Early combination disease modifying antirheumatic drug treatment for rheumatoid arthritis

Most people presenting with rheumatoid arthritis today can expect to achieve disease suppression, can avoid or substantially delay joint damage and deformities, and can maintain a good quality of life. Optimal management requires early diagnosis and treatment, usually with combinations of conventional disease modifying antirheumatic drugs (DMARDs). If these do not effect remission, biological DMARDs may be beneficial. Lack of recognition of the early signs of rheumatoid arthritis, ignorance of the benefits of early application of modern treatment regimens, and avoidable delays in securing specialist appointments may hinder achievement of best outcomes for many patients. Triage for recognising possible early rheumatoid arthritis must begin in primary care settings with the following pattern of presentation as a guide: involvement of three or more joints; early-morning joint stiffness of greater than 30 minutes; or bilateral squeeze tenderness at metacarpophalangeal or metatarsophalangeal joints.

Who's really hypertensive? - Quality control issues in the assessment of blood pressure for randomized trials

The characterization of blood pressure in treatment trials assessing the benefits of blood pressure lowering regimens is a critical factor for the appropriate interpretation of study results. With numerous operators involved in the measurement of blood pressure in many thousands of patients being screened for entry into clinical trials, it is essential that operators follow pre-defined measurement protocols involving multiple measurements and standardized techniques. Blood pressure measurement protocols have been developed by international societies and emphasize the importance of appropriate choice of cuff size, identification of Korotkoff sounds, and digit preference. Training of operators and auditing of blood pressure measurement may assist in reducing the operator-related errors in measurement. This paper describes the quality control activities adopted for the screening stage of the 2nd Australian National Blood Pressure Study (ANBP2). ANBP2 is cardiovascular outcome trial of the treatment of hypertension in the elderly that was conducted entirely in general practices in Australia. A total of 54 288 subjects were screened; 3688 previously untreated subjects were identified as having blood pressure >140/90 mmHg at the initial screening visit, 898 (24%) were not eligible for study entry after two further visits due to the elevated reading not being sustained. For both systolic and diastolic blood pressure recording, observed digit preference fell within 7 percentage points of the expected frequency. Protocol adherence, in terms of the required minimum blood pressure difference between the last two successive recordings, was 99.8%. These data suggest that adherence to blood pressure recording protocols and elimination of digit preferences can be achieved through appropriate training programs and quality control activities in large multi-centre community-based trials in general practice. Repeated blood pressure measurement prior to initial diagnosis and study entry is essential to appropriately characterize hypertension in these elderly patients.

The impact of a reduction in drug supply on demand for and compliance with treatment for drug dependence

Background: In early 2001, Australia experienced a sudden, dramatic and;sustained decrease in heroin availability that was accompanied by sharp increases in price and decreases in street level purity-the so-called heroin shortage. These unprecedented changes occurred in a context of widespread treatment availability, which made it possible for the first time to examine the impact of a sharp reduction in heroin supply in New South Wales (NSW) on entry to and adherence with treatment for heroin dependence. Given the evidence of drug substitution by some users. the current paper also examines the effects of the shortage on entry to treatment for other forms of drug dependence. Methods: Interrupted time-series analysis of the number of persons entering opioid pharmacotherapy and other treatment modalities in NSW for heroin dependence and for the treatment for other types of drug dependence. Findings: The heroin shortage was associated with a reduction in the number of younger persons entering opioid pharmacotherapy. There was a dramatic decrease in the number of persons entering heroin withdrawal or assessment only treatment episodes. There appear to have been small improvements in adherence to and retention in heroin treatment after the reduction in heroin supply. Relatively small increases were observed in numbers being treated for cocaine dependence. Conclusions: In the context of good treatment provision, a reduction in heroin supply appeared to produce modest improvements in intermediate outcomes. Supply and demand reduction measures, when both are implemented successfully, may be complementary. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Methadone maintenance treatment reduces heroin injection in New South Wales prisons

The purpose of this study was to examine whether methadone maintenance treatment reduces injecting risk behaviour land therefore transmission of blood-borne viral infections) among prisoners in New South Wales (NSW), using comparison of retrospective reports of drug use in prisons for people who received standard drug treatment, time-limited methadone treatment and methadone maintenance treatment, The setting for the study was the NSW prison system. One hundred and eighty-five injecting drug users who had been recently released from NSW prisons were recruited in 1993, Self-reported drug use and injecting risk behaviour were compared in inmates who received standard drug treatment (counselling), time-limited methadone treatment and methadone maintenance treatment. HIV status was determined by serology, Intervention comprised high and low dose methadone treatment and counselling. The groups were similar in terms of most basic demographic characteristics but subjects who had been maintained on methadone reported a significantly lower prevalence of heroin injection, syringe sharing and scored lower on an HIV Risk-taking Behavioural Scale than subjects who received standard drug treatment and time-limited methadone treatment, This study suggests that methadone treatment is associated with reduced injecting risk behaviour in prison with adequate (greater than 60 mg) dose and duration in treatment. These treatment conditions are known to increase effectiveness in community-based methadone programmes. Prospective studies are required to evaluate the effectiveness of methadone programmes in the prevention of HIV and other blood-borne viral infections among IDU prisoners.

