Personalised treatment using serum drug levels of adalimumab in patients with rheumatoid arthritis: an evaluation of costs and effects.

OBJECTIVE: To evaluate the cost-effectiveness of personalised treatment for rheumatoid arthritis (RA) using clinical response and serum adalimumab levels. METHODS: A personalised treatment algorithm defined, based on clinical (European League Against Rheumatism) response and drug levels at 6 months, whether adalimumab treatment should be continued in a specific dose or discontinued and/or switched to a next biological. Outcomes were simulated using a patient level Markov model, with 3 months cycles, based on a cohort of 272 adalimumab-treated patients with RA for 3 years and data of patients from the Utrecht Rheumatoid Arthritis Cohort. Costs, clinical effectiveness and quality adjusted life years (QALYs) were compared with outcomes as observed in usual care and incremental cost-effectiveness ratios were calculated. Analyses were performed probabilistically. RESULTS: Clinical effectiveness was higher for the cohort simulated to receive personalised care compared with usual care; the average difference in QALYs was 3.84 (95 percentile range -8.39 to 16.20). Costs were saved on drugs: €2 314 354. Testing costs amounted to €10 872. Mean total savings were €2 561 648 (95 percentile range -3 252 529 to -1 898 087), resulting in an incremental cost-effectiveness ratio of €666 500 or €646 266 saved per QALY gained from a societal or healthcare perspective, respectively. In 72% of simulations personalised care saved costs and resulted in more QALYs, in 28% it was cost saving with lower QALYs. Scenario analyses showed cost saving along with QALYs gain or limited loss. CONCLUSIONS: Tailoring biological treatment to individual patients with RA starting adalimumab using drug levels and short-term outcome is cost-effective. Results underscore the potential merit of personalised biological treatment in RA.

Once versus twice daily LMWH for the initial treatment of venous thromboembolism.

BACKGROUND: In the initial treatment of venous thromboembolism (VTE) low molecular weight heparin (LMWH) is administered once or twice daily. A once daily treatment regimen is more convenient for the patient and may optimise home treatment. However, it is not clear whether a once daily treatment regimen is as safe and effective as a twice daily treatment regimen. OBJECTIVES: To compare the efficacy and safety of once daily versus twice daily administration of LMWH. SEARCH STRATEGY: We identified trials through searching the Specialised Register of the Cochrane Peripheral Vascular Diseases Group (last searched April 2005), the Cochrane Central Controlled Trials Register (CENTRAL) (last searched Issue 2, 2005), handsearches of relevant journals, checking cross-references and through personal communication with experts. SELECTION CRITERIA: Randomised clinical trials in which LMWH given once daily is compared to LMWH given twice daily for the initial treatment of venous thromboembolism. DATA COLLECTION AND ANALYSIS: Two authors assessed trials for inclusion and extracted data independently. MAIN RESULTS: Five studies were included with a total of 1508 participants. The pooled data showed a statistically non-significant difference in recurrent venous thromboembolism between the two treatment regimens (OR 0.82, 0.49 to 1.39). A comparison of major haemorrhagic events (OR 0.77, 0.40 to 1.45) and mortality (OR 1.14, 0.62 to 2.08) also showed a statistically non-significant difference between the two treatment regimens. AUTHORS' CONCLUSIONS: Once daily treatment with LMWH is as effective and safe as twice daily treatment with LMWH. However, the 95% confidence interval implies that there is a possibility that the risk of recurrent VTE might be higher when people are treated once daily. Hence, the decision to treat a person with a once daily regimen will depend on the evaluated balance between increased convenience and the potential for a lower efficacy.

Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome.

