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1.
Clin Cardiol ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31596518

RESUMO

BACKGROUND: We aimed to assess associations between circulating IL-18 concentrations and cardiovascular outcomes in patients with acute coronary syndromes (ACS). HYPOTHESIS AND METHODS: Plasma IL-18 concentrations were measured at admission, discharge, 1 month, and 6 months in patients with ACS in the PLATelet inhibition and patient Outcomes (PLATO) trial. Associations with outcomes were evaluated with Cox regression models on the composite of CV death, spontaneous myocardial infarction (sMI), or stroke; and on CV death or sMI separately, including adjustment for clinical risk factors and biomarkers (cTnT-hs, NT-proBNP, cystatin C, CRP-hs, and GDF-15). RESULTS: Median IL-18 concentrations at baseline, discharge, 1 month, and 6 months were 237, 283, 305, and 320 ng/L (n = 16 636). Male sex, obesity, diabetes, and plasma levels of cystatin C, GDF-15, and CRP-hs were independently associated with higher IL-18 levels. Higher baseline IL-18 levels were associated with the composite endpoint and with CV death (hazard ratio [HR] 1.05, 95% confidence interval [95% CI] 1.02-1.07 and HR 1.10, 95% CI 1.06-1.14, respectively, per 25% increase of IL-18 levels). Associations remained significant after adjustment for clinical variables but became non-significant after adjustment for all biomarkers (HR 1.01, 95% CI 0.98-1.04 and HR 1.04, 95% CI 1.00-1.08, respectively). There were no associations with sMI. CONCLUSIONS: In ACS patients, IL-18 concentrations increased after the acute event and remained increased for 6 months. Baseline IL-18 levels were significantly associated with CV mortality, independent of clinical characteristics and indicators of renal/cardiac dysfunction but this association was attenuated after adjustment for multiple biomarkers.

2.
Lancet ; 394(10204): 1169-1180, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31484629

RESUMO

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, pinteraction=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, pinteraction=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. FUNDING: AstraZeneca.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticagrelor/uso terapêutico , Idoso , Aspirina/uso terapêutico , Doenças Cardiovasculares/mortalidade , Angiografia Coronária , Ponte de Artéria Coronária , Doença da Artéria Coronariana/complicações , Estenose Coronária/diagnóstico por imagem , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemorragia/induzido quimicamente , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Intervenção Coronária Percutânea , Prevenção Secundária , Acidente Vascular Cerebral/epidemiologia
3.
N Engl J Med ; 381(14): 1309-1320, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31475798

RESUMO

BACKGROUND: Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear. METHODS: In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria. RESULTS: A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02). CONCLUSIONS: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.).


Assuntos
Aspirina/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticagrelor/uso terapêutico , Idoso , Aspirina/efeitos adversos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/mortalidade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Hemorragia/mortalidade , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Inibidores da Agregação de Plaquetas/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Ticagrelor/efeitos adversos , Resultado do Tratamento
4.
J Thromb Thrombolysis ; 48(4): 563-569, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31512201

