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1.
Circulation ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597460

RESUMO

Background: Numerous scales exist for classification of major bleeding events. There are limited data comparing the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation (AF). Here we analyze bleeding outcomes according to the ISTH, TIMI, GUSTO, and BARC bleeding scales in the ENGAGE AF (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation)-TIMI 48 trial of edoxaban vs warfarin. Methods: 21,105 patients with AF at risk for stroke (CHADS2 ≥2) were enrolled in the ENGAGE AF-TIMI 48 trial (NCT00781391) comparing warfarin to a higher (HDER; 60/30 mg daily) or lower (LDER; 30/15 mg daily) dose edoxaban regimen. Median follow-up was 2.8 years. Bleeding events occurring among on-treatment patients were examined. Annualized event rates were calculated by the ISTH, TIMI, GUSTO, and BARC scales and compared across treatment arms. Cox proportional hazards for a first bleeding event of each type were calculated for HDER vs warfarin and LDER vs warfarin. Results: 10,311 total bleeding events were reported. Comparing the most severe events in each scale, ISTH Major bleeding was the most common (n=1,289) followed by TIMI Major (n=548), GUSTO Severe/Life-Threatening (n=347), and BARC 3c+5 (n=276). Lower bleeding risk with edoxaban as compared with warfarin was seen regardless of bleeding scale (HDER range: HR 0.47 [0.35-0.62] for BARC 3c+5 to HR 0.80 [0.71-0.91] for ISTH Major; LDER range: HR 0.32 [0.23-0.45] for BARC 3c+5 to HR 0.47 [0.41-0.55] for ISTH Major). Further, a gradient of more pronounced risk reduction with edoxaban was observed for with greater severity of first bleeding event (HDER: HR 0.47 [0.35-0.62] for BARC 3c+5 bleeds vs HR 0.86 [0.81-0.91] for any BARC bleed; LDER: HR 0.32 [0.23-0.45] for BARC 3c+5 bleeds vs HR 0.68 [0.63-0.72] for any BARC bleed). The direction of this trend was consistent for both gastrointestinal and non-gastrointestinal bleeding. Conclusions: Among patients with AF at risk for stroke, there was an approximately four-fold difference in the frequency of the most severe bleeding events across commonly used bleeding scales. Further, the relative safety of edoxaban as compared with warfarin tended to increase with greater severity of bleeding. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT00781391.

3.
J Am Coll Cardiol ; 74(8): 1057-1068, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31439215

RESUMO

BACKGROUND: Addition of ezetimibe to statin therapy reduces the risk of recurrent cardiovascular (CV) events in patients with prior acute coronary syndrome (ACS). The role of biomarkers in identifying subsets of patients who may derive greater clinical benefit with ezetimibe is unknown. OBJECTIVES: This study sought to evaluate the role of established CV biomarkers in assessing likely benefit with ezetimibe added to statin therapy in post-ACS patients. METHODS: In a pre-specified nested analysis within a randomized, double-blind trial of ezetimibe/simvastatin versus placebo/simvastatin (IMPROVE-IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, growth-differentiation factor-15, and high-sensitivity C-reactive protein was measured in 7,195 patients stabilized (1 month post-randomization) after ACS. A multimarker approach based on biomarker values was used to examine the risk of recurrent CV events and clinical benefit with ezetimibe. RESULTS: Elevated levels of each biomarker were independently associated with higher risks of CV death/myocardial infarction/stroke and CV death/heart failure (ptrend < 0.001 for each). There was a pattern of greater absolute risk reduction in CV death/myocardial infarction/stroke with the addition of ezetimibe to statin therapy in patients at higher risk on the basis of biomarker levels. High-risk patients (≥3 biomarkers "positive"; n = 1,437) had an absolute risk difference of -7.3% (95% confidence interval: -13.8% to -0.8%; p = 0.02) with ezetimibe, and intermediate-risk patients (1 to 2 biomarkers positive; n = 3,842) had an absolute risk difference of -4.4% (95% confidence interval: -9.7% to 0.8%), translating into numbers needed to treat at 7 years of 14 and 23, respectively. Low-risk patients (0 biomarkers positive; n = 1,916) did not appear to benefit from the addition of ezetimibe to statin therapy. CONCLUSIONS: A biomarker-based strategy identifies a gradient of risk among patients post-ACS, offering the potential to identify higher-risk patients with a correspondingly high absolute benefit from the addition of ezetimibe to statin therapy.

