Criteria for evaluating treatment guidelines.

This document presents a set of criteria to be used in evaluating treatment guidelines that have been promulgated by health care organizations, government agencies, professional associations, or other entities. Although originally developed for mental health interventions, the criteria presented are equally applicable in other health service areas. This document is organized on the basis of two related dimensions for the evaluation of guidelines. The first dimension is treatment efficacy, the systematic and scientific evaluation of whether a treatment works. The second dimension is clinical utility, the applicability, feasibility, and usefulness of the intervention in the local or specific setting where it is to be offered. This dimension also includes determination of the generalizability of an intervention whose efficacy has been established. To encourage accountability, criteria for evaluating the process of guideline production are also provided. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interferon beta for multiple sclerosis

OBJECTIVE: To introduce readers to the use of a new agent, interferon beta-1b (IFN beta ser), in the treatment of relapsing-remitting multiple sclerosis (RRMS). Therapeutic and economic issues surrounding IFN beta ser are discussed, as are its pharmacology, clinical efficacy, adverse effects, and dosage guidelines. DATA SOURCES: A MEDLINE search was used to identify pertinent literature, including clinical trials and reviews. STUDY SELECTIONS: All available trials were reviewed. DATA EXTRACTION: Since trials evaluating subcutaneously administered interferon beta are sparse, clinical trials evaluating intrathecal IFN beta ser were included, as was toxicology information from the oncology population. DATA SYNTHESIS: IFN beta ser has recently been approved by the Food and Drug Administration for the treatment of RRMS. Its exact mechanism of action is unknown, but it may downregulate interferon gamma (IFN gamma) production and the IFN gamma-stimulated major histocompatibility complex antigen expression, and/or augment T-suppressor cell function. Primary adverse effects include flu-like symptoms, fever, chills, myalgia, sweating, and injection-site reactions. Clinical efficacy has been investigated in 372 ambulatory patients with RRMS. IFN beta ser treatment resulted in a reduction in the annual exacerbation rate and a greater proportion of exacerbation-free patients. Burden of central nervous system disease was also significantly reduced in treated patients. However, no reductions were detected on the Scripps Neurologic Rating Scale or with confirmed endpoint scores on the Kurtzke Expanded Disability Status Scale. Although many questions remain concerning IFN beta ser's long-term efficacy, its benefits in patients with other types of multiple sclerosis (MS), and its effect on progression of disease and ultimate disability, IFN beta ser is the first treatment modality that has substantially altered the natural course of MS in a controlled clinical trial. CONCLUSIONS: IFN beta ser is not a cure for MS, but it is well tolerated and patients with RRMS have shown significant improvements in exacerbation rates and burden of central nervous system disease. IFN beta ser should be considered a definite improvement in RRMS treatment, although many therapeutic issues remain unanswered. Additional clinical trials are needed.     

Clinical research designs for emerging treatments for Alzheimer disease: moving beyond placebo-controlled trials

The design of clinical trials must evolve as new therapies become available. The demonstrated efficacy and clinical use of donepezil and vitamin E for Alzheimer disease (AD) has shifted the options for AD research design. There is now a compelling case for alternatives to trials that include a treatment arm with no active therapy (ie, a placebo control). With an existing therapy, such as donepezil or vitamin E, new drugs that are clearly superior to those drugs should be sought. Combination therapy is a likely strategy for the future, implying that clinical trials, if possible, should replicate actual practice. The long duration of future AD trials also will make placebo-controlled trials more difficult to justify and more difficult to recruit for. Add-on or active-control designs represent the alternative approaches. We believe that definitive clinical trials of new AD drugs that use one or the other of these designs would be more likely to bring about therapeutic advances than would comparisons with inactive treatments. Our argument is not a general rejection of placebo-control designs. Our recommendations apply only to the circumstances in which the field of AD drug therapy now finds itself.     

