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1.
N Engl J Med ; 372(25): 2387-97, 2015 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-26039521

RESUMO

BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , Azetidinas/uso terapêutico , LDL-Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Sinvastatina/uso terapêutico , Idoso , Anticolesterolemiantes/efeitos adversos , Azetidinas/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Método Duplo-Cego , Quimioterapia Combinada , Ezetimiba , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue
2.
N Engl J Med ; 372(19): 1791-800, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25773268

RESUMO

BACKGROUND: The potential benefit of dual antiplatelet therapy beyond 1 year after a myocardial infarction has not been established. We investigated the efficacy and safety of ticagrelor, a P2Y12 receptor antagonist with established efficacy after an acute coronary syndrome, in this context. METHODS: We randomly assigned, in a double-blind 1:1:1 fashion, 21,162 patients who had had a myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All the patients were to receive low-dose aspirin and were followed for a median of 33 months. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. RESULTS: The two ticagrelor doses each reduced, as compared with placebo, the rate of the primary efficacy end point, with Kaplan-Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (hazard ratio for 90 mg of ticagrelor vs. placebo, 0.85; 95% confidence interval [CI], 0.75 to 0.96; P=0.008; hazard ratio for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI, 0.74 to 0.95; P=0.004). Rates of TIMI major bleeding were higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P<0.001 for each dose vs. placebo); the rates of intracranial hemorrhage or fatal bleeding in the three groups were 0.63%, 0.71%, and 0.60%, respectively. CONCLUSIONS: In patients with a myocardial infarction more than 1 year previously, treatment with ticagrelor significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased the risk of major bleeding. (Funded by AstraZeneca; PEGASUS-TIMI 54 ClinicalTrials.gov number, NCT01225562.).


Assuntos
Adenosina/análogos & derivados , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária/administração & dosagem , Adenosina/administração & dosagem , Adenosina/efeitos adversos , Idoso , Aspirina/administração & dosagem , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Hemorragia/induzido quimicamente , Humanos , Hemorragias Intracranianas/induzido quimicamente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Risco , Prevenção Secundária , Ticagrelor
3.
J Thromb Thrombolysis ; 42(3): 376-85, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27324144

RESUMO

Coronary plaque rupture mediating acute ST segment elevation myocardial infarction (STEMI) is associated with a systemic inflammatory response. Whether early temporal changes in inflammatory biomarkers are associated with angiographic and electrocardiographic markers of reperfusion and subsequent clinical outcomes is unclear. In the APEX-AMI biomarker substudy, 376 patients with STEMI had inflammatory biomarkers measured at the time of hospital presentation and 24 h later. The primary outcome was the 90-day composite of death, shock, or heart failure. Secondary reperfusion outcomes were (1) worst least residual ST segment elevation (ST-E: <1 mm, 1 to <2 mm, ≥2 mm) and (2) post-percutaneous coronary intervention (PCI) TIMI flow grade (0/1/2 vs 3) and TIMI myocardial perfusion grade (TMPG 0/1 vs 2/3). The 90-day incidence of death, shock or heart failure was 21.3 % in this cohort. Electrocardiographic reperfusion (worst residual ST-E <1 mm, 1 to <2 mm, ≥2 mm) was associated with differences in 24 h change in N-terminal proB-type natriuretic peptide (NT-proBNP) (1192.8, 1332.5, 1859.0 ng/mL; p = 0.043) and the pro-inflammatory cytokines Interleukin (IL)-6 (14.0, 13.6, 22.1 pg/mL; p = 0.016), IL-12 (-0.5, -0.9, -0.1 pg/mL; p = 0.013), and tumor necrosis factor α (TNFα) (1.0, 0.6, 3.6 pg/mL; p = 0.023). Angiographic reperfusion (TMPG 0/1 vs 2/3) was associated with changes in median NT-proBNP (2649.3, 1382.7 ng/mL; p = 0.002) and IL-6 (28.7, 15.1; p = 0.040). After adjustment for baseline covariates, the 24 h change in the pro-inflammatory cytokine TNFα [hazard ratio (HR) 0.49; 95 % CI 0.26-0.95; p = 0.035] and the anti-inflammatory cytokine IL 10 (HR 1.41; 95 % CI 1.06-1.87; p = 0.018) were independently associated with the primary composite outcome. Successful coronary reperfusion was associated with less systemic inflammatory response and greater temporal inflammatory changes were independently associated with higher 90-day composite of death, shock, or heart failure. These findings provide support for an association between success of reperfusion, an acute STEMI inflammatory response and subsequent clinical outcomes.


