Risk attitudes and personality traits predict perceptions of benefits and risks for medicinal products: a field study of European medical assessors.

BACKGROUND: Risk attitudes and personality traits are known predictors of decision making among laypersons, but very little is known of their influence among experts participating in organizational decision making. METHODS: Seventy-five European medical assessors were assessed in a field study using the Domain Specific Risk Taking scale and the Big Five Inventory scale. Assessors rated the risks and benefits for a mock "clinical dossier" specific to their area of expertise, and ordinal regression models were used to assess the odds of risk attitude or personality traits in predicting either the benefit or the risk ratings. RESULTS: An increase in the "conscientiousness" score predicted an increase in the perception of the drug's benefit, and male assessors gave higher scores for the drug's benefit ratings than did female assessors. Extraverted assessors saw fewer risks, and assessors with a perceived neutral-averse or averse risk profile saw greater risks. CONCLUSIONS: Medical assessors perceive the benefits and risks of medicines via a complex interplay of the medical situation, their personality traits and even their gender. Further research in this area is needed to determine how these potential biases are managed within the regulatory setting.

Value of digoxin in heart failure and sinus rhythm: new features of an old drug?

Digoxin has been a controversial drug since its introduction >200 years ago. Although its efficacy in patients with heart failure and atrial fibrillation is clear, its value in patients with heart failure and sinus rhythm has often been questioned. In the 1980s, reports of some large-scale trials indicated that digoxin, with or without vasodilators or angiotensin-converting enzyme inhibitors, reduced signs and symptoms of congestive heart failure and improved exercise tolerance. This beneficial influence was mainly found in patients with more advanced heart failure and dilated ventricles, whereas the effect in those with mild disease appeared to be less pronounced. In the last few years, new data have shown that digoxin may also have clinical value in mild heart failure, either when used in combination with other drugs or when administered alone. As neurohumoral activation has increasingly been recognized to be a contributing factor in the disease progression of chronic heart failure, the modulating effects of digoxin on neurohumoral and autonomic status have received more attention. Also, there is evidence that relatively low doses of digoxin may be at least as effective as higher doses and have a lower incidence of side effects. Further, the recognition that the use of digoxin too early after myocardial infarction may be harmful and the development of other drugs, in particular angiotensin-converting enzyme inhibitors, have obviously changed the place of digoxin in the treatment of chronic heart failure. The large-scale survival trial by the Digitalis Investigators Group (DIG), whose preliminary results have recently been presented, has shown that although digoxin has a neutral effect on total mortality during long-term treatment, it reduces the number of hospital admissions and deaths due to worsening heart failure. The potentially new features of the old drug digoxin are discussed in this review.

Cardiovascular end-organ damage in Ren-2 transgenic rats compared to spontaneously hypertensive rats.

To compare hypertensive end-organ damage in two genetic forms of hypertension we assessed cardiovascular function in two rat strains of genetic hypertension: transgenic rats overexpressing the mouse Ren-2 gene [(TGR(mREN2)27]) and blood pressure matched spontaneously hypertensive rats (SHR). Despite similarly elevated blood pressure, systolic dp/dt (mmHg/s) was more impaired in transgenic rats (3099 +/- 446) than in SHR (3571 +/- 272) and normals (4342 +/- 119; P < 0.05). Left ventricular weight (mg/g body weight) increased more in the transgenic rats (40 +/- 3) than in SHR (31 +/- 2) and normals (26 +/- 2). Endothelium-dependent relaxation was significantly decreased only in the transgenic rats. This study shows significantly more cardiac and endothelial dysfunction in transgenic, hypertensive TGR (mREN2)27 than in age and blood pressure matched SHR. This supports the hypothesis that chronic activation of the renin-angiotensin system significantly contributes to hypertensive end-organ damage.

Converting enzyme inhibition after experimental myocardial infarction in rats: comparative study between spirapril and zofenopril.

