Clinical Evidence Of Heart Failure Research Articles

An integrated approach to diagnosis and therapeutic management of patients with systolic heart failure in the Copenhagen metropolitan area

Background Studies on the effect of heart failure clinics have been encouraging and convincing with respect to reduced hospitalizations, improved quality of life, and reduced cost. However, previous results have been derived from patient populations either recently discharged and with specific exclusion criteria or from heart transplant lists. We here report the establishment of a heart failure clinic that offers an integrated approach to both diagnosing and managing heart failure patients, the baseline characteristics of the first 283 patients treated, and the impact on heart failure hospitalizations during establishment. Methods Since September 1, 1999, a heart failure clinic has been in operation at Frederiksberg University Hospital. The clinic was designed with both a diagnostic and a therapeutic unit. The diagnostic unit offers open access to all patients with suspected heart failure, either through referral from general practitioners or from the medical departments of the hospital. In the case of confirmed systolic heart failure, the patient is referred to the therapeutic unit for (1) uptitration and optimization of medical therapy and thorough information and education. In addition, the unit offers a rapid access track and the possibility of intravenous diuretic treatment. Results During the 21 months of operation, a total of 460 patients were referred to the clinic. Of these, 320 (70%) were found to have clinical evidence of heart failure, and 283 (88% of the patients with heart failure) had left ventricular systolic dysfunction (defined by an ejection fraction of ≤45%). These patients were seen in the clinic for education, control of fluid retention, and uptitration of medications. These patients with left ventricular dysfunction were predominantly elderly (aged 72.7 ± 10.7 y) and most often male (73%). Ischemic heart disease was the most common etiology (55%). Before referral, most patients with left ventricular dysfunction had been treated with none or only low-dose angiotensin-converting enzyme inhibitor (55%), and fewer than one third received β-blockers (29%). During the first year of operation of the clinic, there was a 23% decline of heart failure-related hospital admissions to the department of cardiology (from 396 to 306). Conclusion Patients with systolic heart failure are not always optimally treated. The establishment of a heart failure clinic, which offers the combination of diagnosing and managing congestive heart failure, appears to be efficient both in terms of therapy optimization and with respect to a concomitant decline in hospitalization for heart failure. (Am Heart J 2002;144:e2.)

Effect of oral administration of testosterone on brachial arterial vasoreactivity in men with coronary artery disease