4.
Circulation ; 140(12): 1004-1014, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31362530

RESUMO

BACKGROUND: Metformin is first-line therapy for type 2 diabetes mellitus, although its effects on the cardiovascular system are unproved. METHODS: In this post hoc analysis, patients in SAVOR-TIMI 53 (Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) with baseline biomarker samples (n=12 156) were classified as ever versus never taking metformin during the trial period. Associations between metformin exposure and outcomes were estimated with inverse probability of treatment weighting Cox modeling for the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, as well as cardiovascular death and all-cause mortality, with biomarkers included as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models. RESULTS: Of the 12 156 patients with baseline biomarker samples, 8971 (74%) had metformin exposure, 1611 (13%) had prior heart failure, and 1332 (11%) had at least moderate chronic kidney disease (estimated glomerular filtration rate ≤45 mL·min-1·1.73 m-2). Metformin use was associated with no difference in risk for the composite end point (hazard ratio for inverse probability of treatment weighting, 0.92 [95% CI, 0.76-1.11]) but lower risk of all-cause mortality (hazard ratio for inverse probability of treatment weighting, 0.75 [95% CI, 0.59-0.95]). There was no significant relationship between metformin use and these end points in patients with prior heart failure or moderate to severe chronic kidney disease. CONCLUSIONS: In a cohort of 12 156 patients with type 2 diabetes mellitus and high cardiovascular risk, metformin use was associated with lower rates of all-cause mortality, including after adjustment for clinical variables and biomarkers, but not lower rates of the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01107886.

5.
JAMA Cardiol ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31461115
6.
Prog Cardiovasc Dis ; 62(4): 298-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31377223

RESUMO

The prevalence of Type 2 diabetes mellitus (T2DM) has reached pandemic proportions. T2DM frequently causes macrovascular and/or microvascular pathologic changes and thereby increases the risks for the development of myocardial infarction, heart failure, stroke, renal failure, and reduced survival. This article describes the important interactions between T2DM, heart failure, and renal dysfunction, forming vicious circles. The interruption of these circles represents important therapeutic goals.

7.
Hypertension ; 74(3): 597-605, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31352829

RESUMO

Hypertension is a risk factor for both stroke and bleeding in patients with atrial fibrillation. Data are sparse regarding the interaction between blood pressure and the efficacy and safety of direct oral anticoagulants. In the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48), 19,679 patients with atrial fibrillation and hypertension were categorized according to average systolic blood pressure (SBP) and diastolic blood pressure (DBP). The primary efficacy and safety end points were the time to the first stroke or systemic embolic event and the time to the first International Society of Thrombosis and Hemostasis major bleeding event, respectively. Risk was calculated using Cox proportional hazards models based on average SBP and DBP and adjusting for 18 clinical characteristics. The efficacy and safety of a higher dose edoxaban regimen (60/30 mg) versus warfarin were evaluated with stratification by average SBP and DBP. Stroke/systemic embolic event occurred significantly more frequently in patients with elevated average SBP (hazard ratio, 2.01; 95% CI, 1.50-2.70 for SBP ≥150 mm Hg relative to 130-139 mm Hg) or DBP (hazard ratio, 2.36; 95% CI, 1.76-3.16 for DBP ≥90 mm Hg relative to 75-<85 mm Hg). The higher dose edoxaban regimen reduced stroke/systemic embolic event across the full range of SBP (Pinteraction=0.55) and DBP (Pinteraction=0.44) compared with warfarin. The higher dose edoxaban regimen reduced the risk of major bleeding events, including intracranial hemorrhage, without modification by average SBP (Pinteraction=0.29). The relative safety of edoxaban was most pronounced in patients with elevated DBP (Pinteraction=0.007). The efficacy and safety of edoxaban were consistent across the full range of SBP, while the superior safety of edoxaban was most pronounced among patients with elevated DBP.