Assuntos
Inflamação/sangue , Reperfusão Miocárdica , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Biomarcadores/sangue , Estudos de Coortes , Angiografia Coronária , Eletrocardiografia , Insuficiência Cardíaca , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Choque Cardiogênico , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue
4.
JAMA ; 315(15): 1591-9, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-27043082

RESUMO

IMPORTANCE: p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes in myocardial infarction (MI). Pilot data in a phase 2 trial in non-ST elevation MI indicated that the p38 MAPK inhibitor losmapimod attenuates inflammation and may improve outcomes. OBJECTIVE: To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acute myocardial infarction. DESIGN, SETTING, AND PATIENTS: LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22,000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk. INTERVENTIONS: Patients were randomized to either twice-daily losmapimod (7.5 mg; n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12. RESULTS: In part A, among the 3503 patients randomized (median age, 66 years; 1036 [29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91-1.47; P = .24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo. CONCLUSIONS AND RELEVANCE: Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02145468.


Assuntos
Ciclopropanos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Idoso , Algoritmos , Proteína C-Reativa/análise , Ciclopropanos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/mortalidade , Isquemia Miocárdica/prevenção & controle , Isquemia Miocárdica/cirurgia , Revascularização Miocárdica , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Recidiva , Prevenção Secundária , Falha de Tratamento
5.
N Engl J Med ; 366(15): 1404-13, 2012 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-22443427

RESUMO

BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).


Assuntos
Doenças Cardiovasculares/prevenção & controle , Lactonas/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Piridinas/uso terapêutico , Receptor PAR-1/antagonistas & inibidores , Idoso , Isquemia Encefálica/tratamento farmacológico , Doenças Cardiovasculares/mortalidade , Método Duplo-Cego , Feminino , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/epidemiologia , Estimativa de Kaplan-Meier , Lactonas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação Plaquetária/efeitos adversos , Piridinas/efeitos adversos , Retratamento , Risco , Prevenção Secundária , Acidente Vascular Cerebral/tratamento farmacológico
6.
Am Heart J ; 169(5): 622-630.e6, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25965709

RESUMO

BACKGROUND: p38 mitogen-activated protein kinase (MAPK) mediates cytokine production and amplification of the inflammatory cascade. Through inhibition of p38 MAPK, losmapimod appears to attenuate the inflammatory response in the vascular wall and thus may help stabilize plaques. STUDY DESIGN: The LATITUDE-TIMI 60 trial is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study planned to be conducted in a 3-stage design. Overall, the trial is designed to include 25,500 patients hospitalized with non-ST-elevation or ST-elevation myocardial infarction (MI) randomized to oral losmapimod (7.5 mg twice daily) versus matching placebo. Part A consists of a leading cohort (n = 3,500) that will provide an initial assessment of safety and exploratory efficacy before progressing to part B. Part B (n = ~22,000) of the study is event driven and will provide the primary assessment of efficacy. An independent safety review will be conducted after 3,500 patients in part B1 to determine whether a more focused schedule of clinic visits and laboratory assessments can be implemented (part B2). All patients are to be treated with study drug until week 12 and followed up until week 24. The primary end point is the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization. The key secondary end point is the composite of cardiovascular death or MI. The trial is designed to provide ≥90% power for the primary end point. CONCLUSIONS: The LATITUDE-TIMI 60 trial will determine the efficacy and safety of short-term p38 MAPK inhibition with losmapimod in acute MI. The trial design adopts a stepwise approach to decision making and collection of data.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Ciclopropanos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Projetos de Pesquisa
7.
Am Heart J ; 164(1): 43-51, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22795281

