Medical care for individual patients: concepts beyond evidence-based medicine.

Todays evidence-based medicine has brought the practicing physician a vast amount of statistical evidence from which various stakeholders in the healthcare system obtain their arguments for and against the use of new therapies. Physicians assume an obligation to prescribe these new treatment options for their patients, firstly because of their eagerness to provide the best medicine, and secondly because of their fear of litigations. On looking at the published data, however, we have observed that the arguments for saving lives with a new treatment are not always supported by the underlying data. Sometimes the data show that the effect of treatment, in real terms, is only a relatively small gain in life-time prolongation. It is concluded that EBM-based concepts such as NNT (number needed to treat), absolute risk and relative risk fall short in ensuring real benefit for the patient. We have, therefore, put forward a mathematic model which takes into account the benefit of a treatment for the individual patient in terms of expected gain in lifetime duration. This model is readily applicable to published results on the clinical effects of a medical therapy and gives the practicing physician a useful tool for deciding whether to administer a medical therapy or not. By looking at the duration of treatment and the individual gain in lifetime expected, we have derived an effectiveness coefficient which can be used to categorize medical treatments into highly effective (close to 100%) and not effective (< 5%), and at the same time arrive at a cost-benefit analysis of the treatment in question. These simple concepts will help physicians and individual patients to make informed decisions based only on those medical therapies which are proven and appropriate. The model we have developed provides a new perspective in therapy for the individual patient using medicines that constitute a rational therapy i.e. a therapy that makes "sense" (sense-orientated medicine = SOM).

[Pharmacokinetics of beta-methyldigoxin and beta-acetyldigoxin in patients with cirrhosis of the liver (author's transl)]. / Zur Pharmakokinetik von beta-Methyldigoxin und beta-Acetyldigoxin bei Patienten mit Leberzirrhose.

In this prospective randomised study 12 patients suffering from cirrhosis of the liver (stable phase) and 12 healthy male volunteers were treated with either 0.3 mg beta-methyldigoxin (Lanitop) or 0.4 mg beta-acetyldigoxin (Novodigal) daily, orally. Every day the total serum digoxin concentrations of the patients and volunteers were measured by radioimmunoassay. Both digoxin and beta-methyldigoxin are measured by this method. In subjects receiving beta-methyldigoxin therapy the ratio of beta-methyldigoxin to digoxin in the serum was determined by liquid chromatography. The digoxin levels in patients with cirrhosis treated with beta-methyldigoxin were statistically significantly higher than in healthy volunteers. In patients with cirrhosis the proportion of serum beta-methyldigoxin averaged 77.7% of the total digoxin concentration, whereas the proportion was only 37.5% in healthy volunteers. With beta-acetyldigoxin there was no statistically significant difference between patients with cirrhosis and healthy volunteers. Alterations in pharmacokinetics may cause the higher total serum digoxin concentrations in cirrhotic patients. The following factors seem to be important: longer elimination half life, changes in distribution volume and reduced renal clearance. There is greater danger of digitalis toxicity in patients with cirrhosis of the liver on standard dosage of beta-methyldigoxin than on standard dosage of beta-acetyldigoxin.

[Digitalis therapy in practice: correlation between clinical evaluation and plasma digoxin concentration (author's transl)]. / Digitalistherapie in der Praxis. Zur Frage der Korrelation zwischen klinischer Beurteilung und Serumdigoxinkonzentration.

In a prospective study 73 patients on maintenance digitalis treatment at the Paracelsus Institute, Bad Hall, were clinically examined and the dosage of the drug was adjusted according to cardiac symptoms. The clinical effects were correlated to digoxin concentrations measured on the day following admission to hospital and on the 21st day of treatment. The following practical conclusions were reached: 1. More than 50% of the patients were underdigitalized. 2. There is often no indication for digitalis therapy in patients with a low daily maintenance digoxin dosage and normal renal funciton. 3. The usual recommended maintenance dosage of digoxin provides serum digoxin levels in the lower region of the therapeutic range. 4. Patients with symptoms of decompensation taking an average dosage of digoxin need more digitalis. There is generally no danger of toxicity when the dosage is increased. 5. The serum digoxin concentration in patients with slightly reduced renal function lies in the upper region of the therapeutic range with usual doses of digoxin.

