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Follow-up study of patients randomly allocated ramipril or placebo for heart failure after acute myocardial infarction: AIRE Extension (AIREX) Study. Acute Infarction Ramipril Efficacy
Abstract
In the Acute Infarction Ramipril Efficacy (AIRE) Study, the effect of angiotensin-converting-enzyme (ACE) inhibition on the survival of patients with clinical heart failure after acute myocardial infarction (AMI), was assessed. At an average follow-up time of 15 months after randomisation, all-cause mortality was reduced from 22.6% (placebo group) to 16.9% (ramipril group) representing an absolute mortality reduction of 5.7% and a relative risk reduction of 27% (95% CI 11-40%; p = 0.002). Our aim in this study was to assess the long-term (3 years after the AIRE Study closed) magnitude, duration, and reliability of the survival benefits observed after treatment with ramipril (target dose 5 mg twice a day) when compared with placebo.
We investigated the mortality status of all 603 patients recruited from the 30 UK centres involved in the AIRE Study. Through government records we were able to confirm the death or survival of all 603 patients exactly 3 years after the close of the AIRE Study. Follow-up was for a minimum of 42 months and a mean of 59 months. The average duration of treatment with masked trial medication was 13.4 months for placebo and 12.4 months for ramipril.
By 0000 h March 1, 1996, death from all causes had occurred in 117 (38.9%) of 301 patients randomly assigned placebo and 83 (27.5%) of 302 patients randomly assigned ramipril, representing a relative risk reduction of 36% (95% CI 15-52%; p = 0.002) and an absolute reduction in mortality of 11.4% (114 additional 5-year survivors per 1000 patients treated for an average of 12.4 months).
Our data provide robust evidence that administration of ramipril to patients with clinically defined heart failure after AMI results in a survival benefit that is not only large in magnitude, but also sustained over many years.
... Esta afirmação baseia-se em numerosos ensaios randomizados, placebo-controlados ou comparativos, que testaram os benefícios desses fármacos nos diferentes estágios evolutivos da IC e de disfunção ventricular sistólica. 130,131,[195][196][197][198] O uso de IECA está fundamentado para diferentes etiologias de IC, bem como em pacientes com disfunção ventricular esquerda pós-infarto do miocárdio. 130,198 O uso de IECA em pacientes com disfunção de VE assintomática (estágio B) também está bem documentado e foi abordado no item 5 de IC Crônica. ...
... 130,131,[195][196][197][198] O uso de IECA está fundamentado para diferentes etiologias de IC, bem como em pacientes com disfunção ventricular esquerda pós-infarto do miocárdio. 130,198 O uso de IECA em pacientes com disfunção de VE assintomática (estágio B) também está bem documentado e foi abordado no item 5 de IC Crônica. Os bloqueadores dos receptores da angiotensina II (BRAs) são alternativa com eficácia comparável aos IECA, 199,200 e estão indicados em pacientes intolerantes ou com alergia documentada a esta classe de fármacos. ...
... In post-AMI patients pharmacological treatment with BB and ACEi/ARB is obligatory [16,23]. BB or ACEi/ARB therapies have oftentimes been investigated for primary prevention of SCD and all-cause death usually in post-AMI patients, such as within the BTimolol^ [24], BMetoprolol Pooled Data^ [25] and BBeta-Blocker Herat Attack^ [26], BSAVE^ [27], AIRE [28], and BTRACE^trials [29]. Furthermore, BB and ACEi/ARB are indicated in patients with heart failure and LVEF < 35% [15] in order to prevent adverse structural remodeling and reduce mortality by preventing SCD [1,17,18,30,31]. ...
... Data from RCTs about BB and ACEi/ARB reveal a clear prognostic benefit of both drug groups in patients with systolic heart failure [28,32,40,41]. Therefore, investigation of a RCT for the evaluation of the secondary preventive effect of each drug itself-similar to the present retrospectively matched study-may be difficult partially due to ethical considerations, since both treatments are established and recommended by international guidelines [19,30] and different types of ventricular tachyarrhythmia can be additionally caused by various and severe comorbidities affecting multiple pathophysiological pathways. ...
Objective:
The study sought to assess the impact of treatment with beta-blocker (BB) or ACE inhibitor/angiotensin receptor blocker (ACEi/ARB) on secondary survival in patients presenting with ventricular tachyarrhythmia.
Background:
Data regarding outcome of patients presenting with ventricular tachyarrhythmia treated with BB and ACEi/ARB is limited.
Methods:
A large retrospective registry was used including consecutive patients presenting with ventricular tachycardia and fibrillation from 2002 to 2016 on admission. Applying propensity-score matching for harmonization, the impact of "BB" and "ACEi/ARB" was comparatively evaluated. The primary prognostic outcome was long-term all-cause death at 3 years.
Results:
A total of 972 matched patients were included. Both patients with BB (long-term mortality rate 18 versus 27%; log rank p = 0.041; HR = 0.661; 95% CI = 0.443-0.986; p = 0.043) and with ACEi/ARB (long-term mortality rate 13 versus 23%; log rank p = 0.004; HR = 0.544; 95% CI = 0.359-0.824; p = 0.004) revealed better secondary survival compared to patients without after presenting with ventricular tachyarrhythmia on admission. The prognostic benefit of BB was comparable to ACEi/ARB (long-term mortality rate 21 versus 26%; log rank p = 0.539).
Conclusion:
BB and ACEi/ARB were associated with improved secondary survival in patients surviving ventricular tachyarrhythmia on admission.
Trial registration:
ClinicalTrials.gov identifier: NCT02982473.
... Aujourd'hui, l'insuffisance cardiaque touche environ 500 000 patients en France et représente 120 000 nouveaux cas par an [2]. Elle est caractérisée par la fréquence importante des hospitalisations itératives [3,4], une altération majeure de la qualité de vie [5] et une mortalité accrue, estimée à 25 000 décès par an en France [6]. ...
... Dans l'essai CONSENSUS I [93], les patients inclus, en classe IV de la classification NYHA, avaient une mortalité de l'ordre de 50% à deux ans et pratiquement 100% à dix ans. L'étude EPICAL [84] sur l'insuffisance cardiaque sévère témoigne d'une mortalité de 35.4 % après un an de suivi.Les statistiques de mortalité donnent pour la France, 24 588 décès en 1998, soit près de 5% du total des décès[6]. En Ecosse, une étude a montré que si 171C était la cause principale de 1.5% des décès, elle contribuait à 14.3% d'entre eux ; plus du tiers des décès agribüés am coïûnaûpaihies pûwaient Stïe ches à l'insuffisance caïdiaqüe i94j.L'insuffisance cardiaque représente un coût financier et social majeur : le montant global de la prise en charge de 1'IC est estimé, pour les pays industrialisés, entre 1 et 2% du budget global de santé[95], soit pour la France environ 6 milliards Se francs par aari[2]. ...
L'insuffisance cardiaque (IC) constitue un grave problème de santé publique dans les pays industrialisés. De nombreux essais ont démontré l'efficacité des Inhibiteurs de L'Enzyme de Conversion (IEC) pour réduire la morbi-mortalité de I'IC systolique. Cependant, la littérature internationale et les résultats du programme régional EPICAL* font état de leur sous-prescription en pratique courante. Dans ce contexte, une étude d'intervention contrôlée randomisée a été conduitedans vingt services de cardiologie lorrains ayant participé au programme EPICAL. L'objectif principal était d'évaluer l'impact de recommandations sur la qualité de la prise en charge par IEC des insuffisants cardiaques. Après appariement, les services ont été randomisés en deux groupes : un groupe "intervention" où les cardiologues ont participé à la formalisation et la mise en ceuvre desrecommandations et un groupe "témoin" où aucune intervention n'a été conduite. Deux enquêtes de pratique ont été menées dans les deux groupes, l'une avant intervention et l'autre après. Au total, 723 insuffisants cardiaques systoliques de moins de 75 ans, ont été inclus. Avant intervention, lesposologies cibles d'IEC et l'information thérapeutique dans le dossier médical étaient les principaux points de non-respect des recommandations par l'ensemble des praticiens. Au final, les taux d'adhésion correspondants, ayant plus nettement augmenté dans le groupe intervention, étaient meilleurs, bien que non significativement, dans ce groupe. Ces résultats suggèrent que le processus deformalisation et mise en oeuvre de recommandations, impliquant les praticiens concernés, est susceptible d'améliorer la prise en charge thérapeutique.
... 14 After a mean 59 months of follow-up, the results from the Acute Infarction Ramipril Efficacy study indicated that death from all causes occurred in 38.9% of patients assigned to placebo and 27.5% of patients treated with ramipril, with a relative risk reduction of 36% (15%-52%; P = 0.002) and an absolute reduction in mortality of 11.4%. 15 At the end of the Acute Infarction Ramipril Efficacy study, 15 months after randomization, all-cause mortalities were 22.6% in the placebo group and 16.9% in the ramipril group, with an absolute mortality reduction of 5.7% and a relative risk reduction of 27% (11%-40%; P = 0.002). 15 The 5-year survival analysis from the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI-3) trial suggested that lisinopril treatment improved survival mainly because of a reduction in cardiac rupture, electromechanical dissociation, and pump failure occurring early (within 4 days) from the onset of MI symptoms. ...
... 15 At the end of the Acute Infarction Ramipril Efficacy study, 15 months after randomization, all-cause mortalities were 22.6% in the placebo group and 16.9% in the ramipril group, with an absolute mortality reduction of 5.7% and a relative risk reduction of 27% (11%-40%; P = 0.002). 15 The 5-year survival analysis from the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI-3) trial suggested that lisinopril treatment improved survival mainly because of a reduction in cardiac rupture, electromechanical dissociation, and pump failure occurring early (within 4 days) from the onset of MI symptoms. The beneficial effects of lisinopril observed at 6 weeks (8 fewer deaths per 1000 treated patients) were maintained up to nearly 5 years (10 fewer deaths per 1000). ...
The SMILE-4 study showed that in patients with left ventricular dysfunction (LVD) after acute myocardial infarction, early treatment with zofenopril plus acetyl salicylic acid is associated with an improved 1-year survival, free from death or hospitalization for cardiovascular (CV) causes, as compared to ramipril plus acetyl salicylic acid. We now report CV outcomes during a 5-year follow-up of the patients of the SMILE-4 study. Three hundred eighty-six of the 518 patients completing the study (51.2%) could be tracked after the study end and 265 could be included in the analysis. During the 5.5 (62.1) years of follow-up, the primary endpoint occurred in 27.8% of patients originally randomized and treated with zofenopril and in 43.8% of patients treated with ramipril [odds ratio (OR) and 95% confidence interval, 0.65 (0.43-0.98), P = 0.041]. Such a result was achieved through a significantly larger reduction in CV hospitalization under zofenopril [OR: 0.61 (0.37-0.99), P = 0.047], whereas reduction in mortality rate with zofenopril did not achieve statistical significance versus ramipril [OR: 0.75 (0.36-1.59), P = 0.459]. These results were in line with those achieved during the initial 1-year follow-up. Benefits of early treatment of patients with LVD after acute myocardial infarction with zofenopril are sustained over many years as compared to ramipril.
