RESUMEN
BACKGROUND: The aim of this article was to investigate whether prior aspirin use in patients with acute coronary syndromes affects clinical outcome. The Efficacy Safety Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study (ESSENCE) and Thrombolysis in Myocardial Infarction (TIMI) 11B trials have shown superiority of enoxaparin over unfractionated heparin (UFH) in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). However, the treatment effect of enoxaparin in the subset of patients reporting prior aspirin use has not been determined. METHODS: The rate of death, myocardial infarction, and urgent revascularization at days 8 and 43 after randomization was compared among patients who received aspirin within the week before randomization with those who did not receive aspirin in the TIMI 11B trial. A total of 3275 patients (84%) were prior aspirin users. RESULTS: The admission diagnosis was similar for prior and nonprior aspirin users. At both day 8 and day 43 the event rate was higher for prior aspirin users than for nonprior aspirin users (odds ratio 1.6 [1.24-2.08], P =.0004 at day 43), even after correction for baseline characteristics. Compared with those prior aspirin users taking UFH, enoxaparin-treated prior aspirin users had a reduced rate of the composite end point of death, myocardial infarction, and urgent revascularization at day 8 (odds ratio 0.82 [0.67-1.00], P =.046) and day 43 (odds ratio 0.83 [0.70-0.98], P =.032). CONCLUSION: Patients with UA/NSTEMI and prior aspirin use had a 60% higher risk of death and cardiac ischemic events compared with nonprior aspirin users. On the basis of this subanalysis, enoxaparin is superior to UFH in all patients. In prior aspirin users the benefit is more clearly demonstrated.
Asunto(s)
Angina Inestable/tratamiento farmacológico , Anticoagulantes/uso terapéutico , Enoxaparina/uso terapéutico , Heparina/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Aspirina/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/uso terapéutico , Pronóstico , Medición de Riesgo , SíndromeRESUMEN
OBJECTIVES: We analyzed the effect of the pharmacologic combination of 2 indirect antithrombin drugs--enoxaparin (low-molecular-weight heparin) and unfractionated heparin--versus enoxaparin alone on the recurrence of ischemia. BACKGROUND: Blocking some key factors of the coagulation cascade supports the concept that an antithrombin effect is needed during the acute phase of ischemia. METHODS: This was a prospective, randomized, pilot trial in patients with an acute coronary ischemic event occurring within the previous 24 hours. A total of 126 patients were allocated to receive aspirin (200 mg/day orally) plus 1 mg/kg subcutaneous enoxaparin at 8 AM and 12.500 IU of subcutaneous unfractionated heparin at 8 PM (group A) or subcutaneous enoxaparin 1 mg/kg (group B). RESULTS: Severe recurrent ischemia provoking urgent coronary revascularization occurred in 12 patients (9.5%), 3 (5%) in group A and 9 (13%) in group B (P = .1). Refractory angina was present in 27 patients (21%), 10 (17%) in group A and 17 (25%) in group B (P = .45). The combination of severe recurrent ischemia and refractory angina occurred in 23% of group A, and 37% of group B (odds ratio 0.49; 95% confidence intervals, 0.21-1.15; P = .07). A total of 7 patients (5%) had acute nonfatal myocardial infarction develop, 3 (5%) in group A and 4 (6%) in group B. Two (1.6%) deaths were observed in the study, both in group B. The incidence of the double end point (death plus nonfatal myocardial infarction) was 5% in group A versus 9% in group B (P = .5) and the triple end point (death, nonfatal myocardial infarction, and severe recurrent ischemia) was 10.5% in group A vs 22% in group B (odds ratio 0.42, 95% confidence intervals, 0.13-1.29; P = .09). CONCLUSIONS: The combination of 2 indirect antithrombin drugs capable of intermittently blocking the coagulation system is not associated with a significant loss of safety.
Asunto(s)
Anticoagulantes/uso terapéutico , Enoxaparina/uso terapéutico , Heparina/uso terapéutico , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/prevención & control , Enfermedad Aguda , Angina de Pecho/epidemiología , Angina de Pecho/etiología , Angina de Pecho/fisiopatología , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Aspirina/uso terapéutico , Quimioterapia Combinada , Enoxaparina/administración & dosificación , Enoxaparina/efectos adversos , Femenino , Heparina/administración & dosificación , Heparina/efectos adversos , Humanos , Incidencia , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Mortalidad , Infarto del Miocardio/epidemiología , Infarto del Miocardio/etiología , Isquemia Miocárdica/epidemiología , Isquemia Miocárdica/fisiopatología , Proyectos Piloto , Prevención Secundaria , Índice de Severidad de la Enfermedad , Método Simple CiegoRESUMEN
It has been shown that plaque composition changes significantly in the setting of acute events, macrophages and T cells being the predominant pattern at the immediate site of fissure or erosion. There appears to be a relation between physical blood stream factors, plaque morphology, and the distribution of inflammatory cells. Furthermore, there is cumulative evidence for the presence of intracellular pathogens in the arterial wall, namely Chlamydia pneumoniae and cytomegalovirus, which affect endothelial cells, monocytes, and macrophages. The ROXIS trial has shown some encouraging evidences for the potential role of intracellular pathogens in acute coronary syndromes. The ongoing WIZARD trial evaluates in a large population whether the addition of an antibiotic provides better outcome for coronary patients.
