Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis.

Essentials Anticoagulants prevent venous thromboembolism but may be associated with greater bleeding risks. Bivariate analysis assumes a non-linear relationship between efficacy and safety outcomes. Extended full-dose betrixaban is favorable over standard enoxaparin in bivariate endpoint. Clinicians must weigh efficacy and safety outcomes in decision-making on thromboprophylaxis. SUMMARY: Background Among acutely ill hospitalized medical patients, extended-duration thromboprophylaxis reduces the risk of venous thromboembolism (VTE), but some pharmacologic strategies have been associated with greater risks of major bleeding, thereby offsetting the net clinical benefit (NCB). Methods To assess the risk-benefit profile of anticoagulation regimens, a previously described bivariate method that does not assume a linear risk-benefit tradeoff and can accommodate different margins for efficacy and safety was performed to simultaneously assess efficacy (symptomatic VTE) and safety (major bleeding) on the basis of data from four randomized controlled trials of extended-duration (30-46 days) versus standard-duration (6-14 days) thromboprophylaxis among 28 227 patients (EXCLAIM, ADOPT, MAGELLAN and APEX trials). Results Extended thromboprophylaxis with full-dose betrixaban (80 mg once daily) was superior in efficacy and non-inferior in safety to standard-duration enoxaparin, and showed a significantly favorable NCB, with a risk difference of - 0.51% (- 0.89% to - 0.10%) in the bivariate outcome. Extended enoxaparin was superior in efficacy and inferior in safety (bivariate outcome: 0.03% [- 0.37% to 0.43%]), whereas apixaban and rivaroxaban were non-inferior in efficacy and inferior in safety (- 0.20% [- 0.49% to 0.17%] and 0.23% [- 0.16% to 0.69%], respectively). Reduced-dose betrixaban did not show a significant difference in either efficacy or safety (0.41% [- 0.85% to 1.94%]). Conclusions In a bivariate analysis that assumes non-linear risk-benefit tradeoffs, extended prophylaxis with full-dose betrixaban was superior to standard-duration enoxaparin, whereas other regimens failed to simultaneously achieve both superiority and non-inferiority with respect to symptomatic VTE and major bleeding in the management of acutely ill hospitalized medical patients.

Multicenter randomized controlled trial on Duration of Therapy for Thrombosis in Children and Young Adults (the Kids-DOTT trial): pilot/feasibility phase findings.

BACKGROUND: Randomized controlled trials (RCTs) on pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies are critical to future RCT success. METHODS: The Kids-DOTT trial is a multicenter RCT investigating non-inferiority of a 6-week (shortened) versus 3-month (conventional) duration of anticoagulation in patients aged < 21 years with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded-endpoint, parallel-cohort RCT design. RESULTS: No eligibility violations or randomization errors occurred. Of the enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in prespecified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Interobserver agreement between local and blinded central determination of venous occlusion by imaging at 6 weeks after diagnosis was strong (k-statistic = 0.75; 95% confidence interval [CI] 0.48-1.0). The primary efficacy and safety event rates were 3.3% (95% CI 0.3-11.5%) and 1.4% (95% CI 0.03-7.4%). CONCLUSIONS: The P/F phase of the Kids-DOTT trial has demonstrated the validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention and endpoint rates to inform the fully powered RCT.

Estrogen or raloxifene during postmenopausal weight loss: adiposity and cardiometabolic outcomes.

OBJECTIVE: Estrogen-based hormone therapy (HT) attenuates abdominal fat gain after menopause, but whether HT improves abdominal fat loss during weight loss is unknown. It was hypothesized that HT or a selective estrogen receptor modulator (raloxifene) would augment reductions in abdominal visceral fat during weight loss when compared to placebo, potentially increasing improvements in glucose tolerance and lipid profile. METHODS: Healthy postmenopausal women (n = 119; age 50-70 yr) underwent a 6-month weight-loss (primarily exercise) intervention with randomization to raloxifene (60 mg/d), HT (conjugated estrogens, 0.625 mg/d), or placebo. Outcomes were change in total and abdominal (visceral and subcutaneous) fat mass, lipid profile, and fasting and post-challenge glucose and insulin. RESULTS: Neither HT nor raloxifene augmented loss of total or abdominal fat mass during exercise-induced weight loss when compared with placebo. Weight loss-induced improvements in risk factors were similar among the three groups, except for a greater reduction in fasted glucose in the HT group (difference in change [95%CI] from placebo; -0.40 [-0.76, -0.05]) and greater reductions in LDL (-0.36 [-0.63, -0.09]) and increases in HDL (0.15 [0.07, 0.24]) in both treatment groups. CONCLUSIONS: Postmenopausal HT and raloxifene did not increase abdominal fat loss during weight loss, but did improve some cardiometabolic outcomes.