[Haemodynamic characterization of a new beta-receptor blocker celiprolol (st1396) at rest and during ergometer exercise compared with propranolol (inderal) (author's transl)]. / Hämodynamische Charakterisierung eines neuen beta-Rezeptorenblockers: Celiprolol (ST1396) in Ruhe und unter Erogometerbelastung, verglichen mit Propranolol (Inderal).

A new beta-receptor blocker (Celiprolol) was characterized in man by haemodynamic studies carried out on a random cross-over basis in 6 volunteers before and after intravenous administration of the drug or propranolol. The studies were performed at rest and in response to ergometer exercise. The studies showed that: 1. Celiprolol is a cardio-selective beta-receptor blocker with pronounced intrinsic sympathomimetic activity. Hence, Celiprolol increases the heart rate and cardiac output at rest. 2. The heart rate was reduced by Celiprolol during pronounced physical exercise. 3. Celiprolol probably has only a very slight blocking effect on those, beta1-receptors which mediate a positive inotropic effect. 4. The increase in blood pressure during exercise was less pronounced during Celiprolol medication than with propranolol.

[Haemodynamic effects after application of nitroglycerin sublingually or as ointment in patients with left ventricular heart failure (author's transl)]. / Hämodynamische Veränderungen nach Applikation von Nitroglycerin sublingual oder in Salbenform bei Patienten mit linksventrikulärer Insuffizienz.

The haemodynamic effects of a 2% nitroglycerin ointment and of sublingual nitroglycerin in patients with left ventricular heart failure were investigated. The well-known pulmonary blood pressure and pulmonary wedge-pressure lowering effect were observed with both forms of administration. Differences exist between onset and duration of the haemodynamic effects. With sublingual administration of nitroglycerin the peak effect was seen after 5 minutes, whilst the pulmonary blood pressure rose again 30 minutes later. After application of nitroglycerin ointment a peak effect was seen 30 minutes later and the effects were sustained for 3 to 6 hours.

Mepindolol sulfate in the hyperkinetic heart syndrome.

In a single-blind test vs placebo in two crossover therapy phases, each lasting 4 weeks, it was shown in six clinical cases of hyperkinetic heart syndrome that 2 X 2.5 mg mepindolol sulfate daily is able to (1) lower significantly the HR and the systolic BP at rest and during exercise on the ergometer, (2) normalize or increase by 100% the restricted effective working capacity, and (3) improve the subjective symptoms. Mepindolol sulfate can accordingly be regarded as an effective therapeutic agent in hyperkinetic heart syndrome.

Relevance of selectivity and non-selectivity in beta-adrenoceptor blocking drugs.

1 The heart rate responses to increasing doses of isoprenaline (n = 6) (during infusion with atropine 0.5 mg/min i.v.) and noradrenaline (n = 5), (during infusion with phentolamine 160 mg/h i.v.) were recorded before and after the intravenous administration of propranolol (15 mg) or metoprolol (15 mg). 2 In the doses used, metoprolol was less potent than propranolol in antagonizing isoprenaline-induced tachycardia, during atropine infusion. 3 In volunteers treated with phentolamine both metoprolol and propranolol produced similar inhibition of noradrenaline-induced tachycardia, indicating comparable beta 1-adrenoceptor blockade in the doses used. 4 The fact that the shift of the dose-response curve of isoprenaline-induced tachycardia was smaller after metoprolol than after propranolol supports the hypothesis that beta 2-adrenoceptors are present in the heart.

Isometric exercise before and after beta-receptor blockade with propranolol and mepindolol sulfate.

The effect of isometric exercise on hemodynamic parameters before and after beta blockade were investigated in two groups of six male volunteers, ages 25-28 years. On the basis of a randomized scheme, the subjects received either 15 mg propranolol i.v. or 0.5 mg mepindolol sulfate i.v. Cardiac output (CO) was determined by means of the Swan-Ganz thermodilution technique, and blood pressure was measured invasively in the radial artery. Analysis of the results pointed to the following conclusions. Isometric contraction brings about a reflex constriction of arterial and venous vessels, and thus an increase in blood pressure, pulmonary artery wedge pressures (PAWP) and CO, as well as a reduction in stroke volume (SV). The circulatory reflex mechanism operative during isometric exercise cannot be significantly influenced by beta blockade with propranolol or mepindolol sulfate. The increase in heart rate during isometric exercise is therefore unlikely to be the result of sympathetic activation, but rather of other (vagal?) reflex mechanisms.

