Partnering with survivors & families to determine research priorities for adult out-of-hospital cardiac arrest: A James Lind Alliance Priority Setting Partnership.

BACKGROUND: Research priority setting in health care has historically been done by expert health care providers and researchers and has not involved patients, family or the public. Survivors & family members have been particularly absent from this process in the field of resuscitation research and specifically adult out of hospital cardiac arrest (OHCA). As such, we sought to conduct a priority setting exercise in partnership with survivors, lay responders and their families in order to ensure that their priorities were visible. We partnered with the James Lind Alliance (UK) and used their commonly used consensus methodology for Public Priority Setting Partnerships (PSPs) to identify research priorities that reflected the perspectives of all stakeholders. METHODS: We used two rounds of public and health care professional surveys to create the initial priority lists. The initial survey collected open-ended questions while the second round consolidated the list of initial questions into a refined list for prioritization. This was done by reviewing existing evidence and thematic categorization by the multi-disciplinary steering committee. An in-person consensus workshop was conducted to come to consensus on the top ten priorities from all perspectives. The McMaster PPEET tool was used to measure engagement. RESULTS: The initial survey yielded more than 425 responses and 1450 "questions" from survivors and family members (18%), lay responders, health care providers and others. The second survey asked participants to rank a short list of 125 questions. The final top 25 questions were brought to the in-person meeting, and a top ten were selected through the JLA consensus process. The final list of top ten questions included how to improve the rate of lay responder CPR, what interventions used at the scene of an arrest can improve resuscitation and survival, how survival can be improved in rural areas of Canada, what resuscitation medications are most effective, what care patient's family members need, what post-discharge support is needed for survivors, how communication should work for everyone involved with a cardiac arrest, what factors best predict neurologically intact survival, whether biomarkers/genetic tests are effective in predicting OHCA and more research on the short and long-term psycho-social impacts of OHCA on survivors. The PPEET showed overwhelmingly positive results for the patient and family engagement experience during the final workshop. CONCLUSIONS: This inclusive research priority setting provides essential information for those doing resuscitation research internationally. The results provide a guide for priority areas of research and should drive our community to focus on questions that matter to survivors and their families in our work. In particular the Canadian Resuscitation Outcomes Consortium will be incorporating the top ten list into its strategic plan for the future.

Association of preoperative anaemia with cardiopulmonary exercise capacity and postoperative outcomes in noncardiac surgery: a substudy of the Measurement of Exercise Tolerance before Surgery (METS) Study.

BACKGROUND: Preoperative anaemia is associated with elevated risks of postoperative complications. This association may be explained by confounding related to poor cardiopulmonary fitness. We conducted a pre-specified substudy of the Measurement of Exercise Tolerance before Surgery (METS) study to examine the associations of preoperative haemoglobin concentration with preoperative cardiopulmonary exercise testing performance (peak oxygen consumption, anaerobic threshold) and postoperative complications. METHODS: The substudy included a nested cross-sectional analysis and nested cohort analysis. In the cross-sectional study (1279 participants), multivariate linear regression modelling was used to determine the adjusted association of haemoglobin concentration with peak oxygen consumption and anaerobic threshold. In the nested cohort study (1256 participants), multivariable logistic regression modelling was used to determine the adjusted association of haemoglobin concentration, peak oxygen consumption, and anaerobic threshold with the primary endpoint (composite outcome of death, cardiovascular complications, acute kidney injury, or surgical site infection) and secondary endpoint (moderate or severe complications). RESULTS: Haemoglobin concentration explained 3.8% of the variation in peak oxygen consumption and anaerobic threshold (P<0.001). Although not associated with the primary endpoint, haemoglobin concentration was associated with moderate or severe complications after adjustment for peak oxygen consumption (odds ratio=0.86 per 10 g L-1 increase; 95% confidence interval, 0.77-0.96) or anaerobic threshold (odds ratio=0.86; 95% confidence interval, 0.77-0.97). Lower peak oxygen consumption was associated with moderate or severe complications without effect modification by haemoglobin concentration (P=0.12). CONCLUSION: Haemoglobin concentration explains a small proportion of variation in exercise capacity. Both anaemia and poor functional capacity are associated with postoperative complications and may therefore be modifiable targets for preoperative optimisation.