RESUMO

BACKGROUND: Reasons for pexelizumab lack of benefit in ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention remain unclear. In a substudy of the APEX-AMI trial, we explored the hypothesis that early complement activation preceding drug administration explained the failure. METHODS: A panel of terminal complement complex proteins and fragments and biomarkers of inflammation, apoptosis, and high-risk features were assessed in serum obtained before and 24 hours after administration of placebo or pexelizumab and primary percutaneous coronary intervention (n = 356) and in human umbilical vein endothelial cell cultures coincubated with serum (n = 45). RESULTS: In the placebo group, C5a and sC5b-9 levels increased by 37% (7.9-14.2 ηg/mL, P = .007) and 96% (442-845 ηg/mL, P < .0001), respectively, during the first 24 hours. Pexelizumab prevented the increase in C5a (P = .01 vs placebo), but not that of sC5b-9 (502-1,157 ηg/mL, not significant vs placebo). Levels of C-reactive protein, interleukin (IL) 6, IL-1ß, Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) or Chemokine C-C motif ligand 5 (CCL5), and N-terminal probrain natriuretic peptide increased significantly in both groups; those of IL-10, IL-12, IL-1ra, and Interferon gamma-induced protein 10 (IP-10) or C-X-C motif chemokine 10 (CXCL10) decreased. Pexelizumab halved the increase in IL-6 (+92% vs 156%, P = .01) without effects on other markers, including C-reactive protein and N-terminal probrain natriuretic peptide. In cell culture, pexelizumab inhibited C5a, sC5b-9, and membrane-bound C5b-9 by 92%, 75%, and 78%, respectively (all P < .0001), without influencing cytokine levels and cell apoptosis. CONCLUSIONS: The blockage of both C5a and terminal complement in cell culture, but of C5a only in vivo with minimal effects on inflammation and risk biomarkers, supports the hypothesis that late administration of pexelizumab after the ischemia/reperfusion insult precluded adequate myocardial protection, resulting in a negative trial.


Assuntos
Angioplastia Coronária com Balão , Anticorpos Monoclonais Humanizados/uso terapêutico , Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores , Infarto do Miocárdio/terapia , Anticorpos de Cadeia Única/uso terapêutico , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Falha de Tratamento
8.
J Thromb Thrombolysis ; 34(1): 106-13, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22307842

RESUMO

Coronary plaque rupture is associated with a systemic inflammatory response. The relationship between baseline N-terminal pro B-type natriuretic peptide (NT-proBNP), a prognostic marker in patients with acute coronary syndromes, and systemic inflammatory mediators in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) is not well described. Of 5,745 STEMI patients treated with primary PCI in the APEX-AMI trial, we evaluated the relationship between baseline NT-proBNP levels and baseline levels of inflammatory markers and markers of myonecrosis in a subset of 772 who were enrolled in a biomarker substudy. Spearman correlations (r (s)) were calculated between baseline NT-proBNP levels and a panel of ten systemic inflammatory biomarkers. Interleukin (IL)-6, a pro-inflammatory cytokine, was significantly positively correlated with NT-proBNP (r (s) = 0.317, P < 0.001). In a sensitivity analysis excluding all heart failure patients, the correlation between baseline IL-6 and NT-proBNP remained significant (n = 651, r (s) = 0.296, P < 0.001). A positive association was also observed with high sensitivity C-reactive protein (r (s) = 0.377, P < 0.001) and there was a weak negative correlation with the anti-inflammatory cytokine IL-10 (r (s) = -0.109, P = 0.003). No other significant correlations were observed among the other testes inflammatory cytokines and chemokines. In STEMI patients undergoing primary PCI, the pro-inflammatory cytokine IL-6 was modestly correlated with baseline NT-proBNP levels. This relationship remained significant in patients without heart failure. This finding is consistent with pre-clinical and clinical research suggesting that systemic inflammation may influence NT-proBNP expression independently of myocardial stretch.


