Sacubitril/valsartan versus ramipril for patients with acute myocardial infarction: win-ratio analysis of the PARADISE-MI trial.

AIM: The win ratio can incorporate different types of outcomes and enhance statistical power, making it a useful method for analysing composite outcomes in cardiovascular trials. The application of this approach to the PARADISE-MI trial provides an additional perspective into understanding the effects of sacubitril/valsartan in patients with acute myocardial infarction. METHODS AND RESULTS: We conducted a post-hoc analysis of the PARADISE-MI trial, which randomly assigned patients with acute myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril/valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to guideline-recommended therapy. The principal composite outcome was analysed in the hierarchical order of death due to cardiovascular causes, first hospitalization for heart failure, and first outpatient episode of symptomatic heart failure. We included events confirmed by the clinical events classification (CEC) committee as well as events identified by investigators that did not meet study definitions. Results were analysed by the unmatched win-ratio method. A win ratio that exceeds 1.00 reflects a better outcome. A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril/valsartan and 2831 to receive ramipril. The hierarchical analysis of the principal composite outcome demonstrated a larger number of wins (1 265 767 [15.7%]) than losses (1 079 502 [13.4%]) in the sacubitril/valsartan group (win ratio of 1.17, 95% confidence interval [CI] 1.03-1.33; p = 0.015). Sensitivity analyses using alternative definitions of the composite outcome showed results similar to those of the principal analysis, except for analysis restricted to events that met CEC definitions (win ratio of 1.11, 95% CI 0.96-1.30; p = 0.16). CONCLUSION: In this post-hoc analysis of the PARADISE-MI trial using the win ratio and including investigator-identified events not having CEC confirmation, sacubitril/valsartan was superior to ramipril among high-risk survivors of acute myocardial infarction.

Ramipril Improves Endothelial Function and Increases the Number of Endothelial Progenitor Cells in Patients With Systemic Lupus Erythematosus.

BACKGROUND/OBJECTIVES: Endothelial dysfunction and reduced number of endothelial progenitor cells (EPCs) in peripheral blood are contributing factors to cardiovascular disease in systemic lupus erythematosus (SLE) patients. Endothelial progenitor cell proliferation is regulated by vascular endothelial growth factor (VEGF). Angiotensin-converting enzyme inhibitors reduce cardiovascular mortality in patients with coronary heart disease. METHODS: This was a randomized trial including 37 female SLE patients without cardiovascular risk factors allocated into 2 groups: 19 patients received ramipril 10 mg/d for 12 weeks (IG) and 18 patients maintained without ramipril (CG). Endothelial function was assessed by brachial artery ultrasound measuring flow-mediated dilation, and EPCs were quantified by flow cytometry and cell culture, at baseline and after 12 weeks. Serum VEGF levels were measured by enzyme-linked immunosorbent assay. Statistical analysis was intention to treat. p < 0.05 was considered significant. RESULTS: After 12 weeks, higher flow-mediated dilation (6.17% vs. 11.14%, p < 0.001) was observed in IG, without change in CG (5.37% vs. 5.02%, p = 0.630). Higher number of EPC colony-forming units was also observed in IG (21.3 ± 10.4 vs. 31.6 ± 8.5, p < 0.001), without difference in CG ( p = 0.714). No difference was found in EPCs evaluated by flow cytometry. Vascular endothelial growth factor level increased after 12 weeks in IG ( p = 0.048), with no difference in CG ( p = 0.661). CONCLUSION: Ramipril improved endothelial function and increased the numbers of EPCs evaluated by cell culture and VEGF levels in SLE patients without cardiovascular risk factors. These data suggest that angiotensin-converting enzyme inhibitor bring an extra benefit beyond the hypotensive action and should be considered as a preferred antihypertensive drug in SLE patients.

Efficacy and safety of two ramipril and hydrochlorothiazide fixed-dose combination formulations in adults with stage 1 or stage 2 arterial hypertension evaluated by using ABPM.