Impact of the pan-Canadian Oncology Drug Review on provincial concordance with respect to cancer drug funding decisions and time to funding.

BACKGROUND: The pan-Canadian Oncology Drug Review (pcodr) was implemented in 2011 to address uneven drug coverage and lack of transparency with respect to the various provincial cancer drug review processes in Canada. We evaluated the impact of the pcodr on provincial decision concordance and time from Notice of Compliance (noc) to drug funding. METHODS: In a retrospective review, Health Canada's Drug Product Database was used to identify new indications for cancer drugs between January 2003 and May 2014, and provincial formulary listings for drug-funding dates and decisions between 1 January 2003 and 31 December 2014 were retrieved. Multiple linear models and quantile regressions were used to evaluate changes in time to decision-making before and after the implementation of the pcodr. Agreement of decisions between provinces was evaluated using kappa statistics. RESULTS: Data were available from 9 provinces (all Canadian provinces except Quebec), identifying 88 indications that represented 51 unique cancer drugs. Two provinces lacked available data for all 88 indications at the time of data collection. Interprovincial concordance in drug funding decisions significantly increased after the pcodr's implementation (Brennan-Prediger coefficient: 0.54 pre-pcodr vs. 0.78 post-pcodr; p = 0.002). Nationwide, the median number of days from Health Canada's noc date to the date of funding significantly declined (to 393 days from 522 days, p < 0.001). Exploratory analyses excluding provinces with incomplete data did not change the results. CONCLUSIONS: After the implementation of the pcodr, greater concordance in cancer drug funding decisions between provinces and decreased time to funding decisions were observed.

Survival Analysis in the Presence of Competing Risks: The Example of Waitlisted Kidney Transplant Candidates.

Competing events (or risks) preclude the observation of an event of interest or alter the probability of the event's occurrence and are commonly encountered in transplant outcomes research. Transplantation, for example, is a competing event for death on the waiting list because receiving a transplant may significantly decrease the risk of long-term mortality. In a typical analysis of time-to-event data, competing events may be censored or incorporated into composite end points; however, the presence of competing events violates the assumption of "independent censoring," which is the basis of standard survival analysis techniques. The use of composite end points disregards the possibility that competing events may be related to the exposure in a way that is different from the other components of the composite. Using data from the Scientific Registry of Transplant Recipients, this paper reviews the principles of competing risks analysis; outlines approaches for analyzing data with competing events (cause-specific and subdistribution hazards models); compares the estimates obtained from standard survival analysis, which handle competing events as censoring events; discusses the appropriate settings in which each of the two approaches could be used; and contrasts their interpretation.

HLA-DR and -DQ eplet mismatches and transplant glomerulopathy: a nested case-control study.

We conducted a nested case-control study from a cohort of adult kidney transplant recipients to assess the risk of transplant glomerulopathy (TG) as a function of donor and recipient HLA-DR and -DQ incompatibility at the eplet level. Cases (n = 52) were defined as patients diagnosed with transplant glomerulopathy based on biopsies showing glomerular basement membrane duplication without immune complex deposition. Controls (n = 104) with a similar follow-up from transplantation were randomly selected from the remaining cohort. HLAMatchmaker was used to ascertain the number of DRB1/3/4/5, DQA1 and DQB1 related eplet mismatches (eplet load). Multivariable conditional logistic regression models demonstrated an increase in the odds of TG (odds ratios [OR] of 2.84 [95% confidence interval (CI): 1.03, 7.84] and 4.62 [95% CI: 1.51, 14.14]) in the presence of 27-43 and >43 HLA-DR + DQ related eplet mismatches versus <27 eplet mismatches, respectively. When the eplet load was modeled as a continuous variable, the OR for TG was 1.25 (95% CI: 1.04, 1.50) for every 10 additional HLA-DR + DQ eplet mismatches. Our study suggests that minimization of HLA-DR + DQ eplet mismatches may decrease the incidence of transplant glomerulopathy diagnosed by indication biopsies. The role of eplet immunogenicity/antigenicity as determinants of allograft outcomes requires further study.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion.