Assuntos
Angioplastia Coronária com Balão , Infarto do Miocárdio/sangue , Infarto do Miocárdio/terapia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Idoso , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/sangue , Inflamação/terapia , Interleucina-10/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Necrose
9.
Eur Heart J ; 32(18): 2256-65, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21624900

RESUMO

AIMS: Various definitions of major bleeding have been used to evaluate safety in randomized controlled trials of antiplatelet therapy. We compared the definitions and rates of major bleeding in phase III randomized controlled trials of oral P2Y(12) inhibitors in the management of patients with acute coronary syndromes (ACS). METHODS AND RESULTS: Electronic searches identified six phase III randomized controlled oral P2Y(12) inhibitor trials published between 2001 and 2010 involving 119 020 patients with ACS. The trials compared clopidogrel standard-dose (300-mg loading dose, 75-mg daily thereafter) vs. placebo (CURE, CLARITY-TIMI 28, COMMIT), clopidogrel standard-dose vs. prasugrel (TRITON-TIMI 38) or ticagrelor (PLATO) and clopidogrel standard-dose vs. clopidogrel double-dose (600-mg loading dose, 150-mg daily for 6-days, 75-mg daily thereafter) (CURRENT-OASIS 7). Using the trial definition, major bleeding rates in patients treated with standard-dose clopidogrel ranged from 0.6% in COMMIT to 11.2% in PLATO. The contrast in bleeding rates of standard-dose clopidogrel among the trials was attenuated when using the thrombolysis in myocardial infarction (TIMI) definition for major bleeding (range 1.1-7.7%) and bleeding rates in all the trials were less than 2% when comparing 30 day rates of non-coronary artery bypass graft surgery-related TIMI major bleeding (range 0.3-1.9%). CONCLUSION: Differences in major bleeding rates between trials of P2Y(12) inhibitors in patients with ACS are minimized after standardization of bleeding definitions, timing of reporting of bleeding outcomes, and procedure rates. Interpretation of the risk of bleeding associated with different P2Y(12) inhibitors would be facilitated by a consistent approach to the definition and reporting of bleeding.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Hemorragia/induzido quimicamente , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Adenosina/efeitos adversos , Adenosina/análogos & derivados , Ensaios Clínicos Fase III como Assunto , Clopidogrel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas , Cloridrato de Prasugrel , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Tiofenos , Ticagrelor , Ticlopidina/análogos & derivados
10.
Eur Heart J ; 31(10): 1181-7, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20089518

RESUMO

AIMS: Experimental data point towards a favourable effect of low serum concentrations of complement mannose-binding lectin (MBL) on myocardial ischaemia/reperfusion (I/R) injury. As comparable data on the role of MBL in human I/R injury is lacking, we investigated the influence of low serum MBL concentrations on mortality of patients with acute ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: Mannose-binding lectin was determined in 890 acute STEMI patients that were prospectively recruited in the APEX-AMI trial. This trial had a primary endpoint of death through Day 30 and secondary endpoints of death through Day 90 and the composite of death, cardiogenic shock, or congestive heart failure (CHF) through Days 30 and 90. Samples were taken immediately before PCI and the analysis of MBL limited to patients having received placebo. Patients with serum MBL levels of or below 100 ng/mL were considered to be functionally deficient. Of the 890 patients, 127 had functional MBL deficiency (14.3%). Characteristics of patients with MBL deficiency and those with MBL levels >100 ng/mL did not differ. In patients with MBL deficiency, there was 1 death (0.79%) compared with 42 deaths (5.51%) in patients with MBL levels >100 ng/mL (P = 0.0233) representing an absolute and relative lower mortality in MBL deficient patients of 4.7 and 85%, respectively. Functional MBL deficiency, however, was not associated with decreased risk of the combined endpoints of death and shock or death, shock, and CHF, respectively. CONCLUSION: Functional deficiency of complement MBL is associated with reduced mortality in patients with STEMI undergoing PCI. This unique finding suggests that a component of the innate immune system affects mortality in STEMI patients undergoing primary PCI. TRIAL REGISTRATION: clinicaltrials.gov, Identifier: NCT00091637.


