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• W2007106509 abstract "Numerous clinical studies, using a variety of experimental research designs, have investigated the clinical importance of WBC reduction to prevent transfusion-associated adverse effects such as HLA alloimmunization, febrile nonhemolytic transfusion reactions (FNHTR), transplant rejection, immunomodulation, GVHD, and transmission of HTLV-I, CMV, and other infectious agents.1-5 These studies provide good evidence and a general consensus exists that WBC reduction will reduce the frequency of FNHTR, HLA alloimmunization, and CMV infection; however, the other indications remain controversial despite numerous attempts to define whether a benefit exists. To add to the controversy, some countries have implemented, or will be implementing, universal WBC reduction of RBC and platelet components.6 These countries include: Canada, Germany, New Zealand, Luxembourg, the United Kingdom, Ireland, Portugal, the Netherlands, and France. The rationale to support this policy decision is based largely on the evidence of beneficial immunologic effects and perceived cost benefits. However, in the United States the decision about whether to universally WBC reduce the blood supply has failed to reach a consensus and has sparked a passionate and controversial debate.4, 7, 8 Why does this controversy continue to confuse the decision-making process in the United States, particularly when there are a multitude of published clinical studies evaluating the potential benefits of WBC reduction? There are two possible reasons. First, the evidence for some indications remains controversial because of conflicting study results and methodologic concerns related to study design. Second, there have been no peer-reviewed published studies that demonstrate the clinical benefit of universal WBC reduction compared to selective WBC reduction for specific patient populations considered to be at high risk. This issue of TRANSFUSION contains three additional studies that address the potential various benefits of WBC reduction. Volkova and colleagues9 report a case control study examining the impact of WBC reduction on the cost of hospital care for patients undergoing coronary artery bypass graft surgery. The issue of whether WBC reduction decreases the rate of postoperative infections in patients undergoing cardiac surgery has been addressed by Wallis et al.,10 using a randomized controlled study design. In addition, Dzik and colleagues11 report results from the only randomized controlled trial to address the issue of whether universal WBC reduction of blood components is an effective health-care strategy. Will the results of these three studies narrow the information gap and allow the controversy to end? The answer to this question depends on the scientific community's assessment of the methodologic rigor, overall validity, and quality of reporting in each study. Quality reporting is essential to ensure that the reader has the necessary information to make a judgment about whether the study results are valid. Evidence-based medical practice relies on critical appraisal of the published data. Although most medical journals strive for quality by using a peer review assessment when accepting manuscripts, the process is sometimes flawed; hence, one should not assume that the publication of a clinical study implies that the results necessarily represent truth. A number of frameworks have been developed to guide the process of critical appraisal. The one used in this editorial was developed by the Evidence-Based Working Group at McMaster University, and was introduced in a series of articles in the Journal of the American Medical Association.12, 13 More recently, these concepts have been published in a book entitled “User's Guides to the Medical Literature: a manual for evidence-based clinical practice.”14 This group's approach to critical appraisal uses three discrete questions: Are the results of the study valid? What are the results? How can I apply the results to patient care? The criteria that are applied to answer each of these questions can vary depending on whether the clinical question is one of therapy, harm, prognosis, or the evaluation of a diagnostic test. Studies that investigate potential benefits of WBC reduction fall into the category of therapy. The issues that must be addressed when critically appraising a manuscript about therapy are presented and discussed in detail below and summarized in Table 1.14 To establish the efficacy or effectiveness of a therapy, two groups of patients must be evaluated: those who receive the therapy (i.e., WBC-reduced blood components); and those who receive the standard or placebo treatment (i.e., non-WBC-reduced components). The experimental study design is valid only if the subjects in the two treatment groups have a similar prognosis at study start-up. This is usually achieved by explicitly defining eligibility criteria (who will be included and who will be excluded), with the goal of recruiting a homogeneous patient population into the study. However, specific eligibility criteria do not necessarily ensure that the patients in each treatment group will have a similar prognosis. The likelihood of prognostic similarity can be increased by using randomization, so that each patient has an equal chance of receiving a particular treatment. Although randomization is a powerful clinical research tool, it may not always ensure prognostic similarity of treatment groups. Prognostic imbalances can still occur if the number of patients enrolled in the study is small, or if some type of systematic error (bias) occurs. To minimize the potential for bias, the randomization process should be performed in a way that conceals the