BACKGROUND: Concerns regarding the safety of transfused blood have led to the development of a range of interventions to minimise blood loss during major surgery. Anti-fibrinolytic drugs are widely used, particularly in cardiac surgery and previous reviews have found them to be effective in reducing blood loss and the need for transfusion. Recently, questions have been raised regarding the comparative performance of the drugs and the safety of the most popular agent, aprotinin. OBJECTIVES: To assess the comparative effects of the anti-fibrinolytic drugs aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA) on blood loss during surgery, the need for red blood (RBC) transfusion, and adverse events, particularly vascular occlusion, renal dysfunction, and death. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, and the internet. References in identified trials and review articles were checked and trial authors were contacted to identify any additional studies. The searches were last updated in July 2006. SELECTION CRITERIA: Randomised controlled trials (RCTs) of anti-fibrinolytic drugs in adults scheduled for non-urgent surgery. Eligible trials compared anti-fibrinolytic drugs with placebo (or no treatment), or with each other. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: This review summarises data from 211 RCTs that recruited 20,781 participants. Data from placebo/inactive controlled trials, and from head-to-head trials suggest an advantage of aprotinin over the lysine analogues TXA and EACA in terms of operative blood loss, but the differences were small. Aprotinin reduced the probability of requiring RBC transfusion by a relative 34% (relative risk [RR] 0.66, 95% confidence interval [CI] 0.61 to 0.71). The RR for RBC transfusion with TXA was 0.61 (95% CI 0.54 to 0.69) and it was 0.75 (95% CI 0.58 to 0.96) with EACA. When the pooled estimates from the head-to-head trials of the two lysine analogues were combined and compared to aprotinin alone, aprotinin appeared superior in reducing the need for RBC transfusion: RR 0.83 (95% CI 0.69 to 0.99). Aprotinin reduced the need for re-operation due to bleeding: RR 0.48 (95% CI 0.35 to 0.68). This translates into an absolute risk reduction of just under 3% and a number needed-to-treat (NNT) of 37 (95% CI 27 to 56). Similar trends were seen with TXA and EACA, but the data were sparse and the differences failed to reach statistical significance. The blood transfusion data were heterogeneous and funnel plots indicate that trials of aprotinin and the lysine analogues may be subject to publication bias. Evidence of publication bias was not observed in trials reporting re-operation rates. Adjustment for these effects reduced the magnitude of estimated benefits but did not negate treatment effects. However, the apparent advantage of aprotinin over the lysine analogues was small and may be explained by publication bias and non-equivalent drug doses. Aprotinin did not increase the risk of myocardial infarction (RR 0.92, 95% CI 0.72 to 1.18), stroke (RR 0.76, 95% CI 0.35 to 1.64) renal dysfunction (RR 1.16, 95% CI 0.79 to 1.70) or overall mortality (RR 0.90, 95% CI 0.67 to 1.20). The analyses of myocardial infarction and death included data from the majority of subjects recruited into the clinical trials of aprotinin. However, under-reporting of renal events could explain the lack of effect seen with aprotinin. Similar trends were seen with the lysine analogues but data were sparse. These results conflict with the results of recently published non-randomised studies. AUTHORS' CONCLUSIONS: Anti-fibrinolytic drugs provide worthwhile reductions in blood loss and the need for allogeneic red cell transfusion. Based on the results of randomised trials their efficacy does not appear to be offset by serious adverse effects. In most circumstances the lysine analogues are probably as effective as aprotinin and are cheaper; the evidence is stronger for tranexamic acid than for aminocaproic acid. In high risk cardiac surgery, where there is a substantial probability of serious blood loss, aprotinin may be preferred over tranexamic acid. Aprotinin does not appear to be associated with an increased risk of vascular occlusion and death, but the data do not exclude an increased risk of renal failure. There is no need for further placebo-controlled trials of aprotinin or lysine analogues in cardiac surgery. The principal need is for large comparative trials to assess the relative efficacy, safety and cost-effectiveness of anti-fibrinolytic drugs in different surgical procedures.