8.
JAMA Cardiol ; 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31314050

RESUMO

Importance: Limited evidence is available regarding the benefit and hazard of higher-intensity treatment to lower lipid levels among patients 75 years or older. As a result, guideline recommendations differ for this age group compared with younger patients. Objective: To determine the effect on outcomes and risks of combination ezetimibe and simvastatin compared with simvastatin monotherapy to lower lipid levels among patients 75 years or older with stabilized acute coronary syndrome (ACS). Design, Setting, Participants: In this prespecified secondary analysis of the global, multicenter, prospective clinical randomized Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), outcomes and risks were compared by age among patients 50 years or older after a hospitalization for ACS. Data were collected from October 26, 2005, through July 8, 2010, with the database locked October 21, 2014. Data were analyzed May 29, 2015, through March 13, 2018, using Kaplan-Meier curves and Cox proportional hazards models. Interventions: Double-blind randomized assignment to combined simvastatin and ezetimibe or simvastatin and placebo with follow-up for a median of 6 years (interquartile range, 4.3-7.1 years). Main Outcomes and Measures: The primary composite end point consisted of death due to cardiovascular disease, myocardial infarction (MI), stroke, unstable angina requiring hospitalization, and coronary revascularization after 30 days. Individual adverse ischemic and safety end points and lipid variables were also analyzed. Results: Of 18 144 patients enrolled (13 728 men [75.7%]; mean [SD] age, 64.1 [9.8] years), 5173 (28.5%) were 65 to 74 years old, and 2798 (15.4%) were 75 years or older at randomization. Treatment with simvastatin-ezetimibe resulted in lower rates of the primary end point than simvastatin-placebo, including 0.9% for patients younger than 65 years (HR, 0.97; 95% CI, 0.90-1.05) and 0.8% for patients 65 to 74 years of age (hazard ratio [HR], 0.96; 95% CI, 0.87-1.06), with the greatest absolute risk reduction of 8.7% for patients 75 years or older (HR, 0.80; 95% CI, 0.70-0.90) (P = .02 for interaction). The rate of adverse events did not increase with simvastatin-ezetimibe vs simvastatin-placebo among younger or older patients. Conclusions and Relevance: In IMPROVE-IT, patients hospitalized for ACS derived benefit from higher-intensity therapy to lower lipid levels with simvastatin-ezetimibe compared with simvastatin monotherapy, with the greatest absolute risk reduction among patients 75 years or older. Addition of ezetimibe to simvastatin was not associated with any significant increase in safety issues among older patients. These results may have implications for guideline recommendations regarding lowering of lipid levels in the elderly. Trial Registration: ClinicalTrials.gov identifier: NCT00202878.

9.
Circulation ; 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31331193

RESUMO

BACKGROUND: Exploratory analyses of previous randomized trials generated a hypothesis that the clinical response to CETP inhibitor therapy differs by ADCY9 genotype, prompting the ongoing dal-GenE trial in individuals with a particular genetic profile. The randomized placebo-controlled REVEAL trial demonstrated the clinical efficacy of the CETP inhibitor anacetrapib among patients with pre-existing atherosclerotic vascular disease. In the present study, we have examined the impact of ADCY9 genotype on response to anacetrapib within the REVEAL trial. METHODS: Individuals with stable atherosclerotic vascular disease, who were treated with intensive atorvastatin therapy, received either anacetrapib 100 mg daily or matching placebo. Cox proportional hazards models, adjusted for the first 5 principal components of ancestry, were used to estimate the effects of allocation to anacetrapib on major vascular events (a composite of coronary death, myocardial infarction, coronary revascularization or presumed ischaemic stroke) and the interaction with ADCY9 rs1967309 genotype. RESULTS: Among 19,210 genotyped individuals of European ancestry, 2,504 (13.0%) had a first major vascular event during 4 years median follow-up: 1,216 (12.6%) among anacetrapib-allocated participants and 1,288 (13.4%) among placebo-allocated participants. Proportional reductions in the risk of major vascular events with anacetrapib did not differ significantly by ADCY9 genotype: HR = 0.92 (95% CI, 0.81-1.05) for GG; HR = 0.94 (95% CI, 0.84-1.06) for AG; and HR = 0.93 (95% CI, 0.76-1.13) for AA genotype carriers respectively; genotypic p for interaction = 0.96. Furthermore, there were no associations between ADCY9 genotype and the proportional reductions in the separate components of major vascular events, or meaningful differences in lipid response to anacetrapib. CONCLUSIONS: The REVEAL trial is the single largest study to date evaluating the ADCY9 pharmacogenetic interaction. It provides no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor anacetrapib. The ongoing dal-GenE study will provide direct evidence as to whether there is any specific pharmacogenetic interaction with dalcetrapib. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov Unique Identifier: NCT01252953; URL: http://www.isrctn.com Unique Identifier: ISRCTN48678192; URL: https://www.clinicaltrialsregister.eu Unique Identifier: 2010-023467-18.