Therapeutic strategies for patients with tuberculosis

OBJECTIVES: To determine the effectiveness of strategies used to promote adherence to anti-tuberculosis treatment. SEARCH STRATEGY: MEDLINE 1966-1996 (August), Cochrane Collaboration Trials Registers (October 1996), LILACS 1982-1996 (September); reference lists in articles on adherence, contact with experts in the fields of TB and adherence research. SELECTION CRITERIA: Randomised or pseudo-randomised controlled trials of interventions to promote compliance with curative or preventive chemotherapy for TB, with at least one measure of adherence. DATA COLLECTION AND ANALYSIS: Data on study methods, participants, interventions and outcomes were collected for each study and methodological quality was assessed. Estimates of effect were assessed for categorical outcomes using the Peto odds ratio, with 95% confidence intervals. MAIN RESULTS: Strategies found to be of benefit were reminder cards sent to defaulters, assistance of patients by lay health workers, monetary incentives offered to patients, and increased supervision of TB clinic staff. It is not possible to determine from current trials whether health education by itself leads to better adherence to treatment. Even though directly-observed therapy (DOT) is widely advocated as the most cost-effective means of ensuring completion of TB treatment, no completed trials could be found which confirm or refute this view. CONCLUSIONS: RCT evidence exists that certain strategies improve adherence to anti-tuberculous therapy, and these should be adopted into clinical practice depending on their appropriateness to practice circumstances. Further innovations should be tested to find solutions that will be useful in low income countries. Randomised trials evaluating the independent effects of directly-observed therapy (DOT) are awaited.     

Moclobemide. An update of its pharmacological properties and therapeutic use

Unlike older monoamine oxidase inhibitors, which irreversibly and nonselectively bind monoamine oxidase (MAO), moclobemide is a reversible and selective inhibitor of the MAO-A isozyme. Moclobemide only weakly potentiates the pressor response induced by tyramine or other indirectly acting sympathomimetics; therefore, there is no need to avoid dietary tyramine or over-the-counter decongestants with moclobemide as there is with older MAO inhibitors. Recent clinical trials and meta-analyses have confirmed the efficacy of moclobemide in the treatment of depressive disorders. Moclobemide has been shown to have similar efficacy to tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and nonselective, irreversible MAO inhibitors. Long term follow-up studies of 6 to 12 months' duration have demonstrated that the antidepressant efficacy of moclobemide is maintained. Moclobemide, given alone or in combination with another antidepressant, has shown some efficacy in patients with refractory depression; however, comparative trials are required to confirm these findings. Data are also available to show clinical efficacy of moclobemide in the management of social phobia. Comparative studies have established that moclobemide is better tolerated at therapeutic dosages and has less toxicity in overdose than TCAs and nonselective, irreversible MAO inhibitors. Moclobemide lacks the anticholinergic, sedative and cardiovascular effects associated with many of the older antidepressants. Compared with SSRIs, moclobemide has a similar overall tolerability, although it tends to cause fewer gastrointestinal effects than the SSRIs and has not been reported to interfere with sexual function. In summary, recent data which confirm and extend its comparative therapeutic efficacy and low potential for adverse effects have established moclobemide as an effective treatment in depressive disorders. The drug is also effective in patients with a primary diagnosis of social phobia. Its lack of adverse anticholinergic, cardiovascular, cognitive and psychomotor effects makes moclobemide a particularly useful option in the elderly or patients with cardiac disease.     

Negative effects on family functioning from psychosocial treatments: A recommendation for expanded safety monitoring.

Whereas biomedical products are required to be tested for safety with respect to vulnerable organ systems, psychosocial treatments are not required to be tested for safety with respect to vulnerable social systems such as the family. This article provides some evidence for the need to document the potential negative effects of psychosocial treatments on family-level outcomes. Three randomized controlled trials are reviewed in which independent ratings or self-reports of family functioning were measured. Each of the 3 studies compared the efficacy of a family and a nonfamily treatment. Totally unexpectedly, the nonfamily treatment in each of the 3 trials demonstrated significant declines in family functioning. The authors suggest that psychosocial treatments with vulnerable populations have the potential to produce negative side effects on families. Therefore, it is important to conduct further research to determine whether safety studies should be required for psychosocial treatments. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Treatment of lichen planus. An evidence-based medicine analysis of efficacy

