Individual Trial Level Research Articles

Accurately modeling Visual Working Memory performance at the individual trial level

Accurately modeling Visual Working Memory performance at the individual trial level

Oral Dabigatran Etexilate Versus Enoxaparin for Prevention of Venous Thromboembolism After Total Hip or Knee Arthroplasty: A Pooled Analysis of Four Randomized Trials

Abstract 2312 Introduction:Thromboprophylaxis after major orthopaedic surgery reduces the risk of venous thromboembolism (VTE). Four randomized, double-blind, non-inferiority trials compared oral dabigatran etexilate doses of 220 mg or 150 mg once daily (qd) with subcutaneous enoxaparin for the primary prevention of VTE in patients undergoing elective total hip or knee arthroplasty. In the hip arthroplasty trials (RE-NOVATE® and RE-NOVATE® II) the treatment duration was 28–35 days; in the knee arthroplasty trials it was 6–10 days (RE-MODEL™) and 12–15 days (RE-MOBILIZE®). Three of the trials used a comparator enoxaparin regimen of 40 mg qd started the evening before surgery, while in RE-MOBILIZE® enoxaparin was given in the North American regimen of 30 mg twice daily starting 12–24 hours after surgery. In countries where dabigatran etexilate is approved, a dose of 220 mg qd is recommended for most patients; 150 mg qd is for patients with moderate renal impairment (creatinine clearance 30–50 mL/min) and elderly patients (> 75 years). Methods:The primary efficacy outcome for each trial was a composite of total VTE (venographic and symptomatic) and death from all causes during the treatment period. The main composite outcome for the pooled analysis of the four trials was major VTE (proximal deep vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death, which was the main secondary endpoint on the individual trial level. This endpoint was chosen for the pooled analysis, because the event rates are similar across hip and knee arthroplasty, whereas the rate of total VTE and all-cause mortality is substantially higher across all treatment groups for the knee compared to the hip. The main safety outcome was major bleeding (clinically overt bleeding associated with ≥ 20 g/L fall in haemoglobin or transfusion ≥ 2 units of packed cells or blood; or bleeding that was fatal, retroperitoneal, intracranial, intraocular, intraspinal, warranted treatment cessation or led to reoperation) measured from a preoperative baseline in all four trials. Results:In the pooled analysis of the four trials, the main efficacy outcome of major VTE and VTE-related death occurred in 2.8% (80/2838) of the dabigatran etexilate 220 mg group, 3.8% (78/2071) of the dabigatran etexilate 150 mg group and 3.5% (102/2891) of the enoxaparin group; risk difference (RD) versus enoxaparin –0.7% (95% confidence interval [CI] –1.6% to 0.2%) for 220 mg and 0.2% (95% CI –0.8% to 1.3%) for 150 mg. The composite of total VTE and all-cause mortality occurred in the pooled hip trials in 6.8% (114/1672) of the dabigatran etexilate 220 mg group, 8.6% (75/874) of the dabigatran etexilate 150 mg group and 7.7% (129/1683) of the enoxaparin group; RD versus enoxaparin –0.8% (95% CI –2.6% to 0.9%) for 220 mg and 0.9% (95% CI –1.3% to 3.2%) for 150 mg. Major bleeding occurred in 1.4% (52/3692), 1.1% (29/2737) and 1.3% (48/3719), of the dabigatran etexilate 220 mg, 150 mg and enoxaparin groups, respectively; RD versus enoxaparin 0.1% (95% CI –0.4% to 0.6%) for 220 mg and –0.2% (95% CI –0.8 to 0.3%) for 150 mg. Conclusions:Prophylaxis with oral dabigatran etexilate 220 mg qd or 150 mg qd was as effective as subcutaneous enoxaparin at reducing the risk of total VTE and all-cause mortality after total hip arthroplasty with a similar bleeding profile. With regard to the endpoint of major VTE and VTE-related death, dabigatran etexilate 220 mg and 150 mg showed similar efficacy versus enoxaparin in the pooled hip and knee arthroplasty trials. Disclosures:Huo:Boehringer Ingelheim: Consultancy. Kurth:Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Clemens:Boehringer Ingelheim: Employment. Hantel:Boehringer Ingelheim: Employment. Feuring:Boehringer Ingelheim: Employment. Friedman:Johnson and Johnson: Consultancy. Eriksson:Bristol-Myers Squibb: Consultancy; Bayer: Consultancy; Astellas: Consultancy.

Dynamic adaptation to history of trial difficulty explains the effect of congruency proportion on masked priming.

In reaction time research, there has been an increasing appreciation that response-initiation processes are sensitive to recent experience and, in particular, the difficulty of previous trials. From this perspective, the authors propose an explanation for a perplexing property of masked priming: Although primes are not consciously identified, facilitation of target processing by a related prime is magnified in a block containing a high proportion of related primes and a low proportion of unrelated primes relative to a block containing the opposite mix (Bodner & Masson, 2001). In the present study, this phenomenon is explored with a parity (even/odd) decision task in which a prime (e.g., 2) precedes a target that can be either congruent (e.g., 4) or incongruent (e.g., 3). It is shown that the effect of congruence proportion with masked primes cannot be explained in terms of the blockwise prime-target contingency. Specifically, with masked primes, there is no congruency disadvantage in a block containing a high proportion of incongruent primes, but there is a congruency advantage when the block contains an equal proportion of congruent and incongruent primes. In qualitative contrast, visible primes are sensitive to the blockwise prime-target contingency. The authors explain the relatedness proportion effect found with masked primes in terms of a model according to which response-initiation processes adapt to the statistical structure of the environment, specifically the difficulty of recent trials. This account is supported with an analysis at the level of individual trials using the linear mixed effects model.

The paradox of equipoise: the principle that drives and limits therapeutic discoveries in clinical research.

Progress in clinical medicine relies on the willingness of patients to take part in experimental clinical trials, particularly randomized controlled trials (RCTs). Before agreeing to enroll in clinical trials, patients require guarantees that they will not knowingly be harmed and will have the best possible chances of receiving the most favorable treatments. This guarantee is provided by the acknowledgment of uncertainty (equipoise), which removes ethical dilemmas and makes it easier for patients to enroll in clinical trials. Since the design of clinical trials is mostly affected by clinical equipoise, the "clinical equipoise hypothesis" has been postulated. If the uncertainty requirement holds, this means that investigators cannot predict what they are going to discover in any individual trial that they undertake. In some instances, new treatments will be superior to standard treatments, while in others, standard treatments will be superior to experimental treatments, and in still others, no difference will be detected between new and standard treatments. It is hypothesized that there must be a relationship between the overall pattern of treatment successes and the uncertainties that RCTs are designed to address. An analysis of published trials shows that the results cannot be predicted at the level of individual trials. However, the results also indicate that the overall pattern of discovery of treatment success across a series of trials is predictable and is consistent with clinical equipoise hypothesis. The analysis shows that we can discover no more than 25% to 50% of successful treatments when they are tested in RCTs. The analysis also indicates that this discovery rate is optimal in helping to preserve the clinical trial system; a high discovery rate (eg, a 90% to 100% probability of success) is neither feasible nor desirable since under these circumstances, neither the patient nor the researcher has an interest in randomization. This in turn would halt the RCT system as we know it. The "principle or law of clinical discovery" described herein predicts the efficiency of the current system of RCTs at generating discoveries of new treatments. The principle is derived from the requirement for uncertainty or equipoise as a precondition for RCTs, the precept that paradoxically drives discoveries of new treatments while limiting the proportion and rate of new therapeutic discoveries.