Trandolapril Cardiac Evaluation Research Articles

Efficacy and Safety of Angiotensin-Converting Enzyme Inhibitors in Patients With Left Ventricular Systolic Dysfunction and Hyponatremia

BackgroundThe presence of hyponatremia has been perceived to increase the risk of adverse events on initiation of treatment with angiotensin-converting enzyme inhibition in heart failure patients. The aim of this study was to investigate if baseline hyponatremia (plasma Na+ <135 mmol/L) predicts development of hypotension and renal impairment in patients with myocardial infarction (MI) and left ventricular dysfunction (LVD) treated with angiotensin-converting enzyme inhibitors. Methods and ResultsA retrospective analysis was performed with data from the Trandolapril Cardiac Evaluation (TRACE) a double-blind randomized study. Plasma sodium levels were available in 1,731 patients, who were considered as the study population. Patients 3–7 days after MI with left LVD (LVEF ≤0.35), were randomized to trandolapril (n = 876) or placebo (n = 873). Baseline hyponatremia did not predict development of hypotension or worsening renal function after 1 month in patients treated with trandolapril compared with placebo (122 ± 19.1 mm Hg vs 123.2 ± 20.4 mm Hg [P = .84]; and creatinine clearance 57.4 ± 21.4 mL/min vs 55.2 ± 21.0 mL/min [P = .8]). There was no interaction between hyponatremia and the effect of trandolapril (P = .68). ConclusionsMild hyponatremia was not a contraindication for the initiation of treatment with angiotensin-converting enzyme inhibitors in patients with post-MI heart failure.

Right and left bundle branch block as predictors of long‐term mortality following myocardial infarction

Patients with acute myocardial infarction (MI) with bundle branch block (BBB) have a poor prognosis, but distinction between left (L)- and right (R)-sided BBB is seldom made in epidemiological studies. We studied long-term mortality associated with RBBB and LBBB in the TRAndolapril Cardiac Evaluation (TRACE) study. TRACE screened consecutive patients presenting with an MI and recorded clinical, electro- and echo-cardiographic variables. Subsequently, deaths were recorded during a minimum follow-up of 15 years. In total, 6676 consecutive patients with MI were hospitalized at 27 centres in Denmark. Of these, 533 (8%) had BBB, of whom 260 (4%) had RBBB and 273 (4%) had LBBB. Overall, 5196 (78%) patients died, 256 (94%) with LBBB and 235 (90%) with RBBB compared with 4705 (77%) of those without BBB (P < 0.001). In multivariable analyses, hazard ratios (HRs) of RBBB and LBBB were 1.23 [95% confidence interval (CI), 1.07-1.42] and 1.05 (95% CI, 0.91-1.20), respectively. There was interaction between each type of BBB and left ventricular (LV) systolic function (P = 0.02). Right BBB was associated with a worse prognosis in patients with reduced LV systolic function [HR = 1.31 with wall motion index (WMI) ≤ 1.5 (95% CI, 1.11-1.55] while LBBB had a poor prognosis in patients with preserved LV systolic (HR if WMI > 1.5, 1.70; 95% CI, 1.12-2.57). Right BBB was a predictor of increased mortality in patients with reduced LV systolic function, whereas LBBB was a marker of increased mortality in patients with preserved LV systolic function.

Renal function at the time of a myocardial infarction maintains prognostic value for more than 10 years

BackgroundRenal function is an important predictor of mortality in patients with myocardial infarction (MI), but changes in the impact over time have not been well described.We examined the importance of renal function by estimated GFR (eGFR) and se-creatinine as an independent long-term prognostic factor.MethodsProspective follow-up of 6653 consecutive MI patients screened for entry in the Trandolapril Cardiac Evaluation (TRACE) study. The patients were analysed by Kaplan-Meier survival analysis, landmark analysis and Cox proportional hazard models. Outcome measure was all-cause mortality.ResultsAn eGFR below 60 ml per minute per 1.73 m2, consistent with chronic renal disease, was present in 42% of the patients. We divided the patients into 4 groups according to eGFR. Overall, Cox proportional-hazards models showed that eGFR was a significant prognostic factor in the two groups with the lowest eGFR, hazard ratio 1,72 (confidence interval (CI) 1,56-1,91) in the group with the lowest eGFR. Using the eGFR group with normal renal function as reference, we observed an incremental rise in hazard ratio. We divided the follow-up period in 2-year intervals. Landmark analysis showed that eGFR at the time of screening continued to show prognostic effect until 16 years of follow-up. By multivariable Cox regression analysis, the prognostic effect of eGFR persisted for 12 years and of se-creatinine for 10 years. When comparing the lowest group of eGFR with the group with normal eGFR, prognostic significance was present in the entire period of follow-up with a hazard ratio between 1,97 (CI 1,65-2,35) and 1,35 (CI 0,99-1,84) in the 2-year periods.ConclusionsOne estimate of renal function is a strong and independent long-term prognostic factor for 10-12 years following a MI.