10.
J Am Coll Cardiol ; 74(2): 179-189, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31296289

RESUMO

BACKGROUND: Patients with liver disease have increased risk of thrombosis and bleeding but are typically excluded from trials of direct oral anticoagulant agents. OBJECTIVES: This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and history of liver disease. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction Study 48) was a randomized, double-blind trial comparing edoxaban with warfarin in patients with AF followed for 2.8 years. History of liver disease was defined as investigator-reported liver disease or >2-fold transaminase elevation at randomization. The primary efficacy and safety endpoints of stroke or systemic embolic event (SSEE) and major bleeding were assessed stratified by history of liver disease. PK/PD assessments of edoxaban included endogenous and extrinsic factor Xa activity and edoxaban concentration. RESULTS: Among 21,105 patients, 1,083 (5.1%) had a history of liver disease; they had a higher prevalence of many comorbidities. The adjusted risks of SSEE were similar (adjusted hazard ratio [HRadj]: 0.90; 95% confidence interval [CI]: 0.67 to 1.22; p = 0.50), but major bleeding was more common in patients with liver disease (HRadj: 1.38; 95% CI: 1.10 to 1.74; p = 0.005). There were no significant differences in PK/PD assessment of edoxaban in patients with versus without liver disease. The HRs for higher-dose edoxaban versus warfarin for SSEE were 0.86 (95% CI: 0.73 to 1.01) in patients without and 1.11 (95% CI: 0.54 to 2.30) with liver disease (p for interaction [pint] = 0.47), major bleeding 0.80 (95% CI: 0.70 to 0.91) in patients without and 0.91 (95% CI: 0.56 to 1.47) with liver disease (pint = 0.63). There were no significant differences in hepatic adverse events between the 2 treatment groups. CONCLUSIONS: Among patients with AF receiving oral anticoagulation, bleeding, but not thromboembolic events, was increased in patients with liver disease. A history of liver disease did not alter the relative efficacy and safety of edoxaban compared with warfarin. Hepatic adverse events were similar between edoxaban and warfarin.

11.
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.

12.
Eur Heart J ; 40(40): 3345-3352, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31093657

RESUMO

AIMS: Circulating high-sensitivity cardiac troponin (hsTn) and soluble ST2 (sST2) reflect myocardial stress in patients with heart failure (HF). Production of cyclic guanosine 3'5' monophosphate (cGMP) in response to activation of natriuretic peptide receptors reduces cardiac afterload and preload. We assessed the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and acute decompensated HF (ADHF). METHODS AND RESULTS: PIONEER-HF was a randomized, double-blind trial of sacubitril/valsartan vs. enalapril in hospitalized patients with ADHF following haemodynamic stabilization. We measured circulating hsTnT, sST2, and urinary cGMP at baseline, 1, 2 (sST2, cGMP), 4, and 8 weeks (n = 694 with all baseline biomarkers). Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril. Compared with enalapril, sacubitril/valsartan led to a significantly greater decline in hsTnT and sST2. This effect emerged as early as 1 week for sST2 and was significant for both at 4 weeks with a 16% greater reduction in hsTnT (P < 0.001) and 9% greater reduction in sST2 (P = 0.0033). Serial urinary cGMP increased with sacubitril/valsartan compared with enalapril (P < 0.001, 1 week). The significant differences between treatment groups for each biomarker were sustained at 8 weeks. In an exploratory multivariable-adjusted analysis of cardiovascular death or HF-rehospitalization, the concentrations of hsTnT, sST2 at week 1 were significantly associated with subsequent outcome. CONCLUSION: Biomarkers of myocardial stress are elevated in patients with ADHF and associated with outcome. Compared with enalapril, sacubitril/valsartan reduces myocardial injury and haemodynamic stress as reflected by biomarkers, with an onset that is apparent within 1-4 weeks. CLINICAL TRIALS REGISTRATION: NCT02554890 clinical.trials.gov.