BACKGROUND: Fixed-dose combinations of antihypertensive agents demonstrate advantages in terms of efficacy, tolerability, and treatment adherence. OBJECTIVE: This study was designed to compare the efficacy and safety of 2 ramipril and hydrochlorothiazide (HCTZ) fixed-dose combinations in patients with hypertension stage 1 or 2. Patients' blood pressure (BP) profiles were evaluated by using 24-hour ambulatory BP monitoring (ABPM). METHODS: This was a multicenter, prospective, randomized, open-label, parallel-group, noninferiority trial of adult patients (age ≥18 years) with hypertension stage 1 or 2 and systolic blood pressure (SBP) within 140 to 179 mm Hg or diastolic blood pressure (DBP) 90 to 109 mm Hg. After a 2-week washout period, eligible patients were randomized to receive 1 of 2 ramipril/HCTZ fixed-dose combination formulations (5/25 mg/d) for 8 weeks. The primary end point was the difference in 24-hour ABPM SBP/DBP mean reductions between groups after 8 weeks of treatment. The secondary end points were the changes in daytime and nighttime ABPM and in office BP. Safety profile and tolerability assessments included monitoring of adverse events. RESULTS: A total of 102 patients with hypertension (54 in group A [test formulation] and 48 in group B [reference formulation]), aged 27 to 85 years, completed the 8-week treatment period. The decreases in SBP and DBP according to 24-hour ABPM from baseline to week 8 were significant and similar in both groups. SBP decreased from 149.1 to 133.0 mm Hg (-16.1 mm Hg) in group A and from 146.2 to 130.6 mm Hg in group B (-15.6 mm Hg) (P = 0.8537); DBP was reduced by 8.8 mm Hg in group A and by 8.5 mm Hg in group B (P = 0.8748). Because the lower 95% CI limit for the difference between groups A and B of 3.96 mm Hg in SBP and 3.54 mm Hg in DBP was lower than that preestablished by the trial protocol (4 mm Hg), noninferiority of the test formulation was demonstrated compared with the reference formulation. For the secondary end points, there was no significant difference between groups in SBP and DBP during daytime or nighttime at the end of week 8. Office BP was significantly reduced in both treatment groups, with no significant differences between groups. The incidence of adverse events was 23.7% in group A and 21.7% in group B. CONCLUSIONS: Both treatment options were well tolerated and equally reduced BP. The results support the conclusion that group A (new fixed-dose combination of ramipril/HCTZ) was noninferior to group B (reference medication in Brazil). ISRCTN Register: ISRCTN05051235.

An 18-week, prospective, randomized, double-blind, multicenter study of amlodipine/ramipril combination versus amlodipine monotherapy in the treatment of hypertension: the assessment of combination therapy of amlodipine/ramipril (ATAR) study.

BACKGROUND: A combination of antihypertensive agents of different drug classes in a fixed-dose combination (FDC) may offer advantages in terms of efficacy, tolerability, and treatment compliance. Combination of a calcium channel blocker with an angiotensin-converting enzyme inhibitor may act synergistically to reduce blood pressure (BP). OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of an amlodipine/ramipril FDC with those of amlodipine monotherapy. METHODS: This 18-week, prospective, randomized, double-blind study was conducted at 8 centers across Brazil. Patients with stage 1 or 2 essential hypertension were enrolled. After a 2-week placebo run-in phase, patients received amlodipine/ramipril 2.5/2.5 mg or amlodipine 2.5 mg, after which the doses were titrated, based on BP, to 5/5 then 10/10 mg (amlodipine/ramipril) and 5 then 10 mg (amlodipine). The primary end point was BP measured in the intent-to-treat (ITT) population. Hematology and serum biochemistry were assessed at baseline and study end. Tolerability was assessed using patient interview, laboratory analysis, and physical examination, including measurement of ankle circumference to assess peripheral edema. RESULTS: A total of 222 patients completed the study (age range, 40-79 years; FDC group, 117 patients [mean dose, 7.60/7.60 mg]; monotherapy, 105 patients [mean dose, 7.97 mg]). The mean (SD) changes in systolic BP (SBP) and diastolic BP (DBP), as measured using 24-hour ambulatory blood pressure monitoring (ABPM) and in the physician's office, were significantly greater with combination therapy than monotherapy, with the exception of office DBP (ABPM, -20.76 [1.25] vs -15.80 [1.18] mm Hg and -11.71 [0.78] vs -8.61 [0.74] mm Hg, respectively [both, P = 0.004]; office, -27.51 [1.40] vs -22.84 [1.33] mm Hg [P = 0.012] and -16.41 [0.79] vs -14.64 [0.75] mm Hg [P = NS], respectively). In the ITT analysis, the mean changes in ambulatory, but not office-based, BP were statistically significant (ABPM: SBP, -20.21 [1.14] vs -15.31 [1.12] mm Hg and DBP, -11.61 [0.72] vs -8.42 [0.70] mm Hg, respectively [both, P = 0.002]; office: SBP, -26.60 [1.34] vs -22.97 [1.30] mm Hg and DBP, -16.48 [0.78] vs -14.48 [0.75] mm Hg [both, P = NS]). Twenty-nine patients (22.1%) treated with combination therapy and 41 patients (30.6%) treated with monotherapy experienced > or =1 adverse event considered possibly related to study drug. The combination-therapy group had lower prevalence of edema (7.6% vs 18.7%; P = 0.011) and a similar prevalence of dry cough (3.8% vs 0.8%; P = NS). No clinically significant changes in laboratory values were found in either group. CONCLUSIONS: In this population of patients with essential hypertension, the amlodipine/ramipril FDC was associated with significantly reduced ambulatory and office-measured BP compared with amlodipine monotherapy, with the exception of office DBP. Both treatments were well tolerated.