Plasma sodium and mortality risk in patients with myocardial infarction and a low LVEF

Hyponatremia is a known prognostic factor for mortality in patients with heart failure but has not been extensively studied in patients with myocardial infarction (MI). This study was, therefore, designed to evaluate whether plasma sodium and hyponatremia (< 135 mM) are associated with mortality risk in patients with MI. In retrospective analyses using data from the Trandolapril Cardiac Evaluation (TRACE) study--a randomized, double-blind, placebo-controlled trial of trandolapril in 1749 patients with MI and left ventricular ejection fraction (LVEF) ≤ 35%--associations between plasma sodium or hyponatremia and more than 15-year mortality risk were evaluated in multivariate Cox proportional hazard models including traditional clinical confounders before and after additional adjustment for renal function, use of diuretics or both. During the extended follow-up time, 1462 patients died. Both hyponatremia [Hazard ratio: 1·30 (95% CI: 1·13-1·50), P < 0·001] and plasma sodium [Hazard Ratio(pro mM increase in P-Na): 0·98 (95% CI: 0·96-0·99), P = 0·004] were associated with mortality risk, and the adjusted parameter estimates were not affected by additional adjustment for renal function, use of diuretics or both. Hyponatremia and plasma concentrations of sodium are associated with long-term mortality risk in patients with MI complicated by left ventricular systolic dysfunction. Importantly, these associations are independent of renal function and use of diuretics. Whether the associations between plasma sodium or hyponatremia and long-term mortality risk reflect a causation or merely the severity of the underlying cardiac disease remains to be clarified.

Thromboembolism and Antithrombotic Therapy in Patients With Heart Failure in Sinus Rhythm

Heart failure (HF) represents a major and growing public health problem because of its prevalence, incidence, morbidity, mortality, and economic costs. The prevalence of HF is 2% to 3% of the general population.1 Five million Americans are affected, with >550 000 cases diagnosed each year.2 The mortality rate from severe HF remains >60% within 5 years of diagnosis, and 50% of hospitalized patients with HF require readmission within 6 months of discharge. In the US estimated costs amount to > $35 billion per year.3 Although several therapies (eg, β-blockers, angiotensin-converting enzyme [ACE] inhibitors, and cardiac resynchronization therapy) have been proven effective in improving HF outcomes, many unanswered questions about optimal treatment remain. One area of ongoing uncertainty is the appropriate role for antithrombotic therapy in patients with HF. Observational data suggest that patients with HF have an increased venous thromboembolism (VTE) risk (deep venous thromboembolism [DVT], pulmonary embolism [PE], peripheral arterial thromboembolism, and stroke).4 These epidemiological findings are supported by multiple mechanisms that can contribute to a hypercoagulable state in patients with HF. Despite this increased risk of VTE, the role of antithrombotic therapy remains unclear. In this article, we provide an overview of epidemiology, pathophysiology, clinical trial data, and therapeutic recommendations for prevention of thromboembolism in HF. We searched PubMed for articles published between 1958 and 2010 using the following search terms: epidemiology of heart failure , thromboembolism and heart failure , thrombogenesis and heart failure , anticoagulation in heart failure , antiplatelet agent and heart failure , aspirin and heart failure , bleeding risk and anticoagulation , and aspirin and angiotensin-converting enzyme inhibitors . We also studied abstracts from national and international cardiovascular meetings to identify unpublished studies using the key words anticoagulation and dilated cardiomyopathy . Data from published observational studies and secondary …

The vanishing story of angiotensin II receptor blockers in the treatment of atrial fibrillation

This editorial refers to ‘Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II Study)’ by T. Yamashita et al. , on page 473. Pharmacological inhibition of the renin–angiotensin system (RAS) is a safe and beneficial intervention in patients with structural heart disease. Furthermore, there is good experimental evidence that AT-1 receptor blocker (ARB) therapy can prevent atrial structural remodelling in atrial fibrillation (AF).1–4 Experiments have proved that by angiotensin-converting enzyme (ACE) inhibitors and ARBs, the degree of atrial fibrosis and thereby the inducibility of AF can be reduced.2–4 In these settings, ACE inhibitors and ARBs were similarly effective. Of note, antiarrhythmic effects of ACE inhibitors and ARBs to prevent AF are supported by retrospective analyses of clinical trials including TRACE (Trandolapril Cardiac Evaluation), ValHeFT (Valsartan Heart Failure Trial), SOLVD (Studies of Left Ventricular Dysfunction), CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), and LIFE (Losartan Intervention For Endpoint reduction in hypertension).1,5 Given the observation that AF induces atrial fibrosis and contributes to electrophysiological changes, ARBs appear as a reasonable and safe additive antiarrhythmic therapy in AF, which is supported by recent meta-analyses.1,5 Yamashita et al .6 present the important data of J-RHYTHM II (Japanese Rhythm Management Trial II for Atrial …