Balancing risk and benefit in venous thromboembolism trials: concept for a bivariate endpoint trial design and analytic approach.

Antithrombotic trials in venous thromboembolism treatment and prevention, including those evaluating the new oral anticoagulants, have typically evaluated thromboembolism risk as an efficacy endpoint and bleeding risk as a separate safety endpoint. Findings often occur in opposition (i.e. decreased thromboembolism accompanied by increased bleeding, or vice-versa), leading to variable interpretation of the results, which may ultimately be judged as equivocal. In this paper, we offer an alternative to traditional designs based on the concept of a bivariate primary endpoint that accounts for simultaneous effects on antithrombotic efficacy and harm due to bleeding. We suggest a bivariate endpoint as a general approach to the assessment of 'net clinical benefit' in recently published trials and to the design of future trials. Lastly, we illustrate the bivariate endpoint design using two examples: a recently published superiority trial of rivaroxaban (RECORD1) and an ongoing non-inferiority trial of the duration of anticoagulant therapy in children with venous thrombosis (Kids-DOTT).

Weighing evidence: quantitative measures of the importance of bitemark evidence.

Quantitative measures of the importance of evidence such as the "likelihood ratio" have become increasingly popular in the courtroom. These measures have been used by expert witnesses formally to describe their certainty about a piece of evidence. These measures are commonly interpreted as the amount by which the evidence should revise the opinion of guilt, and thereby summarize the importance of a particular piece of evidence. Unlike DNA evidence, quantitative measures have not been widely used by forensic dentists to describe their certainty when testifying about bitemark evidence. There is, however, no inherent reason why they should not be used to evaluate bitemarks. The purpose of this paper is to describe the likelihood ratio as it might be applied to bitemark evidence. We use a simple bitemark example to define the likelihood ratio, its application, and interpretation. In particular we describe how the jury interprets the likelihood ratio from a Bayesian perspective when evaluating the impact of the evidence on the odds that the accused is guilty. We describe how the dentist would calculate the likelihood ratio based on frequentist interpretations. We also illustrate some of the limitations of the likelihood ratio, and show how those limitations apply to bitemark evidence. We conclude that the quality of bitemark evidence cannot be adequately summarized by the likelihood ratio, and argue that its application in this setting may be more misleading than helpful.

Otago glaucoma surgery outcome study: long-term results of trabeculectomy--1976 to 1995.

OBJECTIVE: To provide data on the long-term results of trabeculectomy performed in the province of Otago, New Zealand. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: A total of 289 eyes of 193 patients (excluding 4 eyes lost to follow-up soon after operation); all trabeculectomies performed for the first time on cases of primary glaucoma from 1976 through 1995. INTERVENTION: Standard Cairns trabeculectomy. MAIN OUTCOME MEASURES: Intraocular pressure, visual acuity, visual field damage. RESULTS: Trabeculectomy was effective in controlling intraocular pressure at a level of 21 mmHg or less, with probabilities of 0.93 (95% confidence interval [CI], 0.90-0.97), 0.87 (95% CI, 0.82-0.93), and 0.85 (95% CI, 0.77-0.92) at 5, 10, and 15 years, respectively, after surgery. The mean visual acuity improved from 20/60 to 20/40 immediately after trabeculectomy but then declined steadily over the postoperative years. The decline in visual acuity led to blindness in 47 eyes. The Kaplan-Meier estimated probability of retaining useful vision (visual acuity > 20/400 and visual field > 5 degrees radius) in the overall group was 0.87 (95% CI, 0.79-0.91), 0.72 (95% CI, 0.60-0.79), and 0.6 (95% CI, 0.43-0.69) at 5, 10, and 15 years, respectively, after surgery. Those eyes that had good preoperative visual acuity (visual acuity > or = 20/30) had a significantly better chance of retaining useful vision (P = 0.02). CONCLUSIONS: The intraocular pressure was well controlled by trabeculectomy, but a steady long-term decline in visual acuity and visual field occurred, decreasing the probability of an eye retaining useful vision up to the time of death to approximately 0.6.