treatment allocation that the patient receives (often referred to as blinding or masking). Ideally, physicians, health-care workers, and patients should be unaware of which treatment the patient is receiving. It is also important to blind treatment allocation when the outcome measure is assessed. This is especially critical if the outcome measure is subjective. Information on the eligibility criteria and the use of randomization (including stratification and blocking techniques) must be present in sufficient detail to allow the reader to determine if these important elements were present and applied in such a way as to minimize the risk of bias. The authors should also present demographic, clinical and prognostic information, by treatment group, to allow for a judgment of group similarity. Two other factors that can affect the validity of the study results include the compliance in follow up and whether or not the patients were analyzed in the group to which they were randomly assigned (referred to as an intention-to-treat analysis). When patients are lost to follow up, or if follow up is incomplete, the power of the study to detect a difference between treatment groups is low and the potential for bias increases.12, 14 In clinical research, the outcome measure is an estimate of the treatment effect. Most of the trials related to WBC reduction express this estimate as a dichotomous value (i.e., presence or absence of infection; presence or absence of alloimmunization) and the proportion of individuals with the outcome in each treatment group is expressed as a percentage. There are a number of ways that these proportions can be presented. The absolute risk reduction (also known as the risk difference) is the difference between the two proportions. The relative risk is the risk among patients in the experimental treatment arm relative to the risk among patients in the control group. The relative risk reduction is an estimate of the proportion of the baseline risk that is removed by the therapy (calculated as 1 –[relative risk]). There are limitations to each of these reporting measures, a discussion of which is beyond the scope of this editorial; however, the important message is that the measure used must be clearly reported. When a general statement such as “the risk decreased by 20 percent” is used, the reader is unclear as to whether the decrease is relative or absolute. Without sufficient information to apply principles of critical appraisal, it is not possible to assess the clinical relevance of the reported results. If a clinical trial is repeated numerous times, even at the same center, it is unlikely that the same estimate of treatment effect would be obtained each time. This was illustrated in two clinical trials performed at our center to look at the effectiveness of WBC reduction and plasma removal to prevent FNHTR. In the first study, 17 percent of plasma-reduced platelets were associated with acute reactions; in the second study, the frequency was 21.3 percent using the same study centers and the same patient population.2, 3 Each study provided the best estimate of the true treatment effect—sometimes called the point estimate. The precision of this estimate can be expressed by calculating the 95 percent CI. CIs should always be reported, because they provide the reader with important information when deciding whether or not an experimental treatment may be useful. In a positive study, where the authors conclude that the treatment is effective, one should look at the lower boundary of the 95 percent CI to determine whether the treatment effect is still clinically important. For example, is the relative risk reduction at the lower boundary of the CI still large enough that you would recommend the treatment? If the study result is negative (experimental treatment appears to be no better than the control), then check the upper boundary of the 95 percent CI. If the value at the upper boundary would normally be considered clinically significant, then the study has failed to exclude an important treatment effect, possibly because the sample size was inadequate. Alone, p values provide little or no information about the magnitude of the treatment effect.14 The sample size calculations and the assumptions on which these calculations are based must also be considered during the critical appraisal process. Studies of WBC reduction have all been based on hypothesis testing. The calculation of sample size for hypothesis testing requires five elements: 1) the probability of erroneously concluding that a difference exists (alpha error, frequently set at 0.05); 2) the probability of erroneously dismissing an actual treatment effect (beta error, frequently set at 0.1 or 0.2); 3) an estimate of the frequency of the outcome measure in patients who have not received WBC-reduced blood; 4) the variance associated with this frequency estimate; and 5) an estimate of the treatment effect difference that would be considered clinically relevant. Careful consideration must go into the selection of this final element to ensure that it is based on assumptions that would be considered plausible by the scientific community. All five elements must be described in the manuscript to allow for an assessment of whether a study has adequate power to detect a clinically significant difference.14 In this issue of TRANSFUSION, the study by Dzik et al.11 is an excellent example of comprehensive reporting, because all of the required sample size elements are stated clearly. However, does the assumption that was used to estimate the clinically significant difference stand up to the expectations of the transfusion community? Specifically, should one expect all hospital patients to have their length of stay decreased by 1.5 