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A total of 114 patients with critical lower limb ischemia from 11 hospitals were randomized to either Pentoxifylline 600 mg or placebo given intravenously twice a day. Rest pain was evaluated both by the investigator and the patient. Pain was evaluated with the patient in the supine as well as in the sitting position using a pain score scale, a pain relief scale and a visual analogue scale. All patients underwent a clinical examination, measurement of ankle systolic blood pressure and arteriography. These arteriograms were evaluated by a radiologist who did not know which treatment had been given. If no beneficial effect of the treatment was observed after one week, further medication was discontinued. Otherwise the treatment continued for two additional weeks. There was no statistically significant difference in pain-free or absolute walking distance between the two groups. Evaluating the patients with the most pronounced amelioration of rest pain in the supine position (divided by 4 to divided by 2 points), there was a beneficial effect of Pentoxifylline compared to placebo. Evaluation of the total material did not, however, show any statistical significances between the groups. From further subgroup analysis excluding patients who had only slight pain at the entrance of the study, there was a significant improvement in rest pain in favour of Pentoxifylline following seven days of treatment. In this group the pain evaluated according to this visual analogue scale had decreased 37 points (54%) compared to 14 points (25%) in the placebo group. More side effects, mainly gastrointestinal, were observed in the Pentoxifylline group. Most of these could be eliminated by increasing the infusion time. Further investigations are necessary to evaluated the place of Pentoxifylline in the treatment of patients with critical limb ischemia.
BACKGROUND: In October 1992, an ongoing prospective study on primary gastrointestinal (GI) lymphoma was initiated to evaluate histological features, sites of involvement, and management. PATIENTS AND METHODS: Until May 1996, 352 patients were enrolled, with 279 being evaluable for clinical features (208 patients presented with primary gastric lymphoma). Standardized diagnostic workup included central histologic review and endoscopic and radiologic evaluation of the complete GI tract. Primary surgery or conservative management depended on the physician's decision, followed by radiotherapy with or without chemotherapy. Treatment outcome is evaluable in 122 patients with gastric lymphoma. RESULTS: In 279 evaluable patients, the distribution of NHL was as follows: stomach 74.6%, small bowel 8.6%, ileocoecal region 6.5%, multilocal GI involvement 6.8%. In gastric lymphoma, low-grade NHLs accounted for 39%. Of the remaining high-grade NHLs, 36.1% showed simultaneous low-grade components, thus being also of MALT origin. Of 208 patients with gastric NHL, 71.1% were classified as stage I and II1. CCR rate in stomach lymphoma is significantly higher compared to those of the small bowel, whereas involvement of multiple GI organs has the worst prognosis. So far only 7 patients with gastric NHL in stages I and II presented with progressive disease or relapse. Over all stages there seems to be no difference in therapeutic outcome in surgically or conservatively treated patients. Even after R0-resection in limited stages patients appear to have no better outcome. CONCLUSION: The value of surgery in treatment of primary gastric lymphoma--as favored by most authors--should be reexamined.
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BACKGROUND: Tacrolimus (FK506) may represent a major advance in the management of allograft rejection after solid organ transplantation. In August 1994 a European heart transplantation pilot study was initiated to assess the efficacy and safety of tacrolimus when administered exclusively through an oral route. METHODS: Eighty-two heart transplant recipients were randomized to treatment (2:1 ratio) with either tacrolimus- (n=54) or cyclosporine-based therapy (n=28). RESULTS: No significant differences were evident between the two treatment groups in either rejection or survival rates at 1 year. Kaplan-Meier estimates of the freedom from rejection were 26.3% and 18.5%, respectively, for the tacrolimus and cyclosporine treatment groups (p=.444). Survival rates were 79.6% and 92.9% (p=.125). At 3 of the 5 centers, patients received antithymocyte globulin during the immediate postoperative period and fared better than those who did not (with acute rejection-free rates of 49.2% and 26.7% for tacrolimus and cyclosporine, respectively [p=.080], as opposed to 7.1% and 8.3% [p=.965]; patient survival rates of 84.6% and 93.3% [p=.382] vs 75.0% and 92.3% [p=.243]). The overall rates of infection, impaired renal function (31.5% vs 21.4%), and glucose intolerance (7.0% vs 4.3%) did not differ significantly between the tacrolimus and cyclosporine treatment groups. Tacrolimus seemed to possess an advantage with regard to a reduced requirement for antihypertensive therapy (59.5% vs 87.5%, p=.025). CONCLUSIONS: Immunosuppression with oral tacrolimus provides a viable alternative to treatment with cyclosporine, particularly when administered in conjunction with antibody therapy. Further studies are warranted to optimize the administration of tacrolimus in this indication.