Feasibility, limits and problems of clinical studies in Intensive Care Unit.

In critical care medicine there is still a paucity of evidence on how to manage most of the clinical problems commonly encountered in critically ill patients. Randomized controlled trials (RCTs) are the most powerful instruments to evaluate the efficacy of a therapeutic intervention and to generate evidence for clinical practice. Unfortunately, the design and conduct of RCTs in our field are particularly complicated, because of some intrinsic and structural problems (e.g. lack of reliable nosography, concomitant use of different therapies, problems in the definition of end-points besides mortality) that will be discussed in this review. Further challenges are represented by the lack of tradition of large ICU networks, difficulties in linking or integrating physiologic and therapeutic objectives in designing clinical protocols, scarcity of independent or non-profit funds. A particularly stimulating opportunity of development is represented also by the relationship of critical care to EBM. Because of the above problems, metanalyses could be less informative than in other areas of medicine, as they are based on few trials which are often contradictory and of unsatisfactory quality. Few suggestions are formulated which could help looking forwards.

Use of vascular risk-modifying medications for diabetic patients differs between physician specialties.

AIMS: Although heart disease and stroke are the underlying causes of death in most people with diabetes, vascular risk modification targets are frequently not met. This study examined whether vascular risk-modifying medication utilization for diabetic patients differed among physician specialties. METHODS: A population-based study using administrative data from 105 715 people aged >/= 65 years with newly diagnosed diabetes in Ontario between 1994 and 2001. The receipt of antihypertensive and lipid-lowering drugs was compared between patients who had regular care from endocrinologists, internists/geriatricians and family physicians. Hierarchical logistic regression adjusted for patient-level differences, physician-level differences and patient clustering within physicians. RESULTS: Only two-thirds of patients received antihypertensive drugs and about one-quarter received lipid-lowering drugs. Compared with patients of family physicians, the adjusted odds ratios for antihypertensive drug use were 1.27 [95% confidence interval (CI) 1.16, 1.38] for patients of internists/geriatricians and 1.03 (95% CI 0.94, 1.12) for patients of endocrinologists. For lipid-lowering drugs, the odds ratios were 1.20 (95% CI 1.11, 1.30) for patients of internists/geriatricians and 1.58 (95% CI 1.42, 1.76) for patients of endocrinologists. CONCLUSIONS: Despite recommendations to use vascular risk-modifying medication for most older people with diabetes, many patients were not receiving these medications. Medication utilization differed between physician specialties, with family physicians having the lowest rates of use. Notably, although blood pressure control has the greatest evidence of benefit and is cost-saving, endocrinologists did not use antihypertensive drugs more often than family physicians after adjustment for other differences.

A decision aid for autologous pre-donation in cardiac surgery--a randomized trial.

OBJECTIVES: The objective of this randomized, controlled study was to determine the usefulness of a decision aid on pre-donation of autologous blood before elective open heart surgery. METHODS: The decision aid (DA) group received a tape and booklet which described the options for peri-operative transfusion in detail. The no decision aid (NDA) group received information usually given to patients about autologous donation. RESULTS: A total of 120 patients were randomized. The DA group rated themselves better prepared for decision making and showed significant improvements in knowledge (p = 0.001) and realistic risk perceptions (p = 0.001). In both groups there was an increase in the proportion of patients choosing allogeneic blood between baseline and follow-up (p = 0.001). Patients in the DA group were significantly more satisfied with the amount of information they received, how they were treated and with the decision they made, than patients in the NDA group. CONCLUSION: The decision aid is useful in preparing patients for decision making. PRACTICE IMPLICATIONS: The next stage is to explore strategies to make it available to all appropriate patients.

