Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

The obesity paradox in heart failure patients with preserved versus reduced ejection fraction: a meta-analysis of individual patient data.

BACKGROUND: In heart failure (HF), obesity, defined as body mass index (BMI) ≥30 kg m(-2), is paradoxically associated with higher survival rates compared with normal-weight patients (the 'obesity paradox'). We sought to determine if the obesity paradox differed by HF subtype (reduced ejection fraction (HF-REF) versus preserved ejection fraction (HF-PEF)). PATIENTS AND METHODS: A sub-analysis of the MAGGIC meta-analysis of patient-level data from 14 HF studies was performed. Subjects were divided into five BMI groups: <22.5, 22.5-24.9 (referent), 25-29.9, 30-34.9 and ≥35 kg m(-2). Cox proportional hazards models adjusted for age, sex, aetiology (ischaemic or non-ischaemic), hypertension, diabetes and baseline blood pressure, stratified by study, were used to examine the independent association between BMI and 3-year total mortality. Analyses were conducted for the overall group and within HF-REF and HF-PEF groups. RESULTS: BMI data were available for 23 967 subjects (mean age, 66.8 years; 32% women; 46% NYHA Class II; 50% Class III) and 5609 (23%) died by 3 years. Obese patients were younger, more likely to receive cardiovascular (CV) drug treatment, and had higher comorbidity burdens. Compared with BMI levels between 22.5 and 24.9 kg m(-2), the adjusted relative hazards for 3-year mortality in subjects with HF-REF were: hazard ratios (HR)=1.31 (95% confidence interval=1.15-1.50) for BMI <22.5, 0.85 (0.76-0.96) for BMI 25.0-29.9, 0.64 (0.55-0.74) for BMI 30.0-34.9 and 0.95 (0.78-1.15) for BMI ≥35. Corresponding adjusted HRs for those with HF-PEF were: 1.12 (95% confidence interval=0.80-1.57) for BMI <22.5, 0.74 (0.56-0.97) for BMI 25.0-29.9, 0.64 (0.46-0.88) for BMI 30.0-34.9 and 0.71 (0.49-1.05) for BMI ≥35. CONCLUSIONS: In patients with chronic HF, the obesity paradox was present in both those with reduced and preserved ventricular systolic function. Mortality in both HF subtypes was U-shaped, with a nadir at 30.0-34.9 kg m(-2).

Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.

BACKGROUND: Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations. Irbesartan is an angiotensin receptor-blocking agent that reduces blood pressure and has other vascular protective effects. METHODS AND RESULTS: ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind, placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these studies are composites of vascular events. A total of 14000 patients will be enrolled in these trials. CONCLUSIONS: ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in patients with AF.

Prognostic significance of anaemia in patients with heart failure with preserved and reduced ejection fraction: results from the MAGGIC individual patient data meta-analysis.

BACKGROUND: Anaemia is common among patients with heart failure (HF) and is an important prognostic marker. AIM: We sought to determine the prognostic importance of anaemia in a large multinational pooled dataset of prospectively enrolled HF patients, with the specific aim to determine the prognostic role of anaemia in HF with preserved and reduced ejection fraction (HF-PEF and HF-REF, respectively). DESIGN: Individual person data meta-analysis. METHODS: Patients with haemoglobin (Hb) data from the MAGGIC dataset were used. Anaemia was defined as Hb < 120 g/l in women and <130 g/l in men. HF-PEF was defined as EF ≥ 50%; HF-REF was EF < 50%. Cox proportional hazard modelling, with adjustment for clinically relevant variables, was undertaken to investigate factors associated with 3-year all-cause mortality. RESULTS: Thirteen thousand two hundred and ninety-five patients with HF from 19 studies (9887 with HF-REF and 3408 with HF-PEF). The prevalence of anaemia was similar among those with HF-REF and HF-PEF (42.8 and 41.6% respectively). Compared with patients with normal Hb values, those with anaemia were older, were more likely to have diabetes, ischaemic aetiology, New York Heart Association class IV symptoms, lower estimated glomerular filtration rate and were more likely to be taking diuretic and less likely to be taking a beta-blocker. Patients with anaemia had higher all-cause mortality (adjusted hazard ratio [aHR] 1.38, 95% confidence interval [CI] 1.25-1.51), independent of EF group: aHR 1.67 (1.39-1.99) in HF-PEF and aHR 2.49 (2.13-2.90) in HF-REF. CONCLUSIONS: Anaemia is an adverse prognostic factor in HF irrespective of EF. The prognostic importance of anaemia was greatest in patients with HF-REF.