H igh androgen levels in men have been regarded as a risk factor for coronary artery disease (CAD). However, it has recently been demonstrated that supplements of androgens inhibit atheroma formation in castrated male animals, suggesting that testosterone may be antiatherosclerotic. In men with angina pectoris, a significant inverse correlation was found between plasma testosterone levels and the extent of CAD, demonstrating that low testosterone levels could be a risk factor for CAD. Other reports suggest that testosterone replacement therapy in men with CAD has a beneficial effect on angina pectoris and exercise-induced ST-segment depression. Another study showed that testosterone enhanced endotheliumindependent coronary artery dilation and flow-mediated brachial arterial vasoreactivity in men with CAD. In this study, we assessed the effects of oral testosterone administration on brachial arterial vasoreactivity in men with CAD. • • • Thirty-five men (aged 58 8 years) with CAD were randomized to placebo (n 17) or treatment group (n 18). Demographics of the study group are summarized in Table 1. Diagnostic criteria of CAD are a history of unstable and stable angina pectoris with angiographic evidence ( 50% stenosis of lumen diameter). Exclusion criteria were inflammatory disease or malignancy, ejection fraction 45%, clinical evidence of heart failure, and Q-wave myocardial infarction within 3 months before the study. The treatment group completed oral administration of 160 mg of testosterone undecanoate (Andriol, N.V. Organon, Oss, The Netherlands) daily for 4 weeks followed by 80 mg testosterone undecanoate for 8 weeks, in addition to their current medication. Using high-resolution ultrasound, we assessed brachial arterial vasoreactivity to reactive hyperemia (flow-mediated dilation) and sublingual nitroglycerin (nitroglycerin-mediated dilation) at baseline and after 12 weeks of treatment. Patients taking nitrates discontinued therapy 24 hours before the study to avoid nitrate tolerance. A 10-MHz linear phased-array ultrasound transducer (GE Vigmed Ultrasound, Horten, Norway) was used to image the dominant arm brachial artery longitudinally 3 to 5 cm just above the antecubital fossa. All patients rested in the supine position for 10 minutes in a quiet room. After the depth and gain setting were optimized to identify the vessel wall, the brachial artery diameter was measured from the anterior to the posterior interface between the media and the adventitia and determined at end-diastole on B mode. Reactive hyperemia was induced by inflation and then deflation of a pneumatic cuff placed around the upper arm. The blood pressure cuff was inflated to 250 mm Hg for 5 minutes. After release of the cuff, brachial artery diameter was measured within the first 15 seconds of reactive hyperemia. The brachial artery was allowed to return to the baseline level until 10 minutes after cuff release. Then, a further baseline brachial artery diameter was obtained. Nitroglycerin, 0.6 mg, was then given sublingually, and the brachial artery diameter was measured for the ensuing 3 minutes. The percent change in diameter caused by reactive hyperemia was calculated by dividing the difference from baseline end-diastolic diameter by the baseline value. The percent change in diameter caused by nitroglycerin administration was also calculated in the same way. Blood pressure and heart rate were measured before the examination. All data were calculated as an average of 4 consecutive cardiac cycles. Early morning blood sampling for fasting lipid profiles was performed and plasma-free testosterone levels were obtained immediately before ultrasound imaging and 12 weeks later. A standard radioimmunoassay method was used for analysis (DSL-4900 kit, Diagnostic System Laboratory Inc., Houston, Texas). All descriptive data are presented as mean SD and analyzed using SPSS for Windows 9.0 (SPSS Inc., Chicago, Illinois) From the Cardiology Division, Yonsei Cardiovascular Center and Cardiovascular Research Institute, College of Medicine, Seoul; and Department of Food and Nutrition, College of Ecology, Yonsei University, Seoul, South Korea. Dr. Jang’s address is: Cardiology Division, Yonsei Cardiovascular Center, Yonsei University College of Medicine, 134, Shinchon-Dong, Seodaemun-Gu, Seoul 120-752, South Korea. E-mail: jangys1212@yumc.yonsei.ac.kr. Manuscript received August 10, 2001; revised manuscript received and accepted December 10, 2001. TABLE 1 Clinical Characteristics of Study Group

Left ventricular diastolic function predicts outcome in uncomplicated hypertension

Whereas left ventricular systolic function has been shown to predict outcome in hypertensive patients without clinical evidence of heart failure, the prognostic power of diastolic function has not been examined. We assessed the relation of mean pulmonary capillary wedge pressure as an index of left ventricular diastolic function to mortality and the incidence of cardiovascular events in patients with uncomplicated hypertension at baseline. Invasive hemodynamic measurements were performed in the period 1972 to 1982 in 172 hypertensive patients without evidence of cardiovascular disease, cardiomegaly or heart failure, and their outcome was ascertained in 1994. Age at baseline averaged 37 ± 12 years, brachial artery pressure was 162 ± 30/88 ± 18 mm Hg, and mean pulmonary wedge pressure 6.3 ± 3.0 mm Hg. During 2675 patient-years of follow-up, 15 patients died and 34 suffered at least one fatal or nonfatal cardiovascular event. Cox regression analysis showed that pulmonary wedge pressure was a significant predictor of total mortality and of cardiovascular events, after control for age and gender ( P < .05). Each 1 mm Hg increase in wedge pressure was associated with a 23% increase in the risk of all-cause mortality and a 13% increase in the risk of a cardiovascular event. The prognostic power was independent of mean brachial artery pressure, body mass index, serum cholesterol, electrocardiographic left ventricular hypertrophy, and smoking at baseline. We conclude that mean pulmonary wedge pressure, which is likely to reflect left ventricular diastolic function in the selected patients of the current study, is a significant and independent predictor of mortality and of cardiovascular events in uncomplicated hypertension.

