Dipyridamole in the treatment of angina pectoris: a meta-analysis.

A meta-analysis was performed to reevaluate the efficacy of dipyridamole for prophylaxis of angina pectoris. We found 10 articles that reported 11 randomized control trials published between 1960 and 1970. Three trials found a statistically significant benefit for the drug vs placebo, four showed a positive trend, two found no difference, and two showed a slight trend favoring placebo. When the results of all 11 trials were combined, two different statistical methods showed a statistically significant benefit from the drug. These combined results must be interpreted cautiously because of excluded patients and other methodologic variations in the studies, as well as evidence from other studies that dipyridamole may aggravate angina. Nevertheless, we conclude that there is some evidence for efficacy of the drug and believe the question should be restudied in larger and better-designed trials.

Pteridines. 41. Synthesis and dihydrofolate reductase inhibitory activity of some cycloalka[g]pteridines.

A number of homologous 2,4-diaminocycloalka[g]pteridines varying in ring size from 5 to 15 were prepared by (a) condensation of aminomalononitrile tosylate with alpha-oximinocycloalkanones, deoxygenation of the resulting 2-amino-3-cyanocycloalka[b]pyrazine 1-oxides, and guanidine cyclization; (b) guanidine cyclization of the above pyrazine 1-oxides to give 2,4-diaminocycloalka[g]pteridine 8-oxides, followed by deoxygenation; or (c) condensation of 2,4,5,6-tetraaminopyrimidine with a cycloalka-1,2-dione (for the cyclohepta- and cycloocta[g]pteridines only). These compounds were examined for their activity as dihydrofolate reductase inhibitors against Lactobacillus casei, rat liver, L1210, and Trypanosoma cruzi. Activity was found to depend upon ring size, with the greatest activity exhibited by the cyclododeca derivatives 31.

Meta-analysis of randomized controlled trials as a method of estimating rare complications of non-steroidal anti-inflammatory drug therapy.

The design of randomized controlled trials to assess the efficacy of pharmacological measures for the prevention of the gastrointestinal side-effects of anti-inflammatory drugs requires an accurate estimate of excess risk under controlled conditions. Photocopies of 952 randomized controlled trial publications were obtained after scanning titles and abstracts of a MEDLINE computer search, 427 were excluded for obvious reasons, and 525 were again photocopied after obliterating source and results. Selection criteria were: the presence of a non-anti-inflammatory drug control group; at least 4 days of therapy; at least 3 days without anti-inflammatory drugs before randomization; no complicating background drugs; mention of side-effects; and a clear differentiation of gastrointestinal complications. Observer error, with two independent readings, for inclusion suitability in the study was 19% for Methods and 9% for Results. For the 44 aspirin trials, the mean therapy duration was 357 days; the unweighted rate difference between therapy and control groups ( +/- 1 S.E.M.) for ulcer was 0.006 +/- 0.003, for gross haemorrhage 0.006 +/- 0.002 and for unspecified gastric symptoms 0.03 +/- 0.01. In 123 non-aspirin non-steroidal anti-inflammatory drug (NA-NSAID) trials, the mean duration was 67 days; the unweighted rate difference for ulcer was 0.0005 +/- 0.0003, for gross haemorrhage 0.007 +/- 0.004 and for unspecified gastric symptoms 0.02 +/- 0.005. Risk differences were also pooled using the DerSimonian and Laird method, which weights studies inversely according to variance. Using this method, only the unspecified gastric symptoms for non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs) and the haemorrhage for aspirin were found to be statistically significant. Longer studies have higher risk differences. Randomized control trials to determine prophylactic efficacy against haemorrhage (that is, to demonstrate a reduction of ulcer rate in the therapy group to the rate of controls) would require 190 patients in each group for NA-NSAIDs in studies of 2-6 months; 950 subjects would be needed to detect a 50% reduction. Randomized control trials to determine a reduction in ulcer rate to that of controls in patients on aspirin for more than 6 months would require 700 subjects in each group; 3346 subjects would be needed to detect a 50% reduction. Such studies are feasible.

HIV/AIDS education in a prenatal clinic: an assessment.