BACKGROUND: About 30% of patients with an episode of adequately treated deep venous thrombosis (DVT) develop the postthrombotic syndrome (PTS) within 2 years. During treatment with vitamin K antagonists (VKA) patients spend only 60% of time between an International Normalized Ratio (INR) of 2.0 and 3.0. We hypothesized that patients who spend a large amount of their time beneath this range will have an increased risk of the PTS. OBJECTIVE: To investigate the relation between the quality of anticoagulant therapy with VKA and the risk of the development of the PTS. METHODS: The time spent beneath the therapeutic range was calculated for patients with a first episode of DVT, who were treated with VKA for at least 3 months. At follow-up assessments for a maximum of 5 years, presence and severity of signs and symptoms of PTS were recorded. RESULTS: A total of 244 patients, with a median duration of follow-up of 4.9 years were included for analysis. Of these, 81 patients (33%) developed the PTS. The multivariate model showed that patients who spend more than 50% of their time beneath an INR level of 2.0 are at higher risk for PTS [odds ratio (OR): 2.71, 95% CI: 1.44-5.10]. CONCLUSIONS: Low quality treatment with VKA, which is a common condition, is related to the occurrence of the PTS in patients with DVT. Strategies aimed at improving the quality of long-term anticoagulation might have the potential to reduce the incidence of this complication.

Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism.

BACKGROUND: Low molecular weight heparins (LMWH) have been shown to be effective and safe in preventing venous thromboembolism (VTE), and may also be effective for the initial treatment of VTE. OBJECTIVES: To determine the effect of LMWH compared with unfractionated heparin (UFH) for the initial treatment of VTE. SEARCH STRATEGY: Trials were identified from the Cochrane Peripheral Vascular Diseases Group's Specialised Register, CENTRAL and LILACS. Colleagues and pharmaceutical companies were contacted for additional information. SELECTION CRITERIA: Randomised controlled trials comparing fixed dose subcutaneous LMWH with adjusted dose intravenous or subcutaneous UFH in people with VTE. DATA COLLECTION AND ANALYSIS: At least two reviewers assessed trials for inclusion and quality, and extracted data independently. MAIN RESULTS: Twenty-two studies were included (n = 8867). Thrombotic complications occurred in 151/4181 (3.6%) participants treated with LMWH, compared with 211/3941 (5.4%) participants treated with UFH (odds ratio (OR) 0.68; 95% confidence intervals (CI) 0.55 to 0.84, 18 trials). Thrombus size was reduced in 53% of participants treated with LMWH and 45% treated with UFH (OR 0.69; 95% CI 0.59 to 0.81, 12 trials). Major haemorrhages occurred in 41/3500 (1.2%) participants treated with LMWH, compared with 73/3624 (2.0%) participants treated with UFH (OR 0.57; 95% CI 0.39 to 0.83, 19 trials). In eighteen trials, 187/4193 (4.5%) participants treated with LMWH died, compared with 233/3861 (6.0%) participants treated with UFH (OR 0.76; 95% CI 0.62 to 0.92). Nine studies (n = 4451) examined proximal thrombosis; 2192 participants treated with LMWH and 2259 with UFH. Subgroup analysis showed statistically significant reductions favouring LMWH in thrombotic complications and major haemorrhage. By the end of follow up, 80 (3.6%) participants treated with LMWH had thrombotic complications, compared with 143 (6.3%) treated with UFH (OR 0.57; 95% CI 0.44 to 0.75). Major haemorrhage occurred in 18 (1.0%) participants treated with LMWH, compared with 37 (2.1%) treated with UFH (OR 0.50; 95% CI 0.29 to 0.85). Nine studies (n = 4157) showed a statistically significant reduction favouring LMWH with respect to mortality. By the end of follow up, 3.3% (70/2094) of participants treated with LMWH had died, compared with 5.3% (110/2063) of participants treated with UFH (OR 0.62; 95% CI 0.46 to 0.84). REVIEWERS' CONCLUSIONS: LMWH is more effective than UFH for the initial treatment of VTE. LMWH significantly reduces the occurrence of major haemorrhage during initial treatment and overall mortality at follow up.

Once versus twice daily LMWH for the initial treatment of venous thromboembolism.