Left ventricular systolic dysfunction in 75-year-old men and women; a population-based study.

To determine the prevalence of left ventricular systolic dysfunction in 75-year-old men and women. In a population-based random sample of 75-year-old subjects (n=433; response rate 70.1%) the left ventricular systolic function was determined using two echocardiographic methods: (1) wall motion in nine left ventricular segments was visually scored and wall motion index was calculated as the mean value of the nine segments and (2) ejection fraction as measured by the disc summation method. Presence of heart failure was determined by a cardiologist's clinical evaluation. Wall motion index was achievable in 95% of the participants while ejection fraction was measurable in 65%. Normal values were obtained from a healthy subgroup (n=108) and left ventricular systolic dysfunction was defined as the 0.5th percentile of the wall motion index (i.e. <1.7). In participants in whom both ejection fraction and wall motion index were achievable, wall motion index <1.7 predicted ejection fraction <43% with a sensitivity and specificity of 84.0% and 99.6%, respectively. The prevalence of left ventricular systolic dysfunction was 6.8% (95% CI, 5.6--8.0%) and was greater in men than in women (10.2% vs 3.4%, P=0.006). Clinical evidence of heart failure was absent in 46% of the participants with left ventricular systolic dysfunction. Left ventricular systolic dysfunction is common among 75-year-olds with a prevalence of 6.8% in our estimate. The condition is more likely to affect men than women. In nearly half of 75-year-olds with left ventricular systolic dysfunction there is no clinical evidence of heart failure.

Diagnostic potential of cardiac natriuretic peptides in dialysis patients

In the general population, the plasma concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are useful to predict left ventricular hypertrophy (LVH) and LV systolic dysfunction. Whether these cardiac hormones have a similar diagnostic potential in dialysis patients is unknown. We studied the diagnostic value of ANP and BNP for alterations in LV mass and function in a cohort of 246 dialysis patients without clinical evidence of heart failure. Both ANP and BNP were independently related to left ventricular mass (P < 0.0001) as well as to ejection fraction (P < 0.0001). In an analysis based on a prospectively defined threshold (95th percentile of the normal range), BNP had a significantly higher (P < 0.01) sensitivity (88%) than ANP (51%) for the diagnosis of LVH, but the positive predictive value of the two peptides was very similar (92 and 87%, respectively, P = NS). However, the negative predictive value of BNP for excluding LVH was 22% higher than that of ANP (53 vs. 31%, P = 0.05). Both natriuretic peptides had a high sensitivity for the detection of LV dysfunction (87 and 94%), but their positive predictive value was low (25 and 15%). Importantly, both ANP and BNP proved to be very useful for excluding this alteration (negative predictive value 97 and 96%, respectively). An analysis based on the "best cut-offs" of each peptide as identified on the basis of the ROC curves augmented the positive and negative prediction values of BNP for the diagnosis of LVH to 95 and 61%, respectively. This approach also raised the BNP-positive prediction value for the identification of LV dysfunction to 31% but did not modify the diagnostic potential of ANP (either for LVH or for LV dysfunction). Measuring the plasma concentration of cardiac natriuretic hormones, particularly BNP, may be useful for the identification of dialysis patients with LVH or for excluding systolic dysfunction.

ACE inhibitors in heart failure: an update.

