RESUMEN
This large multicenter study, tested the antihypertensive effects of isradipine, a dihydropyridine calcium channel blocker and enalapril, an angiotensin-converting enzyme inhibitor, in salt-sensitive hypertensive patients under low and high salt intake diets. After a 3-week (weeks -9 to -6) of ad lib salt diet, those patients who had a sitting diastolic blood pressure (SDBP) of > or =95 but < or =115 mm Hg qualified to enter a 3-week (weeks -6 to -3) placebo run-in low salt diet (50 to 80 mmol Na+/day). Then high salt (200 to 250 mmol Na+/day) was added to the placebo treatment for 3 weeks (weeks -3 to 0). Those patients who demonstrated an increase in SDBP > or =5 mm Hg from the low to high salt diet were considered salt sensitive and were randomized into a 4-week (weeks 0 to 4) double-blind treatment period of either isradipine 2.5 to 10 mg twice a day, enalapril 2.5 to 20 mg twice a day, or placebo. Then they entered a 3-week (weeks 4 to 7) placebo washout phase of low salt diet (50 to 80 mmol Na+/day). After week 7 and while the low salt diet was continued the patients were restarted on their double-blind treatment for 4 more weeks (weeks 7 to 11) and the study was completed. Of 1,916 patients screened, 464 were randomized into the double-blind treatment phase and 397 completed the study. Both isradipine and enalapril decreased the sitting systolic blood pressure (SSBP) and SDBP during the high salt diet, to a similar degree, whereas enalapril caused a greater reduction in SSBP and SDBP than isradipine during the low salt diet (11.3 +/- 1.2/7.7 +/- 0.7 mm Hg v 7.7 +/- 0.9/4.8 +/- 0.6 mm Hg, mean +/- SEM, respectively, P < .02). Within drugs, the effect of isradipine on blood pressure (BP) was higher during the high than the low salt diet (14.9 +/- 1.5 v 7.6 +/- 1.3 mm Hg for SSBP and 10.1 +/- 0.6 v 4.8 +/- 0.9 mm Hg for SDBP, P < .001), but enalapril exerted a similar effect during both diets. Because salt restriction lowered both SSBP and SDBP, the lowest BP achieved with both drugs were during the salt restriction phase.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Enalapril/farmacología , Hipertensión/fisiopatología , Isradipino/farmacología , Cloruro de Sodio Dietético/administración & dosificación , Cloruro de Sodio Dietético/efectos adversos , Factores de Edad , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Método Doble Ciego , Femenino , Interacciones Alimento-Droga/fisiología , Humanos , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Factores Sexuales , Factores de TiempoRESUMEN
Dietary salt restriction is a recommended adjunct with antihypertensive therapy. There may be racial differences in blood pressure response to salt restriction while on antihypertensive therapy. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (black, n=96; Hispanic, n=63; white, n=232). Participants were initially preselected for stage I to III hypertension and then further selected for salt sensitivity (> or = 5 mm Hg increase in diastolic blood pressure after 3 weeks of low salt [< or = 88 mmol/d Na+] and high salt [>190 mmol/d Na+] diet). We compared the antihypertensive effect of an angiotensin-converting enzyme inhibitor (enalapril 5 or 20 mg BID) or a calcium channel antagonist (isradipine 5 or 10 mg BID) during alternating periods of high and low salt intake. The main outcome measure was blood pressure change and absolute blood pressure level achieved with therapy. During the high salt diet (314.7+/-107.5 mmol/d urinary Na+) there was greater downward change in blood pressure with both enalapril and isradipine compared with the low salt diet (90.1+/-50.8 mmol/d Na+); however, the absolute blood pressure achieved in all races was consistently lower on a low salt diet for both agents. Black, white, and Hispanic isradipine-treated salt-sensitive hypertensives demonstrated a smaller difference between high and low salt diets (black, -3.6/-1.6 mmHg; white, -6.2/-3.9 mmHg; Hispanic, -8.1/-5.3 mm Hg) than did enalapril-treated patients (black, -9.0/-5.3 mm Hg; white, -11.8/-7.0 mm Hg; Hispanic, -11.1/-5.6 mm Hg). On the low salt diet, blacks, whites, and Hispanics had similar blood pressure control with enalapril and isradipine. On the high salt diet, blacks had better blood pressure control with isradipine than with enalapril, whereas there was no difference in the blood pressure control in whites and Hispanics treated with either drug. Dietary salt reduction helps reduce blood pressure in salt-sensitive hypertensive blacks, whites, and Hispanics treated with enalapril or isradipine. These data demonstrate that controlling for salt sensitivity diminishes race-related differences in antihypertensive activity.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Antihipertensivos/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Enalapril/administración & dosificación , Hipertensión/tratamiento farmacológico , Isradipino/administración & dosificación , Sodio en la Dieta/administración & dosificación , Adulto , Presión Sanguínea/efectos de los fármacos , Femenino , Humanos , Hipertensión/etnología , Hipertensión/metabolismo , Masculino , Persona de Mediana Edad , Grupos Raciales , Resultado del TratamientoRESUMEN