STUDY OBJECTIVE: The aim was to compare the effects of two novel angiotensin converting enzyme (ACE) inhibitors, spirapril and zofenopril, on cardiac remodelling in rats with congestive heart failure after myocardial infarction. Spirapril contains no sulphydryl group, whereas zofenopril is a sulphydryl containing ACE inhibitor. DESIGN: Experimental myocardial infarction was induced by ligation of the left coronary artery. Sham operated animals served as controls. Treatment with spirapril (2-2.5 mg.kg-1.d-1) or zofenopril (12-15 mg.kg-1.d-1) added to the drinking water was started immediately after myocardial infarction or sham operation and continued for six weeks. After the treatment period, all rats were killed. The heart was rapidly removed and perfused as described by Langendorff. Heart rate and left ventricular pressure were measured both at baseline and during stimulation with isoprenaline (6 nM). Heart and lung weights were determined. SUBJECTS: Normotensive male Wistar rats (220-240 g) were used. MEASUREMENTS AND MAIN RESULTS: Experimental myocardial infarction considerably increased left ventricular cavity volume. Chronic treatment with either spirapril or zofenopril significantly attenuated this increase in volume. In infarcted rats, the increase in total heart and lung weight was also significantly reduced by chronic treatment with spirapril and zofenopril, indicating that these compounds reduce cardiac mass and pulmonary congestion in congestive heart failure due to myocardial infarction. There were no significant differences between treatment with spirapril and zofenopril. In the isolated and perfused rat heart, myocardial infarction significantly decreased both heart rate and left ventricular pressure. Converting enzyme inhibition only affected heart rate. Heart rate was significantly higher in infarcted animals treated with spirapril and zofenopril than in untreated infarcted animals. CONCLUSIONS: Both spirapril and zofenopril attenuated ventricular enlargement and cardiac hypertrophy in rats with congestive heart failure after myocardial infarction when treatment was started in the acute phase of myocardial infarction. No additional role could be attributed to the sulphydryl moiety of zofenopril. It is also suggested that these two ACE inhibitors modify cardiac sympathetic activity in rats with congestive heart failure, but more studies are needed to confirm these findings.

Selective and time related activation of the cardiac renin-angiotensin system after experimental heart failure: relation to ventricular function and morphology.

OBJECTIVE: The cardiac renin-angiotensin system is activated in experimental heart failure, but it is unknown at what stage of heart failure it becomes activated, and whether activation is related to ventricular dysfunction and dilatation. Changes in activity of cardiac, renal, and plasma angiotensin converting enzyme (ACE) were therefore examined at different stages of experimental heart failure, with simultaneous measurements of left ventricular pressure, systolic dP/dt, and inner ventricular radius. METHODS: Heart failure was induced by experimental infarction in 17 normotensive male Wistar rats; 14 rats were sham operated. Rats were killed 3, 5, or 80 d after infarction. In an isolated heart perfusion, left ventricular pressure and systolic dP/dT were measured. ACE activity was determined in samples of the left and right cardiac ventricle, kidney, and plasma. Radius of the ventricular cavity was planimetrically determined in transverse sections of the left ventricle. RESULTS: At the different stages both left ventricular pressure and systolic dP/dT progressively decreased and inner radius of the left ventricle increased in all heart failure groups. ACE activity in the left ventricle increased significantly in all heart failure groups and correlated inversely with left ventricular pressure (R = -0.81; p < 0.001) and dP/dt (R = -0.85; p < 0.001). ACE activity in the kidney was only increased 80 d after the induction of heart failure [17(SEM 1) v 11.2(0.5) nM His-Leu generated per min.mg-1, p < 0.01], while plasma ACE activity was not increased in any heart failure group. CONCLUSIONS: Cardiac ACE is activated in the early stage after induction of heart failure and is related to the amount of dysfunction. ACE in the kidney is activated only in the chronic stage. The cardiac renin-angiotensin system therefore already appears to be an important neurohumoral adjustment in the early stage of heart failure and is thereby a suitable target for early intervention by ACE inhibitors.

Relation between myocardial beta-adrenoceptor density and hemodynamic and neurohumoral changes in a rat model of chronic myocardial infarction: effects of ibopamine and captopril.