RESUMO

Diabetes mellitus (DM) and abnormal glucose metabolism are associated with cardiovascular (CV) disease. We investigated the prevalence and prognostic importance of dysglycaemia in patients with acute coronary syndromes (ACS) in the PLATelet inhibition and patient Outcomes (PLATO) trial. Diabetes was defined as known diabetes or HbA1c ≥ 6.5% or non-fasting glucose ≥ 11.1 mmol/L on admission, prediabetes as HbA1c ≥ 5.7% but < 6.5%, and no diabetes as HbA1c < 5.7%. The primary endpoint was the composite of CV death, spontaneous myocardial infarction type 1 (sMI) or stroke at 12 months. Multivariable Cox regression models, adjusting for baseline characteristics, and biomarkers NT-proBNP and troponin I, were used to explore the association between glycaemia and outcome. On admission, 16,007 (86.1%) patients had HbA1c and/or glucose levels available and were subdivided into DM 38.5% (6160) (1501 patients had no previous DM diagnosis), prediabetes 38.8% (6210), and no DM 22.7% (3637). Kaplan Meier event rates at 12 months for CV death, sMI or stroke per subgroups were 14.5% (832), 9.0% (522), and 8.5% (293), respectively with multivariable adjusted HRs, versus no diabetes, for diabetes: 1.71 (1.50-1.95) and for prediabetes 1.03 (0.90-1.19). Corresponding event rates for CV death were 6.9% (391), 3.4% (195) and 3.0% (102), respectively, with adjusted HRs for patients with DM of: 1.92 (1.42-2.60) and for prediabetes 1.02 (0.79-1.32). Abnormal glucose metabolism is common in ACS patients, but only patients with definite DM have an increased CV risk, indicating that prediabetes is not immediately associated with worse CV outcomes.

5.
Eur Heart J Cardiovasc Pharmacother ; 5(4): 200-206, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31218354

RESUMO

AIMS: In PEGASUS-TIMI 54, ticagrelor significantly reduced the risk of the composite of major adverse cardiovascular (CV) events by 15-16% in stable patients with a prior myocardial infarction (MI) 1-3 years earlier. We report the efficacy and safety in the subpopulation recommended for treatment in the European (EU) label, i.e. treatment with 60 mg b.i.d. initiated up to 2 years from the MI, or within 1 year after stopping previous adenosine diphosphate receptor inhibitor treatment. METHODS AND RESULTS: Of the 21 162 patients enrolled in PEGASUS-TIMI 54, 10 779 patients were included in the primary analysis for this study, randomized to ticagrelor 60 mg (n = 5388) or matching placebo (n = 5391). The cumulative proportions of patients with events at 36 months were calculated by the Kaplan-Meier (KM) method. The composite of CV death, MI, or stroke occurred less frequently in the ticagrelor group (7.9% KM rate vs. 9.6%), hazard ratio (HR) 0.80 [95% confidence interval (CI) 0.70-0.91; P = 0.001]. Ticagrelor also reduced the risk of all-cause mortality, HR 0.80 (0.67-0.96; P = 0.018). Thrombolysis in myocardial infarction major bleeding was more frequent in the ticagrelor group 2.5% vs. 1.1%; HR 2.36 (1.65-3.39; P < 0.001). The corresponding HR for fatal or intracranial bleeding was 1.17 (0.68-2.01; P = 0.58). CONCLUSION: In PEGASUS-TIMI 54, treatment with ticagrelor 60 mg as recommended in the EU label, was associated with a relative risk reduction of 20% in CV death, MI, or stroke. Thrombolysis in myocardial infarction major bleeding was increased, but fatal or intracranial bleeding was similar to placebo. There appears to be a favourable benefit-risk ratio for long-term ticagrelor 60 mg in this population. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT01225562.

6.
Am Heart J ; 213: 57-65, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31108273

RESUMO

BACKGROUND: Heart failure (HF) following acute coronary syndromes (ACS) is associated with worse prognosis; however, the efficacy and safety of ticagrelor in patients with HF and if ticagrelor influences the risk of new-onset HF are unknown. METHODS: We examined the efficacy and safety of ticagrelor compared to clopidogrel in patients with ACS in the randomized PLATelet inhibition and patient Outcomes (PLATO) trial subdivided by strata: (1) previous HF and/or clinical signs of HF on admission or (2) no HF on admission. The primary outcome was the combination of cardiovascular death, myocardial infarction, or stroke evaluated by multivariable Cox regression models. The safety outcome was major bleeding. New-onset HF was defined as an HF event after discharge in patients without previous HF. RESULTS: Data were available in 18,556 patients, whom 2,862 (15.4%) patients had HF, including 1,584 (8.5%) patients with previous HF. Patients randomized to ticagrelor had lower risk of the composite end point regardless of HF status: hazard ratio (HR) 0.87 (95% CI: 0.73-1.03) in patients with HF and HR 0.84 (95% CI: 0.75-0.93) in patients with no HF (P = .76). Corresponding HR for major bleeding were HR 1.08 (95% CI: 0.87-1.34) and HR 1.03 (95% CI: 0.94-1.14) (P = .71). There was no difference in new-onset HF at 12 months between patients randomized to ticagrelor (4.1%, n = 278) or clopidogrel (4.0%, n = 276). CONCLUSIONS: In patients with ACS, ticagrelor is more efficacious in protecting against new ischemic events and mortality than clopidogrel irrespective of the presence of HF. There is no difference between ticagrelor or clopidogrel treatment in new-onset HF post-ACS.