BACKGROUND: Based on current patient selection criteria, a significant proportion of recipients of cardiac resynchronization therapy (CRT) do not respond to treatment. The purpose of this analysis is to identify predictors and characterize the timing of response to CRT in patients with advanced heart failure. METHODS: Patients randomized to receive CRT in the MIRACLE and MIRACLE-ICD trials, designed to assess the benefit of CRT compared with standard medical therapy in patients with advanced heart failure, left ventricular ejection fraction <0.35, and QRS > or =130 milliseconds, were included for this analysis. Patients with an improvement of > or =1 New York Heart Association (NYHA) class from baseline to the 6-month follow-up were considered responders and those who had no change or worse NYHA class or died were classified as nonresponders. Responders were subdivided into early (within 1-3 months) and late (6 months). RESULTS: One hundred forty-three (64%) of 224 and 190 (61%) of 313 patients in the MIRACLE and MIRACLE-ICD trials, respectively, responded to therapy, with 81 (57%) of 143 and 100 (53%) of 190 responding early. Several but differing factors predicted CRT response and timing in the two trials with a high sensitivity (89%-90%) but, owing to a low specificity (31%-49%), a modest predictive accuracy (66%-75%). CONCLUSIONS: Based on improvement of > or =1 NYHA class, less than two thirds of patients enrolled in the MIRACLE or MIRACLE-ICD trials responded to CRT, with just more than half responding within the first month. Several factors predicted CRT response and timing, but given their modest predictive accuracy, comparable for both studies, additional methods for selecting candidates most likely to benefit from CRT are needed.
Renal osteodystrophy has become one of the most important aspects related with morbidity in dialysis patients. The aim of our study was to analyse the main biochemical markers of mineral metabolism in 7,422 dialysis patients from 147 Spanish centres. We present data about serum Ca, P, Ca-P, product, Al and vitamin D. Due to the distribution of the analytical results (not normal), non-parametric tests were used. In this analysis a p < 0.01 was considered as significant. The mean total levels were: Ca 9.7 +/- 0.9 mg/dL; P 5.6 +/- 1.6 mg/dL; Ca-P product 54 +/- 16 mg/dL; PTH 294 +/- 360 pg/mL and Al 27 +/- 23 micrograms/L. There was a great variation particularly on serum Ca and PTH levels. On the contrary, serum P and Ca-P product values were less spread: only a quarter of the patients had P levels higher then 6.5 mg/dL and one third Ca-P product higher than 60. Fifty percent of patients had Al levels lower than 20 micrograms/L. Forty one percent of patients (2,811 out of the 7,422) had a PTH equal or lower than 120 pg/mL and 23% have PTH equal or lower than 60 pg/mL. Patients with PTH equal or lower than 60 have serum Ca levels significantly higher than the remaining patients, on the contrary, serum P, Ca-P product and Al levels were significantly lower. In this group, 21% of patients were receiving vitamin D (in spite of low PTH). On the contrary 32% of patients were not receiving calcitriol (despite PTH higher than 250 pg/mL). Forty four percent of patients were receiving vitamin D (46% on haemodialysis and 31% on peritoneal dialysis). Patients on haemodialysis showed serum Ca, P, PTH and Al levels higher than patients on peritoneal dialysis.
To assess if propranolol prevents the first bleeding in cirrhosis, we randomly assigned 174 patients with large varices to either propranolol in doses reducing the resting heart rate by 25% (85 patients) or to a placebo (oral vitamin K, 89 patients). Sixty-nine patients had alcoholic cirrhosis, 24 posthepatitis cirrhosis and 81 cryptogenic cirrhosis. At the time of inclusion, 75 patients (43%) had ascites and according to the Child-Pugh classification, 103 (59%) had Class A disease, 60 (34%) Class B and 11 (7%) Class C. We report here an interim analysis of the study when all patients had been followed for at least 1 year (mean follow-up = 22 months). At this time, the cumulative proportion of patients free of bleeding was 74% (both differences not significant), respectively. A retrospective analysis showed that the cumulative percentage of patients free of bleeding was significantly higher in the propranolol- than in the control-group in the subsets of patients without ascites or in Child-Pugh Class A: respectively, 87 vs. 64% (p = 0.023) and 88 vs. 64% (p = 0.01). No differences in bleeding incidence were found in patients with ascites or in Child-Pugh Class B or C. Propranolol treatment did not affect survival in any subgroup. Twenty-five patients had to be withdrawn from propranolol because of side effects (n = 23) or low compliance (n = 2). If confirmed on a longer follow-up, these results suggest that propranolol could prevent the first bleeding in patients with well-compensated cirrhosis.
