 95% confidence interval, 0.35 to 1.04; P=0.07) resulted in lower rates of ischemic events compared with placebo. The increase in bleeding was more pronounced and the reduction in ischemic events was less evident in patients taking aspirin plus clopidogrel than in those taking aspirin alone. CONCLUSIONS: We observed a dose-related increase in bleeding and a trend toward a reduction in ischemic events with the addition of apixaban to antiplatelet therapy in patients with recent acute coronary syndrome. The safety and efficacy of apixaban may vary depending on background antiplatelet therapy. Further testing of apixaban in patients at risk of recurrent ischemic events is warranted.
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| 18. |
- Alexander, John H., et al.
(author)
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Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome
- 2011
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 365:8, s. 699-708
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Journal article (peer-reviewed)abstract
- Background: Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome.Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events.Results: The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P = 0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P = 0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo.Conclusions: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events.
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| 19. |
- Anand, Sonia S, et al.
(author)
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Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial.
- 2018
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In: Lancet (London, England). - 1474-547X. ; 391:10117, s. 219-229
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Journal article (peer-reviewed)abstract
- Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding.Bayer AG.
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| 20. |
- Angiolillo, Dominick J., et al.
(author)
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International Expert Consensus on Switching Platelet P2Y(12) Receptor-Inhibiting Therapies
- 2017
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In: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 136:20, s. 1955-
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Journal article (peer-reviewed)abstract
- Dual antiplatelet therapy with aspirin and a P2Y(12) inhibitor is the treatment of choice for the prevention of atherothrombotic events in patients with acute coronary syndromes and for those undergoing percutaneous coronary interventions. The availability of different oral P2Y(12) inhibitors (clopidogrel, prasugrel, ticagrelor) has enabled physicians to contemplate switching among therapies because of specific clinical scenarios. The recent introduction of an intravenous P2Y(12) inhibitor (cangrelor) further adds to the multitude of modalities and settings in which switching therapies may occur. In clinical practice, it is not uncommon to switch P2Y(12) inhibitor, and switching may be attributed to a variety of factors. However, concerns about the safety of switching between these agents have emerged. Practice guidelines have not fully elaborated on how to switch therapies, leaving clinicians with limited guidance on when and how to switch therapies when needed. This prompted the development of this expert consensus document by key leaders from North America and Europe with expertise in basic, translational, and clinical sciences in the field of antiplatelet therapy. This expert consensus provides an overview of the pharmacology of P2Y(12) inhibitors, different modalities and definitions of switching, and available literature and recommendations for switching between P2Y(12) inhibitors.
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| 21. |
- Avdic, Tarik, et al.
(author)
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Non-coronary arterial outcomes in people with type 1 diabetes mellitus: a Swedish retrospective cohort study.
- 2024
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In: The Lancet regional health - Europe. - 2666-7762. ; 39
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Journal article (peer-reviewed)abstract
- Observational studies on long-term trends, risk factor association and importance are scarce for type 1 diabetes mellitus and peripheral arterial outcomes. We set out to investigate trends in non-coronary complications and their relationships with cardiovascular risk factors in persons with type 1 diabetes mellitus compared to matched controls.34,263 persons with type 1 diabetes mellitus from the Swedish National Diabetes Register and 164,063 matched controls were included. Incidence rates of extracranial large artery disease, aortic aneurysm, aortic dissection, lower extremity artery disease, and diabetic foot syndrome were analyzed using standardized incidence rates and Cox regression.Between 2001 and 2019, type 1 diabetes mellitus incidence rates per 100,000 person-years were as follows: extracranial large artery disease 296.5-84.3, aortic aneurysm 0-9.2, aortic dissection remained at 0, lower extremity artery disease 456.6-311.1, and diabetic foot disease 814.7-77.6. Persons with type 1 diabetes mellitus with cardiometabolic risk factors at target range did not exhibit excess risk of extracranial large artery disease [HR 0.83 (95% CI, 0.20-3.36)] or lower extremity artery disease [HR 0.94 (95% CI, 0.30-2.93)], compared to controls. Persons with type 1 diabetes with all risk factors at baseline, had substantially elevated risk for diabetic foot disease [HR 29.44 (95% CI, 3.83-226.04)], compared to persons with type 1 diabetes with no risk factors. Persons with type 1 diabetes mellitus continued to display a lower risk for aortic aneurysm, even with three cardiovascular risk factors at baseline [HR 0.31 (95% CI, 0.15-0.67)]. Relative importance analyses demonstrated that education, glycated hemoglobin (HbA1c), duration of diabetes and lipids explained 54% of extracranial large artery disease, while HbA1c, smoking and systolic blood pressure explained 50% of lower extremity artery disease and HbA1c alone contributed to 41% of diabetic foot disease. Income, duration of diabetes and body mass index explained 66% of the contribution to aortic aneurysm.Peripheral arterial complications decreased in persons with type 1 diabetes mellitus, except for aortic aneurysm which remained low. Besides glycemic control, traditional cardiovascular risk factors were associated with incident outcomes. Risk of these outcomes increased with additional risk factors present. Persons with type 1 diabetes mellitus exhibited a lower risk of aortic aneurysm compared to controls, despite presence of cardiovascular risk factors.Swedish Governmental and the county support of research and education of doctors, the Swedish Heart and Lung Foundation, Sweden and Åke-Wibergs grant.