OBJECTIVE: To critically appraise the body of literature concerning treatment of lichen planus (LP). DESIGN: Review of MEDLINE and BIOSIS databases to identify articles published with at least an English abstract before March 1998 that examined treatment of LP. MAIN OUTCOME MEASURES: Forming a primary database on which most recommendations are based. We thus selected 83 clinical trials or small series of patients in the medical literature that referenced clinical data on patients treated for LP. RESULTS: There are no large randomized trials with definitive results in the medical literature examining the efficacy of the various drugs or physical treatments of LP. There are only 3 level B trials (small randomized trials with uncertain results because of moderate to high alpha or beta error) that address efficacy of treatment in LP, i.e., 1 with acitretin in cutaneous LP and 2 with topical corticosteroids in mucosal LP. The remainder of the published trials are observational and are not always prospective. Many of the recommendations of the experts are based on their personal experience. CONCLUSIONS: Although LP may be associated with substantial morbidity and altered quality of life, especially the erosive mucosal LP, definitive clinical trials have not been performed. Acitretin is the first-line therapy in cutaneous LP. The efficacy of systemic corticosteroids and psoralen plus UV-A therapy has not been established with a high level of proof. Topical corticosteroids are the first-line therapy in mucosal erosive LP. Other treatments, such as topical cyclosporine or extracorporeal photochemotherapy, remain to be evaluated. European-US cooperation is warranted to perform large randomized controlled trials in cutaneous and mucosal LP.     

The hormonal and chemotherapy of prostatic cancer

Adenocarcinoma of the prostate is one of the most common malignant tumors in adult males. Hormonal therapy is the treatment of choice for patients with systemic disease concerning 80% response rate. Androgen ablation is now the first hormonal manipulation and can be achieved either by means of bilateral orchiectomy or of LH-HR agonist therapy: both are equally effective. Total androgen blockage (association between orchiectomy or LH-RH agonist and non-steroidal anti-androgens) would be reserved for controlled clinical trials only. Estrogens had the same efficacy, but revealed the serious cardio-vascular events. Endocrine therapy does not prolong survival but provides good palliation. Palliation should be given when there is something to palliate. Prostate cancer is usually not recognized as being sensitive to cytotoxic agents. Single agent or combination chemotherapy has not been shown to have a role as first line treatment of disseminated disease and is usually used for hormone refractory disseminated disease.     

Gamma delta TCR-bearing intraepithelial lymphocytes regulate class II major histocompatibility complex molecule expression on the mouse small intestinal epithelium

OBJECTIVE: To examine the hypothesis that addition of therapeutic plasma exchange (TPEX) to an immunosuppressive drug regimen increases that regimen's efficacy to halt the progression of chronic progressive multiple sclerosis (CPMS). METHODS: The literature was searched for prospective controlled clinical trials evaluating the efficacy of TPEX in CPMS. Six studies were eligible for meta-analysis. Their results were combined, using Cochran's and Peto's methods. Three outcome measures were studied: 1) the change in Kurtzke's disability status scale (DSS) scores, 2) the relative odds of neurologic decline by 1 or more DSS grades, and 3) the relative odds of neurologic improvement by 1 or more DSS grades, in the treatment versus the comparison group of patients. Reported results of neurologic evaluations at 6, 12, 24, and 36 months of follow-up were analyzed separately. RESULTS: TPEX significantly (P < .05) reduced the proportion of patients who experienced neurologic decline (by 1 or more DSS grades) at 12 months of follow-up (relative odds of decline = 0.441, 95% confidence interval = 0.210-0.929). CONCLUSIONS: There is a need for further clinical research into the possibility of a beneficial effect of TPEX in patients with CPMS likely to experience neurologic decline over the ensuring 12 months. Targeting treatment to a particular subgroup of CPMS patients may be necessary for TPEX to prove effective.     

Treatment of pituitary adenoma]

RECOMMENDED TREATMENTS: The different therapeutic strategies proposed for pituitary adenomas are relatively well-known thanks to numerous studies evaluating their effect on outcome. Unfortunately, large comparative clinical trials are difficult to construct due to the small number of cases of this rare condition. Therapeutic recommendations are thus generally based on the opinion of recognized experts. MICROADENOMA: Small (< 10 mm) prolactin-secreting adenomas should be treated surgically, generally by transsphenoidal adenomectomy, or medically by dopaminergic agonists: bromocriptin, quinagolide or cabergolin (the two latter drugs are more effective and better tolerated than their parent compound bromocriptin). MACROADENOMA: The expected success rate for surgical treatment of macroadenomas is low and dopaminergic agonists is generally recommended (including cases with visual impairment since the effect can be very rapid). Prolactin levels can be lowered and tumor volume reduced (in > 70% of cases). ACROMEGALY: Surgery is the firs intention treatment for acromegaly. In case of unsuccessful surgery (the criteria for "cure" are much more strict in 1998 than previously), somatostatin analog and/or hypothalamo-hypophyseal radiotherapy are recommended. Slow release formulations of somatostatin analogs can now be given by monthly (octreotide LP) or biweekly (lanreotide LP) injections. CUSHING'S DISEASE: Cure can be achieved in > 80% of cases with surgery, the first intention treatment of choice. If surgery is unsuccessful, radiotherapy can be proposed associated with anticortisol drugs (mitotane), if needed, while waiting for the late effect of radiotherapy. CLINICALLY SILENT ADENOMAS: Non-functional adenomas should be operated. Some propose adjuvant radiotherapy in all cases and others only if residual tissue persists post-operatively.     

