PROactive 06: cost-effectiveness of pioglitazone in Type 2 diabetes in the UK.

AIMS: To determine the cost-effectiveness of adding pioglitazone to existing treatment regimens in patients with Type 2 diabetes with a history of macrovascular disease who are at high risk of further cardiovascular events. METHODS: We conducted two analyses. A within-trial cost-effectiveness analysis (CEA) based on data from the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) Study was performed to estimate the impact of additional pioglitazone treatment on life expectancy, quality-adjusted life expectancy (QALE) and macrovascular events. PROactive data was then used as a basis for a lifetime modelling analysis using a modified version of the validated CORE diabetes model that simulated the same outcomes over a 35-year time horizon. We accounted for direct medical costs from a health-care payer perspective and related these to the clinical outcomes from the study. Costs and benefits were discounted at 3.5% per annum and extensive sensitivity analyses were performed to account for uncertainty in input parameters. RESULTS: (i) Within-trial CEA: compared with placebo, pioglitazone was associated with improved life expectancy (undiscounted 0.0109 years), increased QALE [0.0190 quality-adjusted life years (QALYs)] and slightly higher costs ( pounds 102 per patient). After a mean treatment period of 3 years, the incremental cost-effectiveness ratio (ICER) of pioglitazone vs. placebo was pounds 5396 per QALY gained. The ICERs were relatively insensitive to cost and utility values and were most sensitive to event rates in the pioglitazone arm. (ii) Long-term CEA: pioglitazone was associated with improvements in clinical outcomes based on model projections beyond the PROactive Study. Patients treated with pioglitazone could expect improved life expectancy (undiscounted 0.406 years), increased QALE (0.152 QALYs) and higher costs of care ( pounds 619 per patient) compared with those on existing treatment alone. The base case analysis indicated that the ICER of pioglitazone vs. placebo was pounds 4060 per QALY gained. The cost-effectiveness acceptability curve showed there was an 84.3% likelihood that pioglitazone would be considered cost-effective in the UK using a willingness-to-pay threshold of pounds 30 000 per QALY gained. These long-term results were most sensitive to variation in the time horizon, the duration of cardiovascular benefit of pioglitazone, and changes in mortality rates. CONCLUSIONS: The addition of pioglitazone to existing therapy in patients with Type 2 diabetes at high risk of further cardiovascular events is cost-effective and represents good value for money by currently accepted standards in the UK.

Dyspepsia in England and Scotland.

A validated postal questionnaire has been used to establish the prevalence of dyspeptic symptoms in five geographical locations from the south coast of England to the north of Scotland. The six month period prevalence of dyspepsia in the 7428 respondents to the questionnaire is 41% and equal between the sexes, with similar prevalence rates in the centres studied. There is considerable overlap between upper abdominal symptoms and symptoms of heartburn; 56% of patients with dyspepsia experience both groups of symptoms. Symptom frequency falls progressively with age in men and women, but the proportion of people seeking medical advice for dyspepsia rises with age. One quarter of the dyspeptic patients studied have consulted a general practitioner about their symptoms. This study suggests that the prevalence of dyspepsia in the community has changed little over the last 30 years, despite evidence that the frequency of peptic ulcer disease is falling. Symptom prevalence is unrelated to social class, but this factor is associated with consultation behaviour, the consultation rate rising from 17% in social class 1 to 29% in social class 4. The use of investigations--barium meal and endoscopy--is similarly related to social class; the lowest rate for ulcer diagnosis (4.7%) is found in social class 1 and the highest (17.1%) in social class 5.

Unexplained spontaneous regression and alpha-interferon as treatment for metastatic renal carcinoma.

A series of 73 patients with measurable metastatic disease referred to a tertiary referral centre for consideration for an experimental treatment protocol were entered into a surveillance protocol in order to establish the incidence of spontaneous regression. Initially, patients were taken off the study if metastases showed greater than 25% increase in products of bidimensional measurement but with increasing confidence patients went into therapy protocols only following the development of symptomatic progression. We observed 3 complete and 2 partial unexplained spontaneous regressions and a further 4 patients had prolonged stable disease for more than 12 months. A group of 21 patients on progression subsequently received treatment with alpha-interferon (Wellferon) as part of a multicentre study which included an additional 61 cases; 12 responded (3 surveillance relapse patients and 9 others). Patients with lung metastases only had the highest response rate (10/17 compared with 5 unexplained responses seen in 38 such patients on surveillance). These results confirm that alpha-interferon is active against metastatic renal carcinoma and that the responses are not totally explicable by spontaneous regression.

The graying of America. Opportunities for physical therapy.

The "graying" of America has riveted the attention of policy makers in the United States on the potential specter of an excess population of sick, poor, disabled, aged Americans. The purpose of this article is to review demographic changes occurring in the United States and their effects on the increasing prevalence of disability among the elderly population. Fries' compression-of-morbidity formulation, which hypothesizes longer, healthier life spans, is used to highlight the opportunities and responsibilities for physical therapists to assert strong leadership in the area of health care promotion. Physical therapy is a key profession that could assume responsibility for developing scientifically based programs that postpone the dysfunctional manifestations of chronic disabling illness among aged individuals.

Natural IFN-alpha therapy in hairy-cell leukaemia (namalva-type IFN--Wellferon).