OBJECTIVES: The purpose of this study was to investigate the changes in beta-adrenoceptor density (Bmax) and distribution in a model of chronic myocardial infarction in rats, and to relate possible changes to hemodynamic and neurohumoral abnormalities. In addition, we examined the effects of 8 weeks treatment with ibopamine and captopril. METHODS: There were 3 experiments: (1) Bmax and plasma catecholamines were examined (n = 46), (2) Bmax was compared in infarcted and non-infarcted tissue (n = 13), and (3) contractile function was evaluated by isolated heart perfusion (n = 40). Of rats in Expts. (1) and (3), 50% had myocardial infarction induced by coronary ligation and 50% were controls. Each group was divided between ibopamine, ibopamine and captopril, or standard (no drug) treatment. RESULTS: Bmax was not decreased in rats with myocardial infarction (10.8 +/- 0.8 fmol/mg protein), compared to normal rats (11.4 +/- 0.6 fmol/mg protein), and the ratio beta 1/beta 2 was also unaffected. In infarcted tissue, Bmax was significantly (P = 0.03) lower than in non-infarcted tissue. Baseline left ventricular pressure, systolic and diastolic dP/dT were all impaired (P < 0.001), and plasma norepinephrine levels were elevated in rats with myocardial infarction (16.03 +/- 230 vs. 1287 +/- 83 pg/ml; P < 0.05), compared to normals. Both ibopamine alone and in combination with captopril reduced the elevated plasma norepinephrine levels in infarcted rats (P < 0.001), but only the combination of the 2 drugs significantly increased Bmax in infarcted rats (14.7 +/- 0.8 fmol/mg protein; P = 0.03 vs. untreated myocardial infarction), while ibopamine alone had no significant effect (13.1 +/- 1.1 fmol/mg protein; p = ns). Also, active drug treatment had no significant effect on the hemodynamic changes. CONCLUSIONS: In this coronary artery ligation model of myocardial infarction in rats, no beta-adrenoceptor down-regulation is observed, despite marked abnormalities in baseline left ventricular function and plasma norepinephrine levels. The combination of ibopamine and captopril significantly increases Bmax in infarcted rats, which is accompanied by a reduction in plasma norepinephrine levels, but not by an improvement in hemodynamic parameters.

High prevalence of concentric remodeling in elderly individuals with isolated systolic hypertension from a population survey.

Echocardiographic determination of left ventricular mass index (LVMI) is shown to be valuable in the assessment of cardiovascular risk. Determination of left ventricular geometry, including concentric remodeling, provides additional prognostic information. In isolated systolic hypertension (ISH), the few echocardiographic studies available show an increased LVMI, but criteria and patient populations differ. No comparison with diastolic hypertension (DH) has been made, nor has left ventricular geometry (with concentric remodeling) been evaluated. We compared both LVMI and left ventricular geometry of newly diagnosed ISH subjects with normotensive and DH subjects, all previously untreated and from the same population. The echocardiographic LVMI of 97 previously untreated ISH subjects (4 x systolic pressure > or = 160 mm Hg, diastolic pressure < 95 mm Hg) was clearly elevated compared with values in age- and sex-matched normotensive subjects (98 and 71 g/m2, respectively; P < .001). The geometric pattern was abnormal in most ISH subjects, with a high prevalence (43%) of concentric remodeling. Both LVMI and left ventricular geometry of ISH subjects did not differ significantly from values in DH subjects (LVMI, 92 g/m2; concentric remodeling, 56%). Sex differences in LV geometry in ISH were present only with the Framingham criteria, not with the Koren criteria. This study shows a high prevalence of concentric remodeling in elderly individuals with previously untreated ISH. The increase of LVMI and abnormality in left ventricular geometry are comparable with those in DH subjects, further defining the place of ISH as a cardiovascular risk factor in the elderly. Whether there are sex differences in cardiac adaptation in ISH and whether the geometric classification can be used to adjust treatment remain to be investigated.

