Post-approval trials of new medicines: widening use or deepening knowledge? Analysis of 10 years of etanercept.

OBJECTIVE: To investigate the main aims of the post-approval randomized controlled trials (RCTs) on etanercept and the extent to which they were designed to gain more comparative information. METHODS: A search of the literature (Medline, Embase), trial registries (Clinical Trials.gov, Controlled Trials.com), and market authorization reports from the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) was carried out to identify all RCTs. A comparison of trial data identified unpublished trials and multiple publications relating to the same study. All RCTs completed and/or published after initial market approval was regarded as post-approval. RESULTS: Up until 2008, we found 84 post-approval trials, 11 (13%) trials on approved extensions of indication, another 30 (36%) trials on the approved indications, and 43 (51%) trials on indications not (yet) approved. Nearly half of the studies on indications not yet approved were initiated and funded by independent sponsors. After the initial approval of etanercept, six head-to-head trials were conducted on the approved indications. Overall, the main objectives of post-approval trials with etanercept were found to confirm efficacy and safety in new indications, and to gather additional information for optimal use on the approved indications. CONCLUSION: Post-approval RCTs on etanercept focus more on studies searching for new indications than on deepening knowledge about use. Ten years after the market entry of etanercept, one of the reasonable demands of clinical practice, for more comparative information, still remains unanswered.

Assessment of outcome in ankylosing spondylitis: an extended radiographic scoring system.

OBJECTIVE: To develop and validate an extensive radiographic scoring system for ankylosing spondylitis (AS). METHODS: The Stoke Ankylosing Spondylitis Spinal Score (SASSS) was modified by adding a score for the cervical spine and defining squaring. This modified SASSS (mSASSS) is the sum of the lumbar and cervical spine score (range 0-72). 370 lateral views of the lumbar and cervical spine were used for development of the mSASSS, standardisation of observers, and for studying reliability. In a 48 week NSAID study of 57 patients, change over time and construct validity were studied. RESULTS: Interobserver correlations of the lumbar and cervical spine scores were good (r>0.95). The interobserver duplicate error was 0.55 in a range from 0 to 36. The mean change in the cervical and lumbar spine scores between weeks 0 and 48 of all patients was 1.45 (range 0-6.0) and 1.06 (0-5.0), respectively (paired t testing, p<0.001). Change in radiological score was seen in 36/57 (63%) patients (lumbar and cervical spine 11, cervical spine 12, lumbar spine 13 patients). CONCLUSION: The mSASSS is useful for assessing extensive radiographic damage in AS. It is reliable, detects changes over 48 weeks, and shows a satisfactory face and construct validity.

Diuretic therapy in elderly heart failure patients with and without left ventricular systolic dysfunction.

Long term prescription of diuretics for heart failure is very prevalent among elderly patients, although the rationale for such a treatment strategy is often unclear, as diuretics are not indicated if volume overload is absent. The concept of diastolic heart failure in the elderly might particularly change the role of diuretic therapy, since diuretics may have additional adverse effects in these patients. This paper reviews the effects of diuretic therapy in elderly patients with heart failure, emphasising the differences between patients with normal and decreased left ventricular systolic function. Studies on diuretic withdrawal in elderly patients with heart failure are discussed, with emphasis on issues involved in decision making such as diuretic dose reduction and withdrawal in elderly patients and factors that have been established to predict successful withdrawal. Existing guidelines on the prescription of diuretics in elderly patients with heart failure with normal and decreased left ventricular systolic function and in those with diastolic heart failure are also discussed. By reducing intravascular volume, diuretics may further impair ventricular diastolic filling in patients with diastolic heart failure and thus reduce stroke volume. Indeed, preliminary studies demonstrate that diuretics may provoke or aggravate hypotension on standing and after meals in these patients. Therefore, it is suggested that elderly patients with heart failure with intact left ventricular systolic function should not receive long term diuretic therapy, unless proven necessary to treat or prevent congestive heart failure. This implies that physicians should carefully evaluate the opportunities for diuretic dose tapering or withdrawal in all of these patients, and that a cautiously guided intermittent diuretic treatment modality may be critical in the care for older patients with heart failure with intact left ventricular systolic function.