More than 50 patients with hairy-cell leukaemia have now been entered into the British Wellferon (IFN) study, at different centres under the coordination of the Wellcome Research Laboratories. While the treatment duration and dosage varied between patients, the initial dose was usually 3 megaunits daily by intramuscular or subcutaneous injection. Although flu-like symptoms and mild somnolence were commonly experienced side-effects; cessation of IFN treatment as a result of such effects was necessary in only three patients. All patients irrespective of previous treatment showed some response and a complete (less than 5% hairy cells, HCs) bone marrow response was observed in 17. The degree of response was related to the duration of therapy. Immunological markers showed that there was no apparent increase in natural killer (NK) cells and no return of normal B lymphocytes. Light-chain-restricted B cells became reduced in parallel with the disappearance of morphological HCs. Absolute numbers of T cells were reduced, Leu2a+ preferentially, resulting in an increase in helper/suppressor ratios. The ratios (saturation index, SI) of saturated to unsaturated 18 carbon fatty acids (C18FA) of erythrocyte or leukocyte membranes, while abnormal in untreated patients, approached normal levels during IFN therapy. It is concluded that prolonged alpha IFN therapy is highly effective in HCL. The mechanism of action of IFN remains unknown, but indirect surface-marker data favours a direct effect on HCs.

The U.K. experience with human lymphoblastoid interferon in HCL: a report of the first 50 cases.

The results of treatment of the first 50 patients with hairy cell leukemia given human lymphoblastoid alpha-interferon (Wellferon) are presented. All patients, irrespective of previous splenectomy or splenomegaly showed evidence of response. Side effects were minor. Surface marker studies provided no clear indication of the mechanism of action of alpha-interferon. It is concluded that Wellferon is highly effective in this disease.

Successful use of interferon alfa-n1 in the treatment of hairy cell leukemia.

Following a report on the beneficial effects of interferon administered to patients with hairy cell leukemia, a trial was initiated to test a highly purified interferon in cytopenic hairy cell leukemia patients undeniably requiring therapy. Their response was followed with detailed immunologic surface marker studies.

Combining interferon with cytotoxic chemotherapy in patients with advanced breast cancer.

Laboratory studies have suggested therapeutic synergy between alpha-interferons and various cytotoxic agents. The present study set out to monitor the toxicity of giving a standard cytotoxic drug regimen with a well evaluated, low-dose, schedule of lymphoblastoid interferon. The combined treatment resulted in significantly greater leucopenia than was seen with cytotoxics alone and two patients developed severe infections. Although total numbers were small there was no evidence of increased therapeutic response in the combined treatment group. We would therefore suggest caution in future studies combining cytotoxic drugs and interferons as dose reductions of one or other modality is probably necessary.

Interferon is effective in hairy-cell leukaemia.

Seventeen patients with hairy-cell leukaemia (HCL) and peripheral cytopenias were given human lymphoblastoid interferon (Wellferon), 3 megaunits daily or 6 megaunits on alternate days intramuscularly, for 4-24 weeks. Twelve of the patients had undergone splenectomy, three had no palpable spleen and had therefore not been offered surgery, and two patients with substantial splenomegaly were given interferon (IFN) as treatment of first choice. Toxic effects were minor except in one patient who experienced a severe form of somnolence syndrome. In all patients hairy cells (HCs) were cleared from the blood and platelet and Hb levels improved in 2-14 weeks. Neutrophils were improved in 14/17 of the patients. In the two patients with splenomegaly, the spleen became impalpable after 5-8 weeks therapy, and haematological improvement occurred at 12-14 weeks. HC infiltration of the marrow was reduced in all patients, but was complete (less than 5%) in only two, both of whom had impalpable spleens. Immunological surface-marker studies confirmed that light-chain-restricted B cells disappeared from the blood in parallel with the clearance of morphological HCs. There was no evidence of HC maturation and no increase in phenotypic NK cells. T cells were moderately reduced and the relatively greater reduction of Leu 2a+ suppressor cells resulted in increased Leu 3a+/2a+ helper/suppressor ratios in 11/17 of the patients. Early experience in the six patients who have stopped IFN suggests that, after an initial further increase in Hb and neutrophil levels, HCs gradually return with slow deterioration of haematological parameters. Interferon is now the treatment of choice for patients becoming cytopenic post-splenectomy or for patients without splenomegaly. IFN is effective first-line therapy in patients with splenomegaly, but further work is needed to establish whether the agent should replace splenectomy in such patients. Some form of maintenance or re-treatment therapy will probably be necessary.

Studies of liposome interactions with rat thymocytes.

1. The consequences of incubating liposomes with rat thymocytes have been studied using liposomes of dipalmitolyphosphatidylcholine and cholesterol or dipalmitoylphosphatidylcholine only. 2. Dipalmitoylphosphatidylcholine-cholesterol liposomes do not bind to the cells can be removed by washing. An increase in cellular cholesterol is observed. However dipalmitoylphosphatidylcholine liposomes bind rapidly to the cells and cannot be removed by repeated washing. Cholesterol is removed from the cells. 3. There are small changes in intracellular cations in the cholesterol-enriched cells, but no transport studies have been made. Cells depleted of cholesterol lose K+ with little change in intracellular Na+. Na+ influx is increased. The majority of this increase appears to be ouabain-sensitive, indicating in pump-mediated Na+ influx. K+ influx is reduced. 4. The significance of these results is discussed.