RESUMEN

PURPOSE: Confounding by indication is common in observational studies of outcomes that treatment is intended to affect. In light of the stepped-care approach to hypertension management, we reexamined the controversy around myocardial infarction (MI) risk in relation to antihypertensive agents by considering past drug history both as a confounder and as an effect modifier. METHODS: Case-control design nested within a cohort of 19,501 adults initiating therapy with angiotensin-converting enzyme inhibitors (ACEI), calcium channel blockers (CCB) or beta-blockers in Saskatchewan (1990-93) and followed up to 1997. MI cases were identified using death certificates and hospital discharge diagnoses (ICD-9,410). Four controls were matched to each case to account for duration and timing of follow-up. RESULTS: 812 MI cases were identified, of which 26% were fatal. At first, current use of CCB and ACEI (versus beta-blockers) appeared to be associated with an increased risk of MI (RR = 2.2; 95% CI = 1.8-2.7 and RR = 1.3; CI = 1.0-1.6 respectively). Adjustment for drug use history attenuated both associations (RR = 1.6; CI = 1.1-2.2 and RR = 1.0; CI = 0.7-1.4). Moreover, the risk for CCB use disappeared when restricted to patients who had already used these agents in the past (RR = 1.1; CI = 0.77-1.7) whereas a high risk of MI for ACEI was found in digoxin users (RR = 9.4; CI = 3.2-27.5). CONCLUSION: Past drug history can be both a confounder and an effect modifier in observational studies. We found adjustment for medication history to attenuate the associations between antihypertensive agents and MI risk. In addition, the estimates significantly varied across drug history profiles thus suggesting the presence of preferential prescribing of specific drug classes to high-risk patients.

Asunto(s)

Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Infarto del Miocardio/epidemiología , Infarto del Miocardio/prevención & control , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Estudios de Casos y Controles , Estudios de Cohortes , Digoxina/uso terapéutico , Prescripciones de Medicamentos/estadística & datos numéricos , Utilización de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Medición de Riesgo , Saskatchewan/epidemiología

Asunto(s)

Suero Antilinfocítico/uso terapéutico , Ciclosporina/farmacocinética , Ciclosporina/uso terapéutico , Trasplante de Corazón/fisiología , Inmunosupresores/farmacocinética , Enfermedad Aguda , Cardiomiopatías/cirugía , Ciclosporina/sangre , Esquema de Medicación , Monitoreo de Drogas , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/epidemiología , Trasplante de Corazón/inmunología , Humanos , Inmunosupresores/sangre , Inmunosupresores/uso terapéutico , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad

RESUMEN

OBJECTIVES: To determine the effect of angiotensin-converting enzyme (ACE) inhibition on brachial flow-mediated vasodilation. BACKGROUND: Quinapril, an ACE inhibitor with high affinity, has been shown to improve coronary endothelial dysfunction in patients with coronary artery disease. The effectiveness of different vasoactive agents to improve human endothelial function is unknown. METHODS: High resolution ultrasound was used to assess endothelium-dependent brachial artery flow-mediated vasodilation (FMD) in patients with coronary disease. We studied 80 patients (mean age 58 +/- 0.9 years) in a partial-block, cross-over design trial. Patients were randomized to one of four different drug sequences to receive quinapril 20 mg, enalapril 10 mg, losartan 50 mg or amlodipine 5 mg daily. Each patient received three drugs with a two-week washout period between treatments. The primary end point was the absolute difference in FMD after eight weeks of each study drug compared with their respective baselines analyzed in a blinded fashion. RESULTS: There was mild impairment of FMD at baseline (7.3 +/- 0.6%). The change in FMD from baseline was significant only for quinapril (1.8 +/- 1%, p < 0.02). No change was seen with losartan (0.8 +/- 1.1%, p = 0.57), amlodipine (0.3 +/- 0.9%, p = 0.97) or enalapril (-0.2 +/- 0.8%, p = 0.84). No significant change in nitroglycerin-induced dilation occurred with drug therapy. The improvement in quinapril response was not seen in those with the DD ACE genotype (0.5 +/- 2.1%) but was seen in those with the ID and II genotype (3.3 +/- 1.2 and 3.2 +/- 1.9%, respectively, p = 0.03). CONCLUSION: Only quinapril was associated with significant improvement in FMD, and this response is related to the presence of the insertion allele of the ACE genotype.

