Pentoxifylline and intermittent claudication: review of clinical trials and cost-effectiveness analyses.

Intermittent claudication (IC) is common in the elderly; the prevalence is approximately 6% in 50- to 60-year-old patients and 10-20% in those over the age of 70. Several risk factors, especially smoking, are associated with increased prevalence. Disease progression results in increasingly debilitating and costly surgical intervention for about 20% of patients. This report reviews findings from some of the clinical studies that demonstrated the efficacy of pentoxifylline, the only U.S.-approved medical therapy for IC. Findings from a recently published cost-effectiveness analysis are presented. IC is difficult to study clinically because pain is both variable and subjective. In two multicenter, randomized, placebo-controlled studies, carefully monitored treadmill testing showed that pentoxifylline-treated patients had significantly improved walking distances even in the presence of a placebo effect. The pentoxifylline effect was pronounced in patients from a clinical target population defined by low baseline resting pressure ratios (< or =0.8) and long disease duration ( > 1 year). To understand the social implications of these findings, treadmill distances were converted to comparable distances on flat ground. Improvements on pentoxifylline therapy translate to walking distances that enable greater daily function. This improvement has significant practical benefit to the quality of life of IC patients. Using Medicare expenditure data, it was found that pentoxifylline therapy reduced average hospital costs per patients by $1,173. Direct medical cost savings of $69 to $3,090 were suggested by sensitivity analyses. In analyses of practical aspects of walking distance as well as cost-effectiveness analyses, pentoxifylline appears to be a highly useful treatment for IC.

Caffeine as an analgesic adjuvant in tension headache.

Six randomized, double-blind, two-period crossover studies, conducted under similar protocols, compared the efficacy of two analgesic combinations containing caffeine with an acetaminophen 1000 mg control and with a placebo in outpatients with episodic tension-type headaches. In four studies, comprising 1900 patients, the caffeine-containing analgesic consisted of a combination of 500 mg acetaminophen, 500 mg aspirin, and 130 mg caffeine (APAP/ASA/CAF). In two studies, comprising 911 patients, the caffeine-containing analgesic consisted of a combination of 1000 mg acetaminophen and 130 mg caffeine (APAP/CAF). Patients self-medicated for moderate or severe headache pain, and with a self-rating record they rated their pain and its relief hourly for 4 hours. In all six studies, the caffeine-containing analgesics were significantly superior both to placebo and to 1000 mg acetaminophen, and acetaminophen was significantly superior to placebo. The significant analgesic adjuvant effect of caffeine was independent of patients' usual caffeine use or their caffeine consumption in the 4 hours before medication. For each treatment, the pooled analgesic responses for the four studies of APAP/ASA/CAF were virtually superimposable on the responses in the two APAP/CAF studies. The combinations produced more stomach discomfort, nervousness, and dizziness than acetaminophen or placebo.

Amiprilose hydrochloride for rheumatoid arthritis.

STUDY OBJECTIVE: To assess the safety and efficacy of amiprilose hydrochloride (HCl), a novel synthetic carbohydrate with anti-inflammatory and immunomodulatory properties, in patients with rheumatoid arthritis. DESIGN: Prospective, multicenter, randomized, parallel group, double-blind placebo-controlled 12-week trial. PATIENTS: Two hundred and one functional class I and II patients with definite or classic rheumatoid arthritis, previously untreated with disease modifying antirheumatic drugs. INTERVENTIONS: Patients were withdrawn from nonsteroidal anti-inflammatory drug therapy. Those who flared were randomly assigned to amiprilose HCl, 6 g/d, or placebo for 12 weeks. No concomitant anti-inflammatory or antirheumatic drug therapy was permitted during the study. Combination acetaminophen and propoxyphene napsylate was the only supplemental analgesic medication allowed. MEASUREMENTS AND MAIN RESULTS: The number of painful joints and swollen joints, joint pain and joint swelling indices, left and right grip strength, investigator global assessment, and patient global assessment returned to baseline for the amiprilose group and showed statistically significant (P less than 0.05) differences from the placebo group within 4 to 6 weeks. The protocol criteria for overall therapeutic response were satisfied by 41% of the amiprilose patients, compared with 21% of the placebo group (P = 0.003). Approximately 0.5 tablet per day less analgesic medication was taken by the amiprilose group (P less than 0.05 at weeks 6 and 12). There were no statistically significant differences in morning stiffness, walking time, erythrocyte sedimentation rate, C-reactive protein, or rheumatoid factor between the groups. A similar number of adverse experiences were reported by the patients on amiprilose (67%) and on placebo (63%). One patient on amiprilose developed thrombocytopenia of unknown cause; no other reported adverse effects were serious. CONCLUSIONS: Amiprilose HCl has significant anti-inflammatory activity and a favorable safety profile when used as the sole antirheumatic therapy in patients with active rheumatoid arthritis. Synthetic carbohydrates may represent an important new class of drugs for the treatment of inflammatory, autoimmune diseases.