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| 22. |
- Bajraktari, Gani, et al.
(author)
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Complete revascularization for patients with multivessel coronary artery disease and ST-segment elevation myocardial infarction after the COMPLETE trial : a meta-analysis of randomized controlled trials
- 2020
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In: IJC Heart & Vasculature. - : Elsevier. - 2352-9067. ; 29
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Journal article (peer-reviewed)abstract
- Background: The recently published COMPLETE trial has demonstrated that patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD), who underwent successful percutaneous coronary intervention (PCI) of both culprit and non-culprit (vs. culprit-only) lesions had a reduced risk of major adverse cardiac events (MACE), but not of cardiovascular or total mortality. The aim of this meta-analysis was to assess the efficacy of complete revascularization on cardiovascular or total mortality reduction using available randomized controlled trials (RCTs) including the COMPLETE trial, in hemodynamically stable STEMI patients with MVD. Methods: PubMed, MEDLINE, Embase, Scopus, Google Scholar, CENTRAL and ClinicalTrials.gov databases search identified 10 RCTs of 7033 patients with STEMI and MVD which compared complete (n = 3420) vs. only culprit lesion (n = 3613) PCI for a median 27.7 months follow-up. Random effect risk ratios were used to estimate for efficacy and safety outcomes. Results: Complete revascularization reduced the risk of MACE (10.4% vs.16.6%; RR = 0.59, 95% CI: 0.47 to 0.74, p < 0.0001), CV mortality (2.87% vs. 3.72%; RR = 0.73, 95% CI: 0.56 to 0.95, p = 0.02), reinfarction (5.1% vs. 7.1%; RR = 0.67, 95% CI: 0.52 to 0.86, p = 0.002), urgent revascularization (7.92% vs.17.4%; RR = 0.47, 95% CI: 0.30 to 0.73, p < 0.001), and CV hospitalization (8.68% vs.11.4%; RR = 0.65, 95% CI: 0.44to 0.96, p = 0.03) compared with culprit only revascularization. All-cause mortality, stroke, major bleeding events, or contrast induced nephropathy were not affected by the revascularization strategy. Conclusion: The findings of this meta-analysis suggest that in patients with STEMI and MVD, complete revascularization is superior to culprit-only PCI in reducing the risk of MACE outcomes, including cardiovascular mortality, without increasing the risk of adverse safety outcomes.
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| 23. |
- Becher, Peter Moritz, et al.
(author)
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Eligibility for sotagliflozin in a real-world heart failure population based on the SOLOIST-WHF trial enrolment criteria: data from the Swedish heart failure registry
- 2023
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In: European Heart Journal - Cardiovascular Pharmacotherapy. - : OXFORD UNIV PRESS. - 2055-6837 .- 2055-6845. ; 9:4, s. 343-352
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Journal article (peer-reviewed)abstract
- Aims The SOLOIST-WHF trial demonstrated efficacy of sotagliflozin in patients with type 2 diabetes mellitus (T2DM) and recent worsening heart failure (HF) regardless of ejection fraction (EF). Selection criteria in trials may limit their generalizability. Therefore, we aimed to investigate eligibility for sotagliflozin based on the SOLOIST-WHF criteria in a real-world HF population. Methods and results SOLOIST-WHF criteria were applied to patients stabilized after HF hospitalization in the Swedish HF Registry according to (i) literal scenario (all inclusion/exclusion criteria) or (ii) pragmatic scenario (only criteria likely to influence treatment decisions). Of 5453 inpatients with T2DM and recent worsening HF, 51.4% had reduced EF (HFrEF), 19.1% mildly reduced (HFmrEF), and 29.5% preserved EF (HFpEF). Eligibility (literal) was: 27.2% (32.4% in HFrEF, 24.7% in HFmrEF, 19.7% in HFpEF) and eligibility (pragmatic) was 62.8% (69.1%, 60.3%, 53.4%, respectively). In the literal scenario, criteria limiting eligibility were HF duration <3 months, eGFR <30 ml/min/1.73 m(2), age >85 years, acute coronary syndrome <3 months, and insufficiently high N-terminal pro-B-type natriuretic peptide levels. Eligible vs. non-eligible patients had more severe HF, higher cardiovascular (CV) comorbidity burden, higher use of HF treatments, and higher event rates (all-cause death 30.8 vs. 27.2 per 100 patient-years, CV death 19.1 vs. 16.6, and HF hospitalization 36.7 vs. 24.0). Conclusion In this large, real-world HF cohort with T2DM, similar to 1/3 of patients were eligible for sotagliflozin in the literal and similar to 2/3 of patients in the pragmatic scenario. Eligible patients had more severe HF and higher event rates, in particular CV and HF events.