A unifying family of group sequential test designs.

Currently, the design of group sequential clinical trials requires choosing among several distinct design categories, design scales, and strategies for determining stopping rules. This approach can limit the design selection process so that clinical issues are not fully addressed. This paper describes a family of designs that unifies previous approaches and allows continuous movement among the previous categories. This unified approach facilitates the process of tailoring the design to address important clinical issues. The unified family of designs is constructed from a generalization of a four-boundary group sequential design in which the shape and location of each boundary can be independently specified. Methods for implementing the design using error-spending functions are described. Examples illustrating the use of the design family are also presented.

A computationally simpler algorithm for the UMVUE of a normal mean following a group sequential trial.

When using data collected in a group sequential clinical trial, the sample mean is no longer the uniform minimum variance unbiased estimator (UMVUE) of the mean of a normal distribution. Emerson (1993, Computers and Biomedical Research, 26, 68-73) described an algorithm for computing the UMVUE in this setting. This algorithm, although computationally expensive, used only the basic software necessary for deriving group sequential boundaries. In this paper, we present an improved algorithm that results in greatly decreased computation times.

Cerebral bloodflow in and around spontaneous malignant gliomas.

Knowledge of the cerebral bloodflow (CBF) in and around malignant gliomas is of crucial importance in developing strategies for hyperthermia-, radiation-, and chemo-therapy of these difficult to cure lesions. To gather data regarding this important physiological variable, the perfusion distributions of 26 patients who had either a glioblastoma multiforme or an anaplastic astrocytoma were determined using stable xenon computed tomography (XeCT). Perfusion values were determined for each of the following anatomical regions: low density tumour core, the enhancing active ring of the tumour, the low density peripheral region of edema, an ipsilateral region of normal brain adjacent to the tumour, and a region of remote normal tissue on the contralateral side of the brain. A multiple regression analysis of the logs of the CBF values was used to analyse: (1) the differences in blood perfusion between the anatomical regions; and (2) the association of blood perfusion with various patient and tumour characteristics. Statistically significant differences in perfusion values were found between all of the anatomically outlined regions with the exceptions that the active tumour and edematous regions do not differ significantly from the ipsilateral normal brain tissue. The ipsilateral normal brain tissue adjacent to the tumour was found to have a relative perfusion (relative to the contra-lateral normal brain tissue perfusion) of 0.84, the edematous tissue had a relative perfusion of 0.52, the active tumour 0.78, and the core 0.39. Significant blood flow was present in the low density tumour core, contradicting the frequent assumption that there is zero or minimal blood flow in such regions. Multiple regression analysis was used to look for other variables that might be associated with blood flow after adjusting for the differences between anatomical regions. This analysis found a significant negative correlation between tumour blood-flow and tumour volume. It also estimated that blood flow in GMB tumours was approximately 67% of that in lower grade tumours. Variables that were found not to be significantly correlated with blood flow were: patient sex, multiple lobe involvement, hemisphere involved, treatment status (initial vs recurrent disease), Karnofsky performance status, age and, lobe involved.

Immunohistochemical analysis of cathepsin D in prostate carcinoma.

Cathepsin D is a carboxyl protease that has been implicated as an important factor in tumor cell invasion. Sixty-nine cases of primary adenocarcinoma of the prostate were studied by the indirect immunoperoxidase method using a primary monoclonal anti-cathepsin D antibody. Immunoreactivity was graded from 0 (negative) to 4+ (intense reaction). The normal tubuloalveolar glands were, in general, negative. However, nine cases revealed focal staining of nonneoplastic luminal cells. Basal cells were negative except in areas of basal-cell hyperplasia, which were intensely positive. Thirty-nine of 78 carcinoma samples revealed 2+ or greater positive punctate lysosomal staining. In the 39 positive-stained cases, the reactivity was diffuse in three and focal in the remainder. The percentage of carcinoma cases whose worst lesions stained 2+ or greater showed a nonsignificant (P = 0.055) relation to Gleason grade but a significant (P = 0.031) relationship to pathologic stage. Thus, cathepsin D may prove to be a useful marker of prostate cancer progression.