Asunto(s)

Angiotensina II/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Circulación Coronaria/efectos de los fármacos , Enfermedad Coronaria/tratamiento farmacológico , Tetrahidroisoquinolinas , Vasodilatación/efectos de los fármacos , Anciano , Amlodipino/administración & dosificación , Amlodipino/efectos adversos , Angiotensina II/fisiología , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Velocidad del Flujo Sanguíneo/fisiología , Bloqueadores de los Canales de Calcio/efectos adversos , Circulación Coronaria/fisiología , Enfermedad Coronaria/fisiopatología , Quimioterapia Combinada , Enalapril/administración & dosificación , Enalapril/efectos adversos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Femenino , Humanos , Isoquinolinas/administración & dosificación , Isoquinolinas/efectos adversos , Losartán/administración & dosificación , Losartán/efectos adversos , Masculino , Persona de Mediana Edad , Quinapril , Vasodilatación/fisiología

RESUMEN

BACKGROUND: Reference-based pricing is a cost-containment policy applied to prescription drugs that are in the same class and deemed to be therapeutically equivalent. Recent reference-based pricing measures have targeted several drug classes, including angiotensin-converting-enzyme (ACE) inhibitors. The objective of this study was to assess whether patients treated for hypertension with various ACE inhibitors differed in their utilization of health care services and hence, whether the various ACE inhibitors should be considered therapeutically equivalent. METHODS: A retrospective cohort was formed from 4709 Saskatchewan residents aged 40-79 years who initiated treatment for hypertension with 1 of the 3 most frequently prescribed ACE inhibitors (captopril, enalapril or lisinopril) between Jan. 1, 1991, and Dec. 31, 1993. Information obtained from universal insurance databases included prescription drug use, the number of visits to a general practitioner (GP) or specialist and the number of hospital admissions during the year before treatment was initiated and during a follow-up period of up to 4 years. Rates were statistically adjusted for potential confounding variables and compared across treatment groups. RESULTS: Of the 4709 patients, 529 were prescribed captopril initially, 2939 enalapril and 1241 lisinopril. After treatment was initiated patients prescribed captopril were dispensed more medications on average, with an overall rate of 18.6 prescriptions per patient per year (v. 16.4 and 14.7 for enalapril and lisinopril users respectively); they were admitted to hospital more often, and they made more visits to GPs and specialists. The adjusted rate ratio of the number of visits to a GP for patients receiving enalapril, relative to captopril, was 0.84 (95% confidence interval [CI] 0.80-0.88), and for those receiving lisinopril it was 0.79 (95% CI 0.74-0.83). The adjusted rate ratios for the number of visits to a specialist were similar but lower, and for the number of hospital admissions they were 0.82 for patients prescribed enalapril initially (95% CI 0.73-0.93) and 0.65 (95% CI 0.56-0.75) for those prescribed lisinopril. INTERPRETATION: Patients with hypertension who are initially prescribed captopril used health care services more than those initially prescribed enalapril or lisinopril. This suggests that ACE inhibitors may not be therapeutically equivalent.

Asunto(s)

Inhibidores de la Enzima Convertidora de Angiotensina/economía , Prescripciones de Medicamentos/economía , Economía Farmacéutica , Servicios de Salud/estadística & datos numéricos , Hipertensión/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/farmacocinética , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Estudios de Cohortes , Control de Costos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Equivalencia Terapéutica

Asunto(s)

Suero Antilinfocítico/uso terapéutico , Rechazo de Injerto/patología , Trasplante de Corazón/inmunología , Trasplante de Corazón/patología , Inmunosupresores/uso terapéutico , Biopsia/métodos , Femenino , Rechazo de Injerto/tratamiento farmacológico , Humanos , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Monitorización Inmunológica/métodos , Muromonab-CD3/uso terapéutico , Estudios Retrospectivos , Factores de Tiempo

Asunto(s)

Enfermedad Coronaria/genética , Trasplante de Corazón/fisiología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Mutación Puntual , Complicaciones Posoperatorias/etiología , Biopsia , Enfermedad Coronaria/etiología , Estudios de Seguimiento , Supervivencia de Injerto , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2) , Complicaciones Posoperatorias/epidemiología , Factores de Riesgo , Factores de Tiempo