Asunto(s)
Antibacterianos/uso terapéutico , Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/microbiología , Arteriosclerosis/patología , Infecciones por Chlamydia/tratamiento farmacológico , Chlamydophila pneumoniae/patogenicidad , Ensayos Clínicos como Asunto , Humanos , Inflamación/tratamiento farmacológicoRESUMEN
BACKGROUND: This study was designed to analyze the impact of treatment with either unfractionated heparin or enoxaparin (low molecular weight heparin) on plasma markers of thrombotic and endogenous thrombolytic activity in patients with non-ST segment elevation acute coronary syndromes. METHODS: A subset of 174 patients derived from the 3,171 patients of the ESSENCE study was evaluated. Eighty-seven patients were assigned to intravenous unfractionated heparin (target aPTT: 55-85 sec) (group UH), and 87 assigned to subcutaneous enoxaparin (1 mg/kg/q12hr) (group ENOX) for a minimum of 48 hours of treatment (average duration of treatment 88+/-45 hours). The thrombin time, and plasma levels of anti-factor Xa activity, prothrombin fragment F 1+2, thrombin-antithrombin complex (TAT), and D-dimer, were assayed at baseline, and at or close to peak activity 24-36 hrs, and at 72-90 hrs for those remaining on treatment with antithrombotic therapy. Major ischemic and hemorrhagic events were assessed throughout hospitalization. The levels of the thrombotic markers measured at or close to peak activity at 36 hours are presented below, and compared to clinical outcome at 30 days. RESULTS: In UH patients, the thrombin time increased 7 fold while the mean value for anti-Xa activity was 0.27 IU/ml; in ENOX patients the thrombin time increased 2.3 fold, and the mean value for anti-Xa activity was 0.83 IU/ml. In UH pts, basal levels of F 1+2, TAT, and D-dimer declined by (deltapaired) -0.8, -3. 3, and -66, respectively. In ENOX pts, basal levels of F 1+2, TAT, and D-dimer declined by (deltapaired) -0.3, -4.7, and -23, respectively. No significant differences were observed between the paired differences in thrombotic markers (UH vs ENOX), nor in the rate of recurrent ischemic events or major hemorrhage. CONCLUSIONS: In this subset of patients enrolled in the ESSENCE study, enoxaparin 1 mg/kg ql2hr significantly increased anti-Xa activity above that seen with unfractionated heparin, and reduced thrombin production without prolonging the thrombin time. The high anti-Xa activity achieved with enoxaparin was not associated with a loss of safety.
Asunto(s)
Enfermedad Coronaria/tratamiento farmacológico , Enoxaparina/uso terapéutico , Fibrinolíticos/uso terapéutico , Heparina/uso terapéutico , Biomarcadores , Enfermedad Coronaria/fisiopatología , Método Doble Ciego , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndrome , Resultado del TratamientoRESUMEN
AIMS: Mounting evidence suggests infection, specifically Chlamydia pneumoniae, plays a role in atherosclerosis. We tested whether antibiotic treatment with the macrolide roxithromycin improves clinical outcome in patients with acute non-Q-wave coronary syndromes. Preliminary reports revealed a reduction in events in the roxithromycin group at 30 days. We now report the long-term follow-up results. METHODS AND RESULTS: Sixty-four per cent of the initial 202 patients with unstable angina who were randomly assigned to receive either roxithromycin or placebo for 30 days completed the active treatment period. At day 30, the primary triple and double end-point rates were 9% and 4% in the placebo group compared to 2% and 0% in the roxithromycin group (unadjusted P = 0.032 and 0.058, respectively). The secondary triple and double end-point rates were again higher in the placebo group at day 90 (12.5% and 6.25% vs 4.37% and 0%, unadjusted P = 0.065 and 0.029, respectively), and at day 180 (14.6% and 7.29% vs 8.69% and 2.17%, unadjusted P = 0.259 and 0.17, respectively). Anti-C, pneumoniae IgG titres were unchanged in both groups while C-reactive protein levels decreased in both strategies, with a more significant decrease in the roxithromycin arm (P = 0.03). Elevated C-reactive protein levels predicted the need for revascularization. CONCLUSIONS: In this pilot trial, roxithromycin appears to extend the clinical benefit of preventing death and re-infarction for at least 6 months after initial treatment.