BACKGROUND: This report is part of a larger, multicenter, placebo-controlled study designed to test the effects of low and high salt intake on the antihypertensive action of enalapril maleate or isradipine in salt-sensitive, hypertensive patients. OBJECTIVE: To present our findings with respect to the effects of race, age, sex, and weight on the blood pressure response to low and high salt intake in salt-sensitive hypertensive patients before randomization into the larger study. PATIENTS AND METHODS: After 3 week (weeks -9 to -6) of ad lib salt intake (100-200 mmol/d of sodium), 1916 patients whose sitting diastolic blood pressure was between 95 and 115 mm Hg entered a 3-week period (week -6 to -3) of low salt intake (50-80 mmol/d of sodium) and then a 3-week period (week -3 to 0) of high salt intake (200-250 mmol/d of sodium). Of the 1916 patients, 624 were identified as being sensitive to salt by demonstrating an increase in sitting diastolic blood pressure of equal to or more than 5 mm Hg from the low to high salt intake. Of these patients, 367 were white, 156 were black, 92 were Hispanic, 8 were Asian, and 1 was American Indian. Also, 315 were men and 309, women; 351 were 55 years or younger and 273 were older than 55 years; and 195 had a body mass index of 27 or less and 429 had a body mass index higher than 27. RESULTS: The sitting blood pressure decreased with salt restriction and increased with salt load in all groups of patients (P < .001). There were no statistically significant differences in the blood pressure changes to salt changes by race, age, sex, and weight. CONCLUSIONS: This large, multicenter study did not demonstrate any statistically significant effect of race, age, sex, and weight on blood pressure response to salt changes in salt-sensitive hypertensive patients.
Asunto(s)
Envejecimiento/metabolismo , Presión Sanguínea/efectos de los fármacos , Peso Corporal , Hipertensión/etiología , Factores Sexuales , Sodio en la Dieta/efectos adversos , Índice de Masa Corporal , Femenino , Humanos , Hipertensión/fisiopatología , Modelos Lineales , Masculino , Persona de Mediana Edad , Grupos Raciales , Sodio en la Dieta/administración & dosificaciónRESUMEN
OBJECTIVE: To compare the rate of progression of mean maximum intimal-medial thickness (IMT) in carotid arteries, using quantitative B-mode ultrasound imaging, during antihypertensive therapy with isradipine vs hydrochlorothiazide. DESIGN: Randomized, double-blind, positive-controlled trial. SETTING: Nine medical center clinics. POPULATION: A total of 883 patients with baseline mean +/- SD systolic and diastolic blood pressure (SBP and DBP, respectively) of 149.7 +/- 16.6 and 96.5 +/- 5.1 mm Hg, age of 58.5 +/- 8.5 years, and maximum IMT of 1.17 +/- 0.20 mm. INTERVENTIONS: Twice daily doses of isradipine (2.5-5.0 mg) or hydrochlorothiazide (12.5-25 mg). MAIN OUTCOME MEASURE (PRIMARY END POINT): Rate of progression of mean maximum IMT in 12 carotid focal points over 3 years. RESULTS: There was no difference in the rate of progression of mean maximum IMT between isradipine and hydrochlorothiazide over 3 years (P=.68). There was a higher incidence of major vascular events (eg, myocardial infarction, stroke, congestive heart failure, angina, and sudden death) in isradipine (n=25; 5.65%) vs hydrochlorothiazide (n=14; 3.17%) (P=.07), and a significant increase in nonmajor vascular events and procedures (eg, transient ischemic attack, dysrhythmia, aortic valve replacement, and femoral popliteal bypass graft) in isradipine (n=40; 9.05%) vs hydrochlorothiazide (n=23; 5.22%) (P=.02). At 6 months, mean DBP decreased by 13.0 mm Hg in both groups, and mean SBP decreased by 19.5 mm Hg in hydrochlorothiazide and 16.0 mm Hg in isradipine (P=.002); the difference in SBP between the 2 groups persisted throughout the study but did not explain the increased incidence of vascular events in patients treated with isradipine. CONCLUSION: The rate of progression of mean maximum IMT in carotid arteries, the surrogate end point in this study, did not differ between the 2 treatment groups. The increased incidence of vascular events in patients receiving isradipine compared with hydrochlorothiazide is of concern and should be studied further.