... Однако ингибитор АПФ рамиприл назначается существенно реже по сравнению с другими представителями этого класса, хотя доказательная база оригинального рамиприла значительно превосходит таковую у многих других ингибиторов АПФ. Результатами многочисленных исследований подтверждены эффективность и высокая безопасность препарата при лечении пациентов с АГ (CARE, DIABHYCAR, DIAL, RACE) [1][2][3][4], хронической сердечной недостаточностью (AIREX, CHARM-Added) [5,6], ишемической болезнью сердца (ИБС) (AIRE, APRES, HEART, ONTARGET) [7][8][9][10] и при заболеваниях почек (AASK, REIN) [11][12][13]. ...
... However, physicians prescribe ACE inhibitor ramipril significantly more rarely than other drugs of the same class, while evidential base of the original ramipril surpasses that of many other ACE inhibitors. A large number of trials confirms efficacy and high safety of the drug in treatment of patients with HT (CARE, DIABHYCAR, DIAL, RACE) [1][2][3][4], chronic heart failure (AIREX, CHARM-Added) [5,6], ischemic heart disease (IHD) (AIRE, APRES, HEART, ONTARGET) [7][8][9][10] renal diseases (AASK, REIN) [11][12][13]. ...
Aim. To compare efficacy of ramipril generic Hartil® (Egis) to original drug Tritace® in patients with arterial hypertension (HT) of 1-2 degree and high cardiovascular risk, and to evaluate target blood pressure (BP) achievement when taking each drug separately and in combination with the calcium channel blocker amlodipine.Material and methods. A total of 27 patients (14 men, 13 women) with HT of 1-2 degree and high risk due to combination of HT with ischemic heart disease, diabetes or previous stroke were included in an open randomized crossover study. Each patient received generic and original ramipril during 6 weeks by turns. Antihypertensive efficacy (the target BP level <130/80) was evaluated every 2 weeks. In case of treatment inefficiency a dose was doubled and amlodipine (Cardilopin, Egis) was added. After 6 weeks of treatment with the first drug of ramipril the second one was administered.Results. After 6-week Hartil treatment the mean systolic BP (sBP) decreased by 20,0 mm Hg compared to the baseline level, while at Tritace treatment – by 22,2 mm Hg. The mean diastolic BP (dBP) decreased by 10,8 and 8,6 mm Hg respectively (differences between the drugs were insignificant). Twenty patients treated with Hartil and 16 patients treated with Tritace required Cardilopin prescription. The target BP<130/80 was achieved in 10 patients (38,5%) who took Hartil and in 13 patients (50%) treated with the original ramipril (differences between the drugs were insignificant).Conclusion. Therapeutic equivalence of the generic ramipril Hartil and the original drug Tritace was demonstrated. Monotherapy efficacy was low in high-risk patients with HT of 1-2 degree, and combined therapy with two antihypertensive drugs was effective in 40-50% of cases.
... О целесообразности раннего назначения иАПФ при ИМ свидетельствует ряд исследований, в которых продемонстрировано снижение риска смерти при их применении в первые 36-42 ч ИМ [38,39]. ...
... 16 Ramipril increases long-term survival in heart failure patients with a history of myocardial infarction in the Acute Infarction Ramipril Efficacy (AIRE) and Acute Infarction Ramipril Efficacy Extension (AIREX) studies and reduces left ventricular mass in the Ramipril Cardioprotective Evaluation (RACE) study. [17][18][19] In particular, in the Maximal Individual Therapy of Acute Myocardial Infarction-PLUS (MITRA-PLUS) study, ramipril was mainly shown in STEMI patients and reduced cerebrovascular accidents and mortality. 20 Although most studies prefer ACEI over ARB, this study found no significant difference in 3-year clinical outcomes between the 2 groups. ...
... В конце испытания (минимальная продолжительность наблюдения -42 мес, средняя -59 мес) умерло 83 (28%) больных из группы рамиприла и 117 (39%) из группы плацебо. Относительный риск смерти снизился на 36% (р=0,002) [8]. Аналогичные результаты были получены и в исследовании TRACE, в котором в качестве иАПФ использовали трандолаприл. ...
Angiotensin converting enzyme inhibitors are the first line medicine for the treatment of the most of cardiovascular diseases. There is no class-effect for these drugs in myocardial infarction therapy. Moreover in myocardial infarction angiotensin converting enzyme inhibitors have significant intra-group differences. Ramipril is the one of the most studied drug of this group recommended for patients after acute myocardial infarction.
... The extension study provided robust evidence that administration of ramipril to patients with clinically defined heart failure after AMI results in a survival benefit that is not only large in magnitude, but also sustained over many years. 16 The heart outcomes prevention evaluation (HOPE) study was a multicenter, double-blind, randomized, placebo-controlled trial. A total of 9297 high-risk patients (aged ≥55 years) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once daily orally) or matching placebo for a mean of 5 years. ...
The renin-angiotensin-aldosterone system (RAAS) is responsible for maintaining hemodynamic stability and thereby impacts multiple organ systems, such as the central nervous system, heart, and kidneys. Angiotensin II (ang II) is the main effector of the RAAS. However, overactivity of the RAAS can give rise to cardiovascular disorders, stroke, and nephrosclerosis. Unfavorable effects on cardiovascular system are attributed to ang II. RAAS activation also results in release and increased activity of several hormonal and inflammatory mediators, trigger formation of a number of secondary messengers and/or activate pathways, which negatively affects blood vessels and tissue. RAAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and calcium channel blockers can protect various organs from damage by blocking the protean manifestation of RAAS activity, either in its circulating or its locally tissue-active form. This review explains on the pleiotropic effects and benefits that go beyond mere blood pressure control. ACEIs in terms of mortality reduction, long‑term survival benefits, cardioprotective and vasculo-protective effects as well as improve fibrinolytic balance. Ramipril has been clinically proven to reduce rates of mortality, myocardial infarction, and stroke. ACEIs and ARBs were associated with lesser risks of COVID-19 infection.
... In our study, smoking was associated with a lower risk of death in ACS, primarily because of the younger age of smokers with ACS and less severe coronary artery disease. Similar data have also been reported elsewhere [37][38][39] . Obesity at ACS presentation is associated with lower in-hospital mortality. ...
It has been demonstrated that pre-hospital emergency care reduces in-hospital mortality in patients admitted with acute coronary syndrome (ACS). The aim of this study was to analyze the relationship between pre-hospital emergency care and in-hospital mortality in ACS patients treated at the University Clinical Centre of Kosovo Emergency Department (UCCK ED). This observational clinical study included 1498 ACS patients treated at UCCK ED and followed-up by phone call for one year after discharge from the hospital. According to multivariate Cox regression analysis, age (HR=2.37, 95% CI 1.67-3.52), pre-hospital emergency care (HR=3.92, 95% CI 2.35-6.54), STEMI (HR=6.17, 95% CI 3.22-15.31), diabetes mellitus (HR=3.01, 95% CI 1.98-3.78), left ventricular ejection fraction <40% (HR=17.63, 95% CI 11.2-30.54) and ex-smoking (HR=2.34, 95% CI 1.57-3.85) were significant predictors of mortality in ACS patients. In-hospital mortality of patients admitted with ACS remains high in Kosovo as compared with developed countries. A better strategy for pre-hospital emergency care in Kosovo is recommended to save lives in these high-risk patients.
... В группе рамиприла отмечалось статистически значимое снижение относительного риска (RR) смерти на 27% (RR=0,73 при 95% ДИ от 11 до 40%; p=0,002) и частоты развития других неблагоприятных клинических исходов [38]. Возможность длительного сохранения достигнутого эффекта применения рамиприла, отмеченная в исследовании AIRE доказана в обсервационном исследовании AIREX (AIRE Extension) [39], в которое были включены 603 участника основного исследования AIRE, наблюдавшиеся дополнительно еще в течение 3 лет. ...
Experts consensus of the Russian Cardiology Society (RSC)
... The ramipril ability to suppress vascular endothelial cell proliferation was first demonstrated in the SECURE study [18], whose results showed a 37 % slower atherosclerosis progression when using ramipril. Later, the AIREX study revealed ACE inhibitors` ability to reduce cardiovascular complications and standardized death rate indicators (∆=-36,0 %) through its angioprotective property [19]. Therefore, patients with an initially high РВР should be prescribed pathogenesis-based therapy affecting systemic hemodynamics parameters to improve their prognosis. ...
... 7,8 However, with the development of highsensitivity cardiac troponin assays we increasingly identify patients with minor myocardial injury. [9][10][11][12] Whether cardiac troponin concentration remains a useful predictor in this group of patients is uncertain. Furthermore, high sensitivity cardiac troponin assays are increasingly used to risk-stratify patients to identify those likely to benefit from hospitalization and/or further investigation. ...
Aims:
Heart failure may occur following acute myocardial infarction, but with the use of high-sensitivity cardiac troponin assays we increasingly diagnose patients with minor myocardial injury. Whether troponin concentrations remain a useful predictor of heart failure in patients with acute coronary syndrome is uncertain.
Methods and results:
We identified all consecutive patients (n = 4748) with suspected acute coronary syndrome (61 ± 16 years, 57% male) presenting to three secondary and tertiary care hospitals. Cox-regression models were used to evaluate the association between high-sensitivity cardiac troponin I concentration and subsequent heart failure hospitalization. C-statistics were estimated to evaluate the predictive value of troponin for heart failure hospitalization. Over 2071 years of follow-up there were 83 heart failure hospitalizations. Patients with troponin concentrations above the upper reference limit (URL) were more likely to be hospitalized with heart failure than patients below the URL (118/1000 vs. 17/1000 person years, adjusted hazard ratio: 7.0). Among patients with troponin concentrations <URL the rate of heart failure hospitalization was 2.80-fold higher [95% confidence interval (95% CI 1.81-4.31)] per doubling of troponin concentration. On adding troponin to a model with demographic, cardiovascular risk factor, and clinical variables, the prediction of heart failure hospitalization improved considerably (C-statistic 0.80 vs. 0.86, P < 0.001).