The role of legal coercion in the treatment of offenders with alcohol and heroin problems

This article discusses the ethical justification for and reviews the American evidence on the effectiveness of; treatment for alcohol and heroin dependence that is provided under legal coercion to offenders whose alcohol and drug dependence has contributed to the commission of the offence with which they have been charged or convicted. The article focuses on legally coerced treatment for drink-driving offenders and heroin-dependent property offenders. it outlines the various arguments that have been made for providing such treatment under legal coercion, namely. the over-representation of alcohol and drug dependent persons in prison populations; the contributory causal role of alcohol and other drug problems in the offences that lead to their imprisonment; the high rates of relapse to drug use and criminal involvement after incarceration; the desirability of keeping injecting heroin users out of prisons as a way of reducing the transmission of infectious diseases such as HIV and hepatitis; and the putatively greater cost-effectiveness of treatment compared with incarceration. The ethical objections to legally coerced drug treatment are briefly discussed before the evidence on the effectiveness of legally coerced treatment for alcohol and other drug dependence is reviewed. The evidence, which is primarily from the USA, gives qualified support for some forms of legally coerced drug treatment provided that these programs are well resourced, carefully implemented, and their performance is monitored to ensure that they provide a humane and effective alternative to imprisonment. Expectations about what these programs can achieve also need to be realistic.

Increasing relevance of pharmacogenetics of drug metabolism in clinical practice

Much of the individual variation in drug response is due to genetic drug metabolic polymorphisms. Clinically relevant examples include acetylator status; cytochrome P450 2D6, 2C9 and 2C19 polymorphisms; and thiopurine methyltransferase deficiency. It is important to be aware of which drugs are subject to pharmacogenetic variability. In the future, population-based pharmacogenetic testing will allow more individualized drug treatment and will avoid the current empiricism.

Can anticonvulsant drug therapy 'cure' epilepsy?

There is now evidence to show that, as time passes, epilepsy, even if untreated, tends to undergo spontaneous remission in a significant proportion of patients. The question therefore arises as to whether anticonvulsant drug therapy increases this chance of the patient with epilepsy ultimately entering a terminal remission which continues after the treatment is withdrawn, Le. whether anticonvulsant drug therapy itself may sometimes cure epilepsy. There are no well-designed studies available in the literature that provide a clear answer to this question. However, data from a number of investigations carried out for other purposes can be used to see whether contemporary anticonvulsant drug therapy is associated with higher rates of expected untreated terminal remission than those that apply for never-treated patients with epilepsy, or for those whose anticonvulsant treatment has probably been inadequate for various social or historical reasons. Despite the admitted uncertainties inherent in drawing conclusions from such material, there appears to be a reasonably consistent tendency for contemporary anticonvulsant drug treatment to be associated with a greater chance of achieving probable cure of epilepsy. Therefore it would appear premature to take the view that contemporary anticonvulsant drug therapy does no more than suppress epileptic seizures until epilepsy remits spontaneously, or fails to remit, with the passing of time.

Rapid genotyping of loci involved in antifolate drug resistance in Plasmodium falciparum by primer extension

Current methods used to genotype point mutations in Plasmodium falciparum genes involved in resistance to antifolate drugs include restriction digestion of PCR products, allele-specific amplification or sequencing. Here we demonstrate that known point mutations in dihydrofolate reductase and dihydropteroate synthase can be scored quickly and accurately by single-nucleotide primer extension and detection of florescent products on a capillary sequencer. We use this method to genotype parasites in natural infections from the Thai-Myanmar border. This approach could greatly simplify large-scale screening of resistance mutations of the type required for evaluating and updating antimalarial drug treatment policies. The method can be easily adapted to other P. falciparum genes and will greatly simplify scoring of point mutations in this and other parasitic organisms. © 2002 Australian Society for Parasitology Inc. Published by Elsevier Science Ltd. All rights reserved.