Angiotensin-converting enzyme (ACE) inhibitors are now accepted as part of the routine management of patients with heart failure. Their use has been mandated in all the new major mortality trials to test the efficacy of beta-blockers in heart failure. Morbidity and mortality remain high in those with heart failure even with the benefits proven for both these groups of agents. In spite of the evidence for benefit of ACE inhibitors they are persistently used in lower doses in clinical practice than tested in the large-scale trials. This was so prevalent as to allow the conduct of a substantial study, the ATLAS trial, to compare high and low dose ACE inhibition. Its equivocal findings have allowed different interpretations. Clinical experience would suggest that starting with a low dose is appropriate but the dose should be titrated then without undue delay to the levels used in the trials wherever possible. The evidence for benefit with these drugs had been obtained largely in patients with impaired systolic function. However the AIRE study selected patients with clinical evidence of heart failure after myocardial infarction rather than with impaired systolic function. A substantial and long-term benefit was found from ACE inhibition. A cohort of patients had ventricular function assessed and as anticipated almost one half had preserved systolic function. Whilst the absolute benefit in lives saved was greater in the higher risk/low ejection fraction group, the relative risk reduction was not significantly different between those with preserved or impaired systolic function. The publication of the HOPE trial, although not a study of patients with heart failure, has clarified the situation considerably for those taking day to day care of patients. The HOPE study selected patients on the basis of high cardiovascular risk excluding those with known impaired systolic function. Although not an entry requirement for the study, ejection fraction was measured in a substantial majority and was above 40% indicating preservation of systolic function. The ACE inhibitor ramipril markedly reduced the combined end-point of cardiovascular death, stroke and myocardial infarction. Importantly there was a highly significant 20% risk reduction in the rate of myocardial infarction, a prospectively defined end-point, over the average four and a half year follow-up. Taken together with the retrospectively derived evidence from the heart failure trials there is now compelling evidence that the ACE inhibitors prevent myocardial infarction. The majority of patients with clinical heart failure have underlying ischaemic heart disease. Prevention of myocardial infarction and control of blood pressure are two key factors in the management of these patients irrespective of systolic ventricular function. The ACE inhibitors like the beta-blockers therefore have a pivotal role in their management. A challenge to current clinical trials is to determine whether these properties are shared to the same degree by the angiotensin antagonists or if even further gains in benefit can come from their combination. The neutral findings of the ELITE II study comparing the angiotensin antagonist, losartan, with the ACE inhibitor, captopril, have heightened interest in the on-going trials addressing these issues.

Renin Angiotensin System Antagonists and Anesthesia

R enin angiotensin system (RAS) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists are increasingly used to treat cardiovascular and other diseases (1–6). These treatments induce a blockade of the RAS that may affect hemodynamics during anesthesia and surgery. In 1978, Miller et al. (7) reported that the RAS is involved in maintaining normal blood pressure during anesthesia. Although anesthesia is not invariably associated with a deleterious hemodynamic event in RAS-blocked patients (8–10), hemodynamic instability, described as unexpected episodes of hypotension, have been reported (11–13). Otherwise, stresses such as surgery or hypotension stimulate the generation of angiotensin II, which induces vasoconstriction (14) to maintain blood pressure but reduces blood flow to organs such as the kidneys and bowels. Accordingly, an angiotensin II-induced reduction in blood flow may contribute to acute renal failure (15) and splanchnic ischemia (16), which are obvious factors in postoperative morbidity (17). RAS blockade with ACE inhibitors decreases some consequences of the stress response on the regional circulation (9,18,19), which may then contribute to body protection. Much of the information regarding the physiology and pathophysiology of the RAS during anesthesia and surgery is based on the effects of ACE inhibitors. Because ACE inhibitors probably act mostly by blocking the RAS, similar effects should be obtained from angiotensin (AT) receptor antagonists. RAS antagonist pharmacology may help us to understand the hemodynamic risk of anesthesia in RAS-blocked patients, to identify predisposing factors, and to determine the potential benefit of RAS antagonists during anesthesia and surgery. Physiology of the RAS Generation of Angiotensin II

QT dispersion as a predictor of long-term mortality in patients with acute myocardial infarction and clinical evidence of heart failure.