Gender differences in survival in advanced heart failure. Insights from the FIRST study.

BACKGROUND: Previous natural history studies in broad populations of heart failure patients have associated female gender with improved survival, particularly in patients with a nonischemic etiology of ventricular dysfunction. This study investigates whether a similar survival advantage for women would be evident among patients with advanced heart failure. METHODS AND RESULTS: The study analysis is based on the Flolan International Randomized Survival Trial (FIRST) study which enrolled 471 patients (359 men and 112 women) who had evidence of end-stage heart failure with marked symptoms (60% NYHA class IV) and severe left ventricular dysfunction (left ventricular ejection fraction 18+/-4.9%). A Cox proportional-hazards model, adjusted for age, gender, 6-minute walk, dobutamine use at randomization, mean pulmonary artery blood pressure, and treatment assignment, showed a significant association between female gender and better survival (relative risk of death for men versus women was 2.18, 95% CI 1.39 to 3.41; P<0.001). Although formal interaction testing was negative (P=0.275), among patients with a nonischemic etiology of heart failure, the relative risk of death for men versus women was 3.08 (95% CI 1.56 to 6.09, P=0.001), whereas among those with ischemic heart disease, the relative risk of death for men versus women was 1.64 (95% CI 0.87 to 3.09, P=0.127). CONCLUSIONS: Women with advanced heart failure appear to have better survival than men. Subgroup analysis suggests this finding is strongest among patients with a nonischemic etiology of heart failure.

Dynamic on-line vectorcardiography improves and simplifies in-hospital ischemia monitoring of patients with unstable angina.

OBJECTIVES: This study sought to validate computerized vectorcardiography against the established technique of Holter electrocardiographic (ECG) monitoring and to compare the feasibility of the two methods for monitoring patients with unstable angina pectoris. BACKGROUND: Detection of myocardial ischemic episodes is an important objective in patients admitted to the hospital for unstable angina pectoris. Standard ECG monitoring may be sufficient for detection of symptomatic episodes but will often overlook silent ischemia. Holter ECG monitoring has a higher likelihood of discovering such episodes, but analysis is time-consuming, and the results are not available on-line. METHODS: We simultaneously monitored 53 consecutive patients with unstable angina, 46 of whom had technically adequate 24-h Holter ECGs and computerized vectorcardiograms. RESULTS: The Holter tapes had a mean (+/- SD) of 15.3 +/- 10.3 h of recording with both channels technically adequate for analysis compared with 23.7 +/- 1.77 h of vectorcardiographic recording that could be analyzed (p < 0.01). Of the 15 symptomatic episodes detected by Holter ECG monitoring, 13 were also detected with dynamic vectorcardiography. In contrast, eight patients had 18 episodes of chest pain, with simultaneous ST segment changes detected by dynamic vectorcardiography; only 9 of these episodes were also detected by Holter ECG monitoring. CONCLUSIONS: Monitoring of myocardial ischemia with dynamic vectorcardiography seems to be more efficient than Holter monitoring and may have a higher sensitivity. Computerized, continuous vectorcardiography has a complete real-time capacity, allowing monitoring over prolonged periods of time, and the results are immediately available without time-consuming analysis.

The effects of moxonidine, a novel imidazoline, on plasma norepinephrine in patients with congestive heart failure. Moxonidine Investigators.