A randomised controlled trial of methadone maintenance treatment versus wait list control in an Australian prison system

Objectives: The aim was to determine whether methadone maintenance treatment reduced heroin use, syringe sharing and HIV or hepatitis C incidence among prisoners. Methods: All eligible prisoners seeking drug treatment were randomised to methadone or a waitlist control group from 1997 to 1998 and followed up after 4 months. Heroin use was measured by hair analysis and self report; drugs used and injected and syringe sharing were measured by self report. Hepatitis C and HIV incidence was measured by serology. Results: Of 593 eligible prisoners, 382 (64%) were randomised to MMT (n = 191) or control (n = 191). 129 treated and 124 control subjects were followed up at 5 months. Heroin use was significantly lower among treated than control subjects at follow up. Treated subjects reported lower levels of drug injection and syringe sharing at follow up. There was no difference in HIV or hepatitis C incidence. Conclusions: Consideration should be given to the introduction of prison methadone programs particular where community based programs exist. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

The burden of major depression avoidable by longer-term treatment strategies

Background: Major depression is the largest single cause of nonfatal disease burden in Australia. Effective drug and psychological treatments exist, yet are underused. Objective: To quantify the burden of disease currently averted in people seeking care for major depression and the amount of disease burden that could be averted in these people under optimal episodic and maintenance treatment strategies. Design: Modeling impact of current and optimal treatment strategies based on secondary analysis of mental health survey data, studies of the natural history of major depression, and meta-analyses of effectiveness data. Monte Carlo simulation of uncertainty in the model. Setting: The cohort of Australian adults experiencing an episode of major depression in 2000 are modeled through "what if" scenarios of no treatment, current treatment, and optimal treatment strategies with cognitive behavioral therapy or antidepressant drug treatment. Main Outcome Measure: Disability-Adjusted Life Year. Results: Current episodic treatment averts 9% (95% uncertainty interval, 6%-12%) of the disease burden of major depression in Australian adults. Optimal episodic treatment with cognitive behavioral therapy could avert 28% (95% uncertainty interval, 19%-39%) of this disease burden, and with drugs 24% (95% uncertainty interval, 19%-30%) could be averted. During the 5 years after an episode of major depression, current episodic treatment patterns would avert 13% (95% uncertainty interval, 10%-17%) of Disability-Adjusted Life Years, whereas maintenance drug treatment could avert 50% (95% uncertainty interval, 40%-60%) and maintenance cognitive behavioral therapy could avert 52% (95% uncertainty interval, 42%-64%), even if adherence of around 60% is taken into account. Conclusions: Longer-term maintenance drug or psychological treatment strategies are required to make significant inroads into the large disease burden associated with major depression in the Australian population.

Cost-effectiveness of cognitive-behavioural therapy and drug interventions for major depression

Objective: Antidepressant drugs and cognitive-behavioural therapy (CBT) are effective treatment options for depression and are recommended by clinical practice guidelines. As part of the Assessing Cost-effectiveness - Mental Health project we evaluate the available evidence on costs and benefits of CBT and drugs in the episodic and maintenance treatment of major depression. Method: The cost-effectiveness is modelled from a health-care perspective as the cost per disability-adjusted life year. Interventions are targeted at people with major depression who currently seek care but receive non-evidence based treatment. Uncertainty in model inputs is tested using Monte Carlo simulation methods. Results: All interventions for major depression examined have a favourable incremental cost-effectiveness ratio under Australian health service conditions. Bibliotherapy, group CBT, individual CBT by a psychologist on a public salary and tricyclic antidepressants (TCAs) are very cost-effective treatment options falling below $A10 000 per disability-adjusted life year (DALY) even when taking the upper limit of the uncertainty interval into account. Maintenance treatment with selective serotonin re-uptake inhibitors (SSRIs) is the most expensive option (ranging from $A17 000 to $A20 000 per DALY) but still well below $A50 000, which is considered the affordable threshold. Conclusions: A range of cost-effective interventions for episodes of major depression exists and is currently underutilized. Maintenance treatment strategies are required to significantly reduce the burden of depression, but the cost of long-term drug treatment for the large number of depressed people is high if SSRIs are the drug of choice. Key policy issues with regard to expanded provision of CBT concern the availability of suitably trained providers and the funding mechanisms for therapy in primary care.

Which drug combination for hormone-refractory prostate cancer

Patients with metastatic hormone-refractory prostate cancer have a progressive disease with a median survival of similar to 11 months, and currently no treatment offers a survival advantage. The standard drug treatment is a corticosteroid and chemotherapy with mitoxantrone. In a comparison of docetaxel every 3 weeks and prednisone, versus mitoxantrone and prednisone, with a follow-up of similar to 21 months, there were less deaths in the docetaxel group than in the mitoxantrone group (166 of 335 patients and 201 of 337 patients, respectively). Docetaxel also prolonged the duration of survival compared with mitoxantrone (18.9 and 16.5 months, respectively). When given with prednisone, docetaxel was also shown to reduce pain and serum prostate specific antigen levels and improve quality of life compared with mitoxantrone/prednisone. In another trial in hormone-resistant prostate cancer patients, which compared docetaxel and estramustine with mitoxantrone and prednisone during a median follow-up of 32 months, there were fewer deaths with docetaxel/estramustine than with mitoxantrone/prednisone, which were 217 of 338 and 235 of 336 patients, respectively. Median survival was also longer in the docetaxel and estramustine group than in the mitoxantrone/prednisone group (17.5 and 15.6 months, respectively). In conclusion, two combinations (docetaxel/prednisone and docetaxel/estramustine) have been shown to be superior to mitoxantrone/prednisone in hormone-refractory prostate cancer and both should be considered for use. With the present information, there is little to distinguish between these combinations.