An introduction to survival analysis: Statistical methods for analysis of clinical trial data.

The randomized controlled clinical trial (RCT) is a prospective study using random assignment of subjects to treatment groups to compare the effect and value of a therapeutic intervention against a control. The RCT is the most definitive clinical research tool for evaluating the efficacy of a new therapy in human subjects. Often the outcome of interest in an RCT is the length of time until an event occurs after treatment or intervention. In this article we introduce statistical methods for evaluating differences in the patterns of time to response between two groups of subjects to determine whether one therapy is better than another. The collection of methods for analyzing such data, known as survival data, is called survival analysis. Using data from a hypothetical clinical trial for the prevention of the recurrence of depression, we illustrate two elementary methods for analyzing survival data. We also discuss generalizations of these methods to incorporate covariates and conclude with a general discussion of clinical trials of psychiatric therapies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent?

OBJECTIVE: To determine whether improvement of more than 20% in core set parameters should be required before patients are characterized as improved in rheumatoid arthritis (RA) clinical trials. METHODS: Data from 6 RA trials were reanalyzed to evaluate the discriminant validity (ability to differentiate active treatment from control) of 4 proposed definitions of improvement: the current American College of Rheumatology (ACR) definition (a 20% threshold for core set parameters [ACR 201), a 50% threshold (ACR 50), a 70% threshold (ACR 70), and an ordinal definition in which a patient could be classified in any of 3 categories (unimproved, ACR 20, or ACR 50). To evaluate the discriminant validity of these 4 definitions of improvement, we characterized each patient in each trial as improved or not, based on each definition, and computed a chi-square value differentiating the active treatment group from the control group, with the corresponding P value. RESULTS: With an increase in the threshold for improvement, the percentage of placebo-treated patients who were classified as experiencing response dropped dramatically in all trials, as did the percentage of patients receiving active therapy (second-line drug, combination therapy, tumor necrosis factor p75-Fc fusion protein) who were classified as experiencing response. Generally, the drop in active treatment response rates was greater than the drop in placebo response rates, leaving the difference between the 2 groups less at the higher thresholds. Therefore, chi-square values fell as the threshold for response was raised. The ordinal definition of improvement yielded chi-square values similar to those obtained using ACR 20 alone. CONCLUSION: Adopting a definition of efficacy in RA trials that requires 50% or 70% improvement in core set parameters would likely compromise statistical power and make it more difficult to distinguish between 2 treatments with different efficacy. ACR 20 should continue to be the primary measure of efficacy in RA trials, with higher thresholds for improvement being determined and reported as secondary efficacy measures.     

The development of hemoglobin solutions as red cell substitutes

It is clear from the trials described here that the number of different products being tested and the potential variation between batches of the same product present major problems in evaluating the safety and efficacy of hemoglobin-based oxygen carriers. The recent CBER "Points to Consider" document [42] makes clear that an understanding of the safety of oxygen carriers in humans is of paramount importance. In the event of phase II or indeed phase III trials being approved, the need may still remain for additional phase I or preclinical studies, particularly as unwanted or toxic properties of the solutions affect efficacy. It is likely that demonstrating safety and efficacy in acute hemorrhagic shock will be the most difficult task, as this is a complex clinical indication and is often accompanied by multisystem damage. The use of a hemoglobin-based oxygen carrier in this setting must have a distinct advantage over a plasma expander alone. In the application of perioperative transfusion, a decreased requirement for red cell transfusion has already been accepted as a basis for the efficacy for erythropoietin. However, in the case of a hemoglobin-based oxygen carrier, the reduction of red cell requirement in perioperative procedures would need to be balanced against any adverse drug reactions or unacceptable hemodynamic effects that may be caused by the product. It appears that there are still numerous hurdles to overcome in the development of hemoglobin-based red cell substitutes. Before these products can become established in medical practice, it is imperative that the potential mechanisms of toxicity of cell-free hemoglobin are clearly understood. Approval of hemoglobin-based oxygen carriers for clinical use will depend not only on clear demonstration of both safety and efficacy but also on risk-versus-benefit issues. Our understanding of the physiological effects of these products will evolve as progress is made in their clinical evaluation.     