OBJECTIVE: To evaluate the dose response relationship of moxonidine on plasma concentration of norepinephrine during acute and chronic administration in patients with congestive heart failure (CHF). BACKGROUND: Sympathetic activation is increased in heart failure. Moxonidine is an imidazoline ligand acting on the central nervous system (CNS) receptors to decrease sympathetic activation. METHODS: Ninety-seven patients with heart failure and New York Heart Association class II-III symptoms and ejection fraction <40% were randomized to placebo or one of three target doses of moxonidine, 0.1, 0.2 or 0.3 mg administered twice daily. An initial dose of moxonidine 0.1 mg twice a day (b.i.d.) was followed by weekly increments of 0.1 mg b.i.d. until target dose. The second and third study days occurred after four weeks (at target dose) and after 12 weeks, respectively. At each study day, repeated blood samples were drawn. RESULTS: There was a significant dose-related decrease of systolic blood pressure across all three study days. Heart rate decreased significantly on study day 3 in a dose-related manner. The acute 2 h decrease in plasma norepinephrine in response to all three doses of moxonidine was significantly different compared with placebo after four and 12 weeks. There was a significant linear relation between dose and plasma norepinephrine after four and 12 weeks in both 2 h peak and the time averaged effect (>8 h). The number of adverse events was similar in the moxonidine and placebo groups. CONCLUSIONS: The increased sympathetic activation in CHF can be reduced by moxonidine through CNS inhibition.

Enalapril: a new angiotensin-converting enzyme inhibitor in chronic heart failure: acute and chronic hemodynamic evaluations.

Hemodynamic effects of the new oral angiotensin-converting enzyme inhibitor, enalapril, were evaluated acutely in 15 patients with chronic heart failure and in 7 patients after 4 weeks of maintenance therapy. Initial hemodynamic effects were characterized by a significant increase in cardiac index (from 2.1 +/- 0.7 to 2.6 +/- 0.7 liters/min per m2) and a decrease in pulmonary capillary wedge pressure (from 30 +/- 6 to 24 +/- 7 mm Hg), right atrial pressure (from 14 +/- 5 to 11 +/- 4 mm Hg), mean arterial pressure (from 96 +/- 16 to 80 +/- 17 mm Hg) and systemic vascular resistance (from 1,820 +/- 480 to 1,200 +/- 410 dynes . s . cm-5) without any significant change in heart rate, pulmonary artery pressure and pulmonary vascular resistance. During maintenance therapy, the dose of diuretic drugs had to be increased because of systemic venous hypertension. Repeat hemodynamic study showed that after chronic therapy, cardiac index (2.1 +/- 0.7 vs. 3.0 +/- 0.08 liters/min per m2) and stroke volume index (24 +/- 10 vs. 36 +/- 7 ml/m2) remained elevated and pulmonary capillary wedge pressure was lower than control (30 +/- 6 vs. 16 +/- 6 mm Hg), indicating sustained improvement in left ventricular performance. Plasma renin activity increased and plasma norepinephrine levels decreased after enalapril therapy and these humoral changes persisted during maintenance therapy. All patients receiving chronic therapy had symptomatic improvement. Significant hypotension, which occurred in five patients at the initiation of therapy, appears to be the major side effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. Angiotensin-converting Enzyme Inhibitor Myocardial Infarction Collaborative Group.