Asunto(s)
Antihipertensivos/uso terapéutico , Arteriosclerosis/tratamiento farmacológico , Arterias Carótidas/patología , Hidroclorotiazida/uso terapéutico , Isradipino/uso terapéutico , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Túnica Íntima/patología , Vasodilatadores/uso terapéutico , Anciano , Antihipertensivos/efectos adversos , Arteriosclerosis/diagnóstico por imagen , Arteriosclerosis/patología , Arterias Carótidas/diagnóstico por imagen , Diástole , Progresión de la Enfermedad , Diuréticos , Método Doble Ciego , Enalapril/uso terapéutico , Femenino , Humanos , Hidroclorotiazida/efectos adversos , Isradipino/efectos adversos , Funciones de Verosimilitud , Masculino , Persona de Mediana Edad , Análisis de Regresión , Inhibidores de los Simportadores del Cloruro de Sodio/efectos adversos , Sístole , Resultado del Tratamiento , Túnica Íntima/diagnóstico por imagen , Ultrasonografía , Vasodilatadores/efectos adversosRESUMEN
Hypertension is a risk factor for the development of atherosclerosis and its complications, which are among the major causes of morbidity and mortality. Although recent clinical trials indicate that antihypertensive treatment reduces morbidity and mortality associated with stroke, congestive heart failure, and renal insufficiency, questions remain as to whether such treatment also prevents coronary heart disease (CHD) mortality. The observed reduction in CHD mortality from pooled clinical trial data was 10-14% and was much less than the expected 20-25% reduction for a 5-6 mm Hg reduction in diastolic pressure. One explanation may be that subtle adverse metabolic effects of treatment may have blunted the beneficial effects. Isradipine, a dihydropyridine calcium antagonist, is a potent antihypertensive drug with antiatherogenic properties in animal models. Therefore, we hypothesized that isradipine may be appropriate for testing the efficacy of antihypertensive treatment in retarding the progression of atherosclerosis in humans. The Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS) is a clinical trial designed to compare the efficacy of isradipine (2.5 or 5 mg b.i.d.) with hydrochlorothiazide (12.5 or 25 mg b.i.d.) in retarding the progression of early carotid atherosclerosis as monitored by high-resolution B-mode ultrasonography.
Asunto(s)
Arteriosclerosis/tratamiento farmacológico , Bloqueadores de los Canales de Calcio/uso terapéutico , Dihidropiridinas/uso terapéutico , Hipertensión/tratamiento farmacológico , Adulto , Anciano , Arteriosclerosis/complicaciones , Arteriosclerosis/diagnóstico por imagen , Arterias Carótidas/diagnóstico por imagen , Método Doble Ciego , Femenino , Humanos , Hidroclorotiazida/uso terapéutico , Hipertensión/complicaciones , Isradipino , Masculino , Persona de Mediana Edad , UltrasonografíaRESUMEN
To explore the relationship between blood lipid levels and a predisposition to thrombosis, levels of three hemostatic factors were measured in 41 human subjects and correlated with serum lipids. Procoagulant activity associated with peripheral blood monocytes isolated and purified after a 2-hour incubation in whole blood was not significantly related to lipid levels. However, activity in monocytes incubated with 100 ng/ml of bacterial endotoxin was significantly correlated with high density lipoprotein (HDL) cholesterol (r = 0.55, p less than 0.005), while net procoagulant activity (endotoxin-challenged minus basal) was significantly correlated with both HDL cholesterol (r = 0.61, p less than 0.005) and total cholesterol (r = 0.50, p less than 0.01). Plasma levels of the fibrinolytic factor, tissue plasminogen activator, were significantly correlated with total cholesterol (r = 0.41, p less than 0.01), while those of the type-1 plasminogen activator inhibitor were significantly correlated with both total cholesterol (r = 0.46, p less than 0.01) and total triglycerides (r = 0.31, p less than 0.05). The balance between the fibrinolytic factors was not significantly related to serum lipids. These results suggest that the expression of procoagulant activity by peripheral blood monocytes exposed to endotoxin may be enhanced in cases where HDL cholesterol levels are high. In addition, these results suggest that hypertriglyceridemia may be associated with a decreased fibrinolytic capacity due to elevated secretion of plasminogen activator inhibitor.