Conclusion:
Cardiac troponin is an excellent predictor of heart failure hospitalization in patients with suspected acute coronary syndrome. The strongest associations were observed in patients with troponin concentrations in the normal reference range, in whom high-sensitivity cardiac troponin assays identify those at increased risk of heart failure who may benefit from further investigation and treatment.
... En el caso de los BßA y los IECA su beneficio está claramente establecido y puede ser incluso más relevante en los sujetos que quedan con insuficiencia cardiaca [4,5,[19][20][21] . Por lo tanto debería preverse que la frecuencia de su prescripción no sea superada por la de bloqueadores de los canales de calcio y antagonistas de la angiotensina II. ...
[Article in Spanish]
Rev Fac Cien Med (Quito) 2007; 32: 22-32.
Context: The PSIAL study was an international project to investigate the characteristics of pharmacological treatment for secondary prevention of acute myocardial infarction (AMI). Clinical data and cardiovascular risk factors (CVRF) were also recorded during the study. This paper shows partial results of the PSIAL-Ecuador component.
Objective: To describe the clinical characteristics and CVRF identified in the patients studied in Ecuador.
Design: Prospective cohort.
Subjects: Patients with a first AMI attended consecutively between 2003-2006 in the following hospitals from Quito-Ecuador: Eugenio Espejo (HEE), Carlos Andrade Marín (HCAM), General No. 1 of the Armed Forces (HGFA), Metropolitano (HM), and Quito Nº1 (HQ).
Main measurements: Data recorded in the first (in-hospital) period of the study, corresponding to 10 CVRF, other antecedents of interest and complications until the time of hospital discharge.
Results: 292 patients (62.6 ± 12.7 years old; male 80.5%) were studied. 25.7% were under 55 years old. More women were older than 70 years (25.5% vs. 40.4%, p = 0.02). Total cholesterol (182.6 ± 45.3 vs. 191.3 ± 53.0 mg / dL), LDL (114.8 ± 40.0 vs. 113.5 ± 41.8 mg / dL) and HDL (37.7 ± 12.0 vs. 41.9 ± 12.3) were similar in both sexes. Sedentary lifestyle (80.8%) and decreased HDL (67.6%) were the most frequent CVRF. Smoking (56.2%) was more common in men (OR = 3.55 [95%CI 1.84-6.91]), while hypertension (47.6%) and diabetes mellitus (19.5%) were associated with female sex (2.92, [1.52-5.67], and 2.89, [1.44-5.80], respectively). Hypercholesterolemia (36.1%), obesity (11.5%), elevated LDL (13.3%) and family history of AMI (10.1%) were uncommon.
An age at risk, sedentary lifestyle, and other factors was less common in HEE patients, but smoking was more common. The subjects' ages were significantly higher in HCAM and HGFA, with hypercholesterolemia predominating in the former and sedentary lifestyle in the latter. In HM, the highest number of cases with obesity and diabetes mellitus was high, with hypercholesterolemia, elevated LDL and decreased HDL being common. In the HQ, sedentary lifestyle predominated.
In the totallty of patients 11.2% had a history of gastroduodenal ulcer and 5.2% chronic obstructive pulmonary disease. 19.5% developed complications and of all those identified, 12.6% were heart failure.
Conclusions: The prevalence of decreased HDL and the low frequency of hypercholesterolemia could suggest the presence of genomic cholesterol polymorphisms in the population. The epidemiology of the AMI, the differences on CVRF and non-pharmacological secondary prevention are priority areas of local research.
... Después de un seguimiento de 15 meses, el uso de ramipril se asoció a 6% de descenso absoluto de la mortalidad y una reducción significativa de la muerte súbita de 30%, con reducción en la progresión de la falla cardíaca pero sin efecto en el reinfarto o stroke (48) . El beneficio de la sobrevida por ramipril se mantiene por largo tiempo (49) . ...
... Por lo menos tres (3) ensayos a gran escala han demostrado que la disminución de mortalidad ocurre cuando se usan los IECA en pacientes con una disfunción VI después del infarto. [36][37][38] Los IECA atenúan la remodelación del VI, la cual probablemente contribuye, en forma importante, a una mejor sobrevida. Este beneficio es igual en aquellos pacientes con o sin signos de IC. 39 En general, los IECA son recetados por tiempo prolongado a pacientes que han sufrido disfunción VI después del IM. ...
En resumen, los medicamentos que inhiben el SRAA son una forma de
terapia muy importante con un fuerte perfil de seguridad y una trayectoria
de supervivencia mejorada a través de una amplia selección de trastornos
cardiovasculares agudos y crónicos, especialmente en Hipertensión arterial,
Infarto del Miocardio, Insuficiencia cardiaca y enfermedad renal. Éstos han
sido exitosos más allá de nuestras expectativas y ahora forman la base del
tratamiento para muchos trastornos cardiovasculares.
El propósito de este capítulo es detallar cómo estos medicamentos, que
están diseñados para bloquear el SRAA, se utilizan para tratar los pacientes
con una enfermedad cardiovascular.
... В дополнительном исследовании AIREX (AIRE: Extention) при наблюдении в течение 3-х лет было показано сохранение эффектов рамиприла. По сравнению с плацебо сердечно-сосудистая смертность у данной группы пациентов, принимавших рамиприл, оставалась ниже [9]. ...
... Рамиприл обладает одной из наиболее внушительных доказательных баз положительного влияния на различные конечные точки практически на всех этапах сердечно-сосудистого континуума у самого широкого круга пациентов с высоким риском сердечно-сосудистых осложнений, АГ (исследование СARE) [17], при гипертрофии левого желудочка у больных с АГ (исследования RACE и HYCAR) [18], с ХСН, с инфарктом миокарда (исследования AIRE, AIREX и MITRА PLUS (Maximal Individual Therapy of Acute Myocardial Infarction PLUS registry) [19][20][21], выявивших преимущество рамиприла по влиянию на выживаемость больных по сравнению с другими ИАПФ, стабильном течении ишемической болезни сердца (исследование НОРЕ, PEACE) [22][23][24][25], диабетической и недиабетической нефропатией (исследования MICRO-HOPE, DIABHYCAR и AASK, REIN) [22,[26][27][28]. ...
The article focuses on the “pros” and “contras” of thiazide containing combinations usage for treatment of arterial hypertension in real clinical practice. Based on evidence, clear indications are formulated for effective and safe application of the ramipril and hyndrochlorothiazide combination.
... Ингибиторы АПФ используются как в острую стадию (первые 36 ч после развития ИМ), так и в более поздние сроки (через 48 ч) от начала ИМ и для длительной терапии в постинфарктном периоде (AIRE [13], AIREX [14], SMILE [15], GISSI-3 [16], SAVE [17]). Благоприятный эффект в этой клинической ситуации был более выражен у пациентов в группе высокого риска, например, у пациентов с сердечной недостаточностью (СН), передним ИМ, сопутствующим СД. ...
Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) slow down progression of cardiovascular diseases and reduce risk of mortality and life threatening complications. What it is better to prescribe for patient in a concrete clinical case – ACE inhibitors or ARB? Authors compare these drug classes (mechanism of action, indications, evidense base of clinical trails, treatment costs and safety). The place of ACE inhibitors and ARB in modern therapy of cardiovascular diseases is defined. Results of the recent trails (ONTARGET, TRANCEND, PRoFESS, I-PRESERVE) are discussed.
... О целесообразности раннего назначения иАПФ при ИМ свидетельствует ряд исследований, в которых продемонстрировано снижение риска смерти при их применении в первые 36-42 ч ИМ [38,39]. ...
The review is devoted to the modern data about mechanisms of cardiovascular dysfunction in patients suffering diabetes mellitus type 2, especially to the role of oxidative stress. It is determined that oxidative stress is involved in the development of myocardial ischemia, reperfusion-syndrome, endothelial dysfunction and atherogenesis. There are data that angiotensin converting enzyme inhibitor, zofenopril, has both cardio- and vasoprotective activities as well as antioxidative effect. These features are rationales to use it in patients with ischemic heart disease and diabetes mellitus.
... В дополнительном исследовании AIREX (AIRE: Extention) при наблюдении в течение 3-х лет было показано сохранение эффектов рамиприла. По сравнению с плацебо сердечно-сосудистая смертность у данной группы пациентов, принимавших рамиприл, оставалась ниже [9]. ...
There is grate interest to ACE inhibitors which have cardioprotective and neproprotective effects. Ramipril efficacy in ischemic heart disease prevention as well as ramipril positive effect on myocardium in adolescents is presented on the base of some trails. Ramipril ability to delay of diabetic and non-diabetic nephropathy progression is also discussed.
... However, hydralazine in treatment was only inferior to optimally dosed RAAS inhibitors and it may have to be considered that optimum doses of RAAS inhibitors (i.e., for treatment of heart failure 10 mg/ day Ramipril or 320 mg/ day Valsartan) are often not reached due to decrease of glomerular iltration rate, hyperkalemia or hypotension. In this regard, hydralazine does not require dose reduction it cases of low GFR, making it a possible substitute to RAAs inhibitors, even when its de-methylating eicacy is not even taken into account [58,59]. In fact, studies comparing eicacy of ACEIs to hydralazine concluded that combination of ACEIs and hydralazine should be tested -but such trials have not yet been done. ...
Chronic progressive kidney disease (CKD) remains an unsolved problem in clinical Nephrology as neither biomarkers to predict progression towards end-stage renal failure in individual patients nor specific drugs to inhibit decline of kidney function are available in the clinic yet. In this regard, the prototypical epigenetic mechanism of CpG island promoter methylation has emerged as modulator of disease progression with utilities both as biomarker and as therapeutic target. Recent studies demonstrated the potential of hydralazine, a long-established antihypertensive drug with de-methylating activity, to reverse aberrant CpG island promoter aberration and ameliorate progression of chronic kidney disease. Here we review contribution of aberrant promoter methylation to progression of fibrogenesis and mechanisms underlying hydralazine’s demethylating activity and discuss possible translational implications
rof David Goldsmith opened the symposium by highlighting the objectives of the meeting. The education objectives of the symposium were to summarise the mechanisms that regulate potassium balance, specifically highlighting how these mechanisms are affected by inhibition of the renin-angiotensinaldosterone system (RAAS); to examine the pathophysiology of hyperkalaemia and illustrate the impact on clinical outcomes; to evaluate current clinical evidence and outline key considerations that help determine the urgency; and to describe recent clinical trial data on investigational oral ion exchangers and the potential future role of these emerging therapies in clinical practice. In the first presentation, Prof Johannes F. E. Mann discussed the predisposing factors of hyperkalaemia by presenting a case of a heart failure (HF) patient with Stage 3 chronic kidney disease (CKD), and also discussed the epidemiology and pathophysiology of hyperkalaemia. Dr Martin H. de Borst then discussed the current therapeutic options available for the outpatient treatment of hyperkalaemia, along with recent clinical data on novel treatments, in particular patiromer and zirconium cyclosilicate (known as ZS-9).