Furosemide withdrawal in elderly heart failure patients with preserved left ventricular systolic function.

To explore the possibilities of furosemide withdrawal in elderly heart failure (HF) patients with intact left ventricular (LV) systolic function and assess its effects on functional status and orthostatic blood pressure homeostasis, we performed a placebo-controlled pilot trial of furosemide withdrawal with 3 months of follow-up in 32 HF patients (aged 75.1 +/- 0.7 years [mean +/- SEM]) with a LV ejection fraction of 60 +/- 2% and without overt congestion. Investigations included repeated clinical assessment, spirometry, standardized 6-minute walking test, and chest x-rays. Measurements of blood pressure response on active standing and Doppler echocardiography were performed before and 3 months after furosemide withdrawal. Recurrent congestive HF occurred in 2 of 21 patients (10%) who discontinued furosemide use, and in 1 of 11 patients (9%) who continued furosemide (p = NS). Three patients restarted furosemide for ankle edema and 1 for blood pressure levels >180/100 mm Hg. After 3 months, there were no differences regarding HF symptom scores, blood pressure, heart rate, spirometric results, 6-minute walking distance, or quality of life scores between patients who discontinued use and patients who continued the therapy. In patients successfully withdrawn, Doppler E/A ratio increased from 0.68 +/- 0.05 to 0.79 +/- 0.06 after withdrawal (p <0.01), and maximum blood pressure decrease on active standing changed from -8 +/- 5 mm Hg to +5 +/- 3 mm Hg systolic (p <0.05). Thus, in this pilot investigation of furosemide withdrawal in elderly HF patients without overt congestion and with a normal LV systolic function, withdrawal was successful in almost all patients and was associated with improvement of LV diastolic filling and blood pressure homeostasis on active standing.

Pharmacovigilance in perspective.

Pharmacovigilance is more than spontaneous reporting alone, and the evaluation of marketed medicines is more than just pharmacovigilance. The positioning of a drug usually takes place during the years following introduction, when worldwide experience has accumulated. Originally a modest appendix of drug regulation, pharmacovigilance has become a major activity. The provision of the information needed for the evaluation of the benefits and risks of drugs is in the first place a scientific challenge. In addition, there are important ethical, logistical, legal, financial and commercial constraints. Good pharmacovigilance practice needs to be developed to ensure that data are collected and used in the right way and for the right purpose. Pharmacovigilance, and more generally the study of the benefits and risks of drugs, plays a major role in pharmacotherapeutic decision-making, be it individual, regional, national or international. In addition, pharmacovigilance is becoming a scientific discipline in its own right. A variety of changes are taking place in the complex system of drug development, regulation and distribution. Pharmacovigilance should be proactive in monitoring their possible consequences.

Prescription patterns of diuretics in Dutch community-dwelling elderly patients.