Long-term effects of amlodipine and lisinopril on left ventricular mass and diastolic function in elderly, previously untreated hypertensive patients: the ELVERA trial.

OBJECTIVE: To compare the effects of a calcium antagonist (amlodipine) and an angiotensin converting enzyme inhibitor (lisinopril) on left ventricular mass and diastolic function in elderly, previously untreated hypertensives. DESIGN: A double-blind randomized parallel group trial. Effects of amlodipine and lisinopril on left ventricular mass and diastolic function (E/A Ratio) (The ELVERA trial). SETTING: Rural northern Netherlands: population screening new diagnosed hypertensive subjects. PATIENTS: The study population comprised 166 newly diagnosed hypertensive (aged 60-75) with diastolic blood pressure between 95-115 mmHg and/or systolic blood pressure between 160-220 mmHg. INTERVENTION: Patients were randomly allocated to receive 5-10 mg amlodipine or 10-20 mg lisinopril for 2 years. MAIN OUTCOME MEASURES: Prior and after 1 and 2 years of treatment left ventricular mass, indexed by body surface (LVMI) was estimated by 2-D mode echocardiography according to Devereux with use of Penn convention. Early to atrial filling ratio (E/A) was assessed by transmitral flow. Change from baseline of LVMI and E/A ratio was evaluated by repeated measurement analysis of the treatment effect in an intention-to-treat analysis. RESULTS: Both amlodipine and lisinopril led to equivalent reduction in systolic and diastolic blood pressure. At the end of the study the amlodipine group led to LVMI decrease by 21.8 g/m < or = [95% confidence interval (CI), 18.3-25.3] and E/A ratio increased by 0.08 (95% CI, 0.05-0.11). In the lisinopril group LVMI decreased by 22.4 g/m < or = (95%, CI, 19.0-25.8) and E/A ratio increased by 0.07 (95% CI, 0.04-0.10). No statistically significant differences were found in changes in LVMI and E/A ratio between amlodipine and lisinopril. CONCLUSION: A long-term study, the ELVERA trial proves that amlodipine and lisinopril reduce left ventricular mass and improve diastolic function to a similar extent in elderly newly diagnosed hypertensive patients.

Acute hemodynamic and hormonal effects of ramipril in chronic congestive heart failure and comparison with captopril.

Acute hemodynamic and hormonal responses to ramipril in comparison with captopril were studied in 10 patients with moderate to severe congestive heart failure in an open, randomized study. Both drugs were given to 5 patients each in 2 increasing doses on 2 successive days. After 5 mg of ramipril angiotensin converting enzyme (ACE) activity was significantly decreased during 24 hours with a maximum decrease 4 hours after administration. Mean arterial blood pressure decreased from 84 +/- 5 to 62 +/- 5 mm Hg at 4 hours and 71 +/- 4 mm Hg at 12 hours, respectively, after this dose. Capillary wedge pressure decreased from 19 +/- 1 mm Hg to 13 +/- 1 mm Hg at 4 hours with a maximum increase in cardiac output from 3.8 +/- 0.3 liters/min to 4.4 +/- 0.3 liters/min at 2 hours. No significant cardiac effects were present 8 hours after administration. After 10 mg of ramipril, cardiac and hormonal effects showed a quicker onset of action and longer duration compared with the 5 mg dose. Mean arterial pressure decreased to 61 +/- 6 mm Hg. Similar effects were seen after captopril, but with a significantly shorter duration. Mean arterial pressure decreased from 82 +/- 4 mm Hg to 64 +/- 5 mm Hg after 12.5 mg and to 58 +/- 6 mm Hg after 25 mg of captopril. In patients with congestive heart failure ramipril has the hemodynamic profile of a long-acting and potent ACE inhibitor. Significant cardiac effects are present during 4 to 8 hours and ACE activity is still significantly inhibited 24 hours after a single dose of ramipril.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison between New York Heart Association classification and peak oxygen consumption in the assessment of functional status and prognosis in patients with mild to moderate chronic congestive heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy.