A two-period crossover design for the comparison of two active treatments and placebo.

This paper discusses a two-period crossover design for the comparison of two active treatments (A and B) and placebo (P) for relief of recurrent symptoms of a chronic health disorder. It is based on blocks of ten patients for which the treatment sequences A:B and B:A are each assigned to three patients and the sequences A:P, P:A, B:P, and P:B are each assigned to one patient; thus, treatment periods have a 2:2:1 allocation for A, B, and P. The principal model for analysis of this design involves additive subject effects, period effects, and treatment effects. Analysis of within-patient differences provides an estimate of the comparison between active treatments with variance (2vw/7r) and an estimate of the comparison between an active treatment and placebo with variance (4vw/7r); here vw is the within-patient variance and r is the number of blocks of ten patients. Analyses which address carryover effects and treatment effects adjusted for carryover effects are also described. An example using simulated data on relief of recurrent gastrointestinal pain illustrates the methodology.

A benefit of spinal manipulation as adjunctive therapy for acute low-back pain: a stratified controlled trial.

Fifty-four subjects volunteered to participate in a controlled study contrasting spinal manipulation with spinal mobilization without the rotational forces and leverage required to move facet joints. All suffered from regional low-back pain for less than 1 month, were ages 18-40, had never previously undergone any form of spinal manipulation, and denied a prior episode of backache within the previous 6 months. Randomization was stratified at outset into those who suffered for less than 2 weeks and those whose discomfort had persisted for 2-4 weeks. Outcome was monitored by a questionnaire assessing functional impairment. A treatment effect of manipulation was demonstrated only in the strata with more prolonged illness at entry. In the first week following manipulation, these patients improved to a greater degree (P = .009, t test) and more rapidly (P less than .025, Wilcoxon rank-sum test).

The assessment of health policy changes using the time-reversed crossover design.

The time-reversed crossover design is a quasi-experimental design which can be applied to evaluate the impact of a change in health policy on a large population. This design makes use of separate sampling and analysis strategies to improve the validity of conclusions drawn from such an evaluation. The properties of the time-reversed crossover design are presented including the use of stratification on outcome in the sampling stage, which is intended to improve external validity. It is demonstrated that, although this feature of the design introduces internal validity threats due to regression toward the mean in extreme-outcome strata, these effects can be measured and eliminated from the test of significance of treatment effects. Methods for within- and across-stratum estimation and hypothesis-testing are presented which are similar to those which have been developed for the traditional two-period crossover design widely used in clinical trials. The procedures are illustrated using data derived from a study conducted by the United Mine Workers of America Health and Retirement Funds to measure the impact of cost-sharing on health care utilization among members of its health plan.

On the design of the Phase III drug trial. The example of rheumatoid arthritis.

No new drug can be marketed in the United States unless a favorable risk-benefit ratio has been demonstrated to the satisfaction of the Food and Drug Administration. Inspection of the fashion in which this is accomplished with reference to rheumatoid arthritis reveals shortcomings in form and substance. Ten issues of design are isolated and options discussed. One design suggested, as a compromise, is 2 20-center trials to supplant late Phase II and Phase III trials. At each center a single investigator evaluates at least a 10-subject, highly selected cohort over 6 months in a 2-drug or a 2-drug plus placebo double-blind format. The active drug versus active drug component of the program will be pivotal in analysis. Advantages include expedience, lower cost, effective detection of short-term stratum-specific toxicity and of investigator bias, and absence of compromise in beta error. With such data and with emphasis on the beta error, the risk-benefit judgment will be more meaningful. Formalized Phase IV monitoring is proposed to detect infrequent or delayed toxicities.

A need-based model to project national dental expenditures.