Advanced chronic kidney disease (CKD) frequently aggravates heart failure (HF). However, these patients have inherently been excluded from most HF trials. We aim to provide updated estimates of the representation of patients with advanced CKD and the provision of baseline renal function indices in HF trials with a focused interest on the landmark trials. Updated systematic review was performed from the inception of MEDLINE to 31 December 2019 to identify all chronic HF randomized trials published in the three major cardiology and medical journals, respectively, which included mortality endpoint. The included studies were analysed based on the representativeness of the advanced CKD population and the reporting of baseline renal function. A total of 187 eligible randomized trials with 322,374 participants were included in our analysis. One hundred and six trials (56.7%) had exclusion criteria related to renal function, which remained a continuing trend–55.1% (27/49) from inception-2000, 53.4% (39/73) from 2001–2010 and 61.5% (40/65) from 2011 (P = 0.64). The exclusion criteria, however, have become less restrictive. There was a temporal improvement in the likelihood of HF trials in providing baseline renal function indices (28.6% from inception-2000 versus 53.4% from 2001–2010 and 83.1% from 2011, P < 0.001). Concordant findings were observed in the landmark trials. Patients with advanced CKD remain underrepresented in HF trials in the contemporary era, even though the exclusion criteria have become less restrictive, and the quality of renal function monitoring has improved. The continued underrepresentation of patients with advanced CKD in HF trials merits measured broadening of eligibility in further trial studies.
Heart failure syndrome is an entity with a high health and social impact. It is triggered by an imbalance between cardiac output and the demands of the organism, that during the last decades has presented great and constant advances that require frequent review and analysis; its etiology is heterogeneous, with arterial hypertension and ischemic heart disease the main causes; Its development includes pathophysiological mechanisms that have not yet been fully clarified. The clinical manifestations include a constellation of nonspecific symptoms caused by alterations in myocardial contractility, ventricular filling or as a consequence of compensation mech- anisms; the diagnostic approach starts from the clinical suspicion, supported by paraclinical tests such as the blood concentration of the natriuretic peptide, radio-diagnostic studies and echocardiography; The therapeutic plan is based on the prevention and control of risk factors, the pharmacological modulation of neurohormonal activity associated with the use of implantable cardiac devices when necessary due to the complexity of the case. The present non-systematic narrative review aims to describe and compile the information from existing research and publications about this cardiovascular disease, providing a theoretical, clinical and therapeutic approach applicable to the three levels of health care.
Angiotensin II (Ang II) is a primary mediator of profibrotic signaling in the heart and more specifically, the cardiac fibroblast. Ang II-mediated cardiomyocyte hypertrophy in combination with cardiac fibroblast proliferation, activation, and extracellular matrix production compromise cardiac function and increase mortality in humans. Profibrotic actions of Ang II are mediated by increasing production of fibrogenic mediators (e.g. transforming growth factor beta, scleraxis, osteopontin, and periostin), recruitment of immune cells, and via increased reactive oxygen species generation. As a result, drugs that inhibit Ang II production or action, collectively referred to as renin angiotensin system (RAS) inhibitors, are first line therapeutics for heart failure. Moreover, transient RAS inhibition has been found to persistently alter hypertensive cardiac fibroblast responses to injury providing a useful tool to identify novel therapeutic targets. This review summarizes the profibrotic actions of Ang II and the known impact of RAS inhibition on cardiac fibroblast phenotype and cardiac remodeling.
Cough is a common side effect of angiotensin converting enzyme inhibitor (ACEi) therapy. The incidence of ACEi-induced cough has been shown to correlate with genetic variation among different populations. This study aimed to determine the association of candidate genetic polymorphisms with ACEi-induced cough among Filipinos. Two hundred twenty (220) participants on ACEi therapy pressure-lowering in an unmatched case-control study (82 cases with ACEi-induced cough and 138 controls). Genomic DNA samples were extracted and genotyped for selected genetic variants. The association of genetic variants and clinical factors with ACEi-induced cough was determined using regression analyses. Univariate logistic regression showed that the BAG6 variant rs805303 is nominally associated with ACEi-induced cough among Filipinos, at a per-comparison error rate (PCER) of 0.05 (OR 2.10, p = 0.016). The association of the variant with ACEi cough was statistically significant after multiple regression analysis (adjusted OR 2.09, p = 0.022) while adjusting for confounding clinical factors (sex, alcohol intake, and diastolic blood pressure). Further studies are needed to validate these findings.
Aims
ACE inhibition reduces mortality and morbidity in patients with heart failure after acute myocardial infarction (AMI). However, there are limited randomised data about the long-term survival benefits of ACE inhibition in this population.
Methods
In 1993, the Acute Infarction Ramipril Efficacy (AIRE) study randomly allocated patients with AMI and clinical heart failure to ramipril or placebo. The duration of masked trial therapy in the UK cohort (603 patients, mean age=64.7 years, 455 male patients) was 12.4 and 13.4 months for ramipril (n=302) and placebo (n=301), respectively. We estimated life expectancy and extensions of life (difference in median survival times) according to duration of follow-up (range 0–29.6 years).
Results
By 9 April 2019, death from all causes occurred in 266 (88.4%) patients in placebo arm and 275 (91.1%) patients in ramipril arm. The extension of life between ramipril and placebo groups was 14.5 months (95% CI 13.2 to 15.8). Ramipril increased life expectancy more for patients with than without diabetes (life expectancy difference 32.1 vs 5.0 months), previous AMI (20.1 vs 4.9 months), previous heart failure (19.5 vs 4.9 months), hypertension (16.6 vs 8.3 months), angina (16.2 vs 5.0 months) and age >65 years (11.3 vs 5.7 months). Given potential treatment switching, the true absolute treatment effect could be underestimated by 28%.
Conclusion
For patients with clinically defined heart failure following AMI, ramipril results in a sustained survival benefit, and is associated with an extension of life of up to 14.5 months for, on average, 13 months treatment duration.
Background:
Approximately half of people with heart failure have chronic kidney disease (CKD). Pharmacological interventions for heart failure in people with CKD have the potential to reduce death (any cause) or hospitalisations for decompensated heart failure. However, these interventions are of uncertain benefit and may increase the risk of harm, such as hypotension and electrolyte abnormalities, in those with CKD.
Objectives:
This review aims to look at the benefits and harms of pharmacological interventions for HF (i.e., antihypertensive agents, inotropes, and agents that may improve the heart performance indirectly) in people with HF and CKD.
Search methods:
We searched the Cochrane Kidney and Transplant Register of Studies through 12 September 2019 in consultation with an Information Specialist and using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Selection criteria:
We included randomised controlled trials of any pharmacological intervention for acute or chronic heart failure, among people of any age with chronic kidney disease of at least three months duration.
Data collection and analysis:
Two authors independently screened the records to identify eligible studies and extracted data on the following dichotomous outcomes: death, hospitalisations, worsening heart failure, worsening kidney function, hyperkalaemia, and hypotension. We used random effects meta-analysis to estimate treatment effects, which we expressed as a risk ratio (RR) with 95% confidence intervals (CI). We assessed the risk of bias using the Cochrane tool. We applied the GRADE methodology to rate the certainty of evidence.
Main results:
One hundred and twelve studies met our selection criteria: 15 were studies of adults with CKD; 16 studies were conducted in the general population but provided subgroup data for people with CKD; and 81 studies included individuals with CKD, however, data for this subgroup were not provided. The risk of bias in all 112 studies was frequently high or unclear. Of the 31 studies (23,762 participants) with data on CKD patients, follow-up ranged from three months to five years, and study size ranged from 16 to 2916 participants. In total, 26 studies (19,612 participants) reported disaggregated and extractable data on at least one outcome of interest for our review and were included in our meta-analyses. In acute heart failure, the effects of adenosine A1-receptor antagonists, dopamine, nesiritide, or serelaxin on death, hospitalisations, worsening heart failure or kidney function, hyperkalaemia, hypotension or quality of life were uncertain due to sparse data or were not reported. In chronic heart failure, the effects of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) (4 studies, 5003 participants: RR 0.85, 95% CI 0.70 to 1.02; I2 = 78%; low certainty evidence), aldosterone antagonists (2 studies, 34 participants: RR 0.61 95% CI 0.06 to 6.59; very low certainty evidence), and vasopressin receptor antagonists (RR 1.26, 95% CI 0.55 to 2.89; 2 studies, 1840 participants; low certainty evidence) on death (any cause) were uncertain. Treatment with beta-blockers may reduce the risk of death (any cause) (4 studies, 3136 participants: RR 0.69, 95% CI 0.60 to 0.79; I2 = 0%; moderate certainty evidence). Treatment with ACEi or ARB (2 studies, 1368 participants: RR 0.90, 95% CI 0.43 to 1.90; I2 = 97%; very low certainty evidence) had uncertain effects on hospitalisation for heart failure, as treatment estimates were consistent with either benefit or harm. Treatment with beta-blockers may decrease hospitalisation for heart failure (3 studies, 2287 participants: RR 0.67, 95% CI 0.43 to 1.05; I2 = 87%; low certainty evidence). Aldosterone antagonists may increase the risk of hyperkalaemia compared to placebo or no treatment (3 studies, 826 participants: RR 2.91, 95% CI 2.03 to 4.17; I2 = 0%; low certainty evidence). Renin inhibitors had uncertain risks of hyperkalaemia (2 studies, 142 participants: RR 0.86, 95% CI 0.49 to 1.49; I2 = 0%; very low certainty). We were unable to estimate whether treatment with sinus node inhibitors affects the risk of hyperkalaemia, as there were few studies and meta-analysis was not possible. Hyperkalaemia was not reported for the CKD subgroup in studies investigating other therapies. The effects of ACEi or ARB, or aldosterone antagonists on worsening heart failure or kidney function, hypotension, or quality of life were uncertain due to sparse data or were not reported. Effects of anti-arrhythmic agents, digoxin, phosphodiesterase inhibitors, renin inhibitors, sinus node inhibitors, vasodilators, and vasopressin receptor antagonists were very uncertain due to the paucity of studies.
Authors' conclusions:
The effects of pharmacological interventions for heart failure in people with CKD are uncertain and there is insufficient evidence to inform clinical practice. Study data for treatment outcomes in patients with heart failure and CKD are sparse despite the potential impact of kidney impairment on the benefits and harms of treatment. Future research aimed at analysing existing data in general population HF studies to explore the effect in subgroups of patients with CKD, considering stage of disease, may yield valuable insights for the management of people with HF and CKD.