Diabetes is an independent predictor of survival 17 years after myocardial infarction: follow-up of the TRACE registry

BackgroundIn patients hospitalized for myocardial infarction, there are limited data examining the long-term prognostic effect of diabetes.The aim of this study was to systematically evaluate the development of diabetes as an independent long-term prognostic factor after myocardial infarction.MethodsProspective follow-up of 6676 consecutive MI patients screened for entry in the Trandolapril Cardiac Evaluation (TRACE) study. The patients were analysed by Kaplan-Meier survival analysis, landmark analysis and Cox proportional hazard models and outcome measure was all-cause mortality.ResultsThe mortality in patients with diabetes was 82,7% at 10 years of follow-up and 91,1% at 15 years of follow-up, while patients without diabetes had a mortality of 60,2% at 10 years of follow-up and 72,9% at 15 years of follow-up (p < 0.0001). Landmark analysis continued to show prognostic significance of diabetes throughout the duration of follow-up. Multivariable Cox proportional-hazards model showed that the hazard ratio for death in patients with diabetes overall was 1.47 (95% confidence intervals (CI) 1.35-1.61) and varied between 1.19 (CI 1.04-1.37) and 2.13 (CI 1.33-3.42) in the 2-year periods of follow-up.ConclusionsDiabetes is an important independent long-term prognostic factor after MI and continues to predict mortality even 17 years after index MI.This underscores the importance of aggressive diagnostic and therapeutic approach in diabetes patients with MI.

Mortality in patients with atrial fibrillation: improving or not?

This editorial refers to ‘Mortality in patients with atrial fibrillation has significantly decreased during the last three decades: 35 years of follow-up in 1627 pacemaker patients’ † by S. Asbach et al. on page 391 Atrial fibrillation (AF) is the commonest sustained arrhythmia, with an increasing incidence. 1 With the increasing elderly population, the prevalence of AF is estimated to rise, conferring a significant mortality and morbidity. In the Framingham study, the presence of AF independently increased mortality in men by 1.5-fold and in women by 1.9-fold. 2 Given that the average lifetime risk of developing AF is 25% 3 and the high economic cost associated with AF, 4 it is clear that we are dealing with a condition with major public health implications. The mortality and morbidity associated with AF are probably not homogeneous when taking into consideration related co-morbidities, complications, and treatment strategies. The lowest risk group is probably that with the so-called ‘lone AF’, which is essentially a diagnosis of exclusion, where AF is associated with no obvious pre-disposing factor on thorough clinical history and examination, with a structurally normal heart on echocardiography, normal ECG (except for AF), normal blood tests, and normal chest X-ray. 5 As we recently highlighted, some series even report an increased mortality with lone AF patients. 6 This may reflect how hard we look for associated co-morbidities, and furthermore, as patients get older, new co-morbidities will intervene. 5 At the other extreme, the presence of AF in patients with acute coronary syndromes, 7 congestive cardiac failure, and in the post-operative setting conditions associated with greater risk of adverse events. For example, an analysis from the TRAndolapril Cardiac Evaluation (TRACE) 7 study reported AF to increase total mortality by 33%, with a risk ratio for sudden cardiac death (SCD) of 1.31 (95% CI: 1.07– 1.60; P , 0.009). Furthermore, the adjusted risk ratio of AF for non-SCD was 1.43 (95% CI: 1.21–1.70; P , 0.0001). Similarly, data from the Framingham Heart Study 8 reported that AF associated with the subsequent development of heart failure resulted in an increased mortality [men: hazard ratio (HR) 2.7, 95% CI: 1.9–3.7 and women: HR 3.1, 95% CI: 2.2–4.2]. Clearly, AF in association with heart disease is not a good combination. Perhaps what has attracted much interest in AF is the morbidity and mortality associated with stroke and thrombo-embolism. 9 Overall, AF increases the risk of stroke by up to 5-fold, but this risk is not homogeneous. 9,10 Stroke risk in AF is increased with the presence of associated stroke risk factors such as previous stroke, increasing age, hypertension, diabetes mellitus, and so on—with the risk being cumulative with increasing co-morbidities. 11,12 For example, this risk increases with age, with stroke occurring in 1.5% of the under 60 year olds and rising to 23.5% in the over 80s 11 and is further increased (for example) by concomitant hypertension. Given the improvements in the recognition and management of the co-morbid conditions associated with AF— especially hypertension, heart failure, and coronary artery disease—one would expect an improvement in the clinical outcome and prognosis of this arrhythmia. Is this really the case?