Oxidant stress with hydrogen peroxide attenuates calcium paradox injury: role of protein kinase C and ATP-sensitive potassium channel

Available literature on the use of pharmacologic agents for the treatment of sleep-disordered breathing was reviewed by evidenced-based methodology. Evidence tables were created and studies were graded according to study design and the number of subjects included. Scores for each group of studies evaluating each pharmacologic agent were established so that the quality of research for different drugs could be compared. The use of various ventilatory stimulants, psychotropic drugs, and antihypertensive agents were reviewed. The most objective data are available on theophylline and opioid antagonist/nicotine groups. Although more controlled studies would be helpful, relatively clear-cut indications for the use of ventilatory stimulants exist for hypercapnic obesity-hypoventilation patients (medroxyprogesterone), myxedema (thyroid replacement), central apnea (acetazolamide), and periodic breathing in congestive heart failure (theophylline). Few randomized, well-controlled trials have been published that evaluate pharmacologic agents in the treatment of classic OSA. To date, no one agent stands out as being useful for OSA. Future research will need to characterize subjects so that various subsets of patients can be tried on one or on a combination of various pharmacologic agents.     

Bacteriologic surveillance of nosocomial septicemia and bacteremia in a pediatric hospital

OBJECTIVE: To review the literature pertaining to the use of adjunctive thrombolytic therapy for the treatment of peritoneal dialysis-associated peritonitis (PDAP). DATA SOURCES: A MEDLINE search was conducted (January 1966-December 1997) to find articles using the terms peritonitis, peritoneal dialysis, and each thrombolytic drug. References from these articles were then reviewed to identify further sources. DATA EXTRACTION: Representative case reports and clinical trials are summarized in this report. Information regarding thrombolytic dosing, administration techniques, and reported efficacy rates are included from both case reports and clinical trials. DISCUSSION: Thrombolytic agents administered intraperitoneally appear to facilitate antibiotic penetration into the biofilm formed by certain bacteria. Numerous case reports of intraperitoneal thrombolytic adjunctive therapy for recurrent or persistent PDAP have indicated that these agents may have a role in the treatment of selected patients. Urokinase and streptokinase are the only thrombolytics that have been studied. They appear to have similar efficacy, but the adverse drug event rate with streptokinase is unacceptably high. The efficacy of therapy with urokinase is probably inferior to removal of the peritoneal dialysis catheter, but, if successful, allows for the continuation of peritoneal dialysis therapy. CONCLUSIONS: In conjunction with appropriate antibiotic therapy, intraperitoneal instillation of urokinase should be reserved for patients who develop two or more episodes of recurrent or persistent PDAP in the absence of poor compliance and in whom dialysis catheter removal should be avoided (i.e., they cannot tolerate hemodialysis).     

The efficacy of psychotherapy as the basis for public policy.

Discusses the tremendous growth that has occurred in the number of mental health providers, the rate of use of mental health services, and public and private reimbursement for mental health care. Governmental policymakers and leading insurance officials continue to seek information regarding the appropriateness and efficacy of specific psychotherapeutic techniques with various types of presenting problems. The efforts during the Carter administration to stimulate additional efficacy research and knowledge synthesis regarding the efficacy of psychotherapy are described. A public policy proposal is forwarded that no form of health intervention—physical or mental—should be supported through 3rd-party reimbursement and publicly supported training programs unless it has been demonstrated to be safe and effective. It is argued that randomized controlled clinical trials should be viewed as the most valid, though not exclusive, source of evidence. (10 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discussion of the AED workshop

An overview is given of the different issues that have been discussed, with subsequent recommendation. Standardisation of measurement and reporting of efficacy parameter and side-effects is essential; not only the number of patients achieving complete seizure controlled or have a decrease in seizure frequency and severity should be mentioned but also the number who dropped out and the reasons therefore. More information is needed on the teratogeneticy of a drug, either by performing control trials or by registration of all pregnancies with new anti-epileptic drugs. Appropriate bio-marker for efficacy and toxicity should be developed. Health-related quality of life scales, collecting both subjective and objective information should be developed and used as complimentary tools in understanding more about the disease. A drug that improves the quality of life but is less effective in suppressing seizures should be marketed. Finally, pharmaco-economic studies should be encouraged in the field of epilepsy.     