Different medication has proven efficacy to reduce both morbidity and mortality in patients with heart failure. However, this is only true in patients with reduced left-ventricular ejection fraction (LVEF). Inhibition of the renin-angiotensin-aldosteron system (RAAS) is one of the key treatment strategies in these patients. ACE-inhibition has been introduced first and is the standard to start medication reducing events in heart failure with reduced LVEF (HFrEF). If not tolerated, angiotensinreceptor blockade (ARB) is a good alternative. High doses in chronic treatment should be achieved. As aldosterone may increase after initial reduction when starting ACE-inhibitors, additional mineralocorticoid receptor anatonism (MRA) has been introduced and successfully studied. Thus, the combination of either ACE-inhibition or ARB and MRA is recommended in basically all patients with HFrEF, unless not tolerated. Recently, the addition of neprilysin-inhibition (sacubitril) to ARB (valsartan) has been studied in still symptomatic HFrEF patients. The effect on prognosis was basically twice that of ACE-inhibition. When using RAAS inhibitors, caution is required regarding renal function, hyperkalemia and hypotension; all of which need to be monitored. Angioedema is a potentially lethal side effect and a contraindication for ACE-inhibition, ARB and sacubitril/valsartan. Diuretics are used in the lowest possible dose to completely decongest heart failure patients. This applies to all patients, irrespective of LVEF. Digoxin in only used in patients that remain symptomatic despite the use of all other drugs.
Die Sichtweise der Pathophysiologie und damit die Therapie der Herzinsuffizienz haben sich in den letzten 30 Jahren deutlich verändert. Die Framingham-Studie belegte, daß die häufigste Ursache der chronischen Herzinsuffizienz die chronische Drucküberlastung des Herzens bei arterieller Hypertonie ist.
Bei den unterschiedlichen Ursachen und differenten pathophysiologischen Mechanismen des Syndroms der Herzinsuffizienz wäre es geradezu verwunderlich, wenn es immer durch ein ähnliches oder gleiches Spektrum von Symptomen manifest würde. Bevor die Diagnostik diskutiert werden kann, muß deshalb auf einige herkömmliche Begriffe eingegangen werden, die sich in der klinischen Beschreibung diesesxielfältigenSvndromseingebürgert haben.
BACKGROUND
Only one published trial has directly evaluated the utility of the new National Cholesterol Education Program (NCEP) guidelines in young adults and that study population consisted of young Americans. We examined the utility of the latest NCEP Adult Treatment Panel III (ATP III) guidelines in a group of young Lebanese adults.
METHODS
A group of 234 young adults admitted for myocardial infarction at a Lebanese teaching hospital over a 2-year period were evaluated retrospectively. The Framingham risk predictor model was used to calculate the 10-year risk for coronary events in all subjects.
RESULTS
Two hundred young Lebanese adults with a mean age of 49.7±7.6 years were included in the analysis. The majority of the study population had a history of smoking (67%) and LDL cholesterol <130 mg/dL(70.5%) and were considered overweight and obese (80.5%). As a group, 80% did not meet the criteria to qualify for antilipemic pharmacotherapy prior to their presentation.
CONCLUSION
The predictive model did not detect the majority of these patients. Clinicians should treat modifiable risk factors with the same intensity given to cholesterol even if the patient has a normal lipid profile.
Die Definition der Herzinsuffizienz muß der Pathogenese und der Symptomatik Rechnung tragen. Deshalb hat die WHO in ihrer Definition von 1995 den Symptomenkomplex Herzinsuffizienz einmal pathophysiologisch und einmal klinisch beschrieben.
Trotz vieler möglicher Entstehungsursachen finden sich bei der Herzinsuffizienz typischerweise eine Dilatation der Herzhöhlen und eine Hypertrophie der einzelnen Myokardfasern.Ausnahmen sind hier Speicherkrankheiten (Amyloidose, Glykogenspeicherkrankheiten), die verdickte Herzwände aufweisen können.
Das Lungenödem ist definiert als Vermehrung der extravasalen Flüssigkeit im Interstitium allein oder auch zusätzlich in den Alveolen der Lunge, unabhängig von der zugrundeliegenden Ätiologie. Es entsteht dann, wenn mehr Flüssigkeit aus dem Blut in das Interstitium und in die Alveolen austritt, als aus diesem Bereich in das Blut und in die lymphatischen Gefäße rückresorbiert wird (Harris u. Heath 1986).
Introduction and objectives
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been shown to reduce mortality after myocardial infarction (MI). Current guidelines recommend their prescription in all patients after MI. Limited data are available on whether ACEIs/ARBs still improve prognosis in the contemporary era of non-ST elevation MI (NSTEMI) management. We aimed to evaluate the mortality benefit of ACEIs/ARBs in NSTEMI patients treated successfully with percutaneous coronary intervention (PCI).
Methods
We analyzed 2784 patients with NSTEMI treated successfully with in-hospital PCI. Two groups were formed based on ACEI/ARB prescription at discharge. Two propensity score (PS) analyses were performed to control for differences in covariates: one with adjustment among the entire cohort, and the other with PS matching (n=1626). The outcome variable was all-cause mortality at four-year follow-up.
Results
There were 1902 (68.3%) patients prescribed ACEIs/ARBs at discharge. When adjusted by PS, ACEI/ARB use was associated with a hazard ratio (HR) for mortality of 0.75 (0.60-0.94; absolute risk reduction [ARR] 4.0%) in the whole cohort (p=0.01).
After one-to-one PS matching (n=813 in each group), the mortality rate was significantly lower in patients prescribed ACEIs/ARBs, with HR of 0.77 (0.63-0.94; ARR 3.8%) (p=0.03).
Conclusions
In this observational study of patients with NSTEMI, all of them treated successfully by PCI, the use of ACEIs/ARBs was significantly associated with a lower risk of four-year all-cause mortality.
Introduction and objectives:
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been shown to reduce mortality after myocardial infarction (MI). Current guidelines recommend their prescription in all patients after MI. Limited data are available on whether ACEIs/ARBs still improve prognosis in the contemporary era of non-ST elevation MI (NSTEMI) management. We aimed to evaluate the mortality benefit of ACEIs/ARBs in NSTEMI patients treated successfully with percutaneous coronary intervention (PCI).
Methods:
We analyzed 2784 patients with NSTEMI treated successfully with in-hospital PCI. Two groups were formed based on ACEI/ARB prescription at discharge. Two propensity score (PS) analyses were performed to control for differences in covariates: one with adjustment among the entire cohort, and the other with PS matching (n=1626). The outcome variable was all-cause mortality at four-year follow-up.
Results:
There were 1902 (68.3%) patients prescribed ACEIs/ARBs at discharge. When adjusted by PS, ACEI/ARB use was associated with a hazard ratio (HR) for mortality of 0.75 (0.60-0.94; absolute risk reduction [ARR] 4.0%) in the whole cohort (p=0.01). After one-to-one PS matching (n=813 in each group), the mortality rate was significantly lower in patients prescribed ACEIs/ARBs, with HR of 0.77 (0.63-0.94; ARR 3.8%) (p=0.03).
Conclusions:
In this observational study of patients with NSTEMI, all of them treated successfully by PCI, the use of ACEIs/ARBs was significantly associated with a lower risk of four-year all-cause mortality.
Nationale und internationale Gesellschaften haben Richtlinien zur Behandlung der Herzinsuffizienz aufgestellt: die European Society of Cardiology (ESC), die Weltgesundheitsorganisation (WHO), der American College of Cardiology (ACC)/American Heart Association (AHA) Task Force Report, das US Department of Health and Human Services und die Deutsche Gesellschaft für Kardiologie. Dabei haben sich in den letzten Jahren in der Therapie der Herzinsuffizienz bemerkenswerte Veränderungen ergeben. Die Richtlinien müssen nahezu jährlich aufgrund neuer Ergebnisse prospektiver, randomisierter Studien aktualisiert werden. Ein Konsens konnte bezüglich Allgemeinmaßnahmen und medikamentöser Therapie, nicht aber mechanischer Hilfsmittel, Schrittmacher und chirurgischer Interventionen erreicht werden.
ACE-Hemmer werden mittlerweile als Bestandteil der Routinebehandlung von Patienten mit Herzinsuffizienz anerkannt. Ihre Anwendung wurde in allen neuen Mortalitätsstudien empfohlen, um die Wirksamkeit von β-Blockern bei der Herzinsuffizienz zu erforschen. Morbidität und Mortalität als Folge von Herzinsuffizienz treten weiterhin sehr häufig auf trotz des Nutzens dieser beiden Wirkstoffgruppen.
Trotz des Nachweises für den Erfolg der ACE-Hemmer werden diese weiterhin in der klinischen Anwendung in niedrigerer Dosierung eingesetzt im Vergleich zu den Dosierungen, die in den großen Studien angewendet wurden. Dies war so weit verbreitet, dass darüber eine grundlegende Studie, nämlich die ATLAS-Studie, durchgeführt wurde, die sich mit der ACE-Hemmung in niedriger und hoher Dosierung vergleichend beschäftigte. Ihre mehrdeutigen Ergebnisse haben unterschiedliche Interpretationen zugelassen. Die klinische Erfahrung zeigt, dass es sinnvoll ist, mit einer niedrigen Dosis zu beginnen, dass diese Dosierung dann aber, ohne jede weitere Verzögerung, wenn immer möglich, auftitriert werden sollte, um die in den Studien verwendeten Dosierungen auch zu erreichen. Der Nachweis für den Nutzen dieser Medikamente ist größtenteils bei Patienten mit eingeschränkter systolischer Funktion erhoben worden. Die AIRE-Studie selektierte Patienten mit dem klinischen Nachweis einer Herzinsuffienz nach einem Herzinfarkt eher als solche mit einer eingeschränkten systolischen Funktion. Ein wesentlicher und lang anhaltender Nutzen wurde durch die ACE-Hemmung erreicht. Bei einer Gruppe von Patienten wurde die Ventrikelfunktion untersucht, und, wie vermutet, hatte fast die Hälfte eine intakte systolische Funktion. Während der absolute Nutzen bei der Rettung von Leben größer war in der Gruppe mit höherem Risiko und niedriger Auswurffraktion, so war die Verminderung des relativen Risikos bei Patienten mit intakter oder bei solchen mit verringerter systolischer Funktion nicht signifikant unterschiedlich. Obwohl es sich bei der HOPE-Studie um keine Studie an Patienten mit Herzinsuffizienz handelt, hat sie die Situation besonders für diejenigen geklärt, die sich tagtäglich um das Wohl der Patienten kümmern.