Assuntos
Angioplastia Coronária com Balão , Lectina de Ligação a Manose/deficiência , Infarto do Miocárdio/terapia , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Inativadores do Complemento/uso terapêutico , Proteínas do Sistema Complemento/metabolismo , Creatina Quinase/metabolismo , Creatina Quinase Forma MB/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Traumatismo por Reperfusão Miocárdica/mortalidade , Estudos Prospectivos , Choque Cardiogênico/mortalidade , Anticorpos de Cadeia Única/uso terapêutico
11.
Circulation ; 119(24): 3101-9, 2009 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-19506117

RESUMO

BACKGROUND: Published meta-analyses comparing primary percutaneous coronary intervention with fibrinolytic therapy in patients with ST-segment-elevation myocardial infarction include only randomized controlled trials (RCTs). We aim to obviate the limited applicability of RCTs to real-world settings by undertaking meta-analyses of both RCTs and observational studies. METHODS AND RESULTS: We included all RCTs and observational studies, without language restriction, published up to May 1, 2008. We completed separate bayesian hierarchical random-effect meta-analyses for 23 RCTs (8140 patients) and 32 observational studies (185 900 patients). Primary percutaneous coronary intervention was associated with reductions in short-term (< or =6-week) mortality of 34% (odds ratio, 0.66; 95% credible interval, 0.51 to 0.82) in randomized trials, and 23% lower mortality (odds ratio, 0.77; 95% credible interval, 0.62 to 0.95) in observational studies. Primary percutaneous coronary intervention was associated with reductions in stroke of 63% in RCTs and 61% in observational studies. At long-term follow-up (> or =1 year), primary percutaneous coronary intervention was associated with a 24% reduction in mortality (odds ratio, 0.76; 95% credible interval, 0.58 to 0.95) and a 51% reduction in reinfarction (odds ratio, 0.49; 95% credible interval, 0.32 to 0.66) in RCTs. However, there was no conclusive benefit of primary percutaneous coronary intervention in the long term in the observational studies. CONCLUSIONS: Compared with fibrinolytic therapy, primary percutaneous coronary intervention was associated with short-term reductions in mortality, reinfarction, and stroke in ST-segment-elevation myocardial infarction. Primary percutaneous coronary intervention was associated with long-term reductions in mortality and reinfarction in RCTs, but there was no conclusive evidence for a long-term benefit in mortality and reinfarction in observational studies.


Assuntos
Cateterismo Cardíaco , Fibrinólise , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Terapia Trombolítica , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/etiologia , Fatores de Tempo
12.
Circulation ; 120(22): 2230-9, 2009 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-19917882

RESUMO

BACKGROUND: Interactions of endothelial progenitor cells (EPCs) with vascular and blood cells contribute to vascular homeostasis. Although platelets promote the homing of EPCs to sites of vascular injury and their differentiation into endothelial cells, the functional consequences of such interactions on platelets remain unknown. Herein, we addressed the interactions between EPCs and platelets and their impact on platelet function and thrombus formation. METHODS AND RESULTS: Cultured on fibronectin in conditioned media, human peripheral blood mononuclear cells differentiated, within 10 days of culture, into EPCs, which uptake acetylated low-density lipoprotein, bind ulex-lectin, lack monocyte/leukocyte markers (CD14, P-selectin glycoprotein ligand-1, L-selectin), express progenitor/endothelial markers (CD34, vascular endothelial growth factor receptor-2, von Willebrand factor, and vascular endothelial cadherin), and proliferate in culture. These EPCs bound activated platelets via CD62P and inhibited its translocation, glycoprotein IIb/IIIa activation, aggregation, and adhesion to collagen, mainly via prostacyclin secretion. Indeed, this was associated with upregulation of cyclooxygenase-2 and inducible nitric oxide synthase. However, the effects on platelets in vitro were reversed by cyclooxygenase and cyclooxygenase-2 inhibition but not by nitric oxide or inducible nitric oxide synthase inhibition. Moreover, in a ferric chloride-induced murine arterial thrombosis model, injection of EPCs led to their incorporation into sites of injury and impaired thrombus formation, leading to an incomplete occlusion with 50% residual flow. CONCLUSIONS: Peripheral blood mononuclear cell-derived EPCs bind platelets via CD62P and inhibit platelet activation, aggregation, adhesion to collagen, and thrombus formation, predominantly via upregulation of cyclooxygenase-2 and secretion of prostacyclin. These findings add new insights into the biology of EPCs and define their potential roles in regulating platelet function and thrombosis.