To compare the value of the New York Heart Association (NYHA) classification and measurement of peak oxygen consumption (VO2) in the assessment of functional status and prognosis in patients with mild to moderate chronic congestive heart failure (CHF), 94 patients with clinically stable NYHA class II and III CHF were prospectively studied. In all patients, left ventricular ejection fraction was less than or equal to 40% (mean 22 +/- 9); 49 patients were in NYHA class II, and 45 were in NYHA class III. Mean peak VO2 was 17 +/- 5 ml/min/kg. During a follow-up period of 23 +/- 11 months, 21 patients died. The 1-, 2- and 3-year cumulative survival rates for the 94 patients were 88, 79 and 69%, respectively. Functional status, as assessed both by peak VO2 and NYHA classification, and left ventricular ejection fraction were significantly worse in the group of nonsurvivors. The most powerful independent predictor of mortality was peak VO2. Although mean peak VO2 was significantly higher in NYHA class II than in NYHA class III (20 +/- 4 vs 13 +/- 3 ml/min/kg, p less than 0.0001), categorization into subgroups on the basis of the attained peak VO2 revealed a marked discrepancy with the NYHA classification. Nevertheless, the survival curves of patients subdivided at a peak VO2 of 16 ml/min/kg showed a strong resemblance with survival curves of both NYHA classes.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic value of heart rate variability in chronic congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy.

To study the prognostic value of heart rate (HR) variability in heart failure, risk assessment of clinical and HR variability parameters was performed in 159 patients with stable chronic heart failure. Besides low left ventricular ejection fraction, HR variability parameters reflecting impaired vagal tone (SDNN, pNN50) were found to predict an increased risk of cardiac death and death due to progressive pump failure.

The 4S study. Implications for prescribing.

This article discusses various aspects of cholesterol-lowering therapy using the HMG-CoA reductase inhibitor simvastatin in the light of the large Scandinavian Simvastatin Survival Study (4S). In 4S, patients with proven coronary heart disease (CHD) and plasma total cholesterol > 5.5 mmol/L (212 mg/dl) despite dietary measures received statin therapy or placebo for > or = 5 years. A significant mortality reduction was accomplished in those receiving the statin. Moreover, a significant decrease of nonfatal myocardial infarction and requirement for coronary bypass surgery or angioplasty was demonstrated, which will contribute to the cost-effectiveness of this well tolerated therapy. Plaque stabilisation and improvement of endothelial function are thought to be mediators of this therapeutic success. Responsible drug prescription in the post-4S era may result in the recognition and treatment of more patients with CHD. This is likely to be more beneficial than exhaustive efforts to completely achieve the goals of the most strict guidelines in the individual patient. In patients who carry the highest absolute risk for a recurrent event, aggressive drug therapy may be most justified. Reluctance to initiate lipid lowering drug therapy in patients with proven CHD should now be disputed.

Mode of death in patients with congestive heart failure: comparison between possible candidates for heart transplantation and patients with less advanced disease.

To study whether the relative incidence of sudden death versus progressive congestive heart failure is related to the severity of congestive heart failure as assessed by determination of peak oxygen consumption, we followed 90 ambulatory patients with moderate to severe congestive heart failure for 24.1 +/- 13.1 months. All patients had a left ventricular ejection fraction of 40% or less (mean, 22.6% +/- 9.2%) and a peak oxygen consumption of 20 ml/min/kg or less (mean, 14.7 +/- 3.5 ml/min/kg). Patients with severe congestive heart failure who might be eligible for heart transplantation (group I: n = 37; peak oxygen consumption < or = 14 ml/min/kg, mean, 11.0 +/- 1.8 ml/min/kg; mean left ventricular ejection fraction, 22.3% +/- 9.3%) were compared with those considered too well for heart transplantation (group II: n = 53; peak oxygen consumption > 14 < or = 20 ml/min/kg, mean, 17.1 +/- 1.6 ml/min/kg; mean left ventricular ejection fraction, 22.9% +/- 9.1%). During follow-up, 15 patients (41%) in group I died; 11 patients (21%) in group II died. In group I, seven of the 15 deaths (47%) were sudden; in group II, nine of the 11 deaths (82%) occurred suddenly. Patients who died suddenly had a significantly higher peak oxygen consumption (14.0 +/- 3.5 ml/min/kg) than those who died of progressive congestive heart failure (11.0 +/- 3.1 ml/min/kg; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Captopril reduces purine loss and reperfusion arrhythmias in the rat heart after coronary artery occlusion.