QT interval dispersion is a marker of inhomogeneous ventricular repolarization, and therefore has the potential to predict re-entry arrhythmias. Following acute myocardial infarction, increased QT dispersion has been associated with a higher risk of ventricular arrhythmias. However, whether or not QT dispersion predicts prognosis post-acute myocardial infarction is not clear. We addressed this issue by analysing the AIREX study registry. AIREX was a follow-up study of 603 post-acute myocardial infarction patients who exhibited clinical signs of heart failure and were randomly allocated to ramipril or placebo. An interpretable 12-lead ECG obtained between day 0 and day 9 after the index infarction (median time 2 days) was available in 501 patients. We examined whether QT dispersion was a predictor of all-cause mortality in the AIREX study registry (mean follow-up 6 years). QT dispersion measurements were significantly increased in patients who subsequently died (QT dispersion: 92.0 +/- 38.5 ms vs 82.7 +/- 34.3 ins. P=0.005; rate corrected QT dispersion: 105.7 +/- 42.7 ms vs 93.1 +/- 35.9 ms, P<0.001). Univariate analysis showed that QT dispersion as a predictor of all-cause mortality risk (QT dispersion: hazard ratio per l0 ms 1.05, [95% CI 1.02 to 1.09]. P= 0.004; rate corrected QT dispersion: 1-07 [1.03 to 1.10], P<0.001): an increase of 10 ms added a 5-7%, relative risk of death. QT dispersion remained an independent predictor of all-cause mortality risk on multivariate analysis (QT dispersion: 1.05 [1.01 to 1.09], P=0.027; rate corrected QT dispersion: 1.05 [1.01 to 1.09]. P=0.022). QT dispersion. measured from Li routine 12-lead ECG following acute myocardial infarction complicated by heart failure provides independent information regarding the probability of long-term survival. However. the low sensitivity of this electrocardiographic marker limits its usefulness for risk stratification if used in isolation.

β Blocker treatment and other prognostic variables in patients with clinical evidence of heart failure after acute myocardial infarction: evidence from the AIRE study

ObjectivesTo examine clinical outcomes associated with optional β blockade in a population of patients with evidence of heart failure after myocardial infarction.Design and patientsData from the acute infarction ramipril efficacy...

Intravenous Propafenone for Converting Recent onset Atrial Fibrillation in Emergency Departments: A Randomized Placebo-Controlled Multicenter Trial

Atrial fibrillation (AF) is one of the most frequent dysrhythmias in patients coming to emergency departments (EDs), and pharmacological treatment is frequently performed. The aim of this randomized placebo-controlled multicenter trial was to compare propafenone (a class 1C antidysrhythmic agent), administered i.v. in the ED, with placebo in the treatment of recent-onset AF (<72 h). We randomly allocated 156 patients (88 males; 68 females) from 18 to 80 years old, with recent-onset AF, to receive i.v. propafenone (2 mg/kg for 10 min) or the matching placebo. The patients were followed for 2 h. Exclusion criteria were the presence of one of the following: lack of informed consent, clinical evidence of heart failure, clinical hyperthyroidism, recent acute myocardial infarction, atrioventricular block, cardiac valve dysfunction, a history of bronchial asthma, and current treatment with antidysrhythmic agents including digitalis. The two groups did not differ significantly in terms of sex, age, body weight, or estimated time elapsed since the beginning of atrial fibrillation. Conversion to sinus rhythm occurred in 13 of the 75 patients who received the placebo (17.3%) and in 57 of the 81 patients who were given propafenone (70.3%). In conclusion, intravenous propafenone administration in the ED can be considered a safe and effective approach for converting AF to sinus rhythm.

Beta-blocker therapy in patients with clinical evidence of heart failure after acute myocardial infarction

Beta-blocker therapy in patients with clinical evidence of heart failure after acute myocardial infarction

Investigating heart failure in elderly people: does everyone need an echocardiogram?

Objective: to establish whether an echocardiogram is always necessary when investigating heart failure (HF) in elderly patients. Method: a clinical assessment was compared with echocardiography in 51 elderly patients aged S75 years complaining of breathlessness of more than 1 month's duration. Results: the greater the number of clinical features of HF present, the more likely was echocardiography to reveal a potential cause. It revealed a potential cause of HF in all 16 patients with strong clinical evidence (four or more features present). Of the 20 patients in whom clinical evidence of HF was equivocal (two or three features present), the echocardiogram revealed a potential cause of HF in nine and so was valuable in directing the diagnosis towards or away from HF. In only two of the 15 patients with minimal clinical evidence of HF (one feature or less) did the echocardiogram reveal a potential cause of HF. Severe valvular lesions were common, occurring in 20 (39%) patients. These were difficult to identify clinically as clinical features were non-specific and murmurs were not always present. Conclusions: echocardiography is most useful in those elderly patients in whom the clinical diagnosis of HF is uncertain or for whom valvular surgery might be considered.