Assuntos
Plaquetas/citologia , Plaquetas/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Trombose/fisiopatologia , Lesões das Artérias Carótidas/fisiopatologia , Células Cultivadas , Epoprostenol/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Hemostasia/fisiologia , Humanos , Leucócitos Mononucleares/citologia , Óxido Nítrico/metabolismo , Adesividade Plaquetária/fisiologia , Agregação Plaquetária/fisiologia , Fluxo Sanguíneo Regional
13.
Am Heart J ; 160(2): 272-8, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20691832

RESUMO

OBJECTIVES: The purpose of this study was to determine predictors of 90-day left ventricular function following acute ST-segment elevation myocardial infarction (STEMI) using variables from clinical presentation, biomarker testing, and cardiovascular magnetic resonance imaging (CMR). BACKGROUND: Identifying patients with acute STEMI who experience adverse remodeling and develop left ventricular dysfunction 3 months post-MI is a priority for guiding subsequent therapy. METHODS: The Assessment of Pexelizumab in Acute Myocardial Infarction trial tested pexelizumab treatment in STEMI patients presenting within 6 hours of symptom onset who were to undergo primary percutaneous coronary intervention. We studied 64 patients within this trial according to a prespecified substudy that included paired core laboratory delayed-enhancement CMR at days 3 and 90 as well as plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP; in picograms per milliliter) measured at randomization and 24 hours. A multivariable model predicting day 90 left ventricular ejection fraction (LVEF) was developed from clinical, biomarker, and imaging findings. RESULTS: Patients had a median age of 60 years (52-68), 89% were male, and 60% had anterior STEMI. Time from symptom onset to percutaneous coronary intervention was 3 hours. The median baseline LVEF was 48% (38%-56%) and was 50% (40%-54%) at 90 days: 7 patients (11%) had an LVEF <35% at 90 days. Patients with a lower 90-day LVEF (as a continuous variable) had a higher 24-hour NT-proBNP (P = .02) and a larger baseline infarct size by CMR (median 15% LV [8%-20% LV]) (P < .01). Microvascular obstruction (no reflow) was greater as measured by CMR (median 2.8% [1.4%-6.1%]) in patients with a lower 90-day LVEF (P < .01). Median baseline and 24-hour NT-proBNP levels were 94 pg/mL (54-292 pg/mL) and 1,448 pg/mL (958-2,599 pg/mL), respectively. In a multivariable model with clinical, biomarker, and imaging variables, only 3 variables independently predicted 90-day LVEF: 24-hour NT-proBNP, baseline CMR infarct size, and microvascular obstruction. CONCLUSIONS: Three key pathophysiologic variables of the post-STEMI myocardium measuring baseline infarct size and the extent of microvascular obstruction on CMR and wall tension (24-hour NT-proBNP) independently predicted 90-day LVEF. Further studies linking these measures with earlier use of clinical therapies may be warranted.


Assuntos
Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Disfunção Ventricular Esquerda/epidemiologia , Remodelação Ventricular , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Biomarcadores/sangue , Angiografia Coronária , Feminino , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Precursores de Proteínas/sangue , Medição de Risco , Anticorpos de Cadeia Única/uso terapêutico , Volume Sistólico
15.
Catheter Cardiovasc Interv ; 74(3): 387-94, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19496148