BACKGROUND: In the initial treatment of venous thromboembolism (VTE) low molecular weight heparin (LMWH) is administered once or twice daily. A once daily treatment regimen is more convenient for the patient and may optimise home treatment. However it is not clear whether a once daily treatment regimen is as safe and effective as a twice daily treatment regimen. OBJECTIVES: The objective of this review was to compare the efficacy and safety of once daily administration to a twice daily administration of LMWH. SEARCH STRATEGY: Trials were identified through the Specialised Register of the Cochrane Peripheral Vascular Diseases Group (last searched May 2001), the Cochrane Controlled Trials Register (CCTR/CENTRAL) (last searched Issue 1, 2002), by hand-searching other relevant journals, by checking cross-references and through personal communication with experts. SELECTION CRITERIA: Randomised clinical trials in which a once daily treatment regimen with LMWH is compared to a twice daily regimen in the initial treatment of patients with venous thromboembolism. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trials on criteria for inclusion and extracted the data independently. MAIN RESULTS: Five studies were included with a total of 1508 patients. The pooled data showed a statistically non-significant difference in recurrent venous thromboembolism between the two treatment regimens (OR 0.82; 0.49 - 1.39). A comparison of major haemorrhagic events (OR 0.77; 0.40 - 1.45) and mortality (OR 1.14; 0.62 - 2.08) also showed a statistically non-significant difference between the two treatment regimens. REVIEWER'S CONCLUSIONS: Once daily treatment with LMWH is as effective and safe as twice daily treatment with LMWH. However, the 95% confidence interval implies that there is a possibility that the risk of recurrent VTE might be higher when patients are treated once daily. Hence the decision to treat the patient with a once daily regimen will depend on the evaluated balance between increased convenience and the potential for a lower efficacy.

Smoking and persistent mental illness: an exploratory study.

The rate of smoking is alarmingly high among persons with persistent mental illness and they are no less susceptible to the harmful effects of smoking. Nicotine is a potent, addictive drug which affects neurotransmitters. Smoking can affect psychiatric symptoms as well as blood levels of psychotropic and other medications. Most persons with mental illness are aware of the detrimental health risks of smoking and many are interested in quitting. Poor physical health is associated with efforts to quit. Personal commitment is important to successfully quitting.

A quit smoking group. Pilot study.

1. While the rate of smoking is extremely high among persons with mental illness, there have been efforts to assist this population to quit. A 10-week smoking cessation program was provided for 10 highly nicotine dependent persons with persistent mental illness. 2. No significant differences were found in psychiatric symptoms or drug side effects prior to and after smoking cessation efforts. Four months later, for the 7 subjects who completed the program, 14% were abstinent, 43% maintained reduced tobacco intake, and 43% had resumed previous smoking patterns. 3. Specific barriers to quitting include a lack of nonsmoking coping skills, long-term identity as a smoker, ready access to tobacco products, nicotine addiction, and limited nonsmoking social support.

Self-esteem among persons with severe mental illness.

There has been little research to substantiate the nature and degree of self-esteem among persons with mental illness. The results reported here are from a study involving 92 clients with severe mental illness. The study explored the relation between work status and quality of life, drug attitudes, and self-esteem. In this analysis, positive self-esteem was found among all subjects and was significantly higher in workers than in nonworkers. In stepwise multiple regression analysis, feelings regarding functioning, valuing of work, social relationships, and activities with family explained 50% of the variance in self-esteem. Mental health professionals should not assume that clients with mental illness experience low self-esteem.

Is the treatment worse than the cure? Attitudes toward medications among persons with severe mental illness.

1. Patients' attitudes toward taking long-term psychotropic medications and factors that may influence drug attitudes are important factors in compliance. 2. Patients in this study had generally positive drug attitudes and perceived their medications as important in preventing relapse. 3. Attitudes toward psychotropic medications may be more positive than has been assumed by mental health professionals, as patients seem to realize that the advantages of medications outweight side effects.

Quality of life and self-esteem in working and nonworking persons with mental illness.