An HIV/AIDS education and counseling program was integrated into the routine medical care of women attending the prenatal clinic of a major urban, inner-city, teaching hospital that serves mostly indigent minority women in an area hard hit by the HIV/AIDS epidemic. Pre- and post-intervention questionnaires were administered to a consecutive historical Control Group (n = 98) who did not receive the HIV/AIDS information and an Intervention Group (n = 515) who received all information. The data support our hypothesis that an HIV/AIDS education program would increase the level of general knowledge, but fail to support our hypothesis of a positive effect on attitudes around HIV-antibody testing and an increase in desire for voluntary testing. Our hypothesis that women reporting more risk behaviors would be more likely to agree to HIV-antibody testing was only partially supported.

Incorporating HIV education and counseling into routine prenatal care: a program model.

This article reports how a prenatal clinic in a major urban teaching hospital has developed and integrated an HIV education and counseling program into routine prenatal care. The patient population served are predominantly minority women living in an inner-city community that has been disproportionately affected by the AIDS epidemic. Implementation of the patient program has required training and support for all professional staff. Staff training served as a foundation for this comprehensive patient program, which has reached all prenatal patients regardless of risk behavior. The program has succeeded in involving a large population of women in an educational program, has identified HIV-1 seropositive pregnant women through voluntary testing, and has provided them with the necessary medical and social work services. Principles of program development are identified for use in other settings.

PIP: The process of incorporating HIV education and counseling into the Mount Sinai Medical Center's prenatal clinic in New York City is provided in terms of background, the patient program, evaluation, and conclusions. There have been endorsements for inclusion of HIV testing and education in the practice of prenatal care and reported effectiveness in delaying the onset of AID's associated infections. The prenatal clinic provides health care to predominantly minority women (36% African American and 55% Hispanic) of whom 10-12% report intravenous or nonintravenous drug use; clinic births are about 1600 a year. Early attempts in 1986-7 to provide anonymous testing and counseling demonstrated the need to reach a large audience. Observations were that considerable staff training and support was needed for an effective patient program. Encouragement and support was also needed by patients. 8 one hour training sessions were provided to the nurses, as well as a 21 hour state certification program for the social workers, both groups of whom worked directly with patients. Intense reactions to caring for HIV infected persons occurs and emotional support must be included in the training. Additional staff support was provided through an AIDs prevention grant for a year. Continuous staff training is required. Another grant provided a clinical social worker and program coordinator who worked closely with the clinic director. The target was to integrate the HIV/AIDs information into routine clinic services; specifically, a 45 minute orientation session during patient's first medical visit. The groups discussion session is lead by the nurse's introduction to the clinic, patient care, and screening, and followed by the social worker's comments on voluntary HIV screening. Nonambiguous language which is understood by various educational levels was used. Patients needed more time to discuss the concerns for dealing with their partners about STD's and contraception. Testing was available throughout the prenatal clinic period. Posttest counseling is also provided as a review, and for those seropositive or high risk patients as initial crisis intervention and case management. There was nonjudgemental discussion about termination of pregnancy. 1453 patients out of 1600 were involved in the orientation, with 20% (297) rather than the preceding years 40 screened. Success is attributed to strong collaborative working relationships with medical, nursing, social work, and clerical staffs, and extensive prior education. Those identified as seropositive were followed up in a separate clinic.

Meta-analysis of clinical trials as a scientific discipline. II: Replicate variability and comparison of studies that agree and disagree.

The replicate variability of meta-analyses of controlled clinical trials has been assessed as a measure of scientific precision. 46 of 91 known meta-analysis papers were divided into 20 cohorts of studies of the same therapies. Ten cohorts contained meta-analyses with different statistical conclusions; 14 contained differing clinical conclusions with a wider spread than the statistically differing studies. Possible causes of variability, such as different trials included, different policies regarding the inclusion of non-randomized and unpublished trials, and different statistical methodologies, were not obvious causes of differing conclusions. Further work in this area should include multivariate analyses in order to explore possible interactions in the factors accounting for the variability found in replicate meta-analyses.

The poor quality of early evaluations of magnetic resonance imaging.

To study the quality of early research on the clinical efficacy of diagnostic imaging with magnetic resonance, we assessed 54 evaluations published in the first four years after introduction of this modality using ten commonly accepted criteria of research methodology. The terms sensitivity, specificity, false-positive or false-negative, accuracy, and predictive values were used infrequently. Nineteen percent of the evaluations used three terms appropriately, 48% used one or two terms, and 33% used none. Data were presented appropriately for one or more of the five terms in 59% of evaluations. A "gold standard" comparison with the results of an independent procedure, such as surgical or autopsy findings, was presented in 22% of evaluations. Results of another imaging procedure were described in 63% of evaluations. Only one evaluation clearly described a prospective study design, although 11 evaluations apparently were planned in advance. Not one evaluation contained an appropriate statistical analysis of the distributions of quantitative readings, "blinded" image readers to diagnosis or other test results, measured observer error, or randomized the order of magnetic resonance imaging and other imaging procedures. We conclude that health care professionals paying for expensive innovative diagnostic technology should demand better research on diagnostic efficacy.