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| 24. |
- Berry, Natalia C., et al.
(author)
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Effect of Lesion Complexity and Clinical Risk Factors on the Efficacy and Safety of Dabigatran Dual Therapy Versus Warfarin Triple Therapy in Atrial Fibrillation After Percutaneous Coronary Intervention A Subgroup Analysis From the REDUAL PCI Trial
- 2020
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In: Circulation. Cardiovascular Interventions. - : LIPPINCOTT WILLIAMS & WILKINS. - 1941-7640 .- 1941-7632. ; 13:4
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Journal article (peer-reviewed)abstract
- Background: The REDUAL PCI trial (Evaluation of Dual Therapy With Dabigatran vs Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting) demonstrated that, in patients with atrial fibrillation following percutaneous coronary intervention, bleeding risk was lower with dabigatran plus clopidogrel or ticagrelor (dual therapy) than warfarin plus clopidogrel or ticagrelor and aspirin (triple therapy). Dual therapy was noninferior for risk of thromboembolic events. Whether these results apply equally to patients at higher risk of ischemic events due to lesion complexity or clinical risk factors is unclear. Methods: The primary end point was time to first major or clinically relevant nonmajor bleeding event. The composite efficacy end point was death, thromboembolic event, or unplanned revascularization. Our prespecified subgroup analysis categorized patients by presence of procedural complexity and/or clinical complexity factors at baseline. A modified dual antiplatelet therapy score categorized patients according to degree of clinical risk. Results: Of 2725 patients, 43.1% had clinical complexity factors alone, 9.9% procedural factors alone, 10.0% both, and 37.0% neither. Risk of the primary bleeding end point was lower in both dabigatran dual therapy groups than warfarin triple therapy groups, regardless of procedural and/or clinical lesion complexity (interaction P values: 0.90 and 0.37, respectively). Importantly, a similar risk of the efficacy end point was observed between dabigatran dual and warfarin triple therapy, regardless of the presence of clinical or procedural complexity factors (interaction P values: 0.67 and 0.54, dabigatran 110 and 150 mg dual therapy, respectively). Similar benefit was seen for each dose of dabigatran dual therapy for bleeding events regardless of dual antiplatelet therapy score (interaction P values: 0.53 and 0.54, respectively), with similar risk of thromboembolic events (interaction P values: 0.20 and 0.08, respectively). Conclusions: In patients with atrial fibrillation undergoing percutaneous coronary intervention, dabigatran 110 and 150 mg dual therapy reduced bleeding risk compared with warfarin triple therapy, with a similar risk of thromboembolic outcomes, irrespective of procedural and/or clinical complexity and modified dual antiplatelet therapy score. Registration: URL: ; Unique identifier: NCT02164864.
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| 25. |
- Bhatt, Deepak L., et al.
(author)
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Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI) : a phase 3, placebo-controlled, randomised trial
- 2019
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In: The Lancet. - 0140-6736 .- 1474-547X. ; 394:10204, s. 1169-1180
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Journal article (peer-reviewed)abstract
- Background Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor.Methods The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria:a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population).Findings Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3.3 years (IQR 2.8-3.8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7.3%] of 5558 vs 480 [8.6%] of 5596; HR 0.85 [95% CI 0.74-0.97], p=0.013). The same effect was not observed in patients without PCI (p=0.76, p(interaction)=0.16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3.1%] with ticagrelor vs 183 (3.3%) with placebo; HR 0.96 [95% CI 0.78-1.18], p=0.68), as well as all-cause death (282 [5.1%] vs 323 [5.8%]; 0.88 [0.75-1.03], p=0.11). TIMI major bleeding occurred in 111 (2.0%) of 5536 patients receiving ticagrelor and 62 (1.1%) of 5564 patients receiving placebo (HR 2.03 [95% CI 1.48-2.76], p<0.0001), and fatal bleeding in 6 (0.1%) of 5536 patients with ticagrelor and 6 (0.1%) of 5564 with placebo (1.13 [0.36-3.50], p=0.83). Intracranial haemorrhage occurred in 33 (0.6%) and 31 (0.6%) patients (1.21 [0.74-1.97], p=0.45). Ticagrelor improved net clinical benefit:519/5558 (9.3%) versus 617/5596 (11.0%), HR=0.85, 95% CI 0.75-0.95, p=0.005, in contrast to patients without PCI where it did not, p(interaction)=0.012. Benefit was present irrespective of time from most recent PCI.Interpretation In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk.
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