13.
J Am Heart Assoc ; 8(9): e011444, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31020897

RESUMO

Background Small studies have suggested an association between markers of collagen turnover and adverse outcomes in heart failure ( HF ). We examined C-terminal telopeptide (beta- CT x) and the risk of cardiovascular death or new or worsening HF in non- ST -elevation acute coronary syndrome. Methods and Results We measured baseline serum beta- CT x, NT -pro BNP (N-terminal pro-B-type natriuretic peptide), hsTnT (high-sensitivity cardiac troponin T) and hs CRP (high-sensitivity C-reactive protein) (Roche Diagnostics) in a nested biomarker analysis (n=4094) from a study of patients with non- ST -elevation acute coronary syndrome. The relationship between quartiles of beta- CT x and cardiovascular death or HF over a median follow-up time of 12 months was analyzed using adjusted Cox models. Higher beta- CT x levels identified a significantly higher risk of cardiovascular death/ HF (Q4 10.9% versus Q1 3.8%, Logrank P<0.001). After multivariable adjustment, beta- CT x in the top quartile (Q4) was associated with cardiovascular death/ HF (Q4 versus Q1: adjusted hazard ratio 2.22 [1.50-3.27]) and its components (Q4 versus Q1: cardiovascular death: adjusted hazard ratio 2.48 [1.46-4.21]; HF : adjusted hazard ratio 2.04 [1.26-3.30]). In an adjusted multimarker model including NT -pro BNP , hsTnT, and hs CRP , beta- CT x remained independently associated with cardiovascular death/ HF (Q4 versus Q1: adjusted hazard ratio 1.98 [1.34-2.93]) and its components. Beta- CT x correlated weakly with NT -pro BNP ( r=0.17, P<0.001) and left ventricular ejection fraction ( r=-0.05, P=0.008) and did not correlate with hsTnT ( r=0.02, P=0.20), or hs CRP ( r=-0.03, P=0.09). Conclusions Levels of beta- CT x, a biomarker of collagen turnover, were associated with cardiovascular death and HF in patients with non- ST -elevation acute coronary syndrome. This biomarker, which correlated only weakly or not significantly with traditional biomarkers of cardiovascular death and HF , may provide complementary pathobiological insight and risk stratification in these patients.

15.
Clin Chem ; 65(6): 781-790, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30988169

RESUMO

BACKGROUND: Cardiac and renal diseases commonly occur with bidirectional interactions. We hypothesized that cardiac and inflammatory biomarkers may assist in identification of patients with type 2 diabetes mellitus (T2DM) at high risk of worsening renal function. METHODS: In this exploratory analysis from SAVOR-TIMI 53, concentrations of high-sensitivity cardiac troponin T (hs-TnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP) were measured in baseline serum samples of 12310 patients. The primary end point for this analysis was a ≥40% decrease in estimated glomerular filtration rate (eGFR) at end of treatment (EOT) at a median of 2.1 years. The relationships between biomarkers and the end point were modeled using adjusted logistic and Cox regression. RESULTS: After multivariable adjustment including baseline renal function, each biomarker was independently associated with an increased risk of ≥40% decrease in eGFR at EOT [Quartile (Q) Q4 vs Q1: hs-TnT adjusted odds ratio (OR), 5.63 (3.49-9.10); NT-proBNP adjusted OR, 3.53 (2.29-5.45); hs-CRP adjusted OR, 1.84 (95% CI, 1.27-2.68); all P values ≤0.001]. Furthermore, each biomarker was independently associated with higher risk of worsening of urinary albumin-to-creatinine ratio (UACR) category (all P values ≤0.002). Sensitivity analyses in patients without heart failure and eGFR >60 mL/min provided similar results. In an adjusted multimarker model, hs-TnT and NT-proBNP remained significantly associated with both renal outcomes (all P values <0.01). CONCLUSIONS: hs-TnT, NT-proBNP, and hs-CRP were each associated with worsening of renal function [reduction in eGFR (≥40%) and deterioration in UACR class] in high-risk patients with T2DM. Patients with high cardiac or inflammatory biomarkers should be treated not only for their risk of cardiovascular outcomes but also followed for renal deterioration.