Asunto(s)
Angina Inestable/tratamiento farmacológico , Antibacterianos/administración & dosificación , Roxitromicina/administración & dosificación , Anciano , Angina Inestable/diagnóstico , Angina Inestable/mortalidad , Angina Inestable/fisiopatología , Distribución de Chi-Cuadrado , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/tratamiento farmacológico , Enfermedad Coronaria/mortalidad , Enfermedad Coronaria/fisiopatología , Electrocardiografía/efectos de los fármacos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Tasa de Supervivencia , Síndrome , Resultado del TratamientoRESUMEN
Systemic serum markers of inflammation are elevated in diseases due to atherosclerosis, but have not been associated with the extent of atherosclerotic disease. We examined the role of neopterin, a byproduct of activated macrophage metabolism, in patients with unstable angina. Baseline neopterin samples and clinical histories were obtained in 52 patients admitted with unstable angina pectoris. Coronary angiograms of 27 patients were reviewed using Sullivan's method to assess the total atherosclerotic burden in the coronary arteries. Twenty-six of the 52 patients were eventually diagnosed with a non-Q-wave acute myocardial infarction (AMI) and had higher neopterin levels (10.1 +/- 6.7 vs 7.2 +/- 4.0 nmol/L, p = 0.06) than patients with a final diagnosis of unstable angina. Patients with neopterin >8.7 were more likely to be diagnosed with a non-Q-wave AMI (75% vs 39%, p = 0.035) and were more likely to have significantly more severe and extensive angiographically determined atherosclerosis than patients with low neopterin levels. Neopterin levels correlated with the score of atherosclerotic extension (Spearman's rank correlation coefficient 0.4807, p = 0.034). This study demonstrates a correlation between immune cell activation and the extent of angiographically determined atherosclerosis and the degree of myocardial ischemia.
Asunto(s)
Angina Inestable/sangre , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/sangre , Infarto del Miocardio/sangre , Neopterin/sangre , Anciano , Angina Inestable/complicaciones , Angina Inestable/diagnóstico por imagen , Biomarcadores/sangre , Enfermedad de la Arteria Coronaria/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico por imagenRESUMEN
Coronary heart disease remains the most common cause of death in industrialized countries. Although atherosclerosis is generally asymptomatic in the early stages, progressive plaque development leads to arterial stenosis which is characterized by angina and may eventually lead to unstable angina, myocardial infarction and cardiac death. Evidence that the coagulation cascade is activated during acute coronary events has justified the use of antithrombotic agents such as aspirin, heparin and low molecular weight heparin (LMWH) in the standard management of acute coronary syndromes. The inflammatory process is also known to play a significant role in the pathogenesis of atherosclerosis, resulting in a cycle of continued inflammatory cell activation and ongoing cell recruitment. As the human leukocyte-associated antigen (HLA) system plays a key role in the regulation of the inflammatory process, the expression of HLA antigens in patients with symptomatic coronary heart disease has been investigated. These studies have demonstrated a relationship between the major histocompatibility complex (MHC) class II expression and the most severe pattern of angina refractory to conventional therapy, within the framework of a chronic infectious disease. A number of studies have documented an association between coronary heart disease and the presence of high titres of antibodies to Chlamydia pneumoniae, and this organism has been implicated in plaque instability. Such findings have stimulated interest in the role of C. pneumoniae in the pathogenesis of coronary heart disease, with a view to developing novel and effective treatment approaches. The ROXIS study showed a lower incidence of acute ischaemic events in patients with unstable angina treated with an antichlamydial antibiotic, roxithromycin.