RESUMO

OBJECTIVES: To evaluate the safety and feasibility of myocardial cryotreatment for patients with coronary artery disease (CAD) and severe angina refractory to standard treatment. BACKGROUND: Innovative myocardial revascularization strategies are needed for patients with CAD and severe angina uncontrolled by conventional methods. Preclinical data have demonstrated that cryotherapy can induce myocardial neovascularization through arteriogenesis. METHODS: This was a two center, nonrandomized, study that enrolled 20 patients. All patients had CAD and severe angina (CCS Angina Class III or IV). Safety was the primary endpoint. Treatment involved 8-10 intramyocardial cryoapplications (at < or = -50 degrees C), for 2 min by a specially designed percutaneous catheter at an identified ischemic area of the myocardium. Primary endpoint was safety, with secondary endpoints of angina severity, exercise tolerance, quality of life, and myocardial perfusion assessed by radionuclide scintigraphy. RESULTS: The procedure was successful in 19 patients. There were three device-related events, a pericardial tamponade requiring pericardiocenetesis, a clinically nonsignificant pericardial effusion, and an episode of ventricular tachycardia requiring cardioversion in one patient. Complete 12-month follow-up was obtained in 16 patients. Significant reduction in CCS angina scores and significant improvements in both exercise tolerance and quality of life (P < 0.05) were seen at 6 and 12-month follow-up. Although no significant differences were observed in myocardial perfusion in the overall group, marked improvement was detected in 8 (42%) patients. CONCLUSION: Cryotreatment is feasible and safe in patients with severe angina refractory to standard management. Early efficacy results are encouraging and further clinical study is warranted.


Assuntos
Angina Pectoris/cirurgia , Cateterismo Cardíaco , Doença da Artéria Coronariana/cirurgia , Criocirurgia , Revascularização Miocárdica/métodos , Idoso , Angina Pectoris/diagnóstico por imagem , Angina Pectoris/etiologia , Angina Pectoris/fisiopatologia , Canadá , Cateterismo Cardíaco/efeitos adversos , Cateterismo Cardíaco/instrumentação , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/fisiopatologia , Circulação Coronária , Criocirurgia/efeitos adversos , Criocirurgia/instrumentação , Desenho de Equipamento , Tolerância ao Exercício , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem de Perfusão do Miocárdio/métodos , Revascularização Miocárdica/efeitos adversos , Revascularização Miocárdica/instrumentação , Neovascularização Fisiológica , Qualidade de Vida , Índice de Gravidade de Doença , Fatores de Tempo , Falha de Tratamento
16.
Am J Med Genet B Neuropsychiatr Genet ; 150B(3): 381-8, 2009 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-18618671

RESUMO

Numerous studies suggest that the prevalence of depression is greater among cardiac patients than in the general population. However, little attention has been paid to the possibility of genetic contributions to depressive symptoms in cardiac patients. We conducted a candidate gene study focusing on genes related to inflammation, platelet aggregation, endothelial function and omega-3 fatty acid metabolism as predictors of depressive symptoms among 977 participants with established cardiovascular disease. Results suggested that genetic variation related to endothelial dysfunction is predictive of depressive symptoms and that endothelial dysfunction may be a novel mechanism contributing to depressive symptoms among cardiac patients.


Assuntos
Depressão/genética , Ácidos Graxos Ômega-3/genética , Cardiopatias/genética , Inflamação/genética , Agregação Plaquetária/genética , Alelos , Canadá/epidemiologia , Depressão/complicações , Células Endoteliais/patologia , Ácidos Graxos Ômega-3/metabolismo , Feminino , França/etnologia , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Haplótipos , Cardiopatias/epidemiologia , Homozigoto , Humanos , Íntrons , Modelos Lineares , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Prevalência , Fator de von Willebrand/genética
18.
N Engl J Med ; 352(12): 1179-89, 2005 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-15758000

RESUMO

BACKGROUND: A substantial proportion of patients receiving fibrinolytic therapy for myocardial infarction with ST-segment elevation have inadequate reperfusion or reocclusion of the infarct-related artery, leading to an increased risk of complications and death. METHODS: We enrolled 3491 patients, 18 to 75 years of age, who presented within 12 hours after the onset of an ST-elevation myocardial infarction and randomly assigned them to receive clopidogrel (300-mg loading dose, followed by 75 mg once daily) or placebo. Patients received a fibrinolytic agent, aspirin, and when appropriate, heparin (dispensed according to body weight) and were scheduled to undergo angiography 48 to 192 hours after the start of study medication. The primary efficacy end point was a composite of an occluded infarct-related artery (defined by a Thrombolysis in Myocardial Infarction flow grade of 0 or 1) on angiography or death or recurrent myocardial infarction before angiography. RESULTS: The rates of the primary efficacy end point were 21.7 percent in the placebo group and 15.0 percent in the clopidogrel group, representing an absolute reduction of 6.7 percentage points in the rate and a 36 percent reduction in the odds of the end point with clopidogrel therapy (95 percent confidence interval, 24 to 47 percent; P<0.001). By 30 days, clopidogrel therapy reduced the odds of the composite end point of death from cardiovascular causes, recurrent myocardial infarction, or recurrent ischemia leading to the need for urgent revascularization by 20 percent (from 14.1 to 11.6 percent, P=0.03). The rates of major bleeding and intracranial hemorrhage were similar in the two groups. CONCLUSIONS: In patients 75 years of age or younger who have myocardial infarction with ST-segment elevation and who receive aspirin and a standard fibrinolytic regimen, the addition of clopidogrel improves the patency rate of the infarct-related artery and reduces ischemic complications.