7.
Eur Heart J Acute Cardiovasc Care ; : 2048872619846334, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31017470

RESUMO

AIMS: We investigated the dynamics, associations with patient characteristics, other biomarkers, and clinical outcomes of pentraxin 3 in acute coronary syndrome. METHODS AND RESULTS: In multivariate analyses, pentraxin 3 measured in 5154 patients randomised in the Platelet Inhibition and Patients Outcomes (PLATO) trial (NCT00391872) was compared with leukocytes, high-sensitivity C-reactive protein, interleukin-6, cystatin C, N-terminal prohormone brain natriuretic peptide, high-sensitivity troponin T and growth differentiation factor 15 concerning prediction of clinical outcome. Pentraxin 3 peaked earlier than high-sensitivity C-reactive protein and was more strongly correlated with N-terminal prohormone brain natriuretic peptide and high-sensitivity troponin T than with high-sensitivity C-reactive protein. The frequency of cardiovascular death, spontaneous myocardial infarction or stroke by quartiles of pentraxin 3 at admission was 6.1%, 7.3%, 9.7% and 10.7%, respectively ( p<0.0001). The hazard ratio per 50% increase of pentraxin 3 was 1.13 (95% confidence interval: 1.07-1.19), p<0.0001. This association remained significant after stepwise adjustments for leukocytes/high-sensitivity C-reactive protein (1.09 (1.02-1.15)), p=0.009, interleukin-6 (1.07 (1.01-1.14)), p=0.026, and cystatin C (1.07 (1.00-1.13)), p=0.044, but not after adjustment for N-terminal prohormone brain natriuretic peptide, high-sensitivity troponin T and growth differentiation factor 15. Admission pentraxin 3 was also associated with several of the individual endpoint components (cardiovascular death/spontaneous myocardial infarction; p=0.008, cardiovascular death; p=0.026, and spontaneous myocardial infarction; p=0.017), but not with stroke. Pentraxin 3 measured in the chronic phase (i.e. at one month) was still predictive of the composite endpoint in univariate analysis (1.12 (1.04-1.20) per 50% increase) p=0.0024, but not after adjustment for the other biomarkers. CONCLUSION: Admission level of pentraxin 3 is a modestly stronger predictor than high-sensitivity C-reactive protein and interleukin-6, but not than N-terminal prohormone brain natriuretic peptide or high-sensitivity troponin T, concerning cardiovascular outcome in acute coronary syndrome. Pentraxin 3 is more strongly correlated with N-terminal prohormone brain natriuretic peptide and high-sensitivity troponin T than with high-sensitivity C-reactive protein.