Nitric oxide and cardiac failure.

Cardiac myocytes express two types of nitric oxide (NO) synthase, eNOS and iNOS. eNOS activity is regulated by the contractile state of the heart, while iNOS expression is induced by cytokines. Nitric oxide induced by cytokines causes negative inotropic and lethal effects on cardiac myocytes. Expression of iNOS in the myocardium is increased in patients with dilated cardiomyopathy with clinical evidence of heart failure. Several neurohumoral factors activated in chronic heart failure augment cardiac iNOS expression and could cause cardiac dysfunction and cell damage.

Patients With Mild Heart Failure Worsen During Withdrawal From Digoxin Therapy

Objectives. We investigated whether patients with mild heart failure due to left ventricular systolic dysfunction were at risk of worsening during digoxin withdrawal.Background. Deterioration during digoxin withdrawal is often believed to be restricted to patients with moderate to severe clinical evidence of heart failure. To test this hypothesis, we studied the outcome of patients categorized by treatment assignment and a clinical signs and symptoms heart failure score in two rigorously designed clinical heart failure trials: the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and the Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE) trial.Methods. Potential differences in treatment failure, left ventricular ejection fraction and exercise capacity were evaluated in three groups of patients: those with mild heart failure (score ≤2) who were withdrawn from digoxin (Dig WD Mild); those with moderate heart failure (score >2) who were withdrawn from digoxin (Dig WD Moderate); and patients who continued receiving digoxin regardless of heart failure score (Dig Cont).Results. Heart failure score at randomization did not predict outcome during follow-up in Dig Cont-group patients. Dig WD Mild-group patients were at increased risk of treatment failure and had deterioration of exercise capacity and left ventricular ejection fraction compared with that in Dig Cont-group patients (all p < 0.01). Patients in the Dig WD Moderate group were significantly more likely to experience treatment failure than patients in either the Dig WD Mild or Dig Cont group (both p < 0.05).Conclusions. Patients with systolic left ventricular dysfunction were at risk of clinical deterioration after digoxin withdrawal despite mild clinical evidence of congestive heart failure.(J Am Coll Cardiol 1997;30:42–8)

Effect of ramipril on morbidity and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure

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.

Angiotensin-converting enzyme inhibitors after myocardial infarction: Indications and timing

A number of major studies have examined the impact of angiotensin-converting enzyme inhibitors on mortality in patients with ischemic heart disease. However, in these studies, selection of patients, choice of agent and timing of treatment after myocardial infarction have differed. In the Second Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS II), all patients, unless hypotensive, were treated immediately after thrombolysis with placebo or intravenous enalaprilat followed by oral therapy. In contrast, in the Survival and Ventricular Enlargement (SAVE) study, patients were selected with a reduced radionuclide ejection fraction and without overt ongoing ischemia. Despite these different approaches, both studies were based on the rationale that angiotensin-converting enzyme inhibition would beneficially affect infarct expansion and subsequent remodeling. The SAVE study reported a significant reduction in mortality rate (19% risk reduction, 95% confidence interval [CI] 3% to 32%) over an average follow-up period of 42 months, but with no observable impact on mortality rate until almost 1 year into treatment. The CONSENSUS II trial closed prematurely, with no benefit (a 10% increase in risk, 95% CI 7% reduction to 29% increase) apparent from enalapril after 6 months of follow-up. The recently reported but unpublished findings of Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3) and the Fourth International Study of Infarct Survival (ISIS-4) indicate a small benefit from early (within 24 h) short-term (4 to 6 weeks) treatment of all patients, unless hypotensive, after a myocardial infarction. In contrast, the Acute Infarction Ramipril Efficacy (AIRE) study demonstrated a marked reduction in mortality rate (27% risk reduction, 95% CI 11% to 40%) when the angiotensin-converting enzyme inhibitor ramipril was given to patients manifesting some clinical evidence of heart failure, even if transient, 3 to 10 days after myocardial infarction for an average period of 15 months. Extrapolation from the findings of the AIRE study and from subgroup analyses of GISSI-3 and ISIS-4 indicate that patients manifesting clinical evidence of heart failure after myocardial infarction derive most of the benefit to be gained from the use of angiotensin-converting enzyme inhibitors. Appropriate selection of patients and careful timing of treatment after myocardial infarction to allow patients to achieve clinical stability will maximize potential benefit against potential harm from these effective agents.