AIMS: To describe age- and gender-related prescription patterns of diuretics in community-dwelling elderly, and to compare diuretics to other cardiovascular (CV) medications. METHODS: Cross-sectional study of patient-specific prescription data derived from a panel of 10 Dutch community pharmacies. Determination of proportional prescription rates and prescribed daily dose (PDD) of diuretics, cardiac glycosides, nitrates, angiotensin converting enzyme (ACE) inhibitors, beta-adrenoceptor blockers, and calcium channel blockers in all 5326 patients aged 65 years or older dispensed CV medications between August 1st, 1995 and February 1st, 1996. RESULTS: Diuretics were prescribed to 2677 of 5326 patients (50.3%), 1325 patients (24.9%) using thiazides and 1198 patients (22.5%) using loop diuretics. Prescription rates of loop diuretics increased from 15.1% in patients aged 65-74 years to 37.2% in patients aged 85 years or older. Rates also increased for digoxin and nitrates. Rates for thiazide diuretics remained unchanged with age; rates for beta-adrenoceptor blockers, ACE inhibitors and calcium channel blockers declined with age. Thiazides were prescribed to 30.1% of women compared with 16% of men (P < 0.001). Average PDD was 135 +/- 117% of defined daily dose (DDD) for loop diuretics, and highest for bumetanide (245 +/- 2.01% of DDD, equivalent to 2.5 +/- 2.0 mg). Average PDD was 74 +/- 40% of DDD for thiazides, and highest for chlorthalidone (100 +/- 49% of DDD, equivalent to 25 +/- 12 mg). CONCLUSIONS: Important characteristics of diuretic usage patterns in this elderly population were a steep increase in loop diuretic use in the oldest old, a large gender difference for thiazide use, and high prescribed doses for thiazides.

Mechanisms of drug transfer across the human placenta.

In this review we summarized literature data on the mechanisms of human placental drug transport studied in the isolated perfused placental cotyledon, placental membrane vesicles or trophoblastic cell cultures. Overall human placental drug transport rarely exceeds the transfer of flow-dependent and membrane-limited marker compounds. Interestingly, relatively often placental drug transfer appeared to be much smaller, indicating impaired trans-placental transport, depending on the physico-chemical characteristics of the drug or placental factors such as tissue binding or metabolism. Although in perfusion studies overall human placental drug transport occurs by simple diffusion, at the membrane level several drug transport systems have been found, mainly for drugs structurally related to endogenous compounds.

Loop diuretics in patients aged 75 years or older: general practitioners' assessment of indications and possibilities for withdrawal.

OBJECTIVE: To examine the indications for prescription and possibilities for withdrawal of loop diuretics in community-dwelling patients aged 75 years or older, as reported by their general practitioners (GPs). METHODS: Analysis of dispensary data to identify patients aged 75 years or older using loop diuretics on 1 February 1996. Questionnaires were sent to the GPs of these patients to inquire about the indications for loop diuretic prescription and the necessity for continuation. We subsequently determined loop diuretic prescription rates in the survey population over the next 9 months. SETTING: A panel of nine Dutch community pharmacies. RESULTS: Questionnaires were returned for 338 out of 667 patients (50.7%) using loop diuretics on 1 February 1996. Reported indications for loop diuretic use were heart failure in 223 patients (66.0%), hypertension in 35 patients (10.4%), and a combination of both in 23 patients (6.8%). Loop diuretics were used for ankle edema in 27 patients (8.0%) and for unknown reasons in another 27 patients (8.0%). Continuation of treatment was considered unnecessary by GPs in 66 out of 338 patients (19.5%). However, prescription rates for these 66 patients in the following months were no different from rates for the remaining 272 patients. Loop diuretics were still prescribed to 47 of 66 patients (71.2%) after 12 weeks, and to 26 patients (39.4%) after 36 weeks. CONCLUSIONS: GPs reported substantial opportunities for withdrawal of loop diuretics in patients over 75 years of age, but this did not influence actual prescription rates in these patients. Future studies should explore means of facilitating withdrawal of these medications in this population.

Use of diuretics and opportunities for withdrawal in a Dutch nursing home population.

BACKGROUND: Diuretics are frequently used by elderly patients and overprescription has been suggested. However, the present withdrawal patterns of these medications in clinical practice elderly patients are unclear. METHODS: Retrospective medical record analysis of all 584 patients aged 75 years or older admitted to a 240-bed nursing home facility in the years 1990-1994. One-year follow-up by record review and collection of updated information from nursing home physicians. RESULTS: Two hundred and twenty patients (37.7%) used diuretics, and use increased with age (p < 0.05). Reported indications for prescription were heart failure (n = 77), hypertension (n = 38), ankle edema without heart failure (n = 21), or not reported (n = 84). Diuretics were withdrawn in 82 of 220 patients (37.3%), but a doubtful actual indication for diuretic use was found in 72 of the remaining 138 patients (52.2%). After withdrawal, the probability of remaining free from diuretics for at least one year was 0.47. There were no reports of life-threatening or fatal incidents after withdrawal. Mortality rates for the patients whose diuretics were withdrawn did not differ from patients continuing on diuretics. CONCLUSIONS: Withdrawal of diuretics was frequently performed and often successful. In addition, doubtful indications for diuretics were found in half of the patients continuing on these medications, suggesting additional opportunities for diuretic withdrawal.