A national model on need for dental treatment, as measured by the HANES survey of the National Center for Health Statistics, is described and applied to determine expenditures required to provide necessary dental services under third-party funding of a national dental program. Services have been divided into five components by type of service and age of the population and expenditures are projected for each year, 1980-84. Total expenditures are projected to increase from 18.98 billion dollars in 1980 to 26.42 billion in 1984. Separate projections are also provided for each component and each service. Expenditures derived from this model are compared to direct projections of trends taking place in the current dental care system. Only minor discrepancies in total expenditures are noted but there are large differences for individual services, notably in the areas of prevention and periodontal diseases. Separate comparisons with demand-based projections derived from the experience of the California Dental Service are also presented. Again, the major differences relate to expenditures for individual services, particularly crowns, for which demand expenditures outstripped need by a three-fold margin.

An evaluation of subsidized rural primary care programs: I. A typology of practice organizations.

The design of a comprehensive evaluation of subsidized rural primary care programs on a large national scale is described, Its major purpose is to derive data whose analysis will answer major policy questions about the factors influencing the outcome of the major types of such programs in different communities. This first paper also delineates a typology which was developed of five principal organizational forms of these programs. This classification appears to provide suitable operational definitions of forms of rural practice as a basis for evaluating the differential impact of alternative types of primary care programs.

A review of some statistical methods for covariance analysis of categorical data.

Three general methods for covariance analysis of categorical data are reviewed and applied to an example from a clinical trial in rheumatoid arthritis. The three methods considered are randomization-model nonparametric procedures, maximum likelihood logistic regression, and weighted least squares analysis of correlated marginal functions. A fourth heuristic approach, the unweighted linear model analysis, is an approximate procedure but it is easy to implement. The assumptions and statistical issues for each method are discussed so as to emphasize philosophical differences between their rationales. Attention is given to computational differences, but it is shown that the methods lead to similar results for analogous problems. It is argued that the essential differences between the methods lie in their underlying assumptions and the generality of the conclusions which may be drawn.

Survey approach to estimating demand for physician assistants.

A national probability sample of physicians was surveyed by mail to provide an estimate of the number of job openings for physician assistants (PAs). The responses were used to undertake an empirical analysis of the factors which influence a physician's decision to hire a PA. Estimates were adjusted to account for survey non-response. This approach may be useful for estimating the employment demand for other types of health workers employed by physicians. It was found that in 1976 there was an unconditional demand for 20,338 PAs and a further conditional demand for 3417 PAs. This contrasts sharply with the fact that as a march 1977 only 4845 PAs had graduated from training programs. Approximately 53% of this employment demand was from physicians in the primary care specialties (general/family practice. Obstetrics/gynecology, internal medicine, and pediatrics). Of note was the finding that physicians expected to pay PAs a lower salary than was being received in the market place. Further, 27% of physicians not willing to hire PAs indicated lack of knowledge about them as the main reason for not hiring.

An application of multivariate ratio methods for the analysis of a longitudinal clinical trial with missing data.

This paper presents an analysis of a longitudinal multi-center clinical trial with missing data. It illustrates the application, the appropriateness, and the limitations of a straightforward ratio estimation procedure for dealing with multivariate situations in which missing data occur at random and with small probability. The parameter estimates are computed via matrix operators such as those used for the generalized least squares analysis of catetorical data. Thus, the estimates may be conveniently analyzed by asymptotic regression methods within the same computer program which computes the estimates, provided that the sample size is sufficiently computer program which computes the estimates, provided that the sample size is sufficiently large.

Hand structure and function in an industrial setting.

The influence of patterns of usage on the structure and function of the hands was formally tested. Three groups of female textile workers, each employed in a distinct and defined, atraumatic, repetitive, stereotyped manual task for at least 20 years, were identified in a single rural mill. Replicate data were obtained for the following measures of structure and function: range of motion, a score for the degree of radiographic degenerative changes at each hand joint, malalignment at digital joints determined radiographically, and a quantitative measure of osteophyte formation. Significant and consistent differences in the right hand when compared to the left were detected. Furthermore, highly significant task-related differences were demonstrated. These task-related differences in the structure and function of the hands were consistent with the pattern of usage. Therefore these three patterns of usage influence hand structure and function in the population studied.

The evaluation of Regionalized Perinatal Health Care Programs.

A survey, conducted in the summer of 1974, to determine the extent of regionalized perinatal care in the United States revealed 28 states to have programs in operation. Evaluation was a common concern of these programs. A model for the evaluation of Regionalized Perinatal Care Programs is presented here with the North Carolina program used as an example. Evaluation was mandated as an integral component of the program in North Carolina, and this model has been developed in response to that mandate.