Prevention of cardiovascular events in end-stage renal disease: Results of a randomized trial of fosinopril and implications for future studies

Cardiovascular events (CVEs) are the leading cause of death in chronic hemodialysis patients. Results of trials in non-end-stage renal disease (ESRD) patients cannot be extrapolated to patients with ESRD. It is critical to test cardiovascular therapies in these high-risk patients who are usually excluded from major cardiovascular trials. The study objective was to evaluate the effect of fosinopril on CVEs in patients with ESRD. Eligible patients were randomized to fosinopril 5 mg titrated to 20 mg daily (n=196) or placebo (n=201) plus conventional therapy for 24 months. The primary end point was combined fatal and nonfatal first major CVEs (cardiovascular death, resuscitated death, nonfatal stroke, heart failure, myocardial infarction, or revascularization). No significant benefit for fosinopril was observed in the intent to treat analysis (n=397) after adjusting for independent predictors of CVEs (RR=0.93, 95% confidence interval (CI) 0.68-1.26, P=0.35). The per protocol secondary supportive analysis (n=380) found a trend towards benefit for fosinopril (adjusted RR=0.79 (95% CI 0.59-1.1, P=0.099)). In the patients who were hypertensive at baseline, systolic and diastolic blood pressures were significantly decreased in the fosinopril as compared to the placebo group. After adjustment for risk factors, trends were observed suggesting fosinopril may be associated with a lower risk of CVEs. These trends may have become statistically significant had the sample size been larger, and these findings warrant further study.

Anaemia is an independent predictor of mortality in patients with left ventricular systolic dysfunction following acute myocardial infarction☆

In patients with chronic heart failure (HF), mortality is inversely related to haemoglobin (hgb) concentration. We investigated the prognostic importance of anaemia in patients with acute myocardial infarction (AMI) and left ventricular systolic dysfunction (LVSD) with and without HF. We studied 1731 patients with AMI and left ventricular ejection fraction </=35% from the TRAndolapril Cardiac Evaluation (TRACE) study. Mild anaemia (110 g/L</=hgb<120 g/L in women and 120 g/L</=hgb<130 g/L in men) was present in 264 patients (15%), 114 (7%) had moderate (100 g/L</=hgb<110 g/L in women and 110 g/L</=hgb<120 g/L in men) and 59 (3%) had severe (hgb <100 g/L in women and <110 g/L in men) anaemia. According to the WHO criteria (hgb </=120 g/L in women and <130 g/L in men), 25% had anaemia. Anaemia was associated with increasing age, higher serum creatinine, lower body mass index, history of chronic HF, and worse NYHA class. In multivariable analyses including other prognostic factors only severe anaemia was associated with increased mortality, hazard ratio 1.59 (1.20-2.11). Anaemia was of prognostic importance in patients with HF, but not without HF. In HF patients the hazard ratios were 1.73 (1.26-2.36), 1.20 (0.93-1.56) and 1.05 (0.88-1.25) for severe, moderate and mild anaemia, respectively. Anaemia is an independent predictor of mortality in patients with AMI and LVSD, but prognostic importance of anaemia is confined to the first year following AMI. The increased risk is driven by patients with severe anaemia and HF.

Increased risk of sudden and non-sudden cardiovascular death in patients with atrial fibrillation/flutter following acute myocardial infarction

Atrial fibrillation (AF) is a common complication in patients with acute myocardial infarction and is associated with an increase in the risk of death. The excess mortality associated with AF complicating acute myocardial infarction has not been studied in detail. Observations indicate that AF facilitates induction of ventricular arrhythmias, which may increase the risk of sudden cardiovascular death (SCD). A close examination of the mode of death could potentially provide useful knowledge to guide further investigations and treatments. We analysed the relation between AF/atrial flutter (AFL) and modes of death in 5983 consecutive patients discharged alive after an acute myocardial infarction screened in the TRAndolapril Cardiac Evaluation registry. This cohort of patients with an enzyme-verified acute myocardial infarction was admitted to 27 centres in 1990-92. Survival status was obtained 2 years after screening of the last patient. An independent endpoint committee assessed the modes of death. Left ventricular ejection fraction was determined in all the screened patients and information about presence or absence of AF/AFL was prospectively collected. Sustained or paroxysmal AF/AFL was observed in 1149 patients (19%) during hospitalization. During follow-up, 1659 patients (34%) died: 482 (50%) patients with AF/AFL and 1177 (30%) patients without AF/AFL, P<0.001. SCD occurred in 536, non-SCD occurred in 725, and 398 died of non-cardiovascular causes (includes 142 unclassifiable cases). The adjusted risk ratio of AF/AFL for total mortality was 1.33 (95% CI: 1.19-1.49; P<0.0001) and the risk ratio for SCD was 1.31 (95% CI: 1.07-1.60; P<0.009). The adjusted risk ratio of AF/AFL for non-SCD was 1.43 (95% CI: 1.21-1.70; P<0.0001). The excess mortality observed in patients with AF/AFL following acute myocardial infarction is due to a significant increase in both SCD and non-SCD.

