Suicide risk in placebo-controlled studies of major depression.

OBJECTIVE: The purpose of this study was to determine if fear of an increased risk of attempted suicide in placebo groups participating in placebo-controlled studies is an argument against the performance of placebo-controlled trials in studies of major depression. METHOD: All short-term and long-term, placebo-controlled, double-blind studies that were part of a registration dossier for the indication of major depression that were submitted to the Medicines Evaluation Board, the regulatory authority of the Netherlands, from 1983 to 1997 were reviewed for attempted suicide. In addition, all long-term, placebo-controlled studies from a MEDLINE search that were conducted in the last decade in patients with major depression were assessed for attempted suicide. RESULTS: In 77 short-term studies with 12,246 patients in dossiers from the Medicines Evaluation Board, the incidence of suicide was 0.1% in both placebo groups and active compound groups. The incidence of attempted suicide was 0.4% in both placebo groups and active compound groups. In eight long-term studies with 1,949 patients, the incidence of suicide in the placebo groups was 0.0% and 0.2% in the active compound groups. Attempted suicide occurred in 0.7% of both placebo groups and active compound groups. In seven long-term MEDLINE studies, the incidence of attempted suicide in the placebo groups was not higher than in the groups treated with active compound. CONCLUSIONS: Fear of increased risk of attempted suicide in the placebo groups should not be an argument against performing short-term and long-term, placebo-controlled trials in major depression.

The use of a functional and immunologic assay for plasma protein C in the study of the heterogeneity of congenital protein C deficiency.

Protein C is a vitamin K dependent protein involved in blood coagulation. A congenital deficiency in protein C antigen - which inherits as an autosomal dominant disorder - has been reported to be associated with a high risk for thrombo-embolic disease at relatively young age. In the present paper we report on the development of a functional assay for plasma protein C. In this assay protein C is adsorbed to Al(OH)3, eluted and activated by thrombin, after which the concentration of the activated protein C is measured with a peptide substrate (S2366). Normal values for protein C activity and protein C antigen were determined in healthy volunteers and patients on stable oral anticoagulant treatment. Protein C activity and antigen levels were compared in 28 patients from 9 different pedigrees with both congenital protein C deficiency and thrombotic disease. Two types of protein C deficiency could be recognized: in type I the deficiency is due to the absence or reduced presence of protein C molecules, while in type II the deficiency is caused by the presence of an abnormal protein C molecule with strongly reduced functional activity.

Protein C deficiency in a Dutch family with thrombotic disease.

A rabbit antibody against human protein C was used for the quantitative estimation of protein C in plasma. In healthy individuals protein C antigen ranged from 0.65-1.45 U/ml. Plasma protein C antigen was found to be independent of either age or sex. Under influence of oral anticoagulant treatment the protein C antigen concentration decreased to 0.47 U/ml (at low intensity treatment) or 0.33 U/ml (at high intensity treatment). Using normal ranges of protein C and protein C/factor II and protein C/factor X ratios criteria were developed for the assessment of protein C deficiency. In a Dutch family with a history of thrombotic disease two members were found to have an isolated protein C deficiency, while a third one is suspected of protein C deficiency. In one case it was possible to confirm the diagnosis of suspected protein C deficiency during temporary withdrawal of the anticoagulant therapy.

Hereditary protein S deficiency and venous thrombo-embolism. A study in three Dutch families.

Protein S, a vitamin K-dependent coagulation factor, is involved in the regulation of the anticoagulant activity of activated protein C. Using an immunoradiometric assay for total protein S in plasma we identified 14 patients (7 male and 7 female) in three unrelated Dutch families as fulfilling the criteria for an isolated protein S deficiency. In 9 patients who were not receiving oral anticoagulant treatment the mean total protein S antigen concentration was 0.50 +/- 0.08 U/ml (+/- S.D.) and the calculated free protein S concentration was 0.15 +/- 0.01 U/ml (+/- S.D.). In the five patients who were on oral anticoagulant treatment the mean total protein S antigen was 0.23 +/- 0.05 U/ml (+/- S.D.). Seven of the 14 patients had a history of venous thromboembolism occurring at a mean age of 25 years and often without an apparent cause. Protein S deficiency is inherited as an autosomal dominant trait.

Treatment of hereditary protein C deficiency with stanozolol.

Five type I protein C deficient male patients received 5 mg stanozolol b.i.d. during 4 weeks. After four weeks of treatment plasma protein C activity increased from 0.42 to 0.74 U/ml and protein C antigen from 0.49 to 0.75 U/ml. This approximately 1.6 fold increase in plasma protein C was accompanied by an increase in factor II antigen (1.5 fold), factor V activity (1.6 fold), factor X antigen (1.1 fold), antithrombin III antigen (1.3 fold) and heparin cofactor II antigen (1.5 fold), while the concentration of factor VII, factor VIII, and factor IX activity, and of protein S antigen remained unchanged. Prothrombin fragment F1+2, measured in two patients, increased 1.3 fold. In addition to its effect on procoagulant and anticoagulant factors stanozolol had profibrinolytic effects, reflected in an increase in tPA activity and in the concentration of plasminogen. These data indicate that in type I protein C deficient patients stanozolol increases the concentrations of both procoagulant and anticoagulant factors and favours fibrinolysis. The efficacy of stanozolol in preventing thrombotic disease in type I protein C deficient patients, however, remains to be established. During the four weeks of stanozolol treatment no thrombotic manifestations were observed in the protein C deficient patients.

Recurrent coumarin-induced skin necrosis in a patient with an acquired functional protein C deficiency.