8.
J Am Heart Assoc ; 8(6): e011139, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30857464

RESUMO

Background There are limited data on how the combination of diabetes mellitus ( DM ) and chronic kidney disease ( CKD ) affects cardiovascular outcomes as well as response to different P2Y12 receptor antagonists, which represented the aim of the present investigation. Methods and Results In this post hoc analysis of the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized acute coronary syndrome patients to ticagrelor versus clopidogrel, patients (n=15 108) with available DM and CKD status were classified into 4 groups: DM +/ CKD + (n=1058), DM +/ CKD - (n=2748), DM -/ CKD + (n=2160), and DM -/ CKD - (n=9142). The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke at 12 months. The primary safety end point was PLATO major bleeding. DM +/ CKD + patients had a higher incidence of the primary end point compared with DM -/ CKD - patients (23.3% versus 7.1%; adjusted hazard ratio 2.22; 95% CI 1.88-2.63; P<0.001). Patients with DM +/ CKD - and DM -/ CKD + had an intermediate risk profile. The same trend was shown for the individual components of the primary end point and for major bleeding. Compared with clopidogrel, ticagrelor reduced the incidence of the primary end point consistently across subgroups ( P-interaction=0.264), but with an increased absolute risk reduction in DM +/ CKD +. The effects on major bleeding were also consistent across subgroups ( P-interaction=0.288). Conclusions In acute coronary syndrome patients, a gradient of risk was observed according to the presence or absence of DM and CKD , with patients having both risk factors at the highest risk. Although the ischemic benefit of ticagrelor over clopidogrel was consistent in all subgroups, the absolute risk reduction was greatest in patients with both DM and CKD . Clinical Trial Registration URL : http://www.clinicatrials.gov . Unique identifier: NCT 00391872.

9.
Clin Cardiol ; 42(5): 498-505, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30788847

RESUMO

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.

10.
Int J Stroke ; 14(7): 745-751, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30747613

RESUMO

RATIONALE: In patients with acute cerebral ischemia, the rate of stroke, myocardial infarction, or death during 90 days was reported to be non-significantly lower with ticagrelor compared with aspirin, with no increase in major hemorrhage. Dual antiplatelet therapy may be more effective in this setting. AIM: To investigate whether ticagrelor combined with aspirin are superior to aspirin alone in preventing stroke or death in patients with non-severe, non-cardioembolic ischemic stroke or high-risk transient ischemic attack. DESIGN: The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) trial is a randomized, placebo-controlled, double-blind, event-driven study. Patients will be randomized within 24 h of onset of acute ischemic symptoms. THALES is expected to randomize 13,000 at ∼450 sites worldwide, to collect 764 primary outcome events. Study treatments are ticagrelor 180 mg loading dose on day 1, then 90 mg twice daily on days 2-30, or matching placebo. All patients will also receive open-label aspirin 300-325 mg on day 1, then 75-100 mg once daily on days 2-30. STUDY OUTCOMES: The primary efficacy outcome is time to the composite endpoint of stroke or death through 30-day follow-up. The primary safety outcome is time to first severe bleeding event. DISCUSSION: The THALES trial will provide important information about the benefits and risks of dual antiplatelet therapy with ticagrelor and aspirin in patients with acute cerebral ischemia in a global setting (funding: AstraZeneca). CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov . Unique identifier: NCT03354429.

11.
Eur Heart J ; 40(5): 422-440, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30608523

RESUMO

Transcatheter heart valve interventions have transformed the outcomes of patients with valvular heart disease (VHD) who are unfavourable candidates for surgery. Technological advances have allowed extension of these interventions to younger or lower risk patients and those with other forms of VHD and may in the future permit earlier treatment of VHD in less symptomatic patients or those with moderate disease. The balance of risks and benefits is likely to differ between lower and higher risk patients, and more evidence is needed to evaluate the net benefit of transcatheter technology in these groups. As academic researchers, clinicians, industry, and patient stakeholders collaborate to research these broader indications for transcatheter valve interventions, it is essential to address (i) device durability and deliverability, (ii) specific anatomical needs (e.g. bicuspid aortic valves, aortic regurgitation, mitral and tricuspid valve disease), (iii) operator training, and (iv) the reinforced importance of the multidisciplinary Heart Team.