The Long-Term Impact of the Angiotensin-Converting Enzyme Inhibitor Trandolapril on Mortality and Hospital Admissions in Patients With Left Ventricular Dysfunction After a Myocardial Infarction: Follow-up to 12 Years

Aims To investigate the long-term benefits of treatment with angiotensin-converting enzyme (ACE)-inhibitors in patients with myocardial infarction (MI) and left ventricular dysfunction (LVD). Methods and results In the trandolapril cardiac evaluation (TRACE) study, 1749 patients with LVD (ejection fraction � 35%) were randomized to trandolapril (n ¼ 876) or placebo (n ¼ 873) 3–7 days post-MI. Enrolment lasted from 1990 to 1994; on-treatment follow-up ranged from 2 to 4 years. At study closure, all patients were recommended continued ACE-inhibitor use. National registries were used to track deaths and hospitalizations until 2002. Mortality was analysed with Cox proportional hazard models and hospitalization with Poisson regression models (models adjusted for observation time). Over 10–12 years of follow-up, a total of 1283 deaths and 9220 hospitalizations were registered. Compared with the placebo group, the trandolapril group had a significantly reduced risk of all-cause mortality (relative risk 0.89, 95% CI 0.80–0.99, P ¼ 0.03), all-cause hospitalizations (rate ratio 0.92, 95% CI 0.88–0.96, P , 0.001), and cardiovascular hospitalizations (rate ratio 0.95, 95% CI 0.91–1.00, P ¼ 0.047), including congestive heart failure hospitalizations (rate ratio 0.85, 95% CI 0.77–0.93, P , 0.001). Conclusion In patients with LVD, use of trandolapril shortly after an MI for 2–4 years has long-term benefits. The beneficial effect on mortality and hospitalization rates is maintained for at least 10–12 years.

Sudden cardiovascular death following myocardial infarction: The importance of left ventricular systolic dysfunction and congestive heart failure

Background To study the prognostic information of congestive heart failure (CHF) and left ventricular systolic dysfunction regarding sudden and non-sudden cardiovascular death (SCD and non-SCD) in patients with acute myocardial infarction (MI), as this may indicate the potential benefit of implantable defibrillators. Methods Data from consecutive patients with acute MI screened in 1990–92 for the TRAndolapril Cardiac Evaluation (TRACE) study were entered into a registry. A total of 5502 patients were alive 30 days after the MI and were followed for up to 4 years with respect to cause of death. SCD was defined as cardiovascular death within 1 h of onset of symptoms. An echocardiography was performed 1–6 days after the admission and evaluated centrally using the wall motion index (WMI). Results Half of the patients had CHF and 17% of the patients had WMI ≤1.0 (corresponding to an ejection fraction ≤0.30). During follow-up 431 patients died from SCD and 606 from non-SCD. The risk ratios for SCD and non-SCD associated with WMI ≤1.0 were 3.17 and 2.95, transient CHF 2.01 and 1.46, and permanent CHF 3.71 and 4.42, respectively. No risk factor was a specific marker of SCD or non-SCD. The 3-year probability of SCD was 7.9% for patients with transient CHF, 13.3% for permanent CHF, and 15.5% for WMI ≤1.0. Conclusions CHF and low WMI identify a relevant proportion of patients with MI who are at high absolute risk of SCD. This study indicates the relevance of defibrillators in consecutive post-MI patients with left ventricular dysfunction or clinical signs of heart failure.

The long-term impact of the angiotensin-converting enzyme inhibitor trandolapril on mortality and hospital admissions in patients with left ventricular dysfunction after a myocardial infarction: follow-up to 12 years

