Ibopamine: D1-dopaminergic agonist in the diagnosis of glaucoma.

PURPOSE: The purpose of the study was to assess the effect of ibopamine (3,4 di-isobutyrrylester of N-methyldopamine), a D1-dopamine agonist, on intraocular pressure (IOP) in offspring of parents with primary openangle glaucoma as a consequence of outflow structures impairment. MATERIALS AND METHODS: We included participants aged between 8 and 40 years: group 1, 163 offspring of at least 1 parent with primary openangle glaucoma with normal IOP and without glaucomatous damages; group 2, 108 offspring of healthy parents (without history or existing glaucoma). Ibopamine test was performed by instilling 2 drops, 5 minutes apart, in both eyes followed by repeated IOP measurements over a 45-minute period. The test is considered positive if there is an IOP increase of ≥3 mm Hg 45 minutes after instillation. RESULTS: Baseline IOP before the test was 15.73±2.31 and 15.31±1.86 mm Hg in groups 1 and 2, respectively. Test was positive in 44.33% of cases in group 1 with a mean increase in IOP of 5.57 mm Hg (P<0.001), whereas in all participants of group 2 the test was negative with even 1 to 2 mm Hg IOP reduction. CONCLUSIONS: D1-dopaminergic stimulation due to ibopamine increases IOP as a result of increased production of the aqueous humor in participants with an impaired outflow. The study showed that offspring of at least 1 parent with primary openangle glaucoma--offspring without glaucomatous damages--show an increase of IOP after ibopamine administration, which signifies an impaired function of outflow structures and, therefore, a predisposition to intraocular hypertension and possible glaucoma.

Pigmented deposits on a Boston keratoprosthesis from topical ibopamine.

PURPOSE: To report a case of pigmented deposits on a type I Boston keratoprosthesis (KPro) associated with the use of topical ibopamine as a treatment for hypotony. METHODS: Case report and literature review. RESULTS: The dopamine-like agent ibopamine caused black deposits on the bandage lens and on the front plate of the Boston KPro that resulted in reduced visual acuity. Change to a daily disposable contact lens and regular cleaning of the KPro front plate with diluted baby shampoo eliminated this problem. CONCLUSION: This is the first report of this complication with topical ibopamine use and should be considered when ibopamine is used chronically for hypotony.

Effects of ibopamine eye drops on intraocular pressure and aqueous humor flow in healthy volunteers and patients with open-angle glaucoma.

PURPOSE: On the basis of intraocular pressure measurements and fluorophotometry we assessed the effects of 2% ibopamine eye drops on aqueous humor production in normal and glaucomatous eyes. METHODS: Thirty subjects (15 healthy volunteers and 15 open-angle glaucoma patients with ocular hypertension) were included in a placebo-controlled study with random assignment of treatment from masked containers. All subjects underwent ophthalmologic examinations and intraocular pressure (IOP) measurements. Fluorophotometry was done in both eyes at baseline (without treatment) and during treatment. Each subject was treated with 1 drop of 2% ibopamine in one eye and 1 drop of placebo in the fellow eye 30 minutes before fluorophotometric scans and every hour after the first instillation (for a total of 4 times). Safety was evaluated by recording adverse events and ocular symptoms and signs. Aqueous humor flow data were analyzed using the paired t-test, comparing ibopamine and placebo-treated eyes. RESULTS: No changes in IOP were detected in normal eyes, whereas glaucomatous eyes showed a mean increase of 4 mmHg (95% CI 3.46-4.51) from baseline. The difference in IOP between healthy eyes and those with glaucoma was significant (p < 0.0001). In normal eyes and patients with glaucoma ibopamine led to a significant increase in aqueous humor flow compared with placebo-treated eyes (p < 0.01). The safety profile of ibopamine was very good. CONCLUSIONS: The results seem to confirm that ibopamine increases aqueous humor production in normal and glaucomatous eyes, raising IOP only in eyes with glaucoma.

[The need for 'postmarketing surveillance']. / Noodzaak van 'postmarketing surveillance'.

Postmarketing surveillance of medicines includes two activities: pharmacovigilance and pharmaco-epidemiology. Despite the importance of postmarketing surveillance, too few surveillance studies are performed. The studies carried out by the pharmaceutical industry predominantly consist of 'seeding trials': offering prescribing physicians financial rewards if they prescribe a particular product, thus trying to change the prescription habits. The results of such trials are scientifically worthless. These activities cast a shadow on sincere postmarketing surveillance. A recent nationwide cohort study by the Inspectorate for Health Care on mortality in users of ibopamine demonstrates that Dutch medical doctors and pharmacists are very co-operative if further studying of a particular adverse reaction is warranted.

Achieving appropriate endpoints in heart failure trials: the PRIME-II protocol. The Second Perspective Randomised study of Ibopamine on Mortality and Efficacy.