Desmopressin for minimising perioperative allogeneic blood transfusion.

BACKGROUND: Public concerns regarding the safety of transfused blood have prompted re-consideration of the use of allogeneic (from an unrelated donor) red blood cell (RBC) transfusion, and of a range of techniques designed to minimise transfusion requirements. OBJECTIVES: To examine the evidence for the efficacy of desmopressin acetate (1-deamino-8-D-arginine-vasopressin; DDAVP), in reducing perioperative blood loss and the need for red cell transfusion in patients who do not have congenital bleeding disorders. SEARCH STRATEGY: Articles were identified by: computer searches of MEDLINE, EMBASE, Current Contents (to May 2003), and the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library, Issue 1, 2003). References in the identified trials and review articles were searched and authors contacted to identify additional studies. SELECTION CRITERIA: Controlled parallel group trials in which adult patients, scheduled for non-urgent surgery, were randomised to DDAVP, or to a control group, who did not receive the intervention. DATA COLLECTION AND ANALYSIS: Trial quality was assessed using criteria proposed by Schulz et al. (Schulz 1995) and Jadad et al. (Jadad 1996). Main outcomes measured were: the number of patients exposed to allogeneic red cell transfusion, and the amount of blood transfused. Other outcomes measured were: re-operation for bleeding, blood loss, post-operative complications (thrombosis, infection, non-fatal myocardial infarction), mortality, and length of hospital stay (LOS). MAIN RESULTS: Eighteen trials of DDAVP (n=1295) reported data on the number of patients transfused with allogeneic RBC transfusion. In subjects treated with DDAVP, the pooled relative risk of exposure to perioperative allogeneic RBC transfusion was 0.95 (95%CI = 0.86 to 1.06). The use of DDAVP did not significantly reduce blood loss; weighted mean difference (WMD) = -114.3ml: 95% confidence interval (95%CI) = -258.8 to 30.2ml per patient) or the volume of RBC transfused (WMD = -0.35 units: 95%CI = -0.70 to 0.01 units). In DDAVP-treated patients the relative risk of requiring re-operation due to bleeding was 0.69 (95%CI = 0.26 to 1.83). There was no statistically significant effect overall for mortality and non-fatal myocardial infarction in DDAVP-treated patients compared with control (RR = 1.72: 95%CI = 0.68 to 4.33) and (RR = 1.38: 95%CI = 0.77 to 2.50) respectively. REVIEWER'S CONCLUSIONS: There is no convincing evidence that desmopressin minimises perioperative allogeneic RBC transfusion in patients who do not have congenital bleeding disorders. These data suggest that there is no benefit from using DDAVP as a means of minimising perioperative allogeneic RBC transfusion.

Long-term pulmonary function abnormalities and survival after allogeneic marrow transplantation.

We studied long-term pulmonary function testing (PFT) in a retrospective cohort of 6-month survivors of allogeneic marrow transplant (BMT) between 1980 and 1997. Of 593 patients, 73, 71 and 65% had adequate data to assess for obstruction, restriction and diffusion impairments respectively. Over 5 years, mean declines in 1-s forced expiratory volume/forced vital capacity (FEV1/FVC), total lung capacity (TLC) and diffusion were 4, 7 and 17%, respectively. TLC and diffusion tended to subsequently increase. In all, 6, 12 and 35% of patients met criteria for obstruction, restriction and impaired diffusion, respectively. Obstruction was less common in recent transplants (5 vs 15%, P=0.004), while restriction and diffusion impairment rates remained stable. There was significantly greater mortality with obstruction (HR 2.0 (1.04-3.95)), and a nonstatistically significant higher mortality rate with restriction (HR 1.6 (0.95-2.75)), but not with impaired diffusion (HR=0.99 (0.65-1.50)). cGVHD (OR 16.7 (2.2-129.8)) and busulfan (OR 2.9 (1.01-8.24)) were associated with obstruction. Marrow from nonsibling or mismatched donors (OR 4.9 (2.2-10.7)) was associated with restriction. In summary, after BMT, decreased diffusion capacity is common and benign; obstruction has decreased in frequency, is rare without cGVHD, and is associated with mortality; nonsibling and mismatched donor are risk factors for restriction.