12.
Arterioscler Thromb Vasc Biol ; 39(2): 294-302, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30580572

RESUMO

Objective- The Wnt/wingless signaling antagonist DKK1 (dickkopf-1) regulates platelet-mediated inflammation and may contribute to plaque destabilization. We hypothesized that DKK1 would be associated with cardiovascular outcomes. Approach and Results- We determined DKK1 levels in serum samples obtained before randomization, at discharge, and 1 and 6 months in a subset of 5165 patients with acute coronary syndromes in the PLATO trial (Platelet Inhibition and Patient Outcomes; NCT00391872). The median (interquartile range) DKK1 concentrations were 0.61 (0.20-1.27) ng/mL at baseline and increased during follow-up. The hazard ratio (95% CIs) for the composite end point (cardiovascular death, nonprocedural spontaneous myocardial infarction, or stroke) during 1 year of follow-up, per 50% increase in baseline DKK1 concentration, was 1.06 (1.02-1.10), P=0.0011, and remained significant in fully adjusted analysis with 14 conventional clinical and demographic and 6 biochemical variables, including NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-TnT (high-sensitivity troponin T), and GDF-15 (growth differentiation factor 15; 1.05 [1.00-1.09]; P=0.028). This association was mainly driven by the association with cardiovascular death, where a gradual increase in event rates was observed with increasing quartiles of DKK1 (2.7%, 3.0%, 4.3%, and 5.0%) and remained significant and unmodified in fully adjusted analysis (hazard ratio, 1.10 [1.04-1.17]; P=0.002). Change in DKK1 and levels at 1 month were unrelated to outcomes. A modifying effect of ticagrelor on DKK1 discharge levels was observed but not associated with prognosis. Conclusions- In patients with acute coronary syndromes treated with dual antiplatelet treatment, admission DKK1 levels were independently associated with a composite of cardiovascular death, myocardial infarction, or stroke and with cardiovascular death alone.

13.
JAMA Cardiol ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30427997

RESUMO

Importance: Mortality remains at about 5% within a year after an acute coronary syndrome event. Prior studies have assessed biomarkers in relation to all-cause or cardiovascular deaths but not across multiple causes. Objective: To assess if different biomarkers provide information about the risk for all-cause and cause-specific mortality. Design, Setting, and Participants: The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18 624 patients with acute coronary syndrome to ticagrelor or clopidogrel from October 2006 through July 2008. In this secondary analysis biomarker substudy, 17 095 patients participated. Main Outcomes and Measures: Death due to myocardial infarction, heart failure, sudden cardiac death/arrhythmia, bleeding, procedures, other vascular causes, and nonvascular causes, as well as all-cause death. Exposures: At baseline, levels of cystatin-C, growth differentiation factor-15 (GDF-15), high-sensitivity C-reactive protein, high-sensitivity troponin I and T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were determined. Results: The median (interquartile range) age of patients was 62.0 (54.0-71.0) years. Of 17 095 patients, 782 (4.6%) died during follow-up. The continuous associations between biomarkers and all-cause and cause-specific mortality were modeled using Cox models and presented as hazard ratio (HR) comparing the upper vs lower quartile. For all-cause mortality, NT-proBNP and GDF-15 were the strongest markers with adjusted HRs of 2.96 (95% CI, 2.33-3.76) and 2.65 (95% CI, 2.17-3.24), respectively. Concerning death due to heart failure, NT-proBNP was associated with an 8-fold and C-reactive protein, GDF-15, and cystatin-C, with a 3-fold increase in risk. Regarding sudden cardiac death/arrhythmia, NT-proBNP was associated with a 4-fold increased risk and GDF-15 with a doubling in risk. Growth differentiation factor-15 had the strongest associations with other vascular and nonvascular deaths and was possibly associated with death due to major bleeding (HR, 4.91; 95% CI, 1.39-17.43). Conclusions and Relevance: In patients with acute coronary syndrome, baseline levels of NT-proBNP and GDF-15 were strong markers associated with all-cause death based on their associations with death due to heart failure as well as due to arrhythmia and sudden cardiac death. Growth differentiation factor-15 had the strongest associations with death due to other vascular or nonvascular causes and possibly with death due to bleeding. Trial Registration: ClinicalTrials.gov Identifier: NCT00391872.