OBJECTIVES: We sought to determine whether the clinical effects of early angiotensin-converting enzyme (ACE) inhibitor (ACEi) treatment for acute myocardial infarction (MI) are influenced by the concomitant use of aspirin (ASA). BACKGROUND: Aspirin and ACEi both reduce mortality when given early after MI. Aspirin inhibits the synthesis of vasodilating prostaglandins, and, in principle, this inhibition might antagonize some of the effects of ACEi. But it is uncertain whether, in practice, this influences the effects of ACEi on mortality and major morbidity after MI. METHODS: This overview sought individual patient data from all trials involving more than 1,000 patients randomly allocated to receive ACEi or control starting in the acute phase of MI (0-36 h from onset) and continuing for four to six weeks. Data on concomitant ASA use were available for 96,712 of 98,496 patients in four eligible trials (and for none of 1,556 patients in the one other eligible trial). RESULTS: Overall 30-day mortality was 7.1% among patients allocated to ACEi and 7.6% among those allocated to control, corresponding to a 7% (standard deviation [SD], 2%) proportional reduction (95% confidence interval 2% to 11%, p = 0.004). Angiotensin-converting enzyme inhibitor was associated with similar proportional reductions in 30-day mortality among the 86,484 patients who were taking ASA (6% [SD, 3%] reduction) and among the 10,228 patients who were not (10% [SD, 5%] reduction: chi-squared test of heterogeneity between these reductions = 0.4; p = 0.5). Angiotensin-converting enzyme inhibitor produced definite increases in the incidence of persistent hypotension (17.9% ACEi vs. 9.4% control) and of renal dysfunction (1.3% ACEi vs. 0.6% control), but there was no good evidence that these effects were different in the presence or absence of ASA (chi-squared for heterogeneity = 0.4 and 0.0, respectively; both not significant). Nor was there good evidence that the effects of ACEi on other clinical outcomes were changed by concomitant ASA use. CONCLUSIONS: Both ASA and ACEi are beneficial in acute MI. The present results support the early use of ACEi in acute MI, irrespective of whether or not ASA is being given.

Endogenous catecholamine levels in chronic heart failure. Relation to the severity of hemodynamic abnormalities.

Plasma free epinephrine, norepinephrine, and dopamine concentrations were determined in 48, 63, and 45 patients, respectively, with overt congestive heart failure, and compared with those in 26 patients with stable angina but without heart failure. Systemic hemodynamic values were determined to assess the severity of heart failure. Arterial epinephrine levels were not different between patients with heart failure (73 +/- 92 pg/ml) and patients without heart failure (55 +/- 73 pg/ml). In patients with congestive heart failure, norepinephrine (665 +/- 510 pg/ml, mean +/- SD) and dopamine (407 +/- 405 pg/ml) levels were significantly higher than in patients with stable angina without heart failure (norepinephrine 184 +/- 136 pg/ml, p less than 0.001, and dopamine 197 +/- 259 pg/ml, p less than 0.02). However, in patients with congestive heart failure, the plasma norepinephrine levels did not correlate with cardiac index (r = 0.21, p = NS), pulmonary capillary wedge pressure (r = 0.11, p = NS), mean arterial pressure (r = 0.11, p = NS), or systemic vascular resistance (r = 0.18, p = NS). Similarly, there was no correlation between dopamine levels and the hemodynamic abnormalities in patients with congestive heart failure. These findings suggest that although endogenous norepinephrine and dopamine levels are frequently elevated in patients with heart failure, reflecting enhanced sympathetic activity, catecholamine levels do not reflect the severity of heart failure.

Intravenous and oral prenalterol in congestive heart failure. Effects on systemic and coronary hemodynamics and myocardial catecholamine balance.

Systemic and coronary hemodynamic effects of prenalterol, a beta-1 receptor agonist, were determined in patients with chronic congestive heart failure, initially after intravenous administration (10 patients) and then after oral administration (eight patients). Cardiac index increased by 33 percent and 30 percent after intravenous and oral prenalterol, respectively. The increase in stroke volume index and stroke work index and decrease in pulmonary capillary wedge pressure and systemic vascular resistance were not significant. Myocardial oxygen consumption and coronary sinus blood flow increased in the majority of patients, although these changes were not statistically significant. There were no significant changes in transmyocardial norepinephrine or epinephrine balance. The systemic and coronary hemodynamic effects of both intravenous and oral prenalterol were similar. Major side effects included sudden death (two patients) and hypotension and bradycardia (three patients) during oral prenalterol treatment. It is concluded that improved left ventricular function following both intravenous and oral prenalterol may be associated with increased myocardial oxygen consumption, and serious adverse effects may occur during prenalterol therapy.