Pulmonary function abnormalities after allogeneic marrow transplantation: a systematic review and assessment of an existing predictive instrument.

Pulmonary function testing (PFT) is used to characterize non-infectious pulmonary complications after allogeneic BMT. Identifying high-risk patients could facilitate preventive or early therapeutic measures. The objectives of the study were first, to review available data on PFT changes after BMT and second, to validate a previously published predictive index for PFT obstruction in patients transplanted at one center. For the systematic review, frequency, severity and time course of PFT changes after BMT and for the validation study, retrospective cohort comparing predicted with observed PFT, and calculation of indices of predictive accuracy were summarized. The validation study involved 434 patients from Princess Margaret Hospital, Toronto, Canada, who received their first BMT between 1980 and 1997, survived for at least 6 months and had adequate PFT follow-up. The systematic review included 20 studies. After BMT, decreased diffusion and total lung capacity were common and partially reversible. Obstruction was less common. The validation study of a previously published index, performed in 434 patients, found a sensitivity and specificity of 48% and 68% for identifying patients who develop obstruction. We concluded that PFT changes after BMT are common. A published predictive index is not sufficiently accurate to identify high-risk patients for potential preventive or early therapeutic strategies.

Meta-analysis of randomised controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation.

OBJECTIVE: To conduct a meta-analysis of randomised controlled trials to estimate the effectiveness of antiarrhythmic drugs at promoting sinus rhythm in patients with atrial fibrillation. DESIGN: Articles were identified by using a comprehensive search of English language papers indexed in Medline from 1966 to August 2001. For the outcomes of sinus rhythm and death, a random effects model was used to model repeated assessments within a study at different time points. SETTING: Emergency departments and ambulatory clinics. PATIENTS: Patients with atrial fibrillation. INTERVENTIONS: Antiarrhythmic agents grouped according to their Vaughan-Williams class. MAIN OUTCOME MEASURES: Sinus rhythm and mortality. RESULTS: 91 articles met a priori criteria for inclusion in the analysis. Median duration of follow up was one day (range 0.04-1096, mean (SD) 46 (136) days). The median proportion of patients in sinus rhythm at follow up was 55% (range 0-100%) and 32% (range 0-90%) receiving active treatment and placebo, respectively. Median survival was 99% (range 55-100%) and 99% (range 55-100%). Compared with placebo, the following drug classes were associated with increased sinus rhythm at follow up: IA (treatment difference 21.5%, 95% confidence interval (CI) 16.3% to 26.8%); IC (treatment difference 33.1%, 95% CI 23.3% to 42.9%); and III (treatment difference 17.4%, 95% CI 11.5% to 23.3%). Class IC drugs were associated with increased sinus rhythm at follow up compared with class IV drugs (treatment difference 43.2%, 95% CI 11.5% to 75.0%). There was no significant difference in mortality between any drug classes. CONCLUSIONS: Class IA, IC, and III drugs are associated with increased sinus rhythm at follow up compared with placebo. It is unclear whether any antiarrhythmic drug class is associated with increased or decreased mortality.

The use of technologies to decrease peri-operative allogenic blood transfusion: results of practice variation in Israel.