To investigate the long-term benefits of treatment with angiotensin-converting enzyme (ACE)-inhibitors in patients with myocardial infarction (MI) and left ventricular dysfunction (LVD). In the trandolapril cardiac evaluation (TRACE) study, 1749 patients with LVD (ejection fraction< or =35%) were randomized to trandolapril (n=876) or placebo (n=873) 3-7 days post-MI. Enrolment lasted from 1990 to 1994; on-treatment follow-up ranged from 2 to 4 years. At study closure, all patients were recommended continued ACE-inhibitor use. National registries were used to track deaths and hospitalizations until 2002. Mortality was analysed with Cox proportional hazard models and hospitalization with Poisson regression models (models adjusted for observation time). Over 10-12 years of follow-up, a total of 1283 deaths and 9220 hospitalizations were registered. Compared with the placebo group, the trandolapril group had a significantly reduced risk of all-cause mortality (relative risk 0.89, 95% CI 0.80-0.99, P=0.03), all-cause hospitalizations (rate ratio 0.92, 95% CI 0.88-0.96, P<0.001), and cardiovascular hospitalizations (rate ratio 0.95, 95% CI 0.91-1.00, P=0.047), including congestive heart failure hospitalizations (rate ratio 0.85, 95% CI 0.77-0.93, P<0.001). In patients with LVD, use of trandolapril shortly after an MI for 2-4 years has long-term benefits. The beneficial effect on mortality and hospitalization rates is maintained for at least 10-12 years.

Hyperinsulinaemia is associated with increased long-term mortality following acute myocardial infarction in non-diabetic patients?

To study the impact of disturbances in glucose metabolism on total mortality in non-diabetic patients with acute myocardial infarction. Four hundred and ninety four patients with a verified myocardial infarction and no history of diabetes were studied. The study population comprised a subgroup of patients screened for participation in the Trandolapril Cardiac Evaluation (TRACE) study. At baseline, fasting insulin, fasting glucose, glycosylated haemoglobin (HbA1c), and urinary albumin excretion were measured. Survival status was determined after 6-8 years. Patients with hyperinsulinaemia were more obese and more frequently suffered from hypertension, previous myocardial infarction and congestive heart failure. In a univariate regression analysis, values in the upper quartile of insulin, glucose, HbA1c, and urinary albumin were associated with an excess mortality risk (RR=1.8 (1.2-2.7), p=0.002; RR=1.6 (1.2-2.1), p=0.001; RR= 1.9 (1.3-2.9), p=0.001; RR=1.6 (1.2-2.1), p=0.02 respectively). However, only a high insulin level remained significant in a multivariable analysis (RR=1.54 (1.03-2.31), p=0.04) including baseline variables, left ventricular systolic function and in-hospital complications. High fasting plasma insulin is an independent risk factor of all-cause mortality in non-diabetic patients with acute myocardial infarction. This justifies future intervention studies aiming at reducing insulin resistance and using fasting insulin as the target variable.

Impact of obesity on long-term prognosis following acute myocardial infarction

Objective To evaluate the impact of obesity on mortality in patients with acute myocardial infarction. Methods This study comprises 6676 consecutive patients with acute myocardial infarction screened for entry into the Danish Trandolapril Cardiac Evaluation (TRACE) study. At baseline, body mass index (BMI) and waist to hip ratio (WHR) were measured. Survival status was determined after 8–10 years. Results BMI was used to divide patients into 4 groups: underweight, normal weight, overweight and obese. The normal weight group was used as reference for the other groups. WHR was divided in quartiles and the lowest quartile was used as reference for the three other quartiles. The prevalence of overweight (BMI 25–29.9 kg/m 2) and obesity (BMI>30 kg/m 2) were 48% and 13% in males and 31% and 13% in females. Obese patients were younger, less often smokers and more frequently suffered from diabetes and hypertension. In both men and women, there was no association between obesity assessed as BMI and mortality [men: adjusted RR=0.99 (0.85–1.14, p=0.3); women: adjusted RR=0.90 (0.74–1.10, p=0.2)]. Men with WHR in the upper quartile had an increased mortality [adjusted RR=1.21 (1.07–1.37, p<0.01)]. Increasing WHR in women showed a trend of increased mortality, although this was not significant [adjusted RR=1.13 (0.95–1.34, p=0.2)]. Conclusion In patients with acute myocardial infarction overall obesity as assessed by body mass index is inversely related to mortality. However, abdominal obesity appears to be an independent predictor of all-cause mortality in men and perhaps also in women.

Primary Prevention of Sudden Cardiac Death

The trouble with sudden cardiac death (SCD) is just that—it is sudden and individually unpredictable. Recent data from the Centers for Disease Control showed that SCD accounted for >460 000 deaths, or about 63% of deaths due to cardiac disease, in 1999.1 Typically, a cardiac arrest results from sustained ventricular tachycardia (VT) or ventricular fibrillation that progresses to death if effective resuscitative efforts are not started within several minutes of the arrest.2 It is not surprising that the overall survival rate of patients with out-of-hospital cardiac arrest in the United States is low, estimated to be <5%.3 Although more widespread use of automated external defibrillators could lead to a reduction in SCD,3 it is unrealistic to expect too much from this technology, especially because most cardiac arrests either are unwitnessed or occur in a location without ready access to an automated external defibrillator. The epidemic proportions of SCD have led to decades of research and randomized clinical trials designed to predict which individuals are at risk of SCD and to determine what methods prevent it. See p 1082 Coronary artery disease (CAD) causes ≈70% of SCD,1 and most clinical trials have evaluated this patient population. The emphasis of this Focused Perspective is on antiarrhythmic drug and device trials, but the reader should remember that selective use of β-adrenergic–blockers and angiotensin-converting enzyme inhibitors has reduced SCD.2,4,5 It has been known for decades that patients at highest risk for SCD after myocardial infarction (MI) have substantial left ventricular dysfunction, frequent premature ventricular complexes (PVCs) or nonsustained VT, or both conditions.2 Early efforts to prevent SCD employed the PVC suppression method. The Cardiac Arrhythmia Suppression Trial (CAST) was a randomized, placebo-controlled study that tested the hypothesis that PVC suppression after MI would reduce arrhythmic death.6 …