Die HOPE-Studie selektierte Patienten auf der Basis eines hohen kardiovaskulären Risikos und schloss all diejenigen mit bekannter eingeschränkter systolischer Funktion aus. Obwohl es keine Eingangsvoraussetzung für die Studie war, wurde die Auswurffraktion bei einem Großteil der Patienten bestimmt. Der Messung zufolge lag die Auswurffraktion über 40 %, was auf eine intakte systolische Funktion hinwies. Der ACE-Hemmer Ramipril verringerte deutlich den gemeinsamen Endpunkt von kardiovaskulärem Tod, Schlaganfall und Herzinfarkt. Bedeutsam war dabei eine hochsignifikante Risikosenkung um 20 % bei der Herzinfarktrate, ein prospektiv definierter Endpunkt, während der durchschnittlichen Beobachtungszeit von 4 1/2 Jahren. Im Zusammenhang mit dem retrospektiv erhaltenen Beweis aus den Herzinsuffizienzstudien ergibt sich jetzt der zwingende Beweis dafür, dass ACE-Hemmer Herzinfarkte verhindern. Der Mehrheit der Patienten mit klinisch manifester Herzinsuffizienz liegt eine ischämische Herzerkrankung zugrunde. Die Prävention von Herzinfarkten und die Kontrolle des Blutdrucks sind zwei Schlüsselfaktoren bei der Behandlung dieser Patienten ohne Berücksichtigung der systolischen ventrikulären Funktion. ACE-Hemmer haben deshalb genau wie β-Blocker eine zentrale Bedeutung bezüglich ihrer Anwendung. Eine Herausforderung an die gegenwärtigen klinischen Untersuchungen ist es herauszufinden, ob diese Eigenschaften in gleichem Maße auch von den Angiotensin-II-Antagonisten geteilt werden, oder ob weitere Erfolge bezüglich des Nutzens in ihrer Kombination bestehen. Die neutralen Ergebnisse der ELITE II-Studie, die den Angiotensin-II-Antagonisten Losartan mit dem ACE-Hemmer Captopril vergleicht, haben das Interesse an weitergehenden Untersuchungen in dieser Richtung erhöht.
In the early 1970s, ACE inhibition was viewed as an effective means to block the renin-angiotensin component contributing to the maintenance of vasoconstriction [1]. Earlier work had already demonstrated the activation of the renin angiotensin system (RAS) in decompensated congestive heart failure (CHF) [2, 3] and its implications in terms of increased hemodynamic burden to the failing heart. A pilot study using an angiotensin II (Ang II) receptor blocker, saralasin, in a short clinical experiment, demonstrated that Ang II blockade could successfully reverse the hemodynamic aberrations of decompensated CHF, while improving myocardial economy [4]. The decrease in myocardial oxygen consumption resulting from the fall in systemic vascular resistance was, paradoxically, accompanied by an increase in coronary blood flow, a fact that goes against the principles governing the regulation of coronary blood flow. This surprising observation was subsequently explained by the finding that the vasculature of vital organs (heart, kidney and brain) is particularly sensitive to the vasoconstrictive action of Ang II. Consequently, unlike other pharmacological vasodilators, RAS inhibition results in a preferential vasodilation of the coronary, renal and cerebral vasculature, thus maintaining or improving perfusion of vital organs, even in the face of falling systemic blood pressure [5, 6].
Die Linksherzinsuffizienz ist eine häufige Erkrankung mit zunehmender Inzidenz (11). Ihre Prävalenz beträgt altersabhängig für Personen unter 50 Jahren 1:1000 und steigt im Alter über 65 Jahren auf 27 pro 1000 an. Die Prognose dieser Erkrankung ist äußerst schlecht und mit denen von Karzinomen vergleichbar. In der Framingham-Studie lebten fünf Jahre nach Auftreten einer Herzinsuffizienz nur noch 25% der Männer und 38% der Frauen (26). Daraus ergibt sich eine mittlere Überlebenszeit von lediglich 1,66 Jahren für Männer und 3,17 Jahren für Frauen. Schließt man Patienten aus, die die ersten 90 Tage nach Manifestation ihrer Herzinsuffizienz nicht überlebt haben, beträgt die mittlere Überlebenszeit 3,2 Jahre für Männer und 5,4 Jahre für Frauen. Als Ursache wird in der Framingham-Studie allein oder in Kombination mit anderen Erkrankungen in 70% die arterielle Hypertonie genannt (31). Allerdings nimmt die Bedeutung der arteriellen Hypertonie seit den 50er Jahren kontinuierlich ab. Koronare Herzerkrankung und Diabetes mellitus steigen demgegenüber als Ursache der Herzinsuffizienz deutlich an (32). So beträgt der Anteil von Patienten mit gesicherter koronarer Herzerkrankung in der SOLVD-Studie nahezu 70% (6). Der Rückgang der arteriellen Hypertonie als Hauptursache der Linksherzinsuffizienz läßt sich durch verbesserte Diagnose- und Therapiemöglichkeiten erklären (76). Auf der anderen Seite konnte die Mortalitätsrate bei Patienten mit akutem Myokardinfarkt durch Einrichtung von Intensivstationen, Durchführung der Lysetherapie und Behandlung mit β-Blockern sowie Acetylsalicylsäure in den letzten 20 Jahren deutlich gesenkt werden (13, 20, 40). Daraus resultiert allerdings, daß Patienten in den folgenden Jahren in Abhängigkeit von der Infarktgröße zunehmend eine ischämische Kardiomyopathie entwickeln.
Die Wirkung einer medikamentösen ACE-Hemmung besteht in einer verminderten Bildung von Angiotensin II aus Angiotensin I. Ebenfalls gehemmt wird der Abbau von Bradykinin. Angiotensin II wirkt stark vasokonstringierend im arteriellen, aber auch im venösen System. Es führt zu einer vermehrten Freisetzung von Aldosteron und Catecholaminen. Nachgewiesen wurden außerdem trophische Effekte in Zellkulturen, die Bedeutung für die vaskulären und kardialen Veränderungen bei Hochdruck- und Nierenkrankheiten haben könnten. Nachdem oral wirksame Angiotensinrezeptorantagonisten entwickelt wurden, von denen sieben Monopräparate mit funf unterschiedlichen Wirkstoffen in dieser Liste erscheinen, hatte sich gezeigt, daß die Rezeptoren für Angiotensin II in mindestens zwei Gruppen, AT1- und AT2- Rezeptoren, mit teilweise gegensätzlichen Effekten gegliedert werden müssen. Die antihypertensive Wirkung erfolgt über AT1-Rezeptorblockade.
Abbildung 1.1
Verordnungen von ACE-Hemmern 1989 bis 1998 Gesamtverordnungen nach definierten Tagesdosen (ab 1991 mit neuen Bundesländern)
Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces mortality among survivors of acute myocardial infarction, but whether to use ACE inhibitors in all patients or only in selected patients is uncertain.
We screened 6676 consecutive patients with 7001 myocardial infarctions confirmed by enzyme studies. A total of 2606 patients had echocardiographic evidence of left ventricular systolic dysfunction (ejection fraction, < or = 35 percent). On days 3 to 7 after infarction, 1749 patients were randomly assigned to receive oral trandolapril (876 patients) or placebo (873 patients). The duration of follow-up was 24 to 50 months.
During the study period, 304 patients (34.7 percent) in the trandolapril group died, as compared with 369 (42.3 percent) in the placebo group (P = 0.001). The relative risk of death in the trandolapril group, as compared with the placebo group, was 0.78 (95 percent confidence interval, 0.67 to 0.91). Trandolapril also reduced the risk of death from cardiovascular causes (relative risk, 0.75; 95 percent confidence interval, 0.63 to 0.89; P = 0.001) and sudden death (relative risk, 0.76; 95 percent confidence interval, 0.59 to 0.98; P = 0.03). Progression to severe heart failure was less frequent in the trandolapril group (relative risk, 0.71; 95 percent confidence interval, 0.56 to 0.89; P = 0.003). In contrast, the risk of recurrent myocardial infarction (fatal or nonfatal) was not significantly reduced (relative risk, 0.86; 95 percent confidence interval, 0.66 to 1.13; P = 0.29).
Long-term treatment with trandolapril in patients with reduced left ventricular function soon after myocardial infarction significantly reduced the risk of overall mortality, mortality from cardiovascular causes, sudden death, and the development of severe heart failure. That mortality was reduced in a randomized study enrolling 25 percent of consecutive patients screened should encourage the selective use of ACE inhibition after myocardial infarction.
To measure the potential for secondary prevention of coronary disease in the United Kingdom.
Cross sectional survey of a representative sample of coronary patients from a retrospective review of hospital medical records and patient interview and examination.
Stratified random sample of 12 specialist cardiac centres and 12 district general hospitals drawn from 34 specialist cardiac centres and 261 district general hospitals in 12 geographic areas in the United Kingdom.
2583 patients < or = 70 yr; 25 consecutive males and 25 consecutive females identified retrospectively in each of four diagnostic categories: coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, acute myocardial infarction, and acute myocardial ischaemia without evidence of infarction.
Risk factor recording and management in medical records; the prevalence and control of risk factors at interview six months after the procedure or event.
Recording of coronary risk factors in patient's records was incomplete and this varied by risk factor. Smoking habit and blood pressure were most completely recorded, whereas a history of hyperlipidaemia and blood cholesterol concentrations were least complete. Risk factor records were more likely to be complete in cardiac centres than in district hospitals. At interview 10% to 27% of patients were still smoking cigarettes and 75% remained overweight, females more severely so. Up to a quarter of patients remained hypertensive, males more severely so than females. Over three quarters had a total cholesterol > 5.2 mmol/l. In patients on medication for blood pressure, cholesterol or glucose, risk factor profiles were little better than in those who were not. Only about one patient in three was taking a beta blocker after infarction. Up to a fifth of patients who had had acute myocardial ischaemia were not taking aspirin at follow up.
There is considerable potential to reduce the risk of a further major ischaemic event in patients with established coronary disease. This can be achieved by effective lifestyle intervention, the rigorous management of blood pressure and cholesterol, and the appropriate use of prophylactic drugs.
Wide geographic variation in the use of coronary angiography after myocardial infarction has been documented internationally and within the United States. An associated variation in clinical outcomes has not been consistently demonstrated.