Captopril was perfused through isolated rat hearts; its effects after local ischemia and reperfusion were assessed. Upon reperfusion all untreated (10 out of 10) but only 4 (out of 10) captopril-treated (80 micrograms/ml) hearts fibrillated (P less than 0.02). Purine overflow increased upon reperfusion but was reduced by captopril (597 +/- 62 and 333 +/- 41 nmol/min gdwt respectively; P less than 0.05). The pressure-rate index and the apex displacement were severely impaired after 30 min of reperfusion (32 +/- 16 and 10 +/- 5% respectively of initial values) but captopril reduced the injury of mechanical function (60 +/- 8; P less than 0.05 and 61 +/- 11; P less than 0.05 respectively). These results show that captopril reduces ventricular fibrillation and the loss of high energy phosphate nucleotides and thereby partly maintains mechanical function impaired by ischemia and reperfusion.

Coronary vasodilation induced by captopril and zofenoprilat: evidence for a prostaglandin-independent mechanism.

In this study, the vasodilating properties of captopril and zofenoprilat, two angiotensin-converting enzyme (ACE) inhibitors containing the sulfhydryl group, are investigated in the isolated rat heart. It is demonstrated that both compounds increase coronary flow in a dose-dependent manner. However, the mean pD2 of zofenoprilat appears to be significantly higher than the mean pD2 of captopril (4.55 +/- 0.06 and 3.35 +/- 0.02 respectively), indicating that zofenoprilat is about ten times more potent in increasing coronary flow than captopril. Possibly this difference in potency between captopril and zofenoprilat can be explained by their physicochemical properties. Since zofenoprilat is more lipophilic than captopril, its concentration in cardiac and vascular tissues at distribution equilibrium is thought to be higher than the tissue concentration of captopril, which may result in a more pronounced vasodilatory action. The precise mechanism of coronary vasodilation induced by ACE inhibitors containing the sulfhydryl group is not yet understood. Several factors have been proposed, such as stimulation of prostacyclin production. However, in this study, concomitant administration of 10(-6) mol/l acetylsalicylic acid shows no antagonism, indicating that under normoxic conditions the vasodilatory effects of captopril and zofenoprilat are independent of the production of vasodilating prostaglandins. Therefore, other factors than stimulation of prostacyclin synthesis seem to be involved, such as prevention of bradykinin breakdown and/or potentiation of endothelium derived relaxing factor (EDRF). Furthermore, despite a marked inhibition of prostacyclin production, 10(-6) mol/l acetylsalicylic acid itself has no effect on coronary flow. These results suggest that prostacyclin does not play an important role in the regulation of coronary flow, at least in the normoxic isolated rat heart.

Cardiac arrhythmias--a new indication for angiotensin-converting enzyme inhibitors?

Ventricular arrhythmias (VA) are a major cause of sudden death. Life-threatening VA may be present in a variety of both acute and chronic conditions in which cardiac function is compromised: during acute myocardial infarction and subsequent reperfusion; some weeks after acute myocardial infarction, due to residual damage (scar formation with zones of heterogeneity); and as a consequence of congestive heart failure (CHF) resulting from myocardial infarction, dilated cardiomyopathy, hypertension or other causes. Symptomatic suppression of potentially life-threatening VA is unlikely to decrease mortality, since classical antiarrhythmic drugs have failed, so far, to improve life expectancy. Drugs that influence the underlying causes of CHF seem to have a better chance of reducing mortality. There is evidence that ACE inhibitors may exert beneficial effects on arrhythmogenicity by several mechanisms in these situations. Under acute ischaemic conditions both cellular damage and undue increases in circulating catecholamines and angiotensin II may be prevented. This has been demonstrated in various animal models and confirmatory clinical evidence is emerging. Two week after experimental myocardial infarction, the pig heart is less vulnerable to programmed electrical stimulation when ACE inhibitors are administered. Finally, in CHF a variety of proarrhythmic factors, such as left ventricular dysfunction, raised catecholamine levels and, in particular, decreased potassium concentrations, are influenced beneficially by ACE inhibitors.