Los baroquimiorreceptores carotídeos: órganos blanco de la hipertensión arterial / Carotid barochemoreceptors: target organs of arterial hypertension

El cuerpo carotídeo (CC) es el principal quimiorreceptor arterial periférico, capaz de sensar los cambios en la PaO2, la PaCO2 y de pH y transducirlos en señales nerviosas reguladoras de respuestas ventilatorias, circulatorias y endócrinas, que permiten una adaptación a la hipoxemia, la acidosis y la hipercapnia. El seno carotídeo, ubicado próximo al CC, con función barorreceptora, genera respuestas cardiovasculares que descienden la tensión arterial (TA). Ambas estructuras son inervadas por el nervio del seno carotídeo (NSC), que a su vez se proyecta al núcleo del tracto solitario (NTS), y se relacionan íntimamente entre sí y reciben la denominación de baroquimiorreceptores. Últimamente estos órganos se han considerado claves en la regulación de respuestas cardiorrespiratorias homeostáticas que podrían estar íntimamente relacionadas con el desarrollo y el mantenimiento de la hipertensión arterial (HTA). Existe escasa información sobre los cambios estructurales que ocurren en estos órganos durante la HTA y/o como consecuencia de ella. Nuestro planteo es que los baroquimiorreceptores carotídeos representarían un nuevo “órgano blanco” de la HTA. En diversos estudios realizados en seres humanos y en modelos de hipertensión sistólica en animales observamos un daño severo en el CC que se correlacionó significativamente con la elevación de la TA. A su vez, considerando que el sistema renina-angiotensina-aldosterona (SRAA) tendría un papel significativo en la fisiopatología del daño observado, demostramos que el ramipril, versus el atenolol, ejerce un efecto protector sobre el CC más allá de la mera reducción de la TA. Incluso el losartán mostró dicho efecto protector, aun cuando los animales utilizados en los modelos fueron normotensos. Nuestros hallazgos indican que el CC se comporta como un órgano blanco de la HTA y que la activación de un SRAA local sería responsable de los cambios morfológicos y funcionales observados.

The carotid body (CB) is the main peripheral arterial chemoreceptor, able to sense changes in PaO2, PaCO2 and pH, and translate them into nervous signals that regulate ventilating, circulating and endocrine responses which allow adaptation to hypoxemia, acidosis, and hypercapnia. The carotid sinus, located next to the CB, with a baroreceptor function, generates cardiovascular responses that decrease arterial hypertension. Both structures are innervated by the carotid sinus nerve (CSN), which is projected to the solitary tract nucleus (STN), closely inter-related and called barochemoreceptors. Lately, these organs have been considered key in the regulation of homeostatic cardiorespiratory responses that could be intimately related to the development and maintenance of arterial hypertension (AHT). There is scant information on the structural changes that occur in these organs during AHT and/or as its consequence. Our hypothesis is that carotid barochemoreceptors would be a new “target organ” of the AHT. In several studies performed in humans and in models of systolic hypertension in animals we observed a severe damage in the CB which was significantly correlated with elevation of the AT. Hence, considering that the renin-angiotensin-aldosterone system(RAAS) would play a significant role in the pathophysiology of the observed injury, we showed that ramipril versus atenolol has a protective effect on the CB further to the mere decrease of the AT. Even though the animal models used had normal pressure, losartan showed this protective effect. Our findings indicate that the CB behaves as a target organ in AHT and the activation of a local RAAS would be responsible for the morphological and functional changes that were observed.