We assessed the risk of death from heart disease and of any heart disease event (death, reinfarction, or rehospitalization) over a follow-up period of one to four years in 6851 patients hospitalized with acute myocardial infarction at 16 Kaiser Permanente hospitals from 1990 through 1992. The percentage of patients who underwent angiography within three months after infarction ranged from 30 to 77 percent. We selected a subcohort of 1109 patients from three hospitals with higher rates of angiography and four with lower rates for a record review to assess the severity of infarction, the number of coexisting conditions, treatments received, and the appropriateness and necessity of angiography, using established criteria.
The rates of angiography were inversely related to the risk of death from heart disease (P= 0.03) and the risk of heart disease events (P<0.001) among the 16 hospitals after adjustment for age, sex, race, coexisting conditions, and the location of the infarction (subendocardial vs. transmural). In the subcohort, 440 patients met criteria indicating that angiography was necessary and 669 did not. Among the former, patients treated at hospitals with higher rates of angiography had a lower risk of death and of any heart disease event than those treated at hospitals with lower rates (hazard ratios, 0.67 and 0.72, respectively). Among the latter, the apparent benefits of being treated at hospitals with higher angiography rates were smaller (hazard ratios, 0.85 to 0.90 for death and any heart disease event, respectively).
During the one to four years after myocardial infarction, patients treated at hospitals with higher rates of angiography had more favorable outcomes than those treated at hospitals with lower rates. This association was stronger among patients for whom published criteria indicated that angiography was necessary.
The incremental cost-effectiveness of ramipril treatment compared with conventional treatment of patients with clinical evidence of heart failure after acute myocardial infarction was estimated for the UK. Effectiveness was based on differential survival and defined as life-years gained using original patient data from the Acute Infarction Ramipril Efficacy Study (AIRE Study). The major cost identified for the ramipril treatment strategy was the cost of the drug, which was offset by a reduction in cost from lower hospitalisation rates. These treatment costs were estimated from the prescription of ramipril and the hospitalisation rates in the AIRE Study and secondary sources. Cost-effectiveness, in terms of costs required for each life-year gained, was calculated over three treatment periods (1, 2, and 3.8 years). Future costs and effectiveness were discounted at 6% per year. The cost-effectiveness from treatment with ramipril for heart failure after acute myocardial infarction ranged from £148 to £426 per life-year gained, depending on the duration of treatment. Ramipril treatment offers a substantial survival benefit to patients. Its cost-effectiveness compares favourably with that of chronic heart failure treatment and other common medical therapies.
The role of thrombolysis in the acute phase of myocardial infarction (AMI) has been definitely established in terms of mortality and ventricular function, as has the equivalence of different thrombolytic agents. The Second Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) trial showed that a large number of patients have either clinical heart failure or severe left ventricular damage on discharge from the hospital, with a large risk of death and poor prospects in terms of quality of life. Additional measures to limit ventricular damage are therefore essential to reducing morbidity. The GISSI-3 study protocol on the effects of lisinopril and nitrates, used atone or in combination, in patients with AMI is described in detail.
Background.
Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently. We studied the effect of an angiotensin-converting—enzyme inhibitor, enalapril, on mortality and hospitalizaron in patients with chronic heart failure and ejection fractions ≤0.35.
Methods.
Patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n = 1284) or enalapril (n = 1285) at doses of 2.5 to 20 mg per day in a double-blind trial. Approximately 90 percent of the patients were in New York Heart Association functional classes II and III. The follow-up averaged 41.4 months.
Results.
There were 510 deaths in the placebo group (39.7 percent), as compared with 452 in the enalapril group (35.2 percent) (reduction in risk, 16 percent; 95 percent confidence interval, 5 to 26 percent; P = 0.0036). Although reductions in mortality were observed in several categories of cardiac deaths, the largest reduction occurred among the deaths attributed to progressive heart failure (251 in the placebo group vs. 209 in the enalapril group; reduction in risk, 22 percent; 95 percent confidence interval, 6 to 35 percent). There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure. Fewer patients died or were hospitalized for worsening heart failure (736 in the placebo group and 613 in the enalapril group; risk reduction, 26 percent; 95 percent confidence interval, 18 to 34 percent; P<0.0001).
Conclusions.
The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and low ejection fractions. (N Engl J Med 1991; 325:293–302.)
13 634 patients entering 650 Chinese hospitals up to 36 h after the onset of suspected acute myocardial infarction (Ml) were randomised between one month of oral captopril (6·25 mg initial dose, 12·5 mg 2 h later, and then 12·5 mg three times daily) or matching placebo. Captopril was associated with a non-significant reduction in 4-week mortality (617 [9·05%] captopril-allocated vs 654 [9·59%] placebo-allocated deaths; 2p=0·3). There was a significant excess of hypotension, mostly early after the start of treatment, but no evidence of any adverse effect on early mortality (even among patients who were hypotensive at entry). Taken together with the other trials of converting enzyme inhibitors started early in acute Ml, these results indicate that such therapy is generally safe and typically prevents about 5 deaths per 1000 patients treated for the first month.
To evaluate the influence of the angiotensin-converting-enzyme inhibitor enalapril (2.5 to 40 mg per day) on the prognosis of severe congestive heart failure (New York Heart Association [NYHA] functional class IV), we randomly assigned 253 patients in a double-blind study to receive either placebo (n = 126) or enalapril (n = 127). Conventional treatment for heart failure, including the use of other vasodilators, was continued in both groups. Follow-up averaged 188 days (range, 1 day to 20 months). The crude mortality at the end of six months (primary end point) was 26 percent in the enalapril group and 44 percent in the placebo group - a reduction of 40 percent (P = 0.002). Mortality was reduced by 31 percent at one year (P = 0.001). By the end of the study, there had been 68 deaths in the placebo group and 50 in the enalapril group - a reduction of 27 percent (P = 0.003). The entire reduction in total mortality was found to be among patients with progressive heart failure (a reduction of 50 percent), whereas no difference was seen in the incidence of sudden cardiac death. A significant improvement in NYHA classification was observed in the enalapril group, together with a reduction in heart size and a reduced requirement for other medication for heart failure. The overall withdrawal rate was similar in both groups, but hypotension requiring withdrawal occurred in seven patients in the enalapril group and in no patients in the placebo group. After the initial dose of enalapril was reduced to 2.5 mg daily in high-risk patients, this side effect was less frequent. We conclude that the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms. The beneficial effect on mortality is due to a reduction in death from the progression of heart failure.
The rationale. design, organization, and outcome definitions of the Acute Infarction Ramipril Efficacy (AIRE) Study are described prospectively. A total of 2,000 patients (1,000 per treatment group) will be recruited to this multicenter, multinational, double-blind, randomized, placebo-controlled study investigating the effect of oral treatment with ramipril (2.5 or 5 mg twice daily) on the total mortality of survivors of an acute myocardial infarction (AMI) with early clinical evidence of heart failure
58,050 patients entering 1086 hospitals up to 24 h (median 8 h) after the onset of suspected acute myocardial infarction (MI) with no clear contraindications to the study treatments (in particular, no cardiogenic shock or persistent severe hypotension) were randomised in a "2 x 2 x 2 factorial" study. The treatment comparisons were: (i) 1 month of oral captopril (6.25 mg initial dose titrated up to 50 mg twice daily) versus matching placebo; (ii) 1 month of oral controlled-release mononitrate (30 mg initial dose titrated up to 60 mg once daily) versus matching placebo; and (iii) 24 h of intravenous magnesium sulphate (8 mmol initial bolus followed by 72 mmol) versus open control. There were no significant "interactions" between the effects of these three treatments, and the results for each are based on the randomised comparison of about 29,000 active versus 29,000 control allocated patients. Captopril There was a significant 7% (SD 3) proportional reduction in 5-week mortality (2088 [7.19%] captopril-allocated deaths vs 2231 [7.69%] placebo; 2p = 0.02), which corresponds to an absolute difference of 4.9 SD 2.2 fewer deaths per 1000 patients treated for 1 month. The absolute benefits appeared to be larger (perhaps about 10 fewer deaths per 1000) in certain higher-risk groups, such as those presenting with a history of previous MI or with heart failure. The survival advantage appeared to be maintained in the longer term (5.4 [SD 2.8] fewer deaths per 1000 at 12 months). Captopril was associated with an increase of 52 (SD 2) patients per 1000 in hypotension considered severe enough to require termination of study treatment, of 5 (SD 2) per 1000 in reported cardiogenic shock, and of 5 (SD 1) per 1000 in some degree of renal dysfunction. It produced no excess of deaths on days 0-1, even among patients with low blood pressure at entry. Mononitrate There was no significant reduction in 5-week mortality, either overall (2129 [7.34%] mononitrate-allocated deaths vs 2190 [7.54%] placebo) or in any subgroup examined (including those receiving short-term non-study intravenous or oral nitrates at entry). Further follow-up did not indicate any later survival advantage. The only significant side-effect of the mononitrate regimen studied was an increase of 15 (SD 2) per 1000 in hypotension. Those allocated active treatment had somewhat fewer deaths on days 0-1, which is reassuring a bout the safety of using nitrates early in acute MI.(ABSTRACT TRUNCATED AT 400 WORDS)
Objectives:
This 6-month follow-up analysis sought to assess whether the early reduction of mortality obtained with a 6-week treatment course of lisinopril or glyceryl trinitrate, or both, in unselected patients with acute myocardial infarction outlasts therapy and is still present after 6 months. The primary outcome of the 6-month follow-up was the combined end point of mortality and severe left ventricular dysfunction.
Background:
The assumption was that the early benefit on remodeling processes may be maintained over a longer period of time, even in the absence of treatment.
Methods:
A total of 19,394 patients with acute myocardial infarction were randomized within 24 h of onset of symptoms to a 6-week treatment course of oral lisinopril or open control and, according to a 2 x 2 factorial design, to glyceryl trinitrate or open control. Randomized treatments were stopped after 6 weeks in the absence of specific indications, and the patients were followed up for 6 months.
Results:
At 6 months, among patients randomized to lisinopril, 18.1% died or developed severe ventricular dysfunction versus 19.3% of those randomized to no lisinopril (2p = 0.03). No difference was found between patients with and without glyceryl trinitrate therapy (18.4% vs. 18.9%, 2p = 0.39).
Conclusions:
Although the systematic administration of glyceryl trinitrate started early and continued for 6 weeks after acute myocardial infarction does not yield evidence of benefit, early treatment with lisinopril appears to improve prognosis. This effect seems to carry over the first 6 months from randomization, even after treatment withdrawal.
Left ventricular dilatation and dysfunction after myocardial infarction are major predictors of death. In experimental and clinical studies, longterm therapy with the angiotensin-converting--enzyme inhibitor captopril attenuated ventricular dilatation and remodeling. We investigated whether captopril could reduce morbidity and mortality in patients with left ventricular dysfunction after a myocardial infarction.