Diuretic usage and withdrawal patterns in a Dutch geriatric patient population.

OBJECTIVES: To describe diuretic usage and withdrawal patterns in a population of very old geriatric patients and to evaluate the long-term probability of remaining free from diuretic therapy after withdrawal. DESIGN: Retrospective analysis of medical records and 1-year follow-up study. SETTING: University Hospital Nijmegen and Rijnstate Hospital Arnhem, a non-academic teaching hospital, The Netherlands. PARTICIPANTS: All 1547 patients, aged 75 years or older, visiting geriatric medicine departments in the two hospitals for the first time in the years 1990 through 1993. MEASUREMENTS: Data on medical history, physical examinations, and medication use were obtained from medical records. Diuretic withdrawal and motivation was recorded as reported. Record review indicating diuretic withdrawal prompted a 1-year follow-up investigation and collection of additional updated information from family care and/or nursing-home physicians. RESULTS: A total of 593 three patients (38.3%) were using diuretics. Use of diuretics increased with age from 33.6% in patients aged 75 to 79 years to 47.4% in patients aged 90 years or older (P < .05). Diuretics were withdrawn in 218 patients (36.8%), in 101 patients because of doubts about the initial or persistent indication for diuretic use and in 91 patients because of adverse effects. No reasons for withdrawal were reported in 26 patients. Withdrawal of diuretics was attempted more often in cases of diuretic prescriptions for unknown reasons (51.2%) or ankle edema without heart failure (45.0%) than when prescriptions were for heart failure (28.5%) or hypertension (35.4%). The overall probability of remaining free of diuretic therapy for 1 year was 0.41. Success of diuretic withdrawal was significantly less when congestive heart failure was the initial indication for prescription (probability 0.24). We did not find other clinical parameters related to the success of withdrawal. CONCLUSIONS: Our study demonstrates that diuretic therapy can be withdrawn for at least a 1-year period in a substantial number of very old geriatric patients receiving these medications, regardless of the initial indications for prescription. However, withdrawal is performed without application of uniform criteria. Future prospective studies should be directed at developing clear guidelines for diuretic withdrawal in order to facilitate identification of eligible patients and to further improve the success of withdrawal attempts.

Principles of signal detection in pharmacovigilance.

Adverse drug effects are manifold and heterogenous. Many situations may hamper the signalling (i.e. the detection of early warning signs) of adverse effects and new signals often differ from previous experiences. Signals have qualitative and quantitative aspects. Different categories of adverse effects need different methods for detection. Current pharmacovigilance is predominantly based on spontaneous reporting and is mainly helpful in detecting type B effects (those effects that are often allergic or idiosyncratic reactions, characteristically occurring in only a minority of patients and usually unrelated to dosage and that are serious, unexpected and unpredictable) and unusual type A effects (those effects that are related to the pharmacological effects of the drug and are dosage-related). Examples of other sources of signals are prescription event monitoring, large automated data resources on morbidity and drug use (including record linkage), case-control surveillance and follow-up studies. Type C effects (those effects related to an increased frequency of 'spontaneous' disease) are difficult to study, however, and continue to pose a pharmacoepidemiological challenge. Seven basic considerations can be identified that determine the evidence contained in a signal: quantitative strength of the association, consistency of the data, exposure response relationship, biological plausibility, experimental findings, possible analogies and the nature and quality of the data. A proposal is made for a standard signal management procedure at pharmacovigilance centres, including the following steps: signal delineation, literature search, preliminary inventory of data, collection of additional information, consultation with the World Health Organization Centre for International Drug Monitoring and the relevant drug companies, aggregated data assessment and a report in writing. A better understanding of the conditions and mechanisms involved in the detection of adverse drug effects may further improve strategies for pharmacovigilance.