Angiotensin-converting enzyme inhibitors after myocardial infarction: Indications and timing

A number of major studies have examined the impact of angiotensin-converting enzyme inhibitors on mortality in patients with ischemic heart disease. However, in these studies, selection of patients, choice of agent and timing of treatment after myocardial infarction have differed. In the Second Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS II), all patients, unless hypotensive, were treated immediately after thrombolysis with placebo or intravenous enalaprilat followed by oral therapy. In contrast, in the Survival and Ventricular Enlargement (SAVE) study, patients were selected with a reduced radionuclide ejection fraction and without overt ongoing ischemia. Despite these different approaches, both studies were based on the rationale that angiotensin-converting enzyme inhibition would beneficially affect infarct expansion and subsequent remodeling. The SAVE study reported a significant reduction in mortality rate (19% risk reduction, 95% confidence interval [CI] 3% to 32%) over an average follow-up period of 42 months, but with no observable impact on mortality rate until almost 1 year into treatment. The CONSENSUS II trial closed prematurely, with no benefit (a 10% increase in risk, 95% CI 7% reduction to 29% increase) apparent from enalapril after 6 months of follow-up. The recently reported but unpublished findings of Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3) and the Fourth International Study of Infarct Survival (ISIS-4) indicate a small benefit from early (within 24 h) short-term (4 to 6 weeks) treatment of all patients, unless hypotensive, after a myocardial infarction. In contrast, the Acute Infarction Ramipril Efficacy (AIRE) study demonstrated a marked reduction in mortality rate (27% risk reduction, 95% CI 11% to 40%) when the angiotensin-converting enzyme inhibitor ramipril was given to patients manifesting some clinical evidence of heart failure, even if transient, 3 to 10 days after myocardial infarction for an average period of 15 months. Extrapolation from the findings of the AIRE study and from subgroup analyses of GISSI-3 and ISIS-4 indicate that patients manifesting clinical evidence of heart failure after myocardial infarction derive most of the benefit to be gained from the use of angiotensin-converting enzyme inhibitors. Appropriate selection of patients and careful timing of treatment after myocardial infarction to allow patients to achieve clinical stability will maximize potential benefit against potential harm from these effective agents.

Indications for immediate angiotensin-converting enzyme inhibition in patients with acute myocardial infarction

When initiated a few days after myocardial infarction, angiotensin-converting enzyme inhibition exerts beneficial effects on survival and morbidity in patients with asymptomatic left ventricular systolic dysfunction or symptomatic heart failure. During the acute phase of a myocardial infarction, angiotensin-converting enzyme inhibition appears to be well tolerated, to prevent the development of heart failure in patients with asymptomatic left ventricular systolic dysfunction and to improve the hemodynamic and clinical variables of heart failure when present. Accordingly, early angiotensin-converting enzyme inhibition is clearly indicated in patients with acute myocardial infarction associated with asymptomatic left ventricular dysfunction or clinical evidence of heart failure. Angiotensin-converting enzyme inhibition may also be beneficial when thrombolytic agents fail to restore coronary patency in patients with acute myocardial infarction.

Ramipril. An updated review of its therapeutic use in essential hypertension and heart failure.