Prognostic importance of the oxidized product of catecholamines, adrenolutin, in patients with severe heart failure.

OBJECTIVES: The purpose of this study was to assess whether adrenolutin, the inert product of the highly reactive molecules aminochromes, is increased in severe chronic heart failure and whether it is associated with a poor prognosis. BACKGROUND: Experimental evidence suggests that oxidative products of catecholamines, aminochromes, are more cardiotoxic than unoxidized catecholamines and may be increased in heart failure. METHODS: Adrenolutin was measured at baseline and at 1 and 3 months in 263 patients with chronic New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 22% +/- 7%. Adrenolutin levels were compared with normal levels, and their relation to prognosis was evaluated. RESULTS: Baseline adrenolutin was increased (55 +/- 90 pg/mL vs 8.4 +/- 9.1 pg/mL for control, P <.02) and remained increased at 1 month (49 +/- 65 pg/mL). During a mean follow-up of 309 +/- 148 days (22-609 days), 57 patients died. Baseline adrenolutin levels correlated with mortality rates by univariate and multivariate analyses (relative risk 1.06, 95% CI 1.01-1.10 for each 17.9-pg/mL rise, P =.032). Left ventricular ejection fraction (P =.013) and New York Heart Association class (P =.009) were the only other variables associated with survival. Age, sex, plasma creatinine, plasma N-terminal atrial natriuretic peptide, and plasma norepinephrine levels were not retained in our model. Adrenolutin levels 1 month after random assignment were not significantly correlated with total mortality rate (P =.061) but were correlated with mortality rate from low output (relative risk 1.14, 95% CI 1.06-1.22, P =.002). CONCLUSIONS: Plasma adrenolutin is increased in patients with heart failure and correlates with a poor prognosis independent of other important predictors of survival. This finding has potentially important pathophysiologic, prognostic, and therapeutic implications.

Initial experience with beta blockers in dilated cardiomyopathy.

In early 1973, Waagstein administered bolus intravenous injections of practolol and, subsequently, alprenolol, 50 mg twice daily, to reduce the heart rate of a 59-year-old woman with refractory, idiopathic dilated congestive cardiomyopathy (DCCM) and resting tachycardia. The patient's condition improved dramatically and continued to improve during subsequent oral therapy. This experience, combined with increasing interest in the role of beta blockade in myocardial protection, led to investigation of oral practolol, 50-400 mg twice daily, for 2-12 months in 6 additional patients with advanced DCCM. These findings, published in 1975, indicated improved ventricular function for all participants. In a 1980 open-label follow-up study, 28 patients with DCCM received alprenolol, metoprolol, practolol, or propranolol. Treatment was associated with improvements in myocardial function as well as in related symptomatology. These effects were reversed following drug withdrawal. The findings suggested that beta blockers possessed potential value in treatment of idiopathic DCCM.

Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).

To evaluate the influence of the angiotensin-converting enzyme inhibitor, enalapril (2.5 to 40 mg/day), on the prognosis of severe congestive heart failure, defined as New York Heart Association functional class IV, a double-blind study was undertaken in which 253 patients were randomized to receive either placebo (n = 126) or enalapril (n = 127) in addition to conventional treatment, including vasodilators. Follow-up averaged 188 days (range 1 day to 20 months). The reduction in crude mortality within 6 months (primary objective) was 40% in the enalapril-treated group (from 44 to 26%, p = 0.002) and within 1 year 31% (p = 0.001). By the end of the study, 68 subjects in the placebo group and 50 in the enalapril group had died--a reduction of 27% (p = 0.003). The entire reduction in total mortality (50%) was found in patients dying from progressive heart failure, whereas no difference was seen in the incidence of sudden cardiac death. There was a significant improvement in New York Heart Association classification in the enalapril group, together with a reduction in heart size and a reduced requirement for other heart failure medication. It is concluded that the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms. The effect seems to be due to a reduction in death from progression of heart failure.