Smart damping modulation of carotid wall energetics in human hypertension: effects of angiotensin-converting enzyme inhibition.

Damping is the conversion of mechanical energy of a structure into thermal energy, and it is related to the material viscous behavior. To evaluate the role of damping in the common carotid artery (CCA) wall in human hypertension and the possible improvement of angiotensin-converting enzyme (ACE) inhibition, we used noninvasive CCA pressure (tonometry) and diameter (B-mode echography) waveforms in normotensive subjects (NT group; n=12) and in hypertensive patients (HT group; n=22) single-blind randomized into HT-placebo (n=10) or HT-treated (ramipril, 5 to 10 mg/d during 3 months; n=12). Vascular smooth muscle (VSM) null tonus condition was achieved from in vitro pressure and diameter waveforms (Konigsberg microtransducer and sonomicrometry) measured in explanted human CCA (n=14). Arterial wall dynamics was described by viscous (eta), inertial (M), and compliance (C) parameters, mean circumferential wall stress, viscous energy dissipation (WD), peak strain energy (WSt), damping ratio (xi=WD/WSt), and modeling isobaric indexes CIso and WSt(Iso). The lack of VSM tonus isobarically increased wall stress and reduced eta, CIso, and damping (P<0.01). Wall stress, eta, and WD were greater in HT than in NT (P<0.015) and arrived near normal in HT-treated (P<0.032 respect to HT), with no changes in HT-placebo. Whereas CIso increased in HT-treated (P<0.01) approaching the NT level, xi did not vary among groups. During hypertension, because of the WSt increase, the arterial wall reacts increasing WD to maintain xi. ACE inhibition modulates VSM activation and vessel wall remodeling, significantly improving wall energetics and wall stress. This protective vascular action reduces extra load to the heart and maintains enhanced arterial wall damping.

Urinary TGF-beta1 reduction related to a decrease of systolic blood pressure in patients with type 2 diabetes and clinical diabetic nephropathy.

With the aim to determine the influence of reducing systolic blood pressure in urinary TGF-beta1 of type 2 diabetes (DM2) with diabetic nephropathy (DN), 21 subjects with type 2 diabetes and proteinuria >500 mg/24 h were studied. Amlodipine and ramipril were added to their previous antihypertensive treatment for 12 weeks. Urinary TGF-beta1 (UTGF-beta1) was determined at 0, 4, 8 and 12 weeks. Plasma TGF-beta1 was determined at 0 and 12 weeks. Subjects whose mean systolic blood pressure (SBP) during treatment were under 140 mmHg were grouped as the better SBP controlled group (n = 11) and those with SBP equal to or greater than 140 mHg were grouped in a moderate SBP controlled group (n = 10). Compared to baseline, mean log UTGF-beta1 at 4, 8 and 12 weeks decreased (-0.22 +/- 0.15 pg/mg; p = 0.04) in better SBP controlled group but not in the moderate SBP controlled group (-0.12 +/- 0.08 pg/mg, p = 0.82). Mean SBP correlated with UTGF-beta1 (r = 0.458, p = 0.0357), and this effect was independent of HbA1c (p = 0.042). By controlling SBP in DM2 subjects with DN we might decrease UTGF-beta1. We propose that reduction of UTGF-beta1 is due to a decrease in renal TGF-beta1 production.

Minimal change disease in association with fire coral (Millepora species) exposure.