RESUMEN

BACKGROUND: Based on the excellent correlation between cyclosporine A 2-hr postdose blood levels (C2) and the area under the concentration versus time curve, we evaluated the clinical benefit of Neoral dose monitoring with C2 compared trough levels (C0) in stable heart transplant patients. METHODS: We studied 114 stable adult patients followed at the heart transplant clinic, who were >1 year after surgery. In May 1996 (period 1, follow-up 10+/-4 months), Neoral dose monitoring was based on C2 (300-600 ng/ml); while in May 1997 (period 2, follow-up 10+/-2 months), it was based on C0 (100-200 ng/ml). Cyclosporine A levels were measured by an enzyme multiplied immunologic technique. Clinical benefit was defined by the absence of acute rejection, no mortality, no fall in left ventricular ejection fraction >10%, and no increase in serum creatinine >10% (compared with baseline). RESULTS: During period 1, Neoral dose, cyclosporine A, C0 and C2, and serum creatinine, decreased by 26, 56, 45, and 2.3%, respectively. At the end of period 2, the same variables increased by 24, 56, 38, and 10%, respectively (P<0.0001). The incidence of acute rejection was similar (period 1: 0.87%, period 2: 0.96%). The left ventricular ejection fraction (initial/final) remained stable (period 1: 57+/-91%/58+/-13%, period 2: 59+/-11d/58+/-10%). Mortality did not differ (period 1: 7.9%, period 2: 9.6%). A clinical benefit was observed in 69.3% of the patients during period 1 vs. 43.3% of the patients during period 2 (P<0.00001). CONCLUSIONS: In stable heart transplant patients, a greater clinical benefit was observed when Neoral dose monitoring was performed according to C2, compared with C0.

Asunto(s)

Ciclosporina/administración & dosificación , Ciclosporina/sangre , Trasplante de Corazón , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Enfermedad Aguda , Anciano , Ciclosporina/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Rechazo de Injerto/epidemiología , Humanos , Inmunosupresores/uso terapéutico , Incidencia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/mortalidad , Volumen Sistólico , Resultado del Tratamiento

RESUMEN

To assess the safety profile of Neoral dose adjustment using cyclosporine (CsA) trough levels (C0) compared with levels obtained 2 h after the morning dose (C2), 30 stable adult heart transplant patients 1 yr or more after surgery were converted from Sandimmune to Neoral. After a baseline visit (before conversion), initial follow-up included two visits (2 and 4-6 wk after conversion). After the first visit, patients were randomized to Group I (C0: 100-200 ng/ml) or Group II (C2: 200-400 ng/ml). Abbreviated pharmacokinetics were obtained for the estimation of the AUC0-4 h. Renal function was assessed by serum creatinine and the cimetidine-modified creatinine clearance. C2 correlated better than C0 with the AUC0-4 h (r = 0.91 vs. 0.63). Initial Neoral dose (mg/kg/d) was similar in both groups (2.8 +/- 0.5 and 2.8 +/- 0.8), and was lower in Group II at the second visit (2.0 +/- 0.7 vs. 3.0 +/- 0.6, p = 0.0001). C2 levels decreased in Group II from 912 +/- 438 to 555 +/- 271 ng/ml (p = 0.01), without evidence of acute rejection on endomyocardial biopsies. After the second visit,-both groups were monitored with C2, and the range was increased to 300-600 ng/ml. At the last visit (additional follow-up of 5 +/- 1 months), Neoral dose (mg/kg/d) was reduced to 2.0 +/- 0.3 in Group I (p < 0.001) and 1.8 +/- 0.4 in Group II. Serum creatinine was lower in Group II at the second visit (138 +/- 59 vs. 168 +/- 37 mumol/L, p = 0.01) and was similar in both groups at the last visit. Neoral dose reduction based on C2 levels was not associated with acute rejection. The better correlation with the AUC0-4 h suggests that C2 may be more reliable than C0 for Neoral dose adjustment.