The purposes of this research were to examine first the relationship between work status and quality of life and self-esteem in persons with severe, persistent mental illness and secondly, the relationship between (a) demographic characteristics, attitudes toward psychotropic medications, and perceptions of the meaning of work and (b) quality of life and self-esteem in working and nonworking persons with severe mental illness. The sample included 92 persons (51 workers and 41 nonworkers). Instruments included the quality of Life (QOL) Interview (Lehman, 1983), Rosenberg's (1965) Self-Esteem Inventory, the Drug Attitude Inventory (DAI) (Hogan, 1983), and a Perception of Work instrument, developed by the researcher. Workers reported significantly higher self-esteem than did nonworkers (t = 2.17, df = 90, p = .033). A significant difference in overall QOL was not found, but workers scored higher on all but one QOL subscale. There were no significant differences in self-esteem, QOL, or valuing of work based on demographic factors. No significant differences in drug attitudes were found based on work status. Workers rated the importance of work higher than did nonworkers (t = 6.46, df = 90, p = .000). Analysis of qualitative data revealed that contrary to the nonworkers' fears, workers reported that work provided a distraction from symptoms and contributed to better mental health.

Use of RN case management and costs and utilization of outpatient mental health services: a pilot study.

The majority of outcome studies on case management seem to have been studied on the chronically mentally ill patients. Little is known regarding the use of a case management approach with general psychiatric populations, which include non-chronically mentally ill patients in an outpatient setting. This study examined the effect of a registered nurse case management (RNCM) model on the delivery and cost of mental health services during an 18-month period for clients in an outpatient psychiatric setting. Sixty clients met the criteria for sample selection. The data indicated that the use of the RNCM model resulted in more nursing than psychiatric care. Despite more frequent visits to the RNCM and longer RNCM visits, RNCM services appeared cost effective and were related to decreased length of hospital stay. A subgroup of high-risk clients was identified, and a significantly greater use of services by this group was substantiated.

Pilot study results: the psychiatric RN case manager.

1. It is important to examine client and staff satisfaction with the RN case management (RNCM) model to enhance the quality of care in psychiatric settings. 2. Ninety-two percent of clients surveyed ranked the RNCM care as "excellent" or "above average." Clients valued most the humanistic role of the RNCM and repeatedly commented on the importance of the nurse being caring, genuine, and supportive. 3. RNCMs expressed high satisfaction with their role, which they described as collaborative with the psychiatrist, yet also professional and independent. Psychiatrists expressed a high degree of confidence that clients were receiving excellent care by competent nurse professionals.

Experiences of family members after a suicide.

BACKGROUND: Survivors of suicide are the family members and significant others in the life of the person who commits suicide. A recent study by the author explored the life experiences of survivors of suicide, affirmed the severity of postsuicide bereavement, and revealed the critical role of the family physician in intervention. METHODS: Thirty-five adult survivors participated in in-depth audiotaped interviews during the 3- to 9-month period after the suicide death of a family member. Demographic data and the transcribed interview data were analyzed through descriptive statistics and systematic methods of qualitative data analysis. RESULTS: Subjects stressed the importance of the family physician understanding the nature of their experiences in order to intervene effectively. All survivors experienced profound disruptions in their lives, including changes in physical, emotional, cognitive, and social functioning. Variations among survivors of suicide, based on the survivor's perception of the victim before his or her death, were evident and are illustrated by three case studies. Interventions for the family physician, including specific suggestions from survivors, are proposed. CONCLUSIONS: Survivors of suicide experience a very severe bereavement, yet significant variations exist among their responses. The family physician is identified as the key individual to initiate and ensure follow-up care for this bereaved population.

Survivors of a family member's suicide: implications for practice.

Survivors of suicide are people who are coping with the loss of a loved one through an act of suicide. Primary health care providers are well-positioned to identify and intervene with this population, which is known to be at high risk for health disturbances. A research study was conducted to further clinicians' understanding of the experiences and needs of survivors. The major research question was, "What do adult survivors report about their perceived life experiences three to nine months after the suicide of a family member?" Data from audiotaped interviews with 35 adult survivors of suicide were analyzed to determine a description of the experiences and needs of this population. A recurrent theme discovered in the lives of survivors was the persistence of agonizing, unanswerable questions related to the death. Surviving family members struggled with why the suicide had occurred and worried about the impact of the death on themselves and others. Profound changes in the emotional, cognitive, physical and social functioning of survivors were also evident. Implications for clinical practice are discussed.

Agonizing questioning: experiences of survivors of suicide victims.