Numerous agents have been associated with minimal change disease. We describe a previously unreported association in a 45-year-old white woman of scuba diving exposure to fire coral (Millepora species) that was followed by the development of nephrotic syndrome, acute renal failure, pulmonary edema, and intubation. The renal biopsy specimen was consistent with minimal change disease. Institution of corticosteroid therapy resulted in symptomatic improvement and resolution of proteinuria. Physicians, particularly those in scuba-diving areas, should consider minimal change disease in exposed patients with proteinuria because a prompt diagnostic and therapeutic approach may potentially limit complications.

Proteção miocárdica pelo ramipril na hipertrofia ventricular esquerda: estudo experimental / Protective effect of ramipril on the left ventricle hypertrophy: experimental study

Introdução: A hipertrofia patológica do ventrículo esquerdo é um poderoso e independente fator de risco para complicações cardiovasculares, estando relacionada com aumento de duas a cinco vezes o risco de infarto do miocárdio, seis a dezessete vezes o risco de insuficiência cardíaca e três a dez vezes o risco de acidente vascular cerebral. Objetivo: avaliar em ratos se o ramipril na dose de 1mg/kg/dia apresenta efeito protetor sobre a hipertrofia do ventrículo esquerdo (HVE), induzida pelo isoproterenol (ISO), administrado por via subcutânea (0,3mg/kg/dia). Método: formados quatro grupos de ratos machos e adultos, com 14 exemplares em cada um, sendo o primeiro o grupo controle (CON), segundo o tratado com ramipril (RAM); o grupo seguinte com isoproterenol (ISO) e o último tratado com ambas as drogas (RAM + ISO). Aferidos: o peso úmido do ventrículo esquerdo (PUVE), peso seco do ventrículo esquerdo (PSVE), relação PSVE pelo peso do animal (PSVE/P) e o índice de massa do ventrículo esquerdo (IMVE). Retiradas amostras do ventrículo esquerdo dos animais para estudo morfológico pela microscopia de luz, e em três animais de cada grupo um fragmento foi processado para estudo ultra-estrutural. Resultados: em relação ao PSVE obtiveram-se os seguintes resultados: Grupo CON: 0,14486; Grupo RAM: 0,13771; Grupo ISO: 0,20400; Grupo RAM + ISO: 0,16000; com diferença significante entre o grupo ISO e os demais (p<0, 05). A análise do PSVE/P demonstrou o mesmo comportamento. Na avaliação microscópica de luz e eletrônica de transmissão, observou-se proteção da HVE no Grupo RAM+ISO, em relação ao grupo ISO Conclusões: as análises morfológica e ultra-estrutural demonstraram que isoproterenol induz hipertrofia dos cardiomiócitos e aumento do tecido conjuntivo, com acentuados depósitos de fibras colágenas No grupo RAM + ISO observou-se ação protetora em relação à hipertrofia muscular e a depósitos de colágeno O uso isolado de ramipril não provocou alterações no que diz respeito ao...

[Effect of ramipril on the glucose/insulin coefficient and the ventricular mass index in patients with light to moderate arterial hypertension]. / Efecto del ramipril sobre el cociente glucosa/insulina y el índice de masa ventricular izquierda en pacientes con hipertensión arterial leve a moderada.

This longitudinal prospective study was designed to assess the effects of the angiotensin converting enzyme inhibitor (ACEI) ramipril on ventricular mass, left ventricle (LV) diastolic function and blood pressure in patients with mild to moderate essential hypertension and hyperinsulinemia. LV diastolic dysfunction is the first target organ alteration occurring in hypertensive patients, while ventricular hypertrophy is the most relevant predictive factor for cardiovascular morbility and mortality in systemic hypertension. Because several studies have demonstrated that there is no direct correlation between blood pressure values and the severity of LV hypertrophy or diastolic dysfunction, it is assumed that other factors are involved in the genesis of these functional alterations. Moreover, the hypertensive effect of insulin is caused by sympathetic stimulation, sodium and water renal retention and protooncogene stimulation leading to myocardial and vascular fibrosis and hypertrophy. We studied 24 hypertensive patients with hyperinsulinemia. All patients underwent an overall and cardiologic clinical evaluation, and electrocardiographic and ecocardiographic studies were performed at baseline and 6 months after being treated with 2.5 to 5 mg/day ramipril. Ramipril treatment significantly reduced systolic (12 mmHg) and diastolic (12 mmHg) pressure levels, basal insulin serum levels (23.62 pmol/dL vs 10.42 pmol/dL), and left ventricle mass index values (143.8 g/m2 vs 118.2 g/m2). Among the variables assessing LV diastolic function, only the transmitral flow E/A wave ratio showed significant differences in women. Ramipril was well tolerated and no significant adverse events were reported.