Causal or casual? The role of causality assessment in pharmacovigilance.

As with any other study method, 'spontaneous reporting' in pharmacovigilance is a process of data acquisition, assessment, presentation and interpretation. The provision of information (i.e. of interpreted data) concerning previously unknown, or otherwise important adverse drug reactions is a major goal. The assessment of case reports in spontaneous reporting takes place in 2 steps: first the assessment of each case individually, and secondly the interpretation of the aggregated data. The latter step is only completed for a minority of case reports, such as when actions or measures are deemed necessary. Uncertainty in case reports regarding the involvement of the suspected drugs is an inherent drawback of spontaneous reporting. Standardised case-causality assessment has become a routine at pharmacovigilance centres around the world. It aims at a decrease in ambiguity of the data and plays a role in data exchange and the prevention of erroneous conclusions. A variety of systems for standardised causality assessment have been developed, ranging from short questionnaires to comprehensive algorithms. Since none of the available assessment systems has been validated (i.e. shown to consistently and reproducibly produce a fair approximation of the truth), causality assessment has only limited scientific value. Causality assessment neither eliminates nor quantifies uncertainty but, at best, categorises it in a semiquantitative way. Routine causality assessment is usually part of the first step in case assessment, and is based on a general system that is intended for all reactions and all drugs. During the subsequent phase of aggregated assessment, causality assessment is likely to be repeated and the use of a specific aetiological-diagnostic system may be more appropriate. It may be recommended to restrict case-causality assessment to selected case reports that are likely to play an active role in pharmacovigilance and to use specific systems, adapted to the reaction or problem involved. It is an inherent limitation of spontaneous reporting that, with the exception of rare proof-positive case reports, conclusive evidence cannot usually be produced. Standardised causality assessment has not really changed this situation. As a rule, confirmation of the connection between a drug and an adverse reaction requires further analytical or experimental study.

Disease activity in ankylosing spondylitis: selection of a core set of variables and a first set in the development of a disease activity score.

A large number of variables are available for the assessment of disease activity in ankylosing spondylitis (AS). The aim of this study was to evaluate the validity of commonly used variables, to select a core set of valid variables for disease activity and finally to compute an AS disease activity score (AS-DAS). Data from two longitudinal studies were used. Principal component analysis and reliability analysis resulted in 11 factors: cervical mobility, lumbar flexion, subjective complaints, functional index (FI), enthesis index (EI), inflammatory response, IgA, IgM, root joints, swollen joints and spinal mobility. Based on discriminating power, reproducibility and correlation with disease duration, seven single variables were selected. In a subsequent discriminant analysis, an AS-DAS was computed of five variables, i.e. subjective complaints, FI, EI, root joints and C-reactive protein, which should be validated in the future. A core set of process variables solves the problem of multiple testing in clinical trials, and improves comparability.

Methotrexate in severe ankylosing spondylitis: an open study.

OBJECTIVE: To study the efficacy and toxicity of methotrexate (MTX) for patients with ankylosing spondylitis (AS) in a 36 week, open, single observer study. METHODS: Patients were selected for study if they had evidence of active disease and had failed to respond to treatment with nonsteroidal antiinflammatory drugs (NSAID) and sulfasalazine. Eleven patients entered the study, and 9 were evaluated at the end. Oral MTX (7.5-15 mg weekly) was given for at least 24 weeks; NSAID were kept at a stable dose. Efficacy was evaluated by calculating the relative difference of assessed variable between Week 0 and 24 and by patient evaluation. RESULTS: Assessed variables showed good relative improvement. Four patients decided to continue MTX; 3 used a lower dose of NSAID; one stopped NSAID: Five patient patients discontinued MTX: 3 of these had disease flares and restarted MTX. Side effects were mild and reversible. CONCLUSION: Results of our study showed that the majority of our patients with AS taking MTX had beneficial effects.