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A 12-week, double blind study was conducted in 140 patients with osteoarthritis to compare the efficacy and toleration of piroxicam 10-20 mg once daily to indomethacin 75-125 mg in divided doses. Seventy-seven percent of piroxicam and 63% of indomethacin patients completed the study. The number of drop-outs due to side effects in the indomethacin group was twice that in the piroxicam group (p less than 0.05). The frequency of GI side effects was similar in both groups. There were more CNS side effects with indomethacin (headache), and more skin side effects with piroxicam. Piroxicam was comparable to indomethacin with respect to efficacy and offered better toleration and a simplified dosage regimen.
CONTEXT: Sequencing of the human genome provides an immense resource for studies correlating DNA variation and epidemiology. However, appropriately powered genetic epidemiology studies often require recruitment from multiple sites. OBJECTIVES: To document the burden imposed by review of multicenter studies and to determine the variability among local institutional review boards (IRBs) in the approval of a multicenter genetic epidemiology study. DESIGN: A PubMed search was performed to determine the frequency of citations of multicenter studies by 5-year intervals from 1974 through 2002. A 7-question survey was sent to all participating study centers to obtain information on frequency of IRB meetings, dates for submission and approval, use/nonuse of a specific consent form, type of review performed, types of consent forms required, preparation time, and number of changes requested by the IRB at each center. Centers also provided a copy of all consent forms they generated and IRB correspondence regarding the study. SETTING AND PARTICIPANTS: Thirty-one of 42 cystic fibrosis care centers in this single US multicenter genetic epidemiology study of cystic fibrosis replied, yielding a 74% response rate. MAIN OUTCOME MEASURES: Frequency of published research studies and consistency among IRBs. RESULTS: The number of all published single-center studies has increased 1.3-fold since 1985, while the number of published epidemiology and genetic epidemiology multicenter studies increased by 8- and 9-fold, respectively, during this same period. Evaluation of the risk of the same genetic epidemiology study by 31 IRBs ranged from minimal to high, resulting in 7 expedited reviews (23%) and 24 full reviews (77%). The number of consents required by the IRBs ranged from 1 to 4; 15 IRBs (48%) required 2 or more consents, while 10 (32%) did not require assent for children. The most common concern (52%) of IRBs pertained to the genetic aspects of the study. CONCLUSIONS: Review of a protocol for a multicenter genetic epidemiology study by local IRBs was highly variable. Lack of uniformity in the review process creates uneven human subjects protection and incurs considerable inefficiency. The need for reform, such as the proposed centralized review, is underscored by the ever increasing rate of genetic discoveries facilitated by the Human Genome Project and the unprecedented opportunity to assess the relevance of genetic variation to public health.
BACKGROUND AND OBJECTIVES: To characterize the impact of multiple Institutional Review Board (IRB) reviews on multicenter observational research studies, and identify strategies for overcoming the identified challenges. MATERIALS AND METHODS: Using PubMed, we identified empirical studies, anecdotal reports, and opinion pieces addressing the process of obtaining initial IRB approval for multicenter clinical trials and observational studies. We also reviewed relevant information from federal and other national sources. RESULTS: A total of 40 peer-reviewed articles were synthesized, plus six reports from commissions or other key sources. These sources identified numerous challenges that researchers may encounter when multicenter studies undergo review by multiple IRBs, such as added time for initial review and approval and different requirements across IRBs. Strategies to alleviate these challenges include planning to accommodate multiple reviews and determining upfront whether certain variations to study protocols are tolerable across sites. Many researchers and commissions have proposed comprehensive reforms, such as centralized review for multicenter projects. CONCLUSION: Policy-makers, researchers, and IRBs should convene to specifically discuss optimal approaches for multicenter review. However, until structural changes are implemented, observational researchers should develop and implement strategic plans for obtaining IRB approval in multicenter studies, including adopting models successfully employed by clinical trials.