Efecto del ramipril sobre el cociente glucosa/insulina y el índice de masa ventricular izquierda en pacientes con hipertensión arterial leve a moderada / Effect of ramipril on the glucose/insulin coefficient and the ventricular mass index in patients with light to moderate arterial hypertension

Este estudio longitudinal, prospectivo se diseñó para evaluar el efecto del ramipril, un inhibidor de la enzima convertidora de angiotensina (IECA) sobre la masa ventricular, la función diastólica del ventrículo izquierdo (VI) y los valores de tensión arterial en pacientes con hipertensión arterial sistémica esencial (HAS) leve a moderada con hiperinsulinemia. La primera alteración del paciente hipertenso es la disfunción diastólica del VI y el dato de mayor peso como factor predictor de morbimortalidad cardiovascular en la HAS es la hipertrofia ventricular. Existen múltiples estudios que demuestran que no existe una correlación directa entre los valores de tensión arterial y el grado de hipertrofia o disfunción diastólica del ventrículo izquierdo, motivo por el cual se asume la participación de otros factores en la génesis de estas alteraciones funcionales. Por otra parte, está descrito que la insulina posee efectos hipertensores por estimulación simpática, por retener sodio y agua a nivel renal y por estimular la expresión de protooncogenes con el subsecuente desarrollo de fibrosis e hipertrofia miocárdica y vascular. A pesar de que existe en el mercado una gran cantidad de fármacos antihipertensivos, algunos de ellos producen efectos metabólicos adversos, mientras que otros como los inhibidores de la enzima convertidora de angiotensina (IECAS), los ARAII y los bloqueadores del calcio además de controlar los niveles de presión arterial tienen un efecto neutro o benéfico sobre dichos parámetros. Considerando el efecto de los IECAS sobre el perfil metabólico, se realizó un estudio con 24 pacientes hipertensos esenciales con hiperinsulinemia, a los cuales se les realizó evaluación clínica cardiológica y general, electrocardiograma y ecocardiograma en condiciones basales y después de 6 meses de tratamiento con ramipril a dosis de 2.5 a 5 mg/día. Los resultados muestran una reducción significativa de la tensión arterial sistólica (12 mmHg) y diastólica (12 mmHg), de los niveles séricos de insulina basal (23.62 pmol/dL vs 10.42 pmol/dL), y del índice de masa ventricular izquierda (143.8 g/m² vs 118.2 g/m²). En las variables que evalúan la función diastólica del VI no hubo diferencias estadísticamente significativas a excepción de la relación onda E/onda A del flujo transmitral en el grupo de mujeres. Ramipril fue bien tolerado y no se reportaron eventos adversos significativos.

This longitudinal prospective study was designed to assess the effects of the angiotensin converting enzyme inhibitor (ACEI) ramipril on ventricular mass, left ventricle (LV) diastolic function and blood pressure in patients with mild to moderate essential hypertension and hyperinsulinemia. LV diastolic dysfunction is the first target organ alteration occurring in hypertensive patients, while ventricular hypertrophy is the most relevant predictive factor for cardiovascular morbility and mortality in systemic hypertension. Because several studies have demonstrated that there is no direct correlation between blood pressure values and the severity of LV hypertrophy or diastolic dysfunction, it is assumed that other factors are involved in the genesis of these functional alterations. Moreover, the hypertensive effect of insulin is caused by sympathetic stimulation, sodium and water renal retention and protooncogene stimulation leading to myocardial and vascular fibrosis and hypertrophy. We studied 24 hypertensive patients with hyperinsulinemia. All patients underwent an overall and cardiologic clinical evaluation, and electrocardiographic and ecocardiographic studies were performed at baseline and 6 months after being treated with 2.5 to 5 mg/day ramipril. Ramipril treatment significantly reduced systolic (12 mmHg) and diastolic (12 mmHg) pressure levels, basal insulin serum levels (23.62 pmol/dL vs 10.42 pmol/dL), and left ventricle mass index values (143.8 g/m² vs 118.2 g/m²). Among the variables assessing LV diastolic function, only the transmitral flow E/ A wave ratio showed significant differences in women. Ramipril was well tolerated and no significant adverse events were reported. (Arch Cardiol Mex 2003; 73:24-30).