Many clinical trials unintentionally include patients with a low risk of the trial endpoints. PRIME II (The Second Perspective Randomised study of Ibopamine on Mortality and Efficacy) was a large international randomised double blind trial comparing the addition of ibopamine or placebo to the therapy of patients with advanced heart failure. The trial was stopped prematurely because ibopamine was associated with an increased fatality rate, but the protocol achieved its objective of including high-risk patients. Here we describe the protocol details that enabled patients with the desired degree of risk to be included. We also amplify our definition of mode of death. The PRIME II protocol was designed with the intention that patients in the placebo group would have an annual fatality rate of 20%. Since the study was to be conducted in some 200 centres in 13 European countries, the inclusion criteria had to be simple and flexible, allowing for different clinical practice. The inclusion criteria, together with the use of simple investigations (which did not have to include angiographic or radionuclide ventriculography) are described. The annual fatality rate in the placebo group was just over 20%. Six categories of mode of death were used, but while they were reasonably easy to apply they did not reveal the reason for the unexpected adverse effect of ibopamine. The inclusion and exclusion criteria used for PRIME II, and the definitions of mode of death, were effective. The PRIME II protocol can be used as a model for future heart failure studies.

Risk factors for mortality in users of ibopamine.

AIMS: In September 1995, the indication for the oral dopamine agonist ibopamine was restricted in the Netherlands and in several other European countries to patients with NYHA-class II heart failure as a result of an interim analysis of the PRIME-II trial. This trial demonstrated an increased risk of mortality in patients with NYHA-class III/IV heart failure on ibopamine. In September 1995, we initiated an assessment of the effects of ibopamine under everyday circumstances in a cohort of users of ibopamine in all NYHA-classes. METHODS: In a nationwide retrospective cohort study all 2147 community pharmacies and drug dispensing general practitioners received a request to list all patients to whom they had dispensed ibopamine in the preceding years. All responding drug dispensing outlets (DDO) received a questionnaire on cardiovascular risk factors and mortality for the general practitioner of a random sample of these patients. DDO were also requested to send an anonymised printout of the complete medication record. On the end-date of follow-up, February 15th 1996, mortality rates were compared across categories of ibopamine use, adjusted for potential confounders. To assess medication use, drug exposure was compared in a 3 months' period before date of death in the deceased, and before a random date in those patients who were still alive. RESULTS: In patients with NYHA-class III/IV heart failure, multivariate analysis indicated that current use of ibopamine was significantly associated with mortality (RR 1.37;95% CI: 1.15-1.64). In patients with NYHA-class I/II heart failure, however, multivariate analysis showed a 2.03 (95% CI: 1.10-3.72) risk of mortality in current users of ibopamine. Apart from current use of ibopamine, male gender and increased serum creatinine were also independent risk factors for mortality in all NYHA-classes. No statistically significant association was found between mortality and current use of amiodarone or use of amiodarone at baseline. CONCLUSIONS: The increased risk of mortality in patients with NYHA-class III and IV heart failure on ibopamine seems to confirm the main finding of the recently published PRIME-II trial. However, our results indicate that also patients with NYHA-class I/II heart failure may be at an increased risk of mortality when using ibopamine. Additional research on the effects of ibopamine in these patients is warranted and the use of ibopamine in NYHA-class II heart failure patients may have to be reconsidered.

Evaluation of ibopamine plus prazosin in congestive heart failure.

STUDY OBJECTIVE: To determine the acute haemodynamic response of a single dose co-administration of ibopamine plus prazosin in patients with congestive heart failure. DESIGN: A double-blind, placebo-controlled randomised crossover study followed by a 2-week, open safety evaluation. SETTING: Wentworth Hospital, Durban. PATIENTS: 12 patients with congestive heart failure who were in functional class (NYHA) II-III. INTERVENTIONS: All patients underwent right heart catheterisation. On days 1 and 2 they received study drug or placebo plus prazosin and underwent haemodynamic recordings for 4 hours. RESULTS: Single-dose (200 mg) ibopamine plus prazosin augmented cardiac output (and index) and an early (0-60 minute) phasic response in the pulmonary capillary wedge pressure (PCWP) that did not appear to be influenced by the presence of prazosin. The increase in cardiac output was accompanied by a moderate decline in systemic vascular resistance (P = NS) without a change in heart rate. In the open evaluation, 8/14 patients reported adverse events. Six events were considered to be related to study medication of which one (dizziness) occurred in the haemodynamic phase. CONCLUSION: This study shows that ibopamine has beneficial haemodynamic effects in patients with moderate to severe heart failure. The increase in cardiac output was mild and sustained but with little change in systemic vascular resistance. The early rise in PCWP is not mediated by the alpha-agonistic vasoconstrictor effects of ibopamine.

A double-blind, cross-over comparison of the effects of a loop diuretic and a dopamine receptor agonist as first line therapy in patients with mild congestive heart failure.