Trandolapril: A newer angiotensin-converting enzyme inhibitor

Background: Trandolapril is a newer angiontensin-converting enzyme (ACE) inhibitor that is approved by the US Food and Drug Administration for the treatment of hypertension and for use in stable patients who have evidence of left ventricular (LV) systolic dysfunction or symptoms of chronic heart failure within the first 2 days after an acute myocardial infarction (AMI). The fixed-dose combination of trandolapril and verapamil extended release (ER) is approved for the treatment of hypertension only. Objective: The purpose of this article was to review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of trandolapril as monotherapy and in fixed-dose combination with verapamil ER. Methods: Relevant studies were identified through a MEDLINE/PubMed search of the English-language literature published between January 1983 and August 2002 and a review of the bibliographies of identified articles. Results: Trandolapril has a sufficient duration of inhibition of plasma ACE activity to allow once-daily dosing. It is converted by esterases to the active trandolaprilat metabolite, with mean terminal disposition half-lives of <1 and ∼75 hours for the prodrug and metabolite, respectively. In comparative trials in the management of hypertension, trandolapril 1 to 4 mg/d was statistically indistinguishable from or superior to captopril 100 mg/d, enalapril 10 or 20 mg/d, hydrochlorothiazide (HCTZ) 25 mg/d, nifedipine ER 30 or 40 mg/d, nitrendipine 20 mg/d, perindopril 4 mg/d, and verapamil ER 120 to 240 mg/d. In the Trandolapril Cardiac Evaluation, trandolapril also significantly reduced all-cause mortality, cardiovascular mortality, sudden death, and progression to severe chronic heart failure in patients with evidence of LV systolic dysfunction after AMI. In comparative trials in the management of hypertension, the combination of trandolapril 1 or 2 mg/d and verapamil ER 180 mg/d was statistically indistinguishable from or superior to the combinations of atenolol 50 or 100 mg/d plus chlorthalidone 12.5 or 25 mg/d, captopril 50 mg/d plus HCTZ 25 mg/d, lisinopril 20 mg/d plus HCTZ 12.5 mg/d, and metoprolol 100 mg/d plus HCTZ 12.5 mg/d. The most common adverse effects of trandolapril monotherapy in clinical trials of ≤1 year's duration included cough, dizziness, and diarrhea (frequency ≤1.9%). The most common adverse effects of trandolapril/verapamil ER therapy in clinical trials of ≤1 year's duration included first-degree atrioventricular block, bradycardia, constipation, cough, diarrhea, dizziness, fatigue, and dyspnea (frequency ≤4.6%). Based on the literature search, there are no published pharmacoeconomic evaluations of trandolapril alone or combined with verapamil ER in the US health care setting. Conclusions: Based on the literature, trandolapril is a well-tolerated and effective antihypertensive agent, whether used alone or in combination with verapamil ER. These products may be valuable in patients with LV systolic dysfunction after AMI, although the combination product is approved for the management of hypertension only.