Does the potential for development of streptokinase antibodies change the risk-benefit ratio in older patients?

In patients with acute myocardial infarction (MI), quick initiation of thrombolytic therapy is the best strategy for improvement of survival and reduction of morbidity. Streptokinase, a purified product of haemolytic streptococci, is the most commonly administered agent. The compound anistreplase (a complex of streptokinase to plasminogen), is available but currently not often used. The non-antigenic competitor for these two compounds for the indication of MI is alteplase (recombinant tissue plasminogen activator, rt-PA). Due to former use of streptokinase or its derivative anistreplase, patients may develop specific antibodies to the foreign protein, whereas cross-reacting antibodies may be due to streptococcal infections. These antibodies may neutralise streptokinase or its derivative in case of (re)administration and may mediate adverse events, sometimes serious. Since advanced age by itself is certainly not a contraindication to thrombolytic therapy, and because reinfarction occurs frequently, the benefit-risk ratio of re-exposure to streptokinase or its derivative is decreased in the elderly who present with reinfarction. In the framework of tailored thrombolytic therapy, alteplase or urokinase appear to be the drugs of choice in these patients.

Acute and chronic effects of ramipril and captopril in congestive heart failure.

We studied the acute and long-term effects of ramipril and captopril in 12 patients with moderate to severe congestive heart failure using an open, parallel design. Drug doses were titrated. Compared with baseline values, maximal haemodynamic and humoral effects after the first dose of both angiotensin converting enzyme inhibitors were similar, but the effects of ramipril (5 mg) demonstrated a slower onset of action and a significantly longer duration than captopril (12.5 mg). After 3 months of treatment a single dose of 5 mg ramipril showed the same 24-hour haemodynamic profile as after the first dose, but the hypotensive effect was less marked. There was no plasma accumulation of ramiprilat. Serum creatinine and potassium remained stable, except for one patient whose renal function deteriorated on captopril treatment. Complex ventricular arrhythmias occurred in 11 patients and were unaffected after treatment with ramipril or captopril. Two patients died suddenly during ramipril therapy and one patient during captopril therapy. In summary, ramipril is an effective, long-acting angiotensin converting enzyme inhibitor, producing long-term haemodynamic effects in patients with congestive heart failure. Using an individualised dosage scheme, neither long-lasting hypotension nor deterioration of renal function occurred. No effect on ventricular arrhythmias was seen.

Effects of dopaminergic agents on cardiac and renal function in normal man and in patients with congestive heart failure.

Dopamine is an effective drug in the management of acute congestive heart failure. Its beneficial action is due to both cardiovascular--peripheral vasodilation and positive inotropy--and renal effects. Dopexamine is one of the newer dopamine agonists. Like dopamine, however, it can only be administered intravenously, and its value in the chronic treatment of congestive heart failure is limited. For this reason, dopamine analogs were developed with oral bioavailability, including levodopa, fenoldopam and biopamine. Although both levodopa and fenoldopam have shown beneficial hemodynamic effects, these agents cannot be recommended for general use in patients with congestive heart failure. Levodopa frequently causes side effects, especially nausea, and fenoldopam induces an increase in neurohumoral activity, which limits its long-term efficacy. Ibopamine has vasodilatory, mild inotropic and diuretic properties and it lowers plasma norepinephrine levels. Since ibopamine is usually well tolerated, it appears to have the most interesting profile of these oral dopaminergic agents.