Assuntos
Aspirina/uso terapêutico , Fibrinolíticos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Terapia Trombolítica , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêutico , Adulto , Idoso , Angioplastia Coronária com Balão , Clopidogrel , Angiografia Coronária , Ponte de Artéria Coronária , Quimioterapia Combinada , Eletrocardiografia , Feminino , Hemorragia/induzido quimicamente , Heparina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacologia , Prevenção Secundária , Ticlopidina/efeitos adversos , Ticlopidina/farmacologia , Grau de Desobstrução Vascular/efeitos dos fármacos
19.
Ann Intern Med ; 147(5): 304-10, 2007 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-17785485

RESUMO

BACKGROUND: A recent randomized, controlled trial, the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS 5) trial, reported that major bleeding was 2-fold less frequent with fondaparinux than with enoxaparin in acute coronary syndromes (ACS). Renal dysfunction increases the risk for major bleeding. OBJECTIVE: To compare the efficacy and safety of fondaparinux and enoxaparin over the spectrum of renal dysfunction observed in the OASIS 5 trial. DESIGN: Subgroup analysis of a randomized, controlled trial. SETTING: Patients presenting to the hospital with non-ST-segment elevation ACS. PATIENTS: 19,979 of the 20,078 patients in the OASIS 5 trial in whom creatinine was measured at baseline. MEASUREMENTS: Death, myocardial infarction, refractory ischemia, and major bleeding were evaluated separately and as a composite end point at 9, 30, and 180 days. Glomerular filtration rate (GFR) was calculated by using the Modification of Diet in Renal Disease formula. RESULTS: The absolute differences in favor of fondaparinux (efficacy and safety) were most marked in patients with a GFR less than 58 mL/min per 1.73 m2; the largest differences occurred in major bleeding events. At 9 days, death, myocardial infarction, or refractory ischemia occurred in 6.7% of patients receiving fondaparinux and 7.4% of those receiving enoxaparin (hazard ratio, 0.90 [95% CI, 0.73 to 1.11]); major bleeding occurred in 2.8% and 6.4%, respectively (hazard ratio, 0.42 [CI, 0.32 to 0.56]). Statistically significant differences in major bleeding persisted at 30 and 180 days. The rates of the composite end point were lower with fondaparinux than with enoxaparin in all quartiles of GFR, but the differences were statistically significant only among patients with a GFR less than 58 mL/min per 1.73 m2. LIMITATIONS: Subgroup analyses warrant caution; the study was powered to detect noninferiority at 9 days. Fondaparinux is not approved for use in patients with ACS in the United States. CONCLUSIONS: The benefits of fondaparinux over enoxaparin when administered for non-ST-segment elevation ACS are most marked among patients with renal dysfunction and are largely explained by lower rates of major bleeding with fondaparinux.


Assuntos
Anticoagulantes/uso terapêutico , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/fisiopatologia , Enoxaparina/uso terapêutico , Rim/fisiopatologia , Polissacarídeos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Angina Pectoris/etiologia , Anticoagulantes/efeitos adversos , Doença das Coronárias/complicações , Morte Súbita Cardíaca/etiologia , Método Duplo-Cego , Enoxaparina/efeitos adversos , Feminino , Fondaparinux , Taxa de Filtração Glomerular , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Polissacarídeos/efeitos adversos , Síndrome
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