Stress, catecholamines and beta-blockade.

In order to investigate the effects of beta-blockade on haemodynamic response to stress, 2 groups of volunteers received either propranolol or mepindolol sulphate under basal conditions and under the stress of mental arithmetic. In control conditions, increases occurred in heart rate (HR), cardiac output (CO) and systolic and diastolic blood pressure in response to calculation stress. Stress-induced increases in HR and CO were significantly reduced by propranolol. Systolic blood pressure during calculation stress under propranolol was slightly less than in control conditions. However, diastolic blood pressure under stress was higher with propranolol than in the control study. Mepindolol sulphate also reduced HR and CO under calculation stress but it produced no significant change in diastolic pressure. A significant increase in plasma adrenaline occurred under stress. The level was not altered by propranolol but was reduced to less than 50% of the untreated stress value by mepindolol. Since beta-blocking agents suppress an increase in heart rate in stressful situations but either fail to prevent or even potentiate increased diastolic pressure, their use in patients without hypertension should be reserved for those showing pathological stress reactions. They do not appear to be indicated for the management of stressful situations in general.

Demonstration of two different types of beta1-receptors in man (selective blockade of the positively inotropic and the positively chronotropic effect of isoproterenol).

The hemodynamic effect of a beta-receptor blockade with mepindolol--a noncardioselective beta-receptor blocker--was studied in 6 male test subjects age 25 to 30 years with an increasing dose of isoproterenol. The cardiac output per min, the heart rate and the stroke volume, the wet blood pressure and the contractility parameters dp/dt max in the right and left ventricles were measured as part of the study. It was found that a dissociated right shift of the dose-effect curves occurred for the stroke volume, contractility parameters and heart rate. The following major conclusions can be made from an exact analysis of this result: 1. Evidence was produced that a distinction must be made in man with respect to the so-called beta1-receptors between those which mediate a specific effect on the heart rate and those which mediate a primarily positively inotropic effect. 2. There are apparently some beta-receptor blockers which inhibit the frequency receptors primarily and the inotropic receptors to a lesser extent. 3. Through their beta 2-effect, noncardioselective beta-receptor blockers can partly compensate for their negatively inotropic effect on the heart by maintaining the Frank Starling mechanism.

[Dehydration in the aged]. / Exsikkose im Alter.

UNLABELLED: The present study seeks to examine the question of the etiology, the diagnostic criteria and therapeutic consequences of exsiccosis in the elderly. The study includes 14 patients (9 males, 5 females) with an average of 76,8 +/- 4,8 years of age, all hospitalized because of dehydration. Following an exact diagnostic procedure a controlled therapy including a discontinuation of treatment was introduced in order to allow an evaluation of the development of dehydration. RESULTS: 1. The diagnosis of senile exsiccosis requires a synthesis of the patient's history, an exact physical examination and laboratory analysis. The central venous pressure (CVP) can be regarded as the most reliable parameter (it was lower than normal in 100% of the patients). There was a strikingly high incidence of increased mean corpuscular volume (MCV)-more than 105 rm3 in 86% of the cases. 2. The mean liquid-deficit of elderly patients with exsiccosis was 4,8 +/- 2,81. 3. The reason for the frequent incidence of exsiccosis in advanced age is to be found in a relative adipsia (the average daily deficit of liquid-intake was 815 +/- 47 ml per patient). Combined with a diminished renal concentration capacity (78,5% of the patients did not reach a specific weight of urine more than 1020 after a concentration test). 4. As a preventive measure, patients with tendency for exsiccosis should receive instructions as to the necessity of daily liquid-intake following exact balancing; furthermore regular weight-controls should be performed.

Comparison of digoxin and dobutamine in patients with severe dilatative cardiomyopathy.