Ion-pair solid-phase extraction of cimetidine from plasma and subsequent analysis by high-performance liquid chromatography.

An improved method is described for the solid-phase extraction of cimetidine from plasma or serum with subsequent analysis by HPLC. New aspects of the method include protein precipitation with metaphosphoric acid (5%, w/v), followed by selective adsorption of cimetidine and the internal standard ranitidine on the surface of a solid-phase phenyl (PH Bond Elut) column, using octanesulfonate as an ion-pairing agent. Separation was achieved on a LiChrosorb RP-18 column with a mobile phase consisting of acetonitrile-0.01 M phosphate buffer pH 3.0 containing 0.005 M octanesulfonate (22:78, v/v). The intra-assay coefficient of variation varied between 0.7 and 4.0%. The procedure provides cleaner and more stable samples and a better recovery (90 +/- 2.3%) and sensitivity (limit of detection 5 ng/ml and limit of quantitation 25 ng/ml) as compared with previous methods.

Second-line treatment in seronegative spondylarthropathies.

The literature concerning second-line treatment of seronegative spondylarethropathies from 1940 to August 1993 was reviewed. Sulfasalazine appeared to be effective in the treatment of ankylosing spondylitis (AS) and promising in reactive arthritis (ReA) and Reiters' syndrome (RS). Methotrexate and azathioprine were associated with a remarkable improvement in some cases of AS and RS. Methylprednisolone and levamisole were both efficacious in AS, but levamisole was associated with occasional severe side effects. Radiation therapy led to short-term improvement in AS, but was abandoned because of severe long-term side effects. Only sulfasalazine has been studied in sufficient detail to allow definitive conclusions, but methotrexate and azathioprine may be promising drugs.

A Dutch version of the functional index for ankylosing spondylitis: development and validation in a long-term study.

A Dutch Functional Index (DFI) for AS has been developed, containing 37 questions in essence this is a modification of a French index with additional questions. Internal consistency, reproducibility, criterion and construct validity and sensitivity to change were studied in different groups of AS patients. In a group of 149 patients the questionnaire was completed and internal consistency calculated (Cronbach's alpha = 0.94) after exclusion of three items. Reproducibility was studied in 39 patients with stable disease; Pearson correlation was 0.94. Criterion validity, against a 'gold standard' i.e. experts' observation of 25 items, was studied in 19 patients; r = 0.85. In a 48-week NSAID study patients were enrolled after a washout period: DFI scores before and after treatment showed significant improvement (P < 0.02). There were 187 DFI with corresponding clinical measurements, correlations varied from -0.30 to 0.68. Estimated measurement-remeasurement correlation was 0.87. The DFI is, thus, a potentially useful instrument, which is valid, reliable and sensitive to the effects of NSAID treatment.

Drug use and adverse drug reactions in 105 elderly patients admitted to a general medical ward.