Adult survivors were asked about their perceived life experiences 3 to 9 months after the suicide death of a family member. Thirty-five subjects participated in in-depth interviews. A constant comparative method of analysis yielded a core variable of "agonizing questioning". Subjects' questioning behavior was evident through their-descriptions of emotional turmoil, cognitive dissonance, physical disturbances, and altered socialization. Evidence of beginning to resolve the loss was apparent among subjects who had achieved some understanding of why the suicide had occurred or recognized that there were no answers to their questions.

On the development of behavioral tolerance to organophosphates. I: Behavioral and biochemical aspects.

The development of tolerance to organophosphates (OPs) was investigated by SC injections of saline and sublethal doses of DFP or soman three times per week or every other day for at least 4 weeks. Shuttlebox performance was tested 1 hr and 24 hr after the injections. Notwithstanding a progressive inhibition of AChE to very low values in various organs, shuttlebox performance was virtually normal 24 hr after the OP injections. However, whereas the performance decrements measured 1 h after the injection of DFP practically disappeared in the course of weeks, the decrements 1 hr after soman remained approximately the same. These differences between the effects of DFP and soman cannot be explained: 1) by differences in inhibition or de novo synthesis of AChE in various regions of the CNS, the striated muscle or blood, 2) by differences in the reductions of the muscarinic receptors in various regions of the CNS, 3) by differences in the number of nicotinic receptors in the diaphragm muscle, or 4) by differences in phosphorylphosphatase (DFP-ase or somanase) activity in blood plasma or liver.

In vitro degradation of the stereoisomers of soman in guinea-pig, mouse and human skin.

The fate of the four stereoisomers of soman [C(-)P(+), C(+)P(+), C(+)P(-) and C(-)P(-)] was studied by incubating 10 microM C(+/-)P(+/-)-soman at pH 7.4 and 37 degrees for various periods in the presence or absence of homogenates (1:10 and 1:20 w/v) of guinea-pig, mouse or human skin. The remaining concentrations of the soman isomers were determined gas chromatographically. Similar rates of spontaneous (non-enzymatic) hydrolysis (K = 0.005 min-1) were found for the four isomers of soman. Hydrolysis of the toxic (C(+/-)P(-)-isomers is not accelerated in the presence of the skin homogenates. In contrast, the non-toxic C(+/-)P(+)-isomers are enzymatically hydrolysed. As the amount of proteins present in the homogenates varied the rate constants for enzyme hydrolysis per protein concentration were calculated. Except for the high hydrolysis rate constant of greater than 0.127/min.g.l for C(+)P(+) in human skin, these values were almost similar (0.031-0.045/min.g.l) for the skin homogenates tested. Irreversible binding sites for the four soman-stereoisomers are only found in homogenates of mouse skin; 122-195 pmol soman-isomer are bound per mg protein. After preincubation of mouse homogenate with 10 microM soman during 18 hr at 0-4 degrees no further binding of the isomers was detected. It is concluded that skin of the three species tested does not contain enzymes that degrade the toxic C(+/-)P(-)-isomers of soman, whereas phosphorylphosphatase activity for the C(+/-)P(+)-isomers is present in the skin of all three species. Binding sites for all four soman isomers are only present in mouse skin.

Contribution of de novo synthesis of acetylcholinesterase to spontaneous recovery of neuromuscular transmission following soman intoxication.

The role of the de novo synthesis of acetylcholinesterase in the spontaneous recovery of neuromuscular transmission was studied in diaphragms isolated from soman-intoxicated rats. Ten minutes after soman (3 X LD50 i.v.), the acetylcholinesterase activity and the neuromuscular transmission appeared to be completely blocked. Acetylcholinesterase activity in endplate and endplate-free regions recovered linearly during a 3 h experiment (1.5 and 2.9%h, respectively); and neuromuscular transmission was also improved. Since both inhibition of the de novo synthesis of acetylcholinesterase by cycloheximide and the re-inhibition of acetylcholinesterase in vitro by soman did not affect the improvement of neuromuscular transmission, it was concluded that this recovery of neuromuscular transmission can not be attributed to synthesis of new acetylcholinesterase.