14.
Br J Clin Pharmacol ; 2018 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-30414387

RESUMO

AIM: To characterize ticagrelor exposure-response relationship for platelet inhibition in patients with stable coronary artery disease (CAD) and a history of myocardial infarction (MI), using non-linear mixed effects modelling and simulation. METHODS: Platelet function data were integrated with plasma concentration data of ticagrelor and its active metabolite AR-C1249010XX in a population pharmacokinetic and pharmacodynamic (PK/PD) model, based on two clinical studies. In the ONSET/OFFSET study, PK and platelet function were assessed in 123 CAD patients receiving placebo, ticagrelor (180 mg followed by 90 mg twice daily) or clopidogrel (600 mg followed by 75 mg once daily). In the PEGASUS-TIMI 54 platelet function substudy, PK and platelet function were assessed during maintenance dosing in 180 prior MI patients receiving placebo, ticagrelor 60 mg or ticagrelor 90 mg twice daily. RESULTS: Platelet inhibition by ticagrelor was described by a sigmoidal Emax model. On average, half maximal inhibition was reached at ticagrelor concentrations of 116 (RSE: 5.3%) nmol/L. Simulations showed that near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At simulated lower doses, platelet inhibition is overall reduced, more variable between patients, and show greater peak-to-trough variability. Ticagrelor antiplatelet response was similar between the studied patient populations. CONCLUSIONS: In patients with stable CAD or a history of MI, near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At modeled doses below 60mg, the response is overall reduced, more variable between patients, and patients will display greater peak-to-trough variability.

15.
Stroke ; 49(7): 1678-1685, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29915123

RESUMO

BACKGROUND AND PURPOSE: SOCRATES (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes), comparing ticagrelor with aspirin in patients with acute cerebral ischemia, found a nonsignificant 11% relative risk reduction for stroke, myocardial infarction, or death (P=0.07). Aspirin intake before randomization could enhance the effect of ticagrelor by conferring dual antiplatelet effect during a high-risk period for subsequent stroke. Therefore, we explored the efficacy and safety of ticagrelor versus aspirin in the patients who received any aspirin the week before randomization. METHODS: A prespecified subgroup analysis in SOCRATES (n=13 199), randomizing patients with acute ischemic stroke (National Institutes of Health Stroke Scale score of ≤5) or transient ischemic attack (ABCD2 score of ≥4) to 90-day treatment with ticagrelor or aspirin. Patients in the prior-aspirin group had received any aspirin within the week before randomization. Primary end point was time to stroke, myocardial infarction, or death. Safety end point was PLATO (Study of Platelet Inhibition and Patient Outcomes) major bleeding. RESULTS: The 4232 patients in the prior-aspirin group were older, had more vascular risk factors, and vascular disease than the other patients. In the prior-aspirin group, the primary end point occurred in 138/2130 (6.5%) of patients on ticagrelor and in 177/2102 (8.3%) on aspirin (hazard ratio, 0.76; 95% confidence interval, 0.61-0.95; P=0.02); in patients with no prior-aspirin usage an event occurred in 304/4459 (6.9%) and 320/4508 (7.1%) on ticagrelor and aspirin, respectively (hazard ratio, 0.96; 95% confidence interval, 0.82-1.12; P=0.59). The treatment-by-prior-aspirin interaction was not statistically significant (P=0.10). In the prior-aspirin group, major bleeding occurred in 0.7% and 0.4% of patients on ticagrelor and aspirin, respectively (hazard ratio, 1.58; 95% confidence interval, 0.68-3.65; P=0.28). CONCLUSIONS: In this secondary analysis from SOCRATES, fewer primary end points occurred on ticagrelor treatment than on aspirin in patients receiving aspirin before randomization, but there was no significant treatment-by-prior-aspirin interaction. A new study will investigate the benefit-risk of combining ticagrelor and aspirin in patients with acute cerebral ischemia (URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429). CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01994720.