17.
Eur J Heart Fail ; 21(4): 462-470, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30773798

RESUMO

AIMS: Klotho, an essential co-receptor for fibroblast growth factor (FGF)-23, has potentially beneficial inhibitory effects on the renin-angiotensin system. Limited data exist on the prognostic value of Klotho and FGF-23 levels in combination or their ability to predict benefit from angiotensin-converting enzyme (ACE) inhibition. METHODS AND RESULTS: A total of 3555 patients with stable ischaemic heart disease and left ventricular ejection fraction > 40% enrolled in the PEACE trial of trandolapril vs. placebo had Klotho levels drawn at randomization. Patients were characterized by quartiles of Klotho and FGF-23 concentrations. Six-year Kaplan-Meier rates and adjusted risk were calculated in the placebo arm for the composite of cardiovascular (CV) death or hospitalization for heart failure and its components. Low [quartile (Q) 1-3] Klotho concentration was associated with an increased rate of CV death or hospitalization for heart failure as compared with Q4 (8.2% vs. 4.2%; P = 0.03). After multivariable adjustment for clinical variables and renal and CV biomarkers (estimated glomerular filtration rate, cystatin-C, urine albumin-to-creatinine ratio, FGF-23, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein), low Klotho concentration remained strongly associated with increased risk of CV death or hospitalization for heart failure [adjusted hazard ratio (HR) 2.62; 95% confidence interval (CI) 1.35-5.08; P < 0.01]. The combination of low Klotho and high (Q4) FGF-23 concentration identified patients at particularly elevated risk (adjusted HR 3.99; 95% CI 1.67-9.56; P < 0.01). This high-risk combination additionally predicted benefit from trandolapril (HR 0.39; 95% CI 0.23-0.68; Pinteraction < 0.01). CONCLUSIONS: Low Klotho concentration is associated with an increased risk of CV death or heart failure hospitalization in patients with stable ischaemic heart disease. The combination of low Klotho and high FGF-23 further identifies patients at distinctly elevated risk who derive clinical benefit from the ACE-inhibitor trandolapril.

18.
Circ Cardiovasc Qual Outcomes ; 12(1): e005041, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30630361

RESUMO

BACKGROUND: Although cholesterol-lowering medications can reduce the risk of recurrent cardiovascular events, premature discontinuation limits effectiveness. Discontinuation rates have not been systematically reported for lipid-lowering trials. METHODS AND RESULTS: We evaluated medication discontinuation in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which evaluated placebo+simvastatin versus ezetimibe+simvastatin in patients hospitalized with the acute coronary syndrome and followed longitudinally postdischarge. Reasons for discontinuation were evaluated from randomization through study end (median 71.9 [interquartile range 51.8-85.8] months). Kaplan-Meier (KM) discontinuation rates were evaluated at 30 days, 1 year, and through year 7, and compared by treatment arm and region, with Cox proportional hazards modeling used to evaluate predictors of discontinuation. Overall, 46.7% of subjects discontinued study medication (KM rate by study end 50.9% [95% CI, 50.1%-51.7%]). The risk of discontinuation was highest early in the trial but decreased with increasing time, with a terminal KM rate per 100 person-years of 8.4 (8.2-8.6) from years 1 to 7. Discontinuation was higher in the placebo+simvastatin versus ezetimibe+simvastatin arm (KM rate 52.0% versus 49.8%, P=0.049) and was highest in the United States (7-year KM rate 57.4%). In multivariable modeling, smoking, prior revascularization, hypertension, unstable angina, female sex, nonwhite race, and US location were associated with higher discontinuation rates. CONCLUSIONS: Although discontinuation was highest early and stabilized to 8% per year, because of prolonged follow-up, most discontinuation occurred after year 1. Adding ezetimibe to statin therapy did not increase discontinuation risk. Geographic differences and patient-level factors should be considered in trial design and analysis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00202878.