Interstitial thermoradiotherapy with ferromagnetic implants for locally advanced and recurrent neoplasms.

PURPOSE: The University of Arizona, University of California at San Francisco, City of Hope Medical Center, and University of Wisconsin participated in a Phase I/II protocol to assess the heating ability and the toxicity of interstitial thermoradiotherapy using ferromagnetic implantation. METHODS AND MATERIALS: Forty-four patients with advanced primary or recurrent extra-cranial solid malignancies were enrolled in this study. Fourteen gauge catheters were implanted into tumors and, once in the department of Radiation Oncology, loaded with ferromagnetic seeds to deliver a 60 min hyperthermia treatment. Multi-point thermometry was continuously used throughout the heating sessions for all patients, sampling the periphery as well as the core of the tumor. After 192Iridium brachytherapy, 18 patients then had an additional treatment. The mean radiation dose while on protocol was 50.0 Gy, with total doses (including prior radiotherapy) ranging from 20.3-151.8 Gy (median = 88.7 Gy). Response and toxicity were assessed by inspection, palpation, and/or radiologic studies. Forty-one patients were evaluable for response, and there were 55 analyzable hyperthermia treatment sessions. RESULTS: The complete response rate was 61% (25/41). The partial response rate was 31.7% and only 7.3% failed to respond. Median duration of local control has not yet been reached. The mean maximum, minimum, and mean time-averaged temperatures for all in-tissue sensors were 43.7 degrees C, 38.7 degrees C, and 41.0 degrees C, respectively. Tumor size was the only factor significantly correlated with temperatures or with complete response rate; larger tumors attained higher temperatures but smaller tumors had a higher response probability. Nineteen patients (43%) experienced toxicities, however there was only a 7% (3/44) rate of serious complications (Grade 3 or 4). Prior treatment with hyperthermia was the only factor significantly correlated with serious toxicity. CONCLUSION: These results, a 93% total response with only 7% serious toxicity, are encouraging especially in the context of the patient population treated. Phase II/III studies involving ferromagnetic implantation are warranted.

Pterygium treated with excision and postoperative beta irradiation.

A retrospective study was done of 338 patients with pterygia treated between October 1974 and May 1990. These patients resided in the desert of the southwestern United States, where the hot, dry, dusty climate is thought to predispose to pterygium formation and subsequent recurrence. The pterygia were excised, and the administration of beta irradiation was initiated within 24 hr of surgery. Sixteen percent of the pterygia were recurrent. Ninety-five percent of the beta irradiation prescriptions consisted of 3 weekly 800 cGy fractions. For patients with a minimum of 6 months follow-up, the crude local control rate was 225/258 (88%). The Kaplan-Meier estimate of the 5-year local control rate was 84% (95% confidence interval: 79-89%). Ten of 33 recurrences were diagnosed within 6 months, and 32/33 recurrences were diagnosed within 5 years of treatment. Previously untreated pterygia were controlled more easily than were recurrent pterygia (p = 0.005). In 86% of the cases, patients judged the cosmetic results to be satisfactory. No severe complications developed. This study and others, when compared with studies involving excision alone, suggest that postoperative beta irradiation reduces the likelihood for pterygium recurrence. When the beta irradiation is fractionated, satisfactory cosmetic results can be achieved with low morbidity.

Recurrent basal cell carcinoma treated with radiation therapy.