16.
Platelets ; : 1-10, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29851527

RESUMO

In the PLATelet inhibition and patient Outcomes (PLATO) study, the P2Y12 inhibitors ticagrelor and clopidogrel were compared in the treatment of acute coronary syndromes (ACS). Ticagrelor was shown to reduce occurrence of the primary end point - a composite of death from vascular causes, myocardial infarction, or stroke - compared to clopidogrel. Ticagrelor's pleiotropic effects on reuptake of adenosine via inhibition of equilibrative nucleoside transporter 1 (ENT1) have been hypothesized to contribute to this. Several polymorphisms of ENT1 are known to exist. We explored the interaction between ENT1 polymorphisms and clinical outcomes in ACS patients participating in the PLATO genetic substudy. Using genotyping data obtained in a genome-wide association study, the gene region encoding ENT1 was assessed and 94 polymorphisms were identified. After quality control filtering, data from 9943 participants were included. Subjects were divided into discovery (phase 1, n = 3970) and replication (phase 2, n = 5973) cohorts. Cox-regression analysis of the relationship between variants and seven efficacy and safety outcomes was performed in discovery, replication, and combined cohorts. Treatment-marker interactions were also determined. Although 35 variants were found with associations to the investigated outcomes reaching p < 0.05 in the discovery cohort, only one of these was replicated in phase 2 of the analysis and also reached the predetermined level of statistical significance in the combined data, taking into account the number of tests performed: the rare polymorphism rs141034817, with a frequency of 0.2%, was significantly associated with bleeding. Thirty-three treatment-marker interactions were found with a significance level of p < 0.05 in phase 1, but none was replicated in phase 2. We found no significant interaction between ENT1 genotype and clinical outcomes in ACS patients treated with ticagrelor or clopidogrel, apart from the association between a rare polymorphism and bleeding that requires further study. If ticagrelor's pleiotropic effects on adenosine uptake are clinically relevant, these do not appear to be significantly affected by variation in the ENT1 gene.

17.
Am Heart J ; 202: 54-60, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29859968

RESUMO

BACKGROUND: Although bradyarrhythmias have been observed with ticagrelor and its use with advanced atrioventricular block is not recommended, questions arise regarding its use in patients with mild conduction abnormalities. The objectives were to compare rates of clinically relevant arrhythmias in relation to any mild baseline conduction abnormality in patients with acute coronary syndrome randomized to ticagrelor versus clopidogrel. METHODS: We included all subjects in the electrocardiographic (ECG) substudy of the Platelet Inhibition and Patient Outcomes trial, excluding those with missing baseline ECG or with a pacemaker at baseline (N = 15,460). Conduction abnormality was defined as sinus bradycardia, first-degree atrioventricular block, hemiblock, or bundle-branch block. The primary arrhythmic outcome was the composite of any symptomatic brady- or tachyarrhythmia, permanent pacemaker placement, or cardiac arrest through 12 months. RESULTS: Patients with baseline conduction abnormalities (n = 4,256, 27.5%) were older and more likely to experience the primary arrhythmic outcome. There were no differences by ticagrelor versus clopidogrel in the composite arrhythmic end point in those with baseline conduction disease (1-year cumulative incidence rate: 17% for both study arms; hazard ratio: 0.99 [0.86-1.15]) or without baseline conduction disease (1-year cumulative incidence rate: clopidogrel 12.8% vs ticagrelor 12.4%; hazard ratio: 0.98 (0.88-1.09). There were also no statistically significant differences between ticagrelor and clopidogrel in the rates of bradycardic (or any individual arrhythmic) events in patients with baseline conduction abnormalities. CONCLUSIONS: Ticagrelor compared to clopidogrel did not increase arrhythmic events even in subjects with acute coronary syndrome who present with mild conduction abnormalities on their baseline ECG.