Costo-eficacia del uso de ramipril en pacientes de alto riesgo vascular en la Argentina / Cost-effectiveness of ramipril in high cardiovascular risk patientes in Argentina

Objetivo: El presente trabajo se encaró con el propósito de realizar un análisis de costo-eficacia del uso de ramipril en pacientes de alto riesgo cardiovascular en la Argentina. Material y métodos: Se realizó un análisis de costo-eficacia del ramipril versus placebo basado en los resultados de eficacia del estudio HOPE y en los costos y uso de recursos de nuestro medio. Se construyó un modelo sobre un árbol de decisiones, con la incorporación de los siguientes eventos: muerte, eventos cardiovasculares, desarrollo de nueva diabetes y complicaciones de la diabetes. El coeficiente de costo-eficacia incremental se calculó según: costo ramipril - costo placebo / expectativa de vida de ramipril - expectativa de vida de placebo. El resultado se expresó en pesos ($) por año de vida salvada, es decir, el costo de un año de vida adicional por el uso de ramipril en relación con el placebo. Para evaluar el efecto de la incertidumbre de algunas asunciones sobre las conclusiones, se realizó análisis de sensibilidad. Resultados: El análisis fue favorable para la utilización de ramipril. Para salvar un año de vida, el ramipril ahorró Pesos 56, debido a una disminución en la incidencia de complicaciones. La relación de costo menor y mayor eficacia se mantuvo estable en el análisis de sensibilidad y solamente en la peor combinación constituyó un costo. Conclusiones: Esta circunstancia para el ramipril, en la cual una estrategia de prevención constituye un ahorro, al combinar menor costo y mayor eficacia, es poco habitual para conductas de prevención cardiovascular, lo cual resalta el papel potencial de los inhibidores de la enzima convertidora aún muy poco utilizados en este contexto (AU)

[Severe hypoglycemia secondary to angiotensin-converting-enzyme inhibitors in the absence of diabetes mellitus. Report of a case]. / Hipoglucemia severa secundaria a inhibidores de la enzima convertidora de angiotensina en ausencia de diabetes mellitus. Reporte de un caso.

We present the first reported case of untreatable hypoglycemia in a woman of 66-years-old, non-diabetic who received captopril for six years, and more recently ramipril. Six months ago, she was seen for the first time in our hospital. We found her disoriented, sweaty and confusing words frequently. Glucose tolerance test one hour after administration of glucose: 53 mg/dl. Test of insulin and C peptide had norms the same as the other contra-regulator hormones except glucagon with moderate elevation. The B.P. increased and we changed to ramipril, which improved the pressure but the hypoglycemia persisted. A new change was made to Losartan plus hydrochlorothiazide; after 72 hours patient improved. A new glucose tolerance test one hour after administration of glucose is absolutely normal. General conditions of the patients are observed more than 3 months and are asymptomatic. The B. P. is normal and we are keeping only the recently installed treatment.

Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy

Background Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes.

Methods 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria,

heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and vitamin E or placebo, according to a two-by-two factorial design. The combined

primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy. Findings The study was stopped 6 months early (after 4·5 years) by the independent data safety and monitoring

board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 12–36, p=0·0004), myocardial infarction by 22% (6–36), stroke by 33% (10–50), cardiovascular

death by 37% (21–51), total mortality by 24% (8–37), revascularisation by 17% (2–30), and overt nephropathy by 24% (3–40, p=0·027). After adjustment for the changes in systolic (2·4 mm Hg) and diastolic (1·0 mm Hg) blood pressures, ramipril

still lowered the risk of the combined primary outcome by 25% (12–36, p=0·0004). Interpretation Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to

the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.