An elderly woman who had been receiving long-term oral anticoagulant therapy developed skin and subcutaneous fat necrosis on five repeated occasions of extreme hypocoagulability, associated with coinciding periods of congestive cardiac failure. In each episode, the skin necrosis developed within days after the prothrombin time (as determined with Thrombotest) exceeded 200 s (International Normalized Ratio greater than 5.4). Widespread thrombosis in the subcutaneous vasculature and interstitial bleeding, as observed in a skin biopsy specimen, were consistent with a diagnosis of coumarin necrosis. On two occasions, an acquired functional protein C deficiency was present. It is hypothesized that an imbalance between anticoagulant and procoagulant vitamin K-dependent factors contributed to the pathogenesis of coumarin-induced skin necrosis. This imbalance was related to repeated periods of congestive heart failure.

Short-term efficacy of tricyclic antidepressants revisited: a meta-analytic study.

The original data from the placebo-arms and the tricyclic-arms of all parallel randomized controlled three-arm studies, which had been conducted in the period 1979-1991 for a drug under development in order to obtain marketing authorization for the indication major depression, were included in a meta-analysis. Thirty-two placebo-controlled studies including 4314 patients were analyzed. The intention to treat analysis resulted in 46% responders (at least 50% improvement on the Hamilton Depression Rating Scale) in the tricyclic antidepressant group and 31% in the placebo-group (CI(95%-difference) 11.5-17.1%). The number needed to treat for responders was 7 (CI(95%) 5-8). In 10 out of 32 studies, a statistically significant difference in favor of tricyclic antidepressant compared to placebo was found for responders. The responder rate in the placebo-group varied from 6 to 52%. We conclude that tricyclic antidepressants are efficacious in the short-term treatment of major depression. However, the magnitude of the effect is rather modest. Because 69% of the placebo-controlled studies with a tricyclic antidepressant did not show a statistically significant difference in favor of tricyclic antidepressant and the placebo rate varied considerably from study to study, equivalence studies with tricyclic antidepressant as comparator without a placebo-control are not sufficient for demonstrating efficacy. Therefore in major depression, placebo-controlled studies are still necessary to demonstrate efficacy.

Differences in attitudes, knowledge and use of economic evaluations in decision-making in The Netherlands. The Dutch results from the EUROMET Project.

OBJECTIVE: To investigate differences in attitudes, knowledge and actual use of economic evaluations in different groups of decision-makers, and to compare the results from the Netherlands with the overall European results of the European Network on Methodology and Application of Economic Evaluation Techniques (EUROMET) project. DESIGN AND SETTING: Members of the EUROMET group conducted interviews and surveys with politicians, regulators, hospital pharmacists and physicians in The Netherlands. Three approaches of investigation could be adopted: (i) a postal questionnaire survey, (ii) semi-structured interviews, and (iii) a focus-group approach. MAIN OUTCOME MEASURES AND RESULTS: In the Netherlands, decision-makers generally have a positive attitude towards economic evaluations. Nevertheless, their actual use and knowledge of economic evaluations are still limited. Hospital pharmacists and regulators are more objective than physicians and politicians, who also base their judgements on other societal values. Hospital pharmacists and regulators have a greater knowledge of economic evaluations, and they use them more often than the other groups. Most decision-makers do not want to base their decisions strictly on a cost-effectiveness ranking alone. Our findings were similar to the findings in other European countries. CONCLUSIONS: Decision-makers prefer to make their own broad comparisons of advantages and disadvantages, and do not base their decisions solely on a single summary measure.

Costs and effects of combining stenting and abciximab (ReoPro) in daily practice.

AIM: The combined use of stents and abciximab in percutaneous coronary intervention has been evaluated in the EPISTENT trial. However, the clinical and economic findings in trials are not necessarily generalisable to a general population setting. We conducted a study in daily clinical practice comparing stented and non-stented patients undergoing coronary angioplasty with abciximab administration. Furthermore, we compare our results with the findings of the EPISTENT trial. METHODS: From 1995 to 1999, refractory unstable patients scheduled for angioplasty and receiving abciximab in a Dutch regional hospital were followed prospectively for 6 months. Total costs were considered in addition to 2 composite clinical endpoints: (1) death or myocardial infarction (MI); and (2) death, MI, or any revascularisation procedure (major adverse cardiac events, MACE). RESULTS: Stented patients (N=101) experienced less MACE than non-stented patients (N=83) (6.9% vs. 16.9%, OR=0.37, P=0.04). The total costs were similar for stented and non-stented patients (EUR 7 844 vs. EUR 7 904, P=0.93). Adjustment for baseline characteristics yielded similar results, although significance subsided. The relative risk reduction of 44% that we found, closely resembles the 42% that was found in the EPISTENT trial. CONCLUSIONS: In everyday practice, as in the EPISTENT trial, the addition of a stent to abciximab treatment does seem to reduce the risk of MACE by about 40% at no additional costs.

[Clinical evaluation of efficacy and adverse effects in the (European) registration of drugs: what does it mean for the doctor and patient?]. / De klinische beoordeling van werkzaamheid en schadelijkheid bij de (Europese) registratie van geneesmiddelen: wat betekent dit voor de dokter en de patiënt?

The clinical criteria for admission of new drugs to the European common market have become more stringent in recent years. Increasingly often, the manufacturer is required to demonstrate that the new drug offers a clinically visible and relevant benefit to the patient. Efficacy and adverse effects should not only be studied by comparative trials with placebo, the registration authorities also expect the drug to be compared with the standard treatment already available. Such trials should prove that the balance between efficacy and adverse effects of the drug is better than that of placebo and at least as good as the standard treatment, as regards not only statistical significance but also clinical relevance. Therefore, Dutch and European assessment reports and product information may be increasingly useful to prescribers, patients and insurers in determining the role and therapeutic value of new drugs within the existing therapeutic possibilities concerning certain diseases.