Is the placebo control obsolete in a world after donepezil and vitamin E?

Recent clinical trials of donepezil and vitamin E have produced active therapeutic drugs for the treatment of patients with Alzheimer disease (AD). The AD research community is now in a gray zone between the absence of accepted therapies and the presence of completely effective therapies. How should these therapies guide the choice of the proper control for future AD clinical trials? The community equipoise principle can guide a process to answer this question. The principle is that a clinical trial should answer clinical questions that are valued by the community who will use the results of that trial. This means that the choice of the proper control for future AD clinical trials ought to be guided by the values of a community who will experience the results of those trials: physicians and patients or their representatives such as caregivers. The values of patients can be included by giving them a voice in the design and review of clinical trials. Community dialogue should be the norm for the design and review of AD clinical trials. We conclude with suggestions to foster this dialogue and issues that should be addressed.     

Mathematical and empirical development of a test of memory for clinical and research use.

H. Buschke (1973, 1974) described a procedure for evaluating verbal learning and memory that has been widely used clinically and in research. The procedure, however, lacks a rational basis for defining certain inherent parameters such as length of list to be learned or number of learning trials to be given. Test structure and scoring have never been standardized. In the present study, computer simulations were used to examine the procedure in terms of a mathematical learning model; optimal scoring procedures; and the effects of varying certain internal parameters such as list length, reinforcement paradigm, number of trials, and number of replications. The theoretical results obtained were applied to clinical research studies of 49 patients with primary degenerative dementia and dementia associated with alcoholism to demonstrate on a preliminary basis feasibility, reliability, and validity in the clinical research setting and to suggest strategies for structuring tests for future use in clinical research. (22 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Rivastigmine. A review of its use in Alzheimer's disease

Rivastigmine (SDZ ENA 713) is a carbamylating, long-acting reversible and noncompetitive carbamate acetylcholinesterase inhibitor that is indicated as an oral treatment for patients with mild to moderately severe Alzheimer's disease. The drug has been evaluated for this use in 3 well designed, adequately powered, phase II/III, 26-week clinical trials that included a total of 1479 rivastigmine and 647 placebo recipients. Most of these patients had concomitant disorders that were being treated with numerous other drugs. Individual and pooled results of these trials indicate that rivastigmine 6 to 12 mg/day usually produces cognitive, global and functional changes that indicate significantly less deterioration than was observed with placebo in patients with mild to moderately severe Alzheimer's disease. Individual results of the 2 pivotal trials and pooled analysis also show that, compared with placebo recipients, significantly more rivastigmine 6 to 12 mg/day recipients respond to therapy. Indeed, after 26 weeks of therapy in the 2 pivotal trials, significantly more rivastigmine 6 to 12 mg/day than placebo recipients achieved clinically meaningful improvements as defined by 3 separate response criteria. The lower dosage range of 1 to 4 mg/day was not as effective as 6 to 12 mg/day, as measured using these criteria and other efficacy parameters. Rivastigmine causes adverse events that are generally those expected from an acetylcholinesterase inhibitor. They are usually mild to moderate, of short duration and responsive to dosage reduction. Unpublished data from 3989 patients indicate that rivastigmine and placebo were associated with similar incidences of serious adverse events and changes in laboratory parameters, ECG and cardiorespiratory vital signs. The most common events were gastrointestinal, central and peripheral nervous system and whole body adverse events. However, compared with placebo, rivastigmine more commonly caused adverse events resulting in treatment withdrawal. These events were most frequently gastrointestinal and were more common in women. CONCLUSION: Rivastigmine is a useful option for the treatment of patients with mild to moderately severe Alzheimer's disease. Although only short term (6- month) comparisons with placebo are available, given the lack of established treatment options it should be considered for first-line use in this population.