19.
Eur Heart J ; 39(13): 1078-1085, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29390064

RESUMO

Aims: To determine whether fibrin clot properties are associated with clinical outcomes following acute coronary syndrome (ACS). Methods and results: Plasma samples were collected at hospital discharge from 4354 ACS patients randomized to clopidogrel or ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. A validated turbidimetric assay was employed to study plasma clot lysis time and maximum turbidity (a measure of clot density). One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO-defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were estimated using Cox proportional hazards models. After adjusting for CV risk factors, each 50% increase in lysis time was associated with CV death/spontaneous MI [HR 1.17, 95% confidence interval (CI) 1.05-1.31; P < 0.01] and CV death alone (HR 1.36, 95% CI 1.17-1.59; P < 0.001). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death (HR 1.24, 95% CI 1.03-1.50; P = 0.024). After adjustment for other prognostic biomarkers (leukocyte count, high-sensitivity C-reactive protein, high-sensitivity troponin T, cystatin C, N-terminal pro B-type natriuretic peptide, and growth differentiation factor-15), the association with CV death remained significant for lysis time (HR 1.2, 95% CI 1.01-1.42; P = 0.042) but not for maximum turbidity. These associations were consistent regardless of randomized antiplatelet treatment (all interaction P > 0.05). Neither lysis time nor maximum turbidity was associated with major bleeding events. Conclusion: Fibrin clots that are resistant to lysis independently predict adverse outcome in ACS patients. Novel therapies targeting fibrin clot properties might be a new avenue for improving prognosis in patients with ACS.

20.
J Am Heart Assoc ; 7(2)2018 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-29330256

RESUMO

BACKGROUND: Elevated levels of osteoprotegerin, a secreted tumor necrosis factor-related molecule, might be associated with adverse outcomes in patients with coronary artery disease. We measured plasma osteoprotegerin concentrations on hospital admission, at discharge, and at 1 and 6 months after discharge in a predefined subset (n=5135) of patients with acute coronary syndromes in the PLATO (Platelet Inhibition and Patient Outcomes) trial. METHODS AND RESULTS: The associations between osteoprotegerin and the composite end point of cardiovascular death, nonprocedural spontaneous myocardial infarction or stroke, and non-coronary artery bypass grafting major bleeding during 1 year of follow-up were assessed by Cox proportional hazards models. Event rates of the composite end point per increasing quartile groups at baseline were 5.2%, 7.5%, 9.2%, and 11.9%. A 50% increase in osteoprotegerin level was associated with a hazard ratio (HR) of 1.31 (95% confidence interval [CI], 1.21-1.42) for the composite end point but was not significant in adjusted analysis (ie, clinical characteristics and levels of C-reactive protein, troponin T, NT-proBNP [N-terminal pro-B-type natriuretic peptide], and growth differentiation factor-15). The corresponding rates of non-coronary artery bypass grafting major bleeding were 2.4%, 2.2%, 3.8%, and 7.2%, with an unadjusted HR of 1.52 (95% CI, 1.36-1.69), and a fully adjusted HR of 1.26 (95% CI, 1.09-1.46). The multivariable association between the osteoprotegerin concentrations and the primary end point after 1 month resulted in an HR of 1.09 (95% CI, 0.89-1.33); for major bleeding after 1 month, the HR was 1.33 (95% CI, 0.91-1.96). CONCLUSIONS: In patients with acute coronary syndrome treated with dual antiplatelet therapy, osteoprotegerin was an independent marker of major bleeding but not of ischemic cardiovascular events. Thus, high osteoprotegerin levels may be useful in increasing awareness of increased bleeding risk in patients with acute coronary syndrome receiving antithrombotic therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

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