The hemodynamic effects of dobutamine were compared with those of digoxin in seven patients with severe diffuse dilatative cardiomyopathy. Dobutamine (7.5 micrograms per kg of body wt per min) was given intravenously for 30 min and then discontinued until hemodynamics returned towards base line. Digoxin (12.5 micrograms per kg) was then given intravenously and hemodynamics were recorded for 120 min. Thereafter, dobutamine was again given at the previous dose. Dobutamine increased cardiac and stroke volume index and decreased pulmonary occlusive (wedge) pressure and systemic vascular resistance without changing heart-rate or arterial pressure. Digoxin also increased cardiac and stroke volume index and decreased pulmonary wedge pressure and systemic vascular resistance with digoxin without changing arterial pressure. In contrast to dobutamine, heart-rate was decreased with digoxin indicating reduced myocardial oxygen demand. Re-infusion of dobutamine did not have any notable hemodynamic effect, with the exception of an increase in heart-rate-systolic pressure production. These data indicate that the positive inotropic properties of digoxin and dobutamine are not additive. Furthermore, concerning the effect of digoxin on the heart-rate, its use seems preferable to the use of sympathomimetic agents such as dobutamine, in patients with diffuse chronic dilatative myocardiopathy.

Contribution to the biochemical characterization of cardiac glycosides concerning their influence on ATP-ases.

1. A comparison of the complex binding constants of different glycosides show no significant differences between these different glycosides at least not in the model containing ATP. 2. There are greater differences regarding the ATP-ase activity of the different glycoside complexes measured by means of the Rb-transport method. 3. The absorption of different proscillaridin and methylproscillaridin preparations was investigated with this method. 4. Using the rat as experimental animal the effect of different glycosides on the Na-K and Ca ATP-ase of the heart muscle was demonstrated showing a remarkable activation of the Ca-activated ATP-ase caused by proscillaridin. In order to find an explanation for the therapeutic and toxic effects these investigations have to be repeated in the pig, which shows more similarities in the ATP-ase distribution to man than the rat.

Haemodynamic effects of bisoprolol in patients with coronary heart disease: influence of various bisoprolol plasma concentrations.

The aim of this study was to investigate the haemodynamics of the beta 1-selective beta-blocker bisoprolol at plasma concentrations that would be expected to block completely the cardiac beta-receptors. Seven patients with stable exercise-dependent angina pectoris received 40 mg bisoprolol, and six patients received 10 mg bisoprolol orally as a single dose. Before and 1.5 h after administration, the following parameters were measured at rest and during physical exercise within the framework of an invasive diagnostic investigation: cardiac output, blood pressure in the systemic and pulmonary circulation, heart rate, and ST-segment change. Further haemodynamic factors were derived from these parameters. Before beta-blockade, the change from rest to exercise resulted in an increase in heart rate, blood pressure, and cardiac index, and also in an increase in pulmonary capillary wedge pressure as an indication of ischaemically induced left-ventricular dysfunction. After 40 mg bisoprolol, under exercise conditions, the cardiac index decreased as a consequence of reduced heart rate, and the mean pulmonary capillary wedge pressure increased slightly, compared with baseline. This finding was attributable to clearer changes in three patients; however, as an overall result, an improvement of oxygen consumption also was achieved in these patients. Measured by reduction in cardiac index, no appreciable increase in effect was achieved at bisoprolol plasma concentrations greater than 60 ng/ml. In angina pectoris patients, bisoprolol possesses the typical haemodynamic profile of a beta-adrenoceptor antagonist. There was no indication of a beta-blockade-independent negative inotropic effect of bisoprolol. Forty mg bisoprolol was shown to be an unnecessarily high dose. It may be deduced that the therapeutic dose range of bisoprolol is between 5 and 20 mg.

Digoxin concentration in cerebrospinal fluid-a study carried out after 9 days of treatment of beta-methyldigoxin or beta-acetyldigoxin.

Two groups of seven healthy volunteers were treated for 9 days with either 0.3 mg beta-methyldigoxin or 0.4 mg beta-acetyldigoxin daily, applied orally. On the 10th day, digoxin concentrations in plasma and cerebrospinal fluid (CSF) were determined by radioimmunoassay. After therapy with beta-methyldigoxin the plasma/CSF digoxin concentration ratio was 3.7:1; after therapy with beta-acetyldigoxin it was 3.2:1. There was no significant difference in the plasma/CSF digoxin concentration ratio after 9 days of treatment with equipotent doses of beta-methyldigoxin and beta-acetyldigoxin.