Within 3 to 16 days after myocardial infarction, 2231 patients with ejection fractions of 40 percent or less but without overt heart failure or symptoms of myocardial ischemia were randomly assigned to receive doubleblind treatment with either placebo (1116 patients) or captopril (1115 patients) and were followed for an average of 42 months.
Mortality from all causes was significantly reduced in the captopril group (228 deaths, or 20 percent) as compared with the placebo group (275 deaths, or 25 percent); the reduction in risk was 19 percent (95 percent confidence interval, 3 to 32 percent; P = 0.019). In addition, the incidence of both fatal and nonfatal major cardiovascular events was consistently reduced in the captopril group. The reduction in risk was 21 percent (95 percent confidence interval, 5 to 35 percent; P = 0.014) for death from cardiovascular causes, 37 percent (95 percent confidence interval, 20 to 50 percent; P less than 0.001) for the development of severe heart failure, 22 percent (95 percent confidence interval, 4 to 37 percent; P = 0.019) for congestive heart failure requiring hospitalization, and 25 percent (95 percent confidence interval, 5 to 40 percent; P = 0.015) for recurrent myocardial infarction.
In patients with asymptomatic left ventricular dysfunction after myocardial infarction, long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events. These benefits were observed in patients who received thrombolytic therapy, aspirin, or beta-blockers, as well as those who did not, suggesting that treatment with captopril leads to additional improvement in outcome among selected survivors of myocardial infarction.
Long-term administration of angiotensin-converting--enzyme (ACE) inhibitors has been shown to improve survival in patients with symptomatic left ventricular failure and to attenuate left ventricular dilatation in patients with myocardial infarction. We studied whether mortality could be reduced during the 6 months after an acute myocardial infarction with use of the ACE inhibitor enalapril.
At 103 Scandinavian centers patients with acute myocardial infarctions and blood pressure above 100/60 mm Hg were randomly assigned to treatment with either enalapril or placebo, in addition to conventional therapy. Therapy was initiated with an intravenous infusion of enalapril (enalaprilat) within 24 hours after the onset of chest pain, followed by administration of oral enalapril.
Of the 6090 patients enrolled, 3046 were assigned to placebo and 3044 to enalapril. The life-table mortality rates in the two groups at one and six months were not significantly different (6.3 and 10.2 percent in the placebo group vs. 7.2 and 11.0 percent in the enalapril group, P = 0.26). The relative risk of death in the enalapril group was 1.10 (95 percent confidence interval, 0.93 to 1.29). Death due to progressive heart failure occurred in 104 patients (3.4 percent) in the placebo group and 132 (4.3 percent) in the enalapril group (P = 0.06). Therapy had to be changed because of worsening heart failure in 30 percent of the placebo group and 27 percent of the enalapril group (P less than 0.006). Early hypotension (systolic pressure less than 90 mm Hg or diastolic pressure less than 50 mm Hg) occurred in 12 percent of the enalapril group and 3 percent of the placebo group (P less than 0.001).
Enalapril therapy started within 24 hours of the onset of acute myocardial infarction does not improve survival during the 180 days after infarction.
The rationale, design, organization, and outcome definitions of the Acute Infarction Ramipril Efficacy (AIRE) Study are described prospectively. A total of 2,000 patients (1,000 per treatment group) will be recruited to this multicenter, multinational, double-blind, randomized, placebo-controlled study investigating the effect of oral treatment with ramipril (2.5 or 5 mg twice daily) on the total mortality of survivors of an acute myocardial infarction (AMI) with early clinical evidence of heart failure. Secondary outcomes of the study include progression to severe/resistant heart failure (at which time the patient will be withdrawn from the study treatment), reinfarction, and stroke. Treatment will be initiated in hospital between day 3 and day 10 following AMI, and follow-up continued for an average of 15 months and a minimum of 6 months. The study data will be analyzed on an intention-to-treat basis: a single formal interim analysis will be conducted after 175 deaths. An Independent Adjudicating Panel will act as the overall ethical supervisory body for the study and will retain the randomization code. An International Steering Committee will be responsible for the clinical definitions of the secondary study outcomes, and will regularly review progress of the study. We believe that early treatment with ramipril may reduce the total mortality of patients surviving an AMI with clinical evidence of heart failure.
The AIRE study--a trial involving over 2,000 patients with clinical heart failure after myocardial infarction--assessed different outcomes. The primary outcome was total mortality. The secondary outcome was time to death, or progression to severe/resistant heart failure, reinfarction or stroke. Tertiary analyses included hospitalization and mode of death. To obtain maximum quality in the validation of outcomes and to optimize the quality of the data in the study, an end-points committee reviewed all data following preset definitions prior to code break. All definitions used are reported here. Experience of the validation process demonstrated that there are wide variations in clinical practice and terminology not only among countries but also among individual investigators. Variation in the clinical handling and treatment of patients makes it imperative to validate outcomes centrally on the basis of available facts.
We carried out a systematic overview using individual patient data from the seven randomised trials that have compared a strategy of initial coronary artery bypass graft (CABG) surgery with one of initial medical therapy to assess the effects on mortality in patients with stable coronary heart disease (stable angina not severe enough to necessitate surgery on grounds of symptoms alone, or myocardial infarction). 1324 patients were assigned CABG surgery and 1325 medical management between 1972 and 1984. The proportion of patients in the medical treatment group who had undergone CABG surgery was 25% at 5 years, 33% at 7 years, and 41% at 10 years: 93.7% of patients assigned to the surgery group underwent CABG surgery. The CABG group had significantly lower mortality than the medical treatment group at 5 years (10.2 vs 15.8%; odds ratio 0.61 [95% CI 0.48-0.77], p = 0.0001), 7 years (15.8 vs 21.7%; 0.68 [0.56-0.83], p < 0.001), and 10 years (26.4 vs 30.5%; 0.83 [0.70-0.98]; p = 0.03). The risk reduction was greater in patients with left main artery disease than in those with disease in three vessels or one or two vessels (odds ratios at 5 years 0.32, 0.58, and 0.77, respectively). Although relative risk reductions in subgroups defined by other baseline characteristics were similar, the absolute benefits of CABG surgery were most pronounced in patients in the highest risk categories. This effect was most evident when several prognostically important clinical and angiographic risk factors were integrated to stratify patients by risk levels and the extension of survival at 10 years was examined (change in survival -1.1 [SE 3.1] months in low-risk group, 5.0 [4.2] months in moderate-risk group, and 8.8 [5.4] months in high-risk group; p for trend < 0.003). A strategy of initial CABG surgery is associated with lower mortality than one of medical management with delayed surgery if necessary, especially in high-risk and medium-risk patients with stable coronary heart disease. In low-risk patients, the limited data show a non-significant trend towards greater mortality with CABG.
Left ventricular dilatation and neuroendocrine activation are common after acute anterior myocardial infarction. Long-term treatment with an angiotensin-converting-enzyme (ACE) inhibitor may improve outcome by attenuating these processes. We investigated whether the ACE inhibitor zofenopril, administered for six weeks after anterior myocardial infarction, could improve both short-term and long-term outcome.
A total of 1556 patients were enrolled within 24 hours after the onset of symptoms of acute anterior myocardial infarction, and they were randomly assigned in a double-blind fashion to receive either placebo (784 patients) or zofenopril (772 patients) for six weeks. At this time we assessed the incidence of death or severe congestive heart failure. The patients were reexamined after one year to assess survival.
The incidence of death or severe congestive heart failure at six weeks was significantly reduced in the zofenopril group (55 patients, 7.1 percent), as compared with the placebo group (83 patients, 10.6 percent); the cumulative reduction in the risk of death or severe congestive heart failure was 34 percent (95 percent confidence interval, 8 to 54 percent; P = 0.018). The reduction in risk was 46 percent (95 percent confidence interval, 11 to 71 percent; P = 0.018) for severe congestive heart failure and 25 percent (95 percent confidence interval, -11 to 60 percent; P = 0.19) for death. After one year of observation, the mortality rate was significantly lower in the zofenopril group (10.0 percent) than in the placebo group (14.1 percent); the reduction in risk was 29 percent (95 percent confidence interval, 6 to 51 percent; P = 0.011).
Treatment with zofenopril significantly improved both short-term and long-term outcome when this drug was started within 24 hours after the onset of acute anterior myocardial infarction and continued for six weeks.
The importance of the effects of ACE inhibitors on sudden death, progressive heart failure and recurrent infarction to the reduction in overall mortality in heart failure and after myocardial infarction is disputed.
The AIRE study randomized 2006 patients with clinical or radiological evidence of heart failure within 2-9 days of a myocardial infarction to receive ramipiril 5 mg b.d. or matching placebo. Outcomes were assessed independently by members of an end-points committee blinded to treatment allocation.
Fewer patients developed severe resistant heart failure as their first validated end-point on rampril, despite the greater number of at-risk survivors, compared to placebo (n = 143 vs 178; risk reduction 23%; CI 5 to 39%; P = 0.017). Ramipril did not alter the rate of reinfarction or stroke. Irrespective of treatment allocation 182 (46%) patients developed resistant heart failure prior to death. A validated acute or remote myocardial reinfarction occurred in 76 (19%) patients prior to death and chest pain occurred in 90 (23%) patients around the time of death suggesting an ischaemic element to these deaths Eighty deaths occurred on the index admission, 167 during re-admission and 145 out-of-hospital. Sudden death accounted for 54% of all deaths and 93% of out-of-hospital deaths. Ramipril reduced the risk of sudden death by 30% (95% CI: 8-47%; P = 0.011). However, overall, 45% of those patients who died suddenly had severe or worsening heart failure prior to their death. Only 39% of sudden deaths were considered to be due to arrhythmias. Ramipril reduced the risk of death from circulatory failure by 18%, but this did not reach statistical significance (95% CI; 41 to -14%; P = 0.237). The magnitude of the effects on sudden death and death due to circulatory failure were not significantly different. However, 38% of the reduction in overall mortality was from the subgroup with sudden death who had developed prior severe resistant heart failure (placebo n = 35, ramipril n = 15), again emphasizing the marked benefit in preventing failure. Ramipril did not selectively alter the proportion of in- to out-of-hospital deaths.
Ramipril reduces mortality and progression to resistant heart failure among patients with evidence of heart failure early after myocardial infarction. Retarding the progression of heart failure appears to be a major factor contributing to the reduction in mortality both by reducing circulatory failure and by reducing sudden death.
The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction
- Ambrosioni
ACE inhibitors post-MI: the case for early, non-selective treatment
- Latini
Evaluation of angiotensin-converting enzyme inhibitor dosage and prescription rates in post-myocardial infarction patient
- Sapsford