Tolerability of enalapril in congestive heart failure.

In a double-blind, randomized trial, 253 patients with heart failure (New York Heart Association functional class IV) received either enalapril (n = 127) or placebo (n = 126) in addition to their conventional therapeutic regimens (digitalis, diuretics and vasodilators other than angiotensin-converting enzyme inhibitors). Enalapril was administered in a dose of 2.5 to 40 mg/day. The placebo group was administered placebo tablets in addition to their conventional therapeutic regimen. The study was discontinued prematurely for ethical reasons because of the highly significant (p = 0.003) difference in mortality between the enalapril (n = 50) and placebo groups (n = 68). The important reduction was observed among patients dying from progressive heart failure. Follow-up ranged from 1 day to 20 months (average 188 days). The reduction in mortality was associated with general improvements in symptoms and signs of left and right ventricular heart failure, reduction of heart size, improvements in New York Heart Association classification, reduction of concurrent cardiovascular medication, and reduction in the number of hospital admissions and duration of hospitalization. The overall rate of withdrawal from the study was low and was comparable in the 2 treatment groups (16%). Induced hypotension was an intentional part of the treatment, and symptomatic hypotension was observed in 17% of treated patients vs 0% of the placebo group. Hypotension was the reason for withdrawal in 7 patients. After the initial dose of enalapril was reduced to 2.5 mg in high-risk patients, hypotension was the reason for withdrawal in only 3% of all patients. Hyperkalemia was observed exclusively among patients concurrently using potassium-sparing agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Enalapril for congestive heart failure.

In a randomized, double-blind trial, 253 patients with congestive heart failure (New York Heart Association class IV) received either enalapril (n = 127) or placebo (n = 126) in addition to their existing therapeutic regimens (consisting of digitalis, diuretics, and vasodilators other than angiotensin-converting enzyme inhibitors). The study was discontinued prematurely for ethical reasons because of the much lower mortality among the patients receiving enalapril (n = 50) than among those receiving placebo (n = 68) (p less than 0.003). The important reduction in mortality was observed among patients dying from progressive heart failure. Follow-up ranged from 1 day to 20 months (average 188 days). The reduction in mortality was associated with general improvements in the symptoms and signs of left and right ventricular heart failure, reduction of heart size, improvements in New York Heart Association classification, reduction of concurrent cardiovascular medication, and reduction of hospital admissions and days spent in the hospital. The overall withdrawal rate was low, and was comparable in the 2 treatment groups (16%; enalapril, n = 22, placebo, n = 18). Symptomatic hypotension was observed in 17% (n = 21) of the enalapril group vs 0% of the placebo group. Hypotension was the reason for withdrawal of enalapril therapy in 7 patients. After the initial dose of enalapril was reduced to 2.5 mg in high-risk patients, hypotension necessitated withdrawal in only 3.2% of the patients. Hyperkalemia was observed exclusively among patients with concurrent use of potassium-sparing agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of neuroendocrine activation on coronary artery disease.

Several independent predictors of the risk of atherosclerosis are known including plasma cholesterol concentration, cigarette smoking, elevated blood pressure, as well as genetic factors such as non-insulin-dependent diabetes and plasma fibrinogen. Also known are the 3 major elements of the pathogenesis of atherosclerosis, involving modification of endothelial function, changes in vascular tone, and clinical sequelae of hyperplasia of smooth muscle cells in the intima of the affected blood vessels. This article further examines vasoconstrictor/vasodilator balance, the role of angiotensin II, and the significant role played by the endothelium in the complex events and interactions that occur both with smooth muscle cells and platelets. Clinical evidence of endothelial dysfunction in coronary artery disease is presented. The importance of the association of the progression of coronary artery disease with signs of neuroendocrine activation, the relation of endothelin-1 to mechanisms of neuroendocrine activation, and how the counteraction of this activation may have beneficial effects on disease progression are discussed.