19.
Eur Heart J ; 40(19): 1541-1550, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-30624719

RESUMO

AIMS: To investigate the relationship between body mass index (BMI) and outcomes in patients with atrial fibrillation (AF). METHODS AND RESULTS: In the ENGAGE AF-TIMI 48 trial, patients with AF were randomized to warfarin (international normalized ratio 2.0-3.0) or edoxaban. The cohort (N = 21 028) included patients across BMI categories (kg/m2): underweight (<18.5) in 0.8%, normal (18.5 to <25) in 21.4%, overweight (25 to <30) in 37.6%, moderately obese (30 to <35) in 24.8%, severely obese (35 to <40) in 10.0%, and very severely obese (≥40) in 5.5%. In an adjusted analysis, higher BMI (continuous, per 5 kg/m2 increase) was significantly and independently associated with lower risks of stroke/systemic embolic event (SEE) [hazard ratio (HR) 0.88, P = 0.0001], ischaemic stroke/SEE (HR 0.87, P < 0.0001), and death (HR 0.91, P < 0.0001), but with increased risks of major (HR 1.06, P = 0.025) and major or clinically relevant non-major bleeding (HR 1.05, P = 0.0007). There was a significant interaction between sex and increasing BMI category, with lower risk of ischaemic stroke/SEE in males and increased risk of bleeding in women. Trough edoxaban concentration and anti-Factor Xa activity were similar across BMI groups >18.5 kg/m2, while time in therapeutic range for warfarin improved significantly as BMI increased (P < 0.0001). The effects of edoxaban vs. warfarin on stroke/SEE, major bleeding, and net clinical outcome were similar across BMI groups. CONCLUSION: An increased BMI was independently associated with a lower risk of stroke/SEE, better survival, but increased risk of bleeding. The efficacy and safety profiles of edoxaban were similar across BMI categories ranging from 18.5 to >40.

20.
Circulation ; 139(6): 760-771, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30586727

RESUMO

BACKGROUND: The ABC (age, biomarker, clinical history)-stroke and ABC-bleeding risk scores incorporate clinical variables and cardiovascular biomarkers to estimate risk of stroke or systemic embolic events and bleeding, respectively, in patients with atrial fibrillation. These scores have been proposed for routine clinical use, but their performance in external cohorts remains uncertain. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS2 score ≥2. We performed a nested prospective biomarker study in 8705 patients, analyzing baseline high-sensitivity troponin T (hsTnT), NT-proBNP (N-terminal B-type natriuretic peptide), and growth differentiation factor-15 (GDF-15), as well as in serial samples after 12 months. The ABC-stroke (age, prior stroke/transient ischemic attack, hsTnT, NT-proBNP) and ABC-bleeding (age, prior bleeding, hemoglobin, hsTnT, and GDF-15) scores were tested. Hazard ratios were adjusted for estimated glomerular filtration rate and the components of the CHA2DS2-VASc and HAS-BLED scores, respectively. Discrimination and reclassification were compared with these established scores. RESULTS: Median baseline hsTnT, NT-proBNP, and GDF-15 levels were 13.7 ng/L (25th-75th percentiles, 9.6-20.4 ng/L), 811 pg/mL (386-1436 pg/mL), and 1661 pg/mL (1179-2427 pg/mL), respectively. Elevated hsTnT, NT-proBNP, and GDF-15 were independently associated with higher rates of stroke or systemic embolic events, and elevated hsTnT and GDF-15 were independently associated with higher rates of major bleeding ( P<0.001 for each). The ABC-stroke and ABC-bleeding scores were well calibrated and yielded higher c indexes than the CHA2DS2-VASc score for stroke or systemic embolic events (0.67 [95% CI, 0.65-0.70] versus 0.59 [95% CI, 0.57-0.62]; P<0.001) and HAS-BLED score for major bleeding (0.69 [95% CI, 0.66-0.71] versus 0.62 [95% CI, 0.60-0.64]; P<0.001), respectively. The ABC-stroke and ABC-bleeding scores stratified patients within CHA2DS2-VASc and HAS-BLED risk categories ( P<0.001 for both). Patients with ABC-bleeding scores predicting a high 1-year risk of bleeding (>2%) derived greater benefit from treatment with edoxaban compared with warfarin. CONCLUSIONS: The ABC-stroke and ABC-bleeding scores evaluated in this anticoagulated clinical trial cohort were well calibrated and outperformed the CHA2DS2-VASc and HAS-BLED scores, respectively. These scores may help identify patients most likely to derive a benefit from treatment with non-vitamin K antagonist oral anticoagulants. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.

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