We compared the effects of the orally active dopamine agonist ibopamine with the loop diuretic frusemide as first-line therapy in patients with mild congestive heart failure. Fourteen patients with New York Heart Association class II congestive heart failure were enrolled in a double-blind, cross-over study. After baseline measurements of clinical and symptomatic status, modified Bruce exercise time, high-level exercise time, corridor walk time, regional blood flow, pedometer scores, 24 h urine volume and sodium excretion and neurohumoural factors, patients were randomly allocated to receive either frusemide 40 mg o.d. or ibopamine 100 mg t.d.s. for 8 weeks. Assessments were performed at 2 weekly intervals. After 8 weeks, patients crossed over into the alternate treatment arm for a further 8 weeks, with further assessments performed every 2 weeks. There were four exacerbations of heart failure during ibopamine treatment and none during frusemide treatment. After 8 weeks of treatment, modified Bruce exercise time was 901 +/- 73 s with frusemide and 646 +/- 134 s with ibopamine (P < 0.05). Twenty-four hour urinary sodium excretion at weeks 2 and 4 (P < 0.05), and 24 h urinary volume at week 2 (P = 0.0001) were lower during ibopamine treatment. At week 8, supine (P = 0.076) and erect renin (P = 0.05) were lower with ibopamine treatment. In conclusion, ibopamine is ineffective as first line therapy for congestive heart failure, probably because of a lesser diuretic potency than frusemide.

Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators.

BACKGROUND: Drugs that improve symptoms in patients with heart failure must also be assessed for their effects on survival. Ibopamine stimulates DA-1 and DA-2 receptors and causes peripheral and renal vasodilatation; the drug improves symptoms of heart failure. We assessed the effect of ibopamine on survival in patients with advanced heart failure in a multicentre, randomised placebo-controlled study. METHODS: Patients with advanced severe heart failure (New York Heart Association classes III and IV) and evidence of severe left-ventricular disease, who were already receiving optimum treatment for heart failure, were randomly allocated oral ibopamine 100 mg three times daily or placebo. The primary endpoint was all-cause mortality. The study was designed to recruit 2200 patients, and the minimum duration of treatment would be 6 months. We did intention-to-treat and on-treatment analyses; a post-hoc subgroup analysis was also done. FINDINGS: After we had recruited 1906 patients the trial was stopped early, because of an excess of deaths among patients in the ibopamine group. 232 (25%) of 953 patients in the ibopamine group died, compared with 193 (20%) of 953 patients in the placebo group (relative risk 1.26 [95% CI 1.04-1.53], p = 0.017). The average length of follow-up was 347 days in the ibopamine group and 363 days in the placebo group. In multivariate analysis, only the use of antiarrhythmic drugs at baseline was a significant independent predictor of increased fatality in ibopamine-treated patients. INTERPRETATION: Ibopamine seems to increase the risk of death among patients with advanced heart failure who are already receiving optimum therapy, but the reasons for this increase are not clear. Our finding that antiarrhythmic treatment was a significant predictor of increased mortality in ibopamine-treated patients may be important, but exploratory analyses must be interpreted with caution.

A nested case-control study on mortality in users of ibopamine.

BACKGROUND: A recent interim analysis of the PRIME II placebo-controlled study showed a significantly higher mortality in the group treated with ibopamine than in the control group. The objective was to study mortality in patients on ibopamine, and to assess risk factors for death. METHODS: All 2147 drug-dispensing outlets (DDO) in the Netherlands were asked to provide a printout of the complete medication history of users of ibopamine. A reaction was received from 92% of the DDO. From the 14,024 identified former or current users of ibopamine, a sample of 3148 patients (22%) was enrolled in the follow-up study. All general practitioners (GP) of these patients received an enquiry pertaining to the vital status of their patient, cause of death, primary cause and NYHA classification of heart failure, echo- and electrocardiographic data, serum creatinine, admissions and the effects of ibopamine. Cases were defined as patients who died during the follow-up period which ended on the day of return of the questionnaire or the day of decease (index date). Two random controls were obtained for each case from the non-deceased patients at the index date. The design was a follow-up study with risk factor assessment in a nested case-control design. RESULTS: Questionnaires were returned regarding almost 70% of the sample. Mortality in this group was 25%. A case-control analysis was performed with the first 104 cases and 208 random controls. Patients with NYHA class IV had a 3-times increased risk of dying. In patients with a serum-creatinine level in the highest quartile the risk of dying was increased threefold. Higher doses of ibopamine seemed to have a protective effect. Significantly more cases than controls used amiodarone. Also, opioids were used more often, which may be related to their use in terminal cardiac failure. CONCLUSION: NYHA classification and serum-creatinine levels were independent risk factors for death in patients with heart failure on ibopamine. Although there were increased risk estimates for current use of ibopamine and amiodarone, these did not reach statistical significance. This may be related, however, to the fact that this analysis was restricted to the first 20% of cases.