Endoscopic hemostasis. An effective therapy for bleeding peptic ulcers.

We performed a meta-analysis of 25 randomized control trials that compared endoscopic hemostasis with standard therapy for bleeding peptic ulcer. For recurrent or continued bleeding, the mean rate in control patients was 0.39, and the pooled rate difference, or reduction due to therapy, was 0.27 +/- 0.15 (95% confidence interval) (69% relative reduction). For emergency surgery, the mean rate in control patients was 0.26, and the pooled rate difference was 0.16 +/- 0.05 (62% relative reduction). Most important, for overall mortality, the mean rate in control patients was 0.10, and the pooled rate difference was 0.03 +/- 0.02 (30% relative reduction). The effects were greatest in patients with spurting or visible blood vessels and equivocal when the ulcer showed only signs of recent bleeding. We conclude that endoscopic hemostasis is clearly effective but that data were insufficient for direct comparisons between modalities. Randomized control trials to compare the different modes of endoscopic therapy should continue.

Meta-analyses of randomized controlled trials.

A new type of research, termed meta-analysis, attempts to analyze and combine the results of previous reports. We found 86 meta-analyses of reports of randomized controlled trials in the English-language literature. We evaluated the quality of these meta-analyses, using a scoring method that considered 23 items in six major areas--study design, combinability, control of bias, statistical analysis, sensitivity analysis, and application of results. Only 24 meta-analyses (28 percent) addressed all six areas, 31 (36 percent) addressed five, 25 (29 percent) addressed four, 5 (6 percent) addressed three, and 1 (1 percent) addressed two. Of the 23 individual items, between 1 and 14 were addressed satisfactorily (mean +/- SD, 7.7 +/- 2.7). We conclude that an urgent need exists for improved methods in literature searching, quality evaluation of trials, and synthesizing of the results.

Meta-analysis of clinical trials as a scientific discipline. I: Control of bias and comparison with large co-operative trials.

Meta-analysis is an important method of bridging the gap between undersized randomized control trials and the treatment of patients. However, as in any retrospective study, the opportunities for bias to distort the results are widespread. Attempts must be made to introduce the controls found in prospective studies by blinding the selection of papers and extraction of data and making blinded duplicate determinations. Informal and personalized methods of obtaining data are probably more liable to error and bias than employing only published data. Publication bias is a serious problem requiring further research. There also need to be more comparisons of meta-analysed small studies with large co-operative trials.

Dipyridamole in the treatment of angina pectoris: a meta-analysis.

A meta-analysis of 11 randomized trials published between 1960 and 1970 was performed to re-evaluate data on the efficacy of dipyridamole in the prevention and treatment of chronic angina pectoris. Three trials significantly favored drug vs placebo, four showed a trend towards drug vs placebo, two showed no difference and two showed a trend towards placebo vs drug. The combined results of these 11 trials showed a statistically significant improvement with dipyridamole. Although this result should be viewed with caution because of methodologic variations in the studies, the available evidence appears to suggest that dipyridamole may have a beneficial effect, and that it may have been prematurely discarded in the treatment of angina pectoris.

A meta-analysis of randomized control trials of progestational agents in pregnancy.

The continued use of progestational agents in attempts to achieve a normal outcome of pregnancy in women with a 'high-risk' pregnancy (previous miscarriage, stillbirth or present preterm labour) prompted this meta-analysis of randomized control trials of such therapy. Of 20 trials of a progestogen 15 had combinable data. Combined comparisons, using odds ratios with confidence intervals, were made of the rates of livebirths at term or preterm and the sum of term and preterm deliveries, miscarriages, stillbirths and neonatal deaths. All but one comparison failed to show a significant benefit. Only the preterm delivery versus the term delivery comparison approached statistical significance. There were average deficiencies of quality apparent in the studies, and a test for heterogeneity among the studies was positive, but these caveats do not diminish the conclusion that progestogens should not be used outside of randomized trials at present. If trials are done, they should include only women with demonstrated hormonal abnormalities who are carrying a live fetus as shown by ultrasonography.