Dynamic QRS-complex and ST-segment monitoring in acute myocardial infarction during recombinant tissue-type plasminogen activator therapy. The TEAHAT Study Group.

Changes of the QRS complex are the electrocardiographic expression of irreversible injury of the myocardium. In humans, the process of infarction occurs over several hours. A more rapid development of QRS changes has been reported in patients treated with thrombolytic agents. Patients with strongly suspected acute myocardial infarction (AMI) included in a placebo-controlled trial of 100 mg of recombinant tissue-type plasminogen activator (rt-PA) were monitored for 24 hours with continuous, on-line vectorcardiography. The magnitude of the QRS vector changes correlated with infarct size estimated by the maximal value of lactate dehydrogenase-1 (r = 0.69, p less than 0.001) as well as with left ventricular ejection fraction 30 days after randomization (r = 0.49, p less than 0.001). Treatment with intravenous rt-PA limited total QRS vector change but the QRS vector changes observed occurred more rapidly and reached a plateau 131 minutes earlier in patients treated with rt-PA than in those receiving placebo (p less than 0.01). A certain pattern of highly variable ST vector magnitude was identified and was associated with higher maximal lactate dehydrogenase-1 values (23 +/- 13 vs 14 +/- 10 mu kat/liter, p less than 0.001) and a tendency to higher 1-year mortality (24 vs 9%, p = 0.08) than in patients without this pattern. In patients with this pattern, rt-PA did not affect maximal lactate dehydrogenase-1, time to maximal creatine kinase and final magnitude of QRS vector change.

Renal function in severe congestive heart failure during treatment with enalapril (the Cooperative North Scandinavian Enalapril Survival Study [CONSENSUS] Trial).

The effect on renal function of long-term treatment with either enalapril (n = 123) or placebo (n = 120) in addition to conventional therapy was studied in a randomized trial in patients with severe congestive heart failure (New York Heart Association functional class IV; the Cooperative North Scandinavian Enalapril Survival Study). Enalapril was administered in a dose of 2.5 to 40 mg/day. The analysis was restricted to the first 6 months of treatment. There was an average initial increase of 10 to 15% (10 to 20 mumol/liter) irrespective of baseline serum creatinine within the first 3 weeks of enalapril treatment, whereafter mean serum creatinine remained on a similar level during the first 6 months. Enalapril was well-tolerated by most patients, and serum creatinine was reduced in 24%. Serum creatinine increased by greater than 100% in 13 patients (11%) in the enalapril group (mainly as a consequence of intercurrent disease or severe hypotension, and usually transiently) and in 4 (3%) in the placebo group. The maximal increase in serum creatinine in the enalapril group was inversely correlated to the diastolic blood pressure (p = 0.008) at baseline and to the mean diastolic and systolic blood pressures measured at the time of the maximal increase in serum creatinine (p = 0.0001). According to multivariate regression analysis, the maximal increase in serum creatinine was also slightly influenced by the dose of furosemide taken. The development of hypotension emerged as the strongest factor explaining an abnormal increase in serum creatinine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of enalapril on long-term mortality in severe congestive heart failure. CONSENSUS Trial Group.

All surviving patients in a double-blind study comparing the effects of enalapril and placebo on survival in severe congestive heart failure were recommended to be treated with active drug after stopping the trial. Two-year follow-up from the end of the blinded trial demonstrated that among 77 survivors of 127 patients originally allocated to the group with enalapril, 38 were still alive. Of 126 patients allocated to the group with placebo 58 survived the blinded study, and after 2-year follow-up 26 were still alive. Thus, the difference between the original treatment groups remained, despite that treatment with enalapril was made available to all surviving patients and that those in the group with enalapril were sicker at baseline than those in the group with placebo. If enalapril was prescribed, the mortality was 47% compared with 75% if it was not. Life-table analysis suggests a marked carry-over effect of treatment in the group with enalapril that lasted for up to 15 months before mortality rates became comparable in the 2 treatment groups. This strongly suggests that enalapril confers structural protection to the failing myocardium.