Asunto(s)
Angina Inestable/microbiología , Infecciones por Chlamydia/diagnóstico , Chlamydophila pneumoniae/aislamiento & purificación , Enfermedad de la Arteria Coronaria/microbiología , Infecciones por Chlamydia/complicaciones , Ensayos Clínicos como Asunto , Humanos , Inflamación/etiologíaRESUMEN
BACKGROUND: There is serological evidence for an association between Chlamydia pneumoniae and coronary heart disease. We investigated the hypothesis that an antichlamydial macrolide antibiotic, roxithromycin, can prevent or reduce recurrent major ischaemic events in patients with unstable angina. METHODS: The effect of roxithromycin was assessed in a double-blind, randomised, prospective, multicentre, parallel-group, placebo-controlled pilot study of 202 patients with unstable angina or non-Q-wave myocardial infarction. Patients were randomly assigned either roxithromycin 150 mg orally twice a day (n = 102) or placebo orally twice a day (n = 100). The treatment was for 30 days. Patients were followed up for 6 months. We report the primary clinical endpoints (cardiac ischaemic death, myocardial infarction, and severe recurrent ischaemia), assessed at day 31, in 202 patients on an intention-to-treat basis. FINDINGS: A statistically significant reduction in the primary composite triple endpoint rates was observed in the roxithromycin group: p = 0.032. The rate of severe recurrent ischaemia, myocardial infarction, and ischaemic death was 5.4%, 2.2%, and 2.2% in the placebo group and 1.1%, 0%, and 0%, in the roxithromycin group, respectively. No major drug-related adverse effects were observed. INTERPRETATION: Antichlamydial antibiotics may be useful in therapeutic intervention in addition to standard medication in patients with coronary-artery disease. Large-scale trials are needed to confirm these preliminary observations.
Asunto(s)
Angina Inestable/tratamiento farmacológico , Antibacterianos/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Roxitromicina/uso terapéutico , Adulto , Anciano , Angina Inestable/mortalidad , Angina Inestable/prevención & control , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Infarto del Miocardio/prevención & control , RecurrenciaRESUMEN
OBJECTIVES: Evidence exists showing an association between Chlamydial infection and infarction. Our purpose was to identify an interactive relationship between Chlamydia pneumoniae and unstable angina. METHODS: We analyzed IgG antibodies for Chlamydia pneumoniae, Mycoplasma pneumoniae, and C reactive protein in patients during the acute phase of unstable angina. RESULTS: Chlamydia antibodies were present in 16.92% (11 cases) of the unstable angina patients. They were also present in 34.61% of those patients who experienced ischemic events vs 5.1% who did not (odds ratio 9.79, 95% CL 1.65 to 75.26, p = 0.002). Mycoplasma pneumoniae antibodies were present in 12.30% of patients but did not emerge as a predictive variable. C-reactive protein was present in 22 cases (33.84%), 9 of which were associated with recurrent events (34.61%) vs 13 which were free of them (odds ratio, p = 0.5). The interactive relationship between infection plus C-reactive protein achieved a statistical significant association with ischemic events (odds ratio 14, 95% CI 1.49-331.1; p = 0.003). CONCLUSIONS: These findings suggest a pathophysiologically based relationship between infective and inflammatory processes related to poor clinical outcome during the in-hospital stay in the setting of unstable angina patients.
Asunto(s)
Angina Inestable/sangre , Antígenos Bacterianos/sangre , Proteína C-Reactiva/análisis , Infecciones por Chlamydia/inmunología , Chlamydophila pneumoniae/inmunología , Inmunoglobulina G/sangre , Mycoplasma pneumoniae/inmunología , Neumonía por Mycoplasma/inmunología , Angina Inestable/inmunología , Angina Inestable/microbiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/etiología , PronósticoRESUMEN
Ischemic electrocardiographic changes were recorded within 2 hours of admission using a 12-lead electrocardiographic continuous monitor with a 20-second scanning interval and an alarm mode for asymptomatic events. Blood samples were obtained at admission and at the moment of asymptomatic events (group A). In the other patients who did not develop ischemia, a second blood sample was taken 12 hours later (group B). We determined prothrombin time, activated partial thromboplastin time, clotting factor VIII activity, tissue plasminogen activator activity, tissue plasminogen activator inhibitor-1, cross-linked fibrin degradation product, and thrombin-antithrombin III complexes. There was a statistically significant difference between group A and B patients when the basal samples were analyzed for thrombin-antithrombin III (p = 0.046) and d-Dimer (p = 0.005). Prothrombin fragment 1 + 2 were significantly reduced, and d-Dimer was elevated when basal blood samples were compared with the second sample in patients who developed silent events (p = 0.008 and 0.055, respectively). A plasma concentration of thrombin-antithrombin III complex was also significantly decreased when sample 2 was compared with the basal blood sample (p = 0.039). Five recurrent episodes of angina and 2 nonfatal infarctions occurred, and 4 urgent revascularization procedures were performed in group A. In group B, there was only 1 nonfatal infarction (p = 0.01). The results of the present study suggest that a time-dependent thrombotic process is detectable in the blood stream as a cyclic movement. Further studies are needed to determine if some other factors, such as intensive shear stress in the vessel wall, may activate plaque instability during asymptomatic episodes.