Angiotensin II and trials of cardiovascular outcomes

Proven cardiovascular benefit from angiotensin-converting enzyme (ACE) inhibition is a cornerstone of evidence-based medicine. The first study to show dramatic benefits from ACE inhibition was the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS-I), in which a 31% decrease in the rate of death was observed in patients with severe heart failure at the end of 1 year of enalapril treatment (p = 0.001). This result led to large long-term studies—including Survival and Ventricular Enlargement (SAVE), Acute Infarction Ramipril Efficacy (AIRE), Trandolapril Cardiac Evaluation (TRACE), and Study of Left Ventricular Dysfunction (SOLVD)—which verified that ACE inhibition decreases heart failure, myocardial infarction (MI), and mortality, and that striking benefit could be observed within 30 days. Short-term studies of patients in the acute phase of a heart attack verified that ACE inhibition provided rapid benefits. A meta-analysis of short-term (up to 8 weeks) studies of ACE inhibition (including CONSENSUS-II, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico [GISSI]-3, International Study of Infarct Survival [ISIS]-4, and the Chinese Captopril Study [CCS]-1) demonstrated that post-MI risk was reduced by 10% within the first day of treatment. The immediacy of the benefit suggested that ACE inhibition not only improved cardiovascular function in failing hearts but also affected important mechanisms in patients without overt heart failure. Effects on more general mechanisms of heart disease suggested that patients with problems other than hypertension or heart failure might benefit from ACE inhibitors. The Heart Outcomes Prevention Evaluation (HOPE) study investigated the hypothesis that ACE inhibition would confer benefits to patients who were at high risk for cardiovascular events, but who were without left ventricular dysfunction or heart failure. Long-term reductions in MI, stroke, cardiac arrest, and heart failure, as well as improvements in mortality, were observed in this population after treatment with ACE inhibitors. Substudies of the HOPE study revealed that ACE inhibition reduced progression of atherosclerosis and improved myocardial remodeling. Taken together, these studies provide evidence that supports treatment of a broad population of patients at risk for cardiovascular events with ACE inhibitors. The next step is to combine ACE inhibition with other treatments to maximize patient benefit. The Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) will compare the efficacy of an ACE inhibitor (ramipril) with an angiotensin receptor blocker (telmisartan), and determine whether these treatments in combination will further reduce morbidity and mortality from cardiovascular disease.

INTRODUCTION

This issue addresses the use of angiotensin-converting enzyme (ACE) inhibition in acute myocardial infarction (AMI), and particularly the use of zofenopril, which has been validated in the SMILE (Survival of Myocardial Infarction Long-term Evaluation) study, a large, randomized, placebo-controlled trial in patients within 24 h of the onset of an anterior AMI and not eligible for thrombolytic therapy. Dr Ambrosioni summarizes this data and also the comparison of zofenopril tested against lisinopril, the only ACE inhibitor currently licensed for use early in AMI [as a result of the GISSI-3 (Gruppo Italiano per lo Studio della Streptochinasi nell'infarto Miocardico) study]. Zofenopril was found to be as effective as lisinopril, and possibly with greater safety in the rather slower (5 day) titration regimen tested in the SMILE study. The safety of this regimen is now confirmed in a new study (SMILE-2) which has tested zofenopril in a large population of patients with AMI in any location, who also received thrombolytics. The biology of angiotensin, particularly the newer information on the effects of angiotensin-II (A-II) blockers on the vasculature and on smooth muscle growth, and the differing actions of ACE inhibitors and A-II blockers (ARBs) is reviewed by George Ertl from Würzburg, while Thomas F. Lüscher from Zürich discussed the work of his group on the interplay of A-II, bradykinin and nitric oxide on endothelial function. These two papers underline the sound theoretical and experimental background for these extended actions of angiotensin, and hence the clinical importance of reducing the impact of angiotensin in clinical states with overt or potential left ventricular dysfunction (LVD) such as heart failure or myocardial infarction. The experimental basis for the use of ACE inhibitors in AMI is reviewed by Scott Solomon from the Harvard team of Mark Pfeffer, whose pioneering work demonstrated the benefit of ACE inhibitors in experimental infarction. There has been considerable debate about whether ACE inhibitors should be given early to most patients with infarction, followed by longer term treatment only in those with LVD, or whether the initial treatment should also only be given to the latter group. The recently released preliminary results of the HOPE (Heart Outcomes Prevention Evaluation) suggest that ACE inhibitors are also beneficial in long-term use in high risk patients without LVD or hypertension. This may therefore encourage the practice [tested in ISIS-4 (Fourth International Study of Infarct Survival) and GISSI-3] of using ACE inhibition in a wider group of patients than just those with LVD [as in the SAVE (Survival and Ventricular Enlargement), AIRE (Acute Infarction Ramipril Efficacy) or TRACE (Trandolapril Cardiac Evaluation) studies]. Finally, Edward Frolich, from the Ochsner Medical Foundation in New Orleans reviews the latest information on the importance of LV hypertrophy and reduced LV compliance for the genesis of so-called diastolic heart failure, an increasingly important source of disability, especially in the elderly. ACE inhibition is a particularly effective strategy in reducing LV hypertrophy. At first sight it might appear dangerous, particularly in AMI, to block the action of the sympathetic and renin-angiotensin systems. Harris pointed out many years ago (1) that the activation of these powerful reflexes by baroreceptor sensing of poor LV function, is an inappropriate evolutionary hangover from the days when an inappropriately low blood pressure was a result of bleeding. Reflexes designed to aid survival after accident or trauma are harmful in the setting of LV damage. We older clinicians have been fascinated to witness the development of the widening clinical applications of ACE inhibition over the last three decades.