days, just because they received WBC-reduced blood? This issue will be discussed in more detail below. The report of a study must contain sufficient detail about the patient population to allow an assessment of whether the results are applicable to one's own patients. Another way of asking the question is to determine whether there is a compelling reason why the results should not apply to a particular patient.13, 14 Treatment should be given only when it is highly likely to benefit the patient; hence, it is essential to use clinically relevant outcome measures when assessing the benefits of a therapy. Some studies of WBC reduction of platelets have traditionally used surrogate outcome measures, such as alloimmunization and refractoriness, as surrogate markers of the risk of morbidity and mortality due to bleeding. Such surrogate measures are often chosen because they reduce the sample size requirement associated with measuring rare events such as bleeding. Selecting a clinically relevant outcome that is feasible can be challenging. In the study by Dzik and colleagues,11 length of stay was selected as the outcome measure to assess universal WBC reduction. The reasons for selecting this endpoint may be defensible, as length of hospital stay has been used as a surrogate outcome measure in studies that assess a particular intervention applied to a broad group of subjects. In addition, the use of this surrogate endpoint can result in a sample size estimate that is feasible to achieve. This second point is illustrated by comparing sample size estimates from the study by Dzik et al.11 with the estimates of a Canadian study designed to assess the impact of implementing universal WBC reduction. The Canadian study is a multicentre retrospective, before and after design, using mortality as the primary outcome measure. One would not argue the clinical relevance of mortality as an outcome measure, but the price tag for using such an endpoint is an estimated sample size of approximately 40,000 patients—14 times the number of patients studied by Dzik et al.11 using length of hospital stay as the primary outcome. Should length of stay be accepted by the scientific community as a clinically appropriate surrogate outcome measure for universal WBC reduction? Bilgin et al.15 reported a statistically higher frequency of infections in patients undergoing coronary artery bypass graft surgery who received non-WBC-reduced blood components; however, the length of hospital stay was similar in the WBC-reduced and non-WBC-reduced treatment groups. This implies that a higher frequency of postoperative infections associated with WBC-reduced blood does not translate into a longer hospital stay. The studies by Volkova et al.9 and Wallis et al.10 in this issue of TRANSFUSION also suggest that the clinical benefits of WBC reduction may not be reflected in a shorter hospital stay; hence, length of hospital stay may not be the appropriate endpoint assessment of universal WBC reduction. Dzik et al.11 concluded that further randomized controlled trials should be performed to assess universal WBC reduction. If such studies proceed, careful consideration should be given when selecting the primary outcome measure. Using a surrogate outcome measure may facilitate the logistics of performing a clinical trial, but the trade-off should also be given important consideration. If the scientific community does not accept the results of a surrogate outcome as clinically relevant, the strategy of using the surrogate potentially invalidates the study. The final consideration addresses the question of whether or not the treatment benefits are worth the potential harm and costs. WBC reduction of blood components is one of few medical interventions that carry minimal or no known risks; hence, the policy decision to use such a component becomes one of assessing benefit versus cost. Clinical studies must provide sufficient detail to allow the reader to critically appraise all aspects of the study. Guidelines for reporting clinical trial results have been developed and published recently as part of the CONSORT (Consolidated Standards of Reporting Trials) statement.16 The key elements of recommended reporting of randomized controlled trials are listed in Table 2. If such guidelines were followed when preparing all manuscripts for publication, the critical appraisal of clinical studies would be facilitated. CONSORT has been supported and adopted by a number of health-care and medical journals,17, 18 because these guidelines improve the quality of reporting.19, 20 The Editorial Board of TRANSFUSION should consider adopting such guidelines as a mechanism to improve the quality of scientific reporting in manuscripts submitted for publication. Most importantly, as consumers of scientific information we must be prepared to critically appraise the medical literature that we read. As researchers, we must be skilled in the art of critical appraisal and apply this skill during protocol development to ensure that the design and execution of experimental studies are the best that they can possibly be. Editorial Boards of scientific medical journals should insist on compliance with standards for reporting clinical research to aim for the highest degree of accuracy, validity, and clinical relevance in the manuscripts that they accept for publication. Finally, our patients deserve to know that their time and efforts spent as participants in clinical studies are contributing to a high quality of knowledge that will define future therapies to improve patient care." @default.
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• W2007106509 title "Evidence‐based clinical reporting: a need for improvement" @default.
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