A retrospective study was performed of 61 recurrent basal cell carcinomas treated with radiation therapy between 1974 and 1990 at the University of Arizona College of Medicine or at Southwestern Radiation Oncology, Tucson, Arizona. The median length of follow-up was 57 months. Applying the American Joint Committee on Cancer staging system to these recurrent tumors, 36 were stage I, 19 were stage II, five were stage III, and one was stage IV. Kaplan-Meier methods were used to estimate the 5-year complete remission rates. The Mantel-Haenszel Test and the Cox Proportional Hazards Model were used to determine if tumor size, stage, histologic subtype, anatomic site, age, sex, dose, number of radiation therapy treatments, length of time over which the radiation therapy was administered, or type of radiation beam used (orthovoltage x-rays vs megavoltage electrons) affected the 5-year complete remission rates. Only tumor size and stage had a statistically significant effect on the complete remission rates. The Kaplan-Meier estimates of the 5-year complete remission rates for 0.5- to 1.0-cm tumors vs tumors larger than 1.0 cm were 96% (95% confidence interval, 88% to 100%) and 81% (95% confidence interval, 64% to 99%), respectively. The Kaplan-Meier estimates of the 5-year complete remission rates for stage I/II tumors vs stage III/IV tumors were 93% (95% confidence interval, 85% to 100%) and 42% (95% confidence interval, 8% to 84%), respectively. Functional and cosmetic results were frequently good to excellent at 5 years. Soft-tissue necrosis developed in two of 61 cases, and was successfully managed in both. This article, combined with a review of the literature, suggests that radiation therapy is an effective method of treating recurrent basal cell carcinomas.

Basal cell carcinoma treated with radiation therapy.

Between 1974 and 1989, 85 patients with 115 biopsy-proven basal cell carcinomas were treated with radiation therapy at the University Medical Center in Tucson. Either orthovoltage or megavoltage photons were used to deliver doses ranging from 2000 cGy in a single treatment to 7300 cGy in 35 fractions over 62 days. The median length of follow-up was 40 months. Kaplan-Meier estimates of the 5-year local control rates are presented by American Joint Committee on Cancer stage. The difference between the local control rates for both previously untreated and recurrent Stage I and II carcinomas (95% at 5 years) and Stage III and IV carcinomas (56% at 5 years) was statistically significant (P = 0.0001, by Mantel-Haensel test). Although recurrent basal cell carcinomas generally have a worse prognosis, the Kaplan-Meier estimate of the 5-year local control rate for recurrent Stage I and II carcinomas treated with radiation therapy was 95%. These results, along with a review of the literature, suggest two points: (1) high cure rates can be obtained when Stage I and II basal cell carcinomas are treated with radiation therapy and (2) radiation therapy is a relatively effective method for treating recurrent basal cell carcinomas, with cure rates surpassed only by Mohs micrographic surgery.

Interstitial thermoradiotherapy: thermal dosimetry and clinical results.

From August 1977 to August 1986, 72 patients with advanced primary or recurrent cancers were treated using interstitial thermoradiotherapy. Sites treated included the pelvis in 49 patients, the head and neck in 15, and other sites in six. Median tumor volume was 52 cm3, and all but nine patients had received prior irradiation. In 69 patients, hollow stainless steel catheters were implanted and used as electrodes with a 0.5 MHz radiofrequency (RF) generator, whereas in three patients, standard plastic Henschke tubes were used with a commercially available interstitial microwave (MW) system operating at 915 MHz. Most patients were heated intraoperatively for 30 minutes, aiming for a minimum measured intratumoral temperature (Tmin) of 42 degrees C. The implant was occasionally preceded by external irradiation, and after hyperthermia, the catheters were afterloaded with 192Ir for brachytherapy. Tmin exceeded 42 degrees, 42.5 degrees, 43 degrees, and 44 degrees in 25, 16, 12, and 3, respectively, of 70 patients with temperature data available, and the probability of successful heating was independent of tumor volume or site. Twenty-five of 69 (36%) evaluable patients achieved a complete response (CR). Probability of CR demonstrated a significant univariate dependence upon Tmin, radiation dose, site treated, and tumor volume, but multivariate analysis showed only three significant predictor variables: tumor volume, radiation dose, and Tmin. The probability of a CR ranged from 95% for patients with small tumors receiving high doses of radiation and adequate heat, to 5% for patients with large tumors receiving low radiation doses and less than adequate heat. Of 25 patients with CR, 10 relapsed; median response duration was less than 18 months, depended marginally upon disease site, and was independent of Tmin, radiation dose, and tumor volume. Seventeen patients sustained a complication, of which nine were severe enough to require hospitalization or surgery. All severe complications occurred in patients with pelvic tumors. The probability of a complication of any severity had a significant univariate association with maximum intratumoral temperature (Tmax) and tumor size. We conclude that interstitial thermoradiotherapy offers the promise of heating large tumors in locations where externally applied hyperthermia has not been successful.