Ramipril is a second generation angiotensin converting enzyme (ACE) inhibitor. Like enalapril, it is a prodrug and is hydrolysed in vivo to release the active metabolite, ramiprilat, which has a long elimination half-life, permitting once-daily administration. The antihypertensive efficacy of ramipril has been confirmed in large-scale noncomparative studies conducted in general practice as well as in more rigorously controlled clinical trials. In the former, approximately 85% of patients with mild to moderate essential hypertension have responded successfully to treatment with ramipril 2.5 or 5 mg/day, while comparative trials indicate that the antihypertensive efficacy of the drug is equivalent to that of other established ACE inhibitors and the beta-adrenoceptor antagonist atenolol. As expected, the response rate to ramipril monotherapy is lower in patients with severe hypertension (around 40%), although the blood pressure lowering effect can be enhanced with the addition of a diuretic such as hydrochlorothiazide or piretanide. The antihypertensive efficacy of ramipril is maintained in patients with diabetes mellitus and preliminary data indicate that the drug has the beneficial effect of decreasing urinary albumin excretion in diabetic patients with nephropathy. Ramipril is superior to atenolol in causing regression of left ventricular hypertrophy, although the clinical significance of this effect per se remains to be established. The large-scale Acute Infarction Ramipril Efficacy (AIRE) study demonstrated that ramipril 5 or 10 mg/day significantly decreased the risk of all-cause mortality by 27% in patients with clinical evidence of heart failure after acute myocardial infarction, even if transient. The beneficial effect of ramipril was apparent by 30 days of treatment and appeared to be greatest in patients with more severe ventricular damage after infarction. Ramipril is well tolerated in general practice, with 5% or fewer patients discontinuing therapy because of drug intolerance. The data available suggest that ramipril shares a similar tolerability profile to that of other established ACE inhibitors. Thus, clinical data confirm ramipril as a useful alternative ACE inhibitor for the treatment of patients with mild to moderate hypertension, and indicate a beneficial effect of the drug in patients with clinical evidence of heart failure after acute myocardial infarction. It is also reasonable to assume that ramipril will be of value in the treatment of patients with more established heart failure or asymptomatic left ventricular dysfunction.

Encircling endocardial cryoablation for ventricular tachycardia after myocardial infarction: Experience with 33 patients

Encircling endocardial cryoablation, consisting of circumferential cryoablation of the infarct scar, can be curative in selected patients with ventricular tachycardia (VT). We describe our experience with and long-term outcome in 33 patients undergoing this procedure. The interval between myocardial infarction and the onset of tachycardia varied from 2 weeks to 22 years (mean 38 ± 63 months and median 3 months). All patients had a left ventricular aneurysm (anterior in 20, posterior in 12, and lateral in 1) and significant coronary artery disease. Fourteen patients had clinical evidence of heart failure preoperatively. Twenty-eight patients had sustained monomorphic VT (incessant in 3); 3 had polymorphic or nonsustained tachycardia; 2 had primary ventricular fibrillation; and 1 had associated Wolff-Parkinson-White syndrome. Surgery was undertaken after failed drug therapy and consideration of left ventricular anatomy and function. At surgery, 32 patients had encircling endocardial cryoablation, and 1 patient had partial right ventricular free-wall disconnection (right ventricular infarct). Thirteen patients underwent concomitant coronary artery bypass grafting. An implantable cardioverter defibrillator (ICD) was implanted in 2 patients and prophylactic ICD patches in 1. One patient died postoperatively; 3 had recurrent VT perioperatively; 1 was treated with amiodarone; and 2 had ICD implantation. During long-term follow-up (mean 5 years), all patients who were free of tachycardia at discharge remained alive and free of arrhythmias or syncope. The patient receiving amiodarone sustained a cardiac arrest subsequently and received an ICD implant. One patient with an ICD continued to receive appropriate shocks frequently and died 2 years after surgery. Nine patients had congestive heart failure postoperatively. There were 8 late deaths (caused by arrhythmia in 1, heart failure in 4, and terminal cancer in 3). Two patients had heart transplantation (1 and 6 years after surgery). The 5-year actuarial survival was 77%.