The aim of this work was to test and compare the accuracy of five different morphological scoring systems to identify malignant ovarian masses in a prospective multicenter study. Four of the systems had previously been reported by Granberg, Sassone, De Priest and Lerner and the fifth is newly developed. A total of 330 ovarian neoplasms were collected in three different centers, which adopted the same diagnostic procedures. Of these, 261 masses were benign (mean diameter 50 +/- 26 mm) and 69 were malignant (mean diameter 69 +/- 33 mm) (prevalence 21%). The area under the receiver operating characteristic (ROC) curve for the multicenter score was 0.84. This was significantly better than the areas of the other four scores which ranged from 0.72 to 0.75. The cut-off levels derived from the five ROC curves achieved a sensitivity that ranged from 74% (Sassone score) to 88% (De Priest score > or = 5), and a specificity from 40% (De Priest) to 67% (multicenter); the highest positive predictive value was 41% (multicenter). With a cut-off level of 9, the accuracy of the multicenter score was significantly better than the scores of Granberg and De Priest (McNemar's test p < 0.0001). Similar results were obtained in 207 ovarian masses of < or = 5 cm in mean diameter, and when 19 borderline and 11 stage 1 cancers only were considered. For the clinical purposes of a screening test we also checked a possible cut-off level of > or = 8, which increased the sensitivity to 93% with a drop of specificity to 56%. With the use of the same criteria for the scores of the different authors, the following values were obtained for sensitivity: 96%, 81%, 93% and 90%; and for specificity: 23%, 56%, 28% and 49%. The multicenter score performed well at distinguishing malignant from benign lesions, and was better than the other four traditional scores, for both large and small masses. This was mainly due to the introduction of two criteria that allowed correction for typical dermoids and endohemorrhagic corpora lutea. A completely reliable differentiation of benign from malignant masses cannot be obtained by sonographic imaging alone.
Multicenter studies involving randomized clinical trials (RCTs) may have different structures. We discuss four general types. The first two, an "ideal" multicenter RCT and decentralized multicenter collaborative RCTs, we feel are, in different circumstances, highly recommended approaches. The other two, the multicenter RCT that ignores site differences and centralized multicenter collaborative RCTs, we argue, are not only not cost-effective but may also produce misleading results, thus impeding scientific progress and possibly putting patients at unnecessary risk.
According to the Food and Drug Administration's Guidelines for the Format and Content of the Clinical and Statistical Sections of New Drug Applications, approval of a new drug "should be supported by more than one well-controlled trial and carried out by independent investigators. This interpretation is consistent with the general scientific demand for replicability." Nevius has described a four-point proposal for assessing statistical evidence in a single multicenter trial. Briefly, these four points are: (1) combined analysis shows significant results, (2) consistency over centers in terms of direction, (3) consistency over centers in terms of producing nominally significant results in centers with sufficient power, and (4) evidence of efficacy after adjustment for multiple comparisons. What is not clear from Nevius' proposal is how to quantify whether the amount of evidence in a single multicenter trial is equivalent to that from two separate trials. It is proposed that the post hoc subdivision of a multicenter trial may address this issue if the inherent multiple testing problem is accommodated. A minimax statistic is developed to test the hypothesis that the effect of the drug has been reproduced in a single multicenter trial. Monte Carlo simulation is used to generate the distribution of the minimax statistic under the null and several alternative hypotheses. Data from a multicenter trial are used to demonstrate the technique. Bootstrapping is used to determine the null distribution of the minimax statistic.
OBJECTIVE: To describe the development, organization, and operation of several collaborative groups conducting investigator-initiated multicenter clinical research in adult critical care. DESIGN: To review the process by which investigator-initiated critical care clinical research groups were created using examples from Europe, Australia, the United States, and Canada. Various models of group structure and function are discussed, highlighting complementary approaches to protocol development, multicenter study management, and project funding. DATA SOURCES: Published peer review research and unpublished terms of reference documents on the structure and function of these groups. DATA SYNTHESIS: The overall goal of clinical critical care research groups engaged in multicenter studies is to improve patient outcomes through conducting large, rigorous investigations. Research programs we reviewed included the following: a) multicenter epidemiologic studies and surveys; b) technology evaluations of mechanical ventilation; c) investigations focused on three priority fields (acute lung injury, infection, and acute brain injury); d) a series of randomized trials of treatments for one syndrome (acute respiratory distress syndrome); and e) diverse methodologies addressing several clinical problems. The structure and function of these research groups differ according to their historical development, research culture, and enabling resources. Specific protocols emerge from clinical questions generated by investigators or from collectively prioritized research agendas. Project funding includes government support, peer-review grants, intensive care foundations, industry, local hospital funds, and hybrid models. Infrastructure for study management varies widely. CONCLUSIONS: Several national and international groups have engaged in investigator-initiated multicenter critical care research. The development, organization, and operational methods of these groups illustrate several collaborative models for clinical investigations in the intensive care unit. Common characteristics of these groups are a cohesive spirit, a sense of mission to achieve shared research goals, and acknowledgment that such an organization is much more than the sum of its parts.