Assessing cost-effectiveness of drug interventions for schizophrenia

Objective: To assess from a health sector perspective the incremental cost-effectiveness of eight drug treatment scenarios for established schizophrenia. Method: Using a standardized methodology, costs and outcomes are modelled over the lifetime of prevalent cases of schizophrenia in Australia in 2000. A two-stage approach to assessment of health benefit is used. The first stage involves a quantitative analysis based on disability-adjusted life years (DALYs) averted, using best available evidence. The robustness of results is tested using probabilistic uncertainty analysis. The second stage involves application of 'second filter' criteria (equity, strength of evidence, feasibility and acceptability) to allow broader concepts of benefit to be considered. Results: Replacing oral typicals with risperidone or olanzapine has an incremental cost-effectiveness ratio (ICER) of A$48 000 and A$92 000/DALY respectively. Switching from low-dose typicals to risperidone has an ICER of A$80 000. Giving risperidone to people experiencing side-effects on typicals is more cost-effective at A$20 000. Giving clozapine to people taking typicals, with the worst course of the disorder and either little or clear deterioration, is cost-effective at A$42 000 or A$23 000/DALY respectively. The least cost-effective intervention is to replace risperidone with olanzapine at A$160 000/DALY. Conclusions: Based on an A$50 000/DALY threshold, low-dose typical neuroleptics are indicated as the treatment of choice for established schizophrenia, with risperidone being reserved for those experiencing moderate to severe side-effects on typicals. The more expensive olanzapine should only be prescribed when risperidone is not clinically indicated. The high cost of risperidone and olanzapine relative to modest health gains underlie this conclusion. Earlier introduction of clozapine however, would be cost-effective. This work is limited by weaknesses in trials (lack of long-term efficacy data, quality of life and consumer satisfaction evidence) and the translation of effect size into a DALY change. Some stakeholders, including SANE Australia, argue the modest health gains reported in the literature do not adequately reflect perceptions by patients, clinicians and carers, of improved quality of life with these atypicals.

Pharmacological treatment and perceived health status during 1-year follow up in patients diagnosed with coronary artery disease, but ineligible for revascularization. Results from the Euro Heart Survey on Coronary Revascularization

Background It has been recognized that a clinically significant portion of patients with coronary artery disease (CAD) continue to experience anginal and other related symptoms that are refractory to the combination of medical therapy and revascularization. The Euro Heart Survey on Revascularization (EHSCR) provided an opportunity to assess pharmacological treatment and outcome in patients with proven CAD who were ineligible for revascularization. Methods We performed a secondary analysis of EHS-CR data. After excluding patients with ST-elevation myocardial infarction and those in whom revascularization was not indicated, 4409 patients remained in the analyses. We selected two groups: (1) patients in whom revascularization was the preferred treatment option (n = 3777, 86%), and (2) patients who were considered ineligible for revascularization (n = 632, 14%). Results Patient ineligible for revascularization had a worse risk profile, more often had a total occlusion (59% vs. 37%, p < 0.001), were treated more often with ACE-inhibitors (65% vs. 55%, p < 0.001) but less likely with aspirin (83% vs. 88%, p < 0.001). Overall, they had higher case-fatality at 1-year (7.0% vs. 3.7%, p < 0.001). Regarding self-perceived health status, measured via the EuroQol 5D (EQ-5D) questionnaire, these same patients reported more problems on all dimensions of the EQ-5D. Furthermore, in the revascularization group we observed an increase between discharge and 1-year follow up (utility score from 0.85 to 1.00) whereas patients ineligible for revascularization did not improve over time (utility score remained 0.80) Conclusion In this large cohort of European patients with CAD, those considered ineligible for revascularization had more co-morbidities and risk factors, and scored worse on self-perceived health status as compared to revascularized patients in the revascularization group. With the exception of ACE-inhibitors and aspirin, there were no major differences regarding drug treatment between the two groups. Given these clinically significant observations, there appears to be a role for nurse-led, multidisciplinary, rehabilitation teams that target clinically vulnerable patients whose symptoms remain refractory to standard medical care.