OBJECTIVE: To examine the influence of admission to hospital on the number of drugs used by the elderly and to study the occurrence of adverse drug reactions (ADRs), their contribution to the need for hospitalization and the relation to hospital stay. PATIENTS AND METHODS: Drug use and its sequelae were studied by one observer in 105 patients aged 65 years and older, successively admitted to a general medical ward. Naranjo's algorithm was used to estimate the probability of an ADR. Multiple regression analysis was used to measure interrelationships between variables. RESULTS: There was a slight but significant increase in drug use per patient (4.9 prescriptions on admission, 5.3 at discharge); 120 ADRs occurred, 57 on admission, 63 during stay. Two ADRs were potentially fatal. Drugs most often involved were diuretics, ADRs occurring mainly on admission. During stay in hospital antimicrobials were mainly responsible. There was a strong correlation of both ADRs on admission and ADRs during stay with duration of hospital stay. ADRs did not correlate with the number of drugs in use on admission or with the number of diagnoses. A direct correlation between the occurrence of ADRs and age could not be confirmed, when corrected for possible confounding factors. Fourteen of 105 admissions were definitely or probably drug-induced; diuretics were incriminated 6 times. CONCLUSIONS: Drug use per patient corresponded with that in the literature. Thirty-seven per cent of patients experienced a definite or probable ADR. The percentage of drug-induced admissions (14.7%) agrees with the literature, although the drugs involved (mainly diuretics in our study) were markedly different. The occurrence of ADRs, both on admission and during stay is correlated with the duration of hospital stay, but not with drugs in use or with the number of diagnoses.

[Changes in drug use during a stay in a psychogeriatric nursing home]. / Veranderingen in geneesmiddelengebruik tijdens verblijf in een psychogeriatrisch verpleeghuis.

OBJECTIVE: To describe the changes in drug intake during institutionalization in a Dutch psychogeriatric nursing home. SETTING: Psychogeriatric nursing home Joachim en Anna in Nijmegen, the Netherlands. DESIGN: Retrospective analysis of medical charts. PATIENTS AND METHODS: In 390 patients drug intake (sixteen drug groups) at admission, after six weeks, at half yearly intervals and on the day of death was recorded in a longitudinal fashion, as were side effects. Increase or decrease in drug intake was tested by means of linear regression analysis. RESULTS: After an initial decrease there was a gradual increase in mean drug intake during institutionalization. Laxatives and to a lesser degree drugs for the respiratory tract and heart were mostly responsible for this increase. In the other groups no change or even decrease was noted. The degree of dependency and the type of dementia had an influence on these changes. At the day of death analgesics, morphinomimetics and bronchodilators were the most frequent drugs. Neuroleptics caused most of the side effects observed. CONCLUSION: Prescription of laxatives is mostly responsible for the increase in mean drug intake in this Dutch psychogeriatric nursing home.

Continuous infusion of furosemide in the treatment of patients with congestive heart failure and diuretic resistance.

OBJECTIVES: To assess the value of treatment with continuous intravenous infusion of furosemide (F) in patients with refractory congestive heart failure. DESIGN: Open uncontrolled dose-response study. SUBJECTS: Patients with congestive heart failure (those with New York Heart Association (NYHA) classes III and IV with an assessed amount of oedema of more than 5 kg and diuretic resistance were included [n = 10]). Diuretic resistance was defined as: failure to lose weight and/or inappropriate urinary sodium excretion (50 mmol 24 h-1) despite bed rest for a period of 2-3 days, salt and water restriction, orally and intravenously administered furosemide in a dose of 250 mg day-1, digoxin, and when possible an ACE inhibitor. Included patients were treated with continuous F infusion at a delivery rate of 20 mg-1 over 24 h. The infusion rate was gradually heightened up to a maximum dose of 160 mg h-1. MAIN OUTCOME MEASURES: Daily physical examination, history of side-effects, determination of serum electrolytes and 24-h electrolyte excretion during treatment with furosemide. RESULTS: Weight loss (mean +/- SD; 12.5 +/- 5 kg) and relief of symptoms was achieved in all patients. Mean (+/- SD) 24-h sodium output rose from 19 +/- 16 mmol 24 h-1 (n = 10) on oral therapy with 250 mg F to 137 +/- 85 mmol 24 h-1 (n = 8) during 80 mg h-1 and to 268 +/- 124 mmol 24 h-1 (n = 3) on the maximal dose of 160 mg h-1. CONCLUSION: Continuous infusion of F under careful monitoring of the patient is a safe, controllable and efficient treatment in patients with severe congestive heart failure and diuretic resistance.