Asunto(s)

Ciclosporina/farmacocinética , Ciclosporina/uso terapéutico , Monitoreo de Drogas , Trasplante de Corazón/inmunología , Inmunosupresores/farmacocinética , Inmunosupresores/uso terapéutico , Adulto , Área Bajo la Curva , Distribución de Chi-Cuadrado , Creatinina/sangre , Ciclosporina/administración & dosificación , Humanos , Inmunosupresores/administración & dosificación , Modelos Lineales , Estudios Prospectivos , Distribución Aleatoria , Factores de Tiempo

Asunto(s)

Angiotensinógeno/genética , Endotelinas/genética , Rechazo de Injerto/genética , Trasplante de Corazón , Óxido Nítrico Sintasa/genética , Peptidil-Dipeptidasa A/genética , Biomarcadores , Humanos , Polimorfismo Genético , Trasplante Homólogo , Enfermedades Vasculares/genética

Asunto(s)

Angiotensinógeno/genética , Endotelinas/genética , Rechazo de Injerto/genética , Trasplante de Corazón , Óxido Nítrico Sintasa/genética , Peptidil-Dipeptidasa A/genética , Marcadores Genéticos , Humanos , Polimorfismo Genético , Trasplante Homólogo

RESUMEN

BACKGROUND: The phenotypic expression of left ventricular hypertrophy (LVH) in patients with hypertrophic cardiomyopathy (HCM) is variable. This phenotypic variability is not completely explained by the responsible mutations or other known factors. Recent data denote a role for the modifier genes and environmental factors. We studied the role of 3 potential modifier genes, i.e., angiotensinogen (AGT), angiotensin II receptor 1a (AT1a), and endothelin-1 (END1) on the phenotypic expression of LVH in patients with hypertrophic cardiomyopathy (HCM). METHODS: The study population was comprised of 108 genetically independent patients with HCM. Left ventricular mass index (LVMI) and LVH score were determined per published protocols. The genotypes of AGT (M235T, T174M, and G-6A), AT1a, and END1 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or mutation-specific PCR (MS-PCR). RESULTS: Male patients had higher mean LVMI and LVH score than female patients (146.0 +/- 33.5 vs 129.4 +/- 33.6, p = 0.01 and 6.0 vs 5.0, p = 0.010, respectively). Gender accounted for 4.8% and 5.4% of the variability of LVMI and LVH score, respectively. The END1 genotypes also had a significant influence on LVH scores accounting for 2.9% of their variability (p = 0.042). The median LVH score was greater in patients with the AA and AG genotypes, as compared to patients with the GG genotype (7.0 vs 5.0, p = 0.034). Neither the AGT nor the AT1 genotypes had a significant influence on the expression of LVH. In multivariate regression analysis, END1 and gender accounted for 7.3% of the variability of the LVH score (p = 0.007). CONCLUSIONS: Our results show that gender and the END1 gene modify the phenotypic expression of hypertrophy in patients with HCM.

Asunto(s)

Angiotensinógeno/genética , Cardiomiopatía Hipertrófica/genética , Endotelina-1/genética , Hipertrofia Ventricular Izquierda/genética , Receptores de Angiotensina/genética , Adulto , Cardiomiopatía Hipertrófica/patología , Cartilla de ADN/química , Femenino , Expresión Génica , Genotipo , Humanos , Hipertrofia Ventricular Izquierda/patología , Masculino , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Caracteres Sexuales

RESUMEN

Hypertrophic cardiomyopathy has been shown to be a genetically heterogeneous disorder, linked to at least four different loci on chromosomes 14, 1, 15, and 11. Thus far, three genes have been identified that harbor mutations leading to hypertrophic cardiomyopathy. These genes--cardiac beta myosin heavy chain, alpha tropomyosin, and troponin T--code for proteins that are integral components of the sarcomere. Other loci and genes remain to be identified. Certain genotype-phenotype correlations appear to exist.

Asunto(s)

Cardiomiopatía Hipertrófica/genética , Mapeo Cromosómico , Humanos

RESUMEN

In this article we review the techniques of molecular biology as they apply to the elucidation of the genetic basis of hypertrophic cardiomyopathy. We review the evidence for linkage to chromosome 14 and the specific mutations described to date. The evidence for genetic heterogeneity is presented. We speculate on the pathophysiology of the disease from the perspective of the known molecular defects and review the clinical implications the evolving information may have.

Asunto(s)

Cardiomiopatía Hipertrófica/genética , Ligamiento Genético/genética , Humanos , Mutación/genética , Miosinas/genética