BACKGROUND: Concern about the side effects of allogeneic blood transfusion has led to increased interest in methods of minimizing peri-operative transfusion. Technologies to minimize allogeneic transfusion include drugs such as aprotinin, desmopressin, tranexamic acid and erythropoietin, and techniques such as acute normovolemic hemodilution, cell salvage and autologous pre-donation. OBJECTIVE: To survey the current use in Israel of these seven technologies to minimize allogeneic blood transfusion. METHODS: Our survey was conducted in 1996-97 in all hospitals in Israel with more than 50 beds and at least one of the following departments: cardiac or vascular surgery, orthopedics, or urology. All departments surveyed were asked: a) whether the technologies were currently being used or not, b) the degree of use, and c) the factors influencing their use and non-use. The survey was targeted at the heads of these departments. RESULTS: Pharmaceuticals to reduce allogeneic blood transfusion were used in a much higher proportion in cardiac surgery departments than in the other three departments. Pre-operative blood donation was used in few of the cardiac, urologic and vascular surgery departments compared to its moderate use in orthopedic departments. The use of acute normovolemic hemodilution was reported in a majority of the cardiac departments only. Moderate use of cell salvage was reported in all departments except urology where it was not used at all. CONCLUSION: There is considerable practice variation in the use of technologies to minimize exposure to peri-operative allogeneic blood transfusion in Israel.

How well is the clinical importance of study results reported? An assessment of randomized controlled trials.

BACKGROUND: The interpretation of the results of randomized controlled trials (RCTs) has traditionally emphasized statistical significance rather than clinical importance. Our aim was to assess the quality of reporting of factors related to clinical importance in a sample of published RCTs. METHODS: A random sample of 27 (of a total of 266) RCTs published in 5 major medical journals over a 1-year period were reviewed by 4 independent reviewers for factors considered important in the interpretation of the clinical importance of study results: identification of a clearly defined primary outcome, reporting of the expected difference between groups used in the calculation of sample size (the delta value) and whether it was based on the minimal clinically important difference of the intervention, the statistical significance of the results, presentation of pertinent confidence intervals, and the authors' interpretation of the clinical importance of the results. RESULTS: Twenty-two of 27 (81%) articles explicitly reported a single primary outcome. Of the 20 articles that included a sample size calculation, 18 (90%) reported a delta value. Two of the 18 (11%) articles explicitly stated that the delta value was chosen to reflect the minimal clinically important difference of the intervention. For the primary outcomes, confidence intervals surrounding the point estimates of the efficacy of the interventions were reported in 11 of 27 (41%) studies. The study results were interpreted from the perspective of clinical importance in 20 of 27 (74%) of the articles. Of these 20 reports, 5 (25%) provided justification for their clinical interpretation of the results. INTERPRETATION: Authors of RCTs published in major general medical and internal medicine journals do not consistently provide their own interpretation of the clinical importance of their results, and they often do not provide sufficient information to allow readers to make their own interpretation.

Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion.

BACKGROUND: Concerns regarding the safety of transfused blood have prompted re-consideration of the use of allogeneic (blood from an unrelated donor) blood transfusion. OBJECTIVES: To assess the effects of the anti-fibrinolytic drugs aprotinin, tranexamic acid, and epsilon aminocaproic acid, on peri-operative red blood cell (RBC) transfusion. SEARCH STRATEGY: We searched MEDLINE (to May 1998), EMBASE (to December 1997), web sites of international health technology assessment agencies (to May 1998). References in identified trials and review articles were checked and authors contacted to identify any additional studies. SELECTION CRITERIA: Randomised controlled trials of anti-fibrinolytic drugs in adults scheduled for non-urgent surgery. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. MAIN RESULTS: We found 61 trials of aprotinin (7027 participants). Aprotinin reduced the rate of RBC transfusion by a relative 30% (RR=0.70: 95%CI: 0.64 to 0.76). The average absolute risk reduction (ARR) was 20.4% (95%CI: 15.6% to 25.3%). On average, aprotinin use saved 1.1 units of RBC (95%CI: 0.69 to 1.47) in those requiring transfusion. Aprotinin also significantly reduced the need for re-operation due to bleeding (RR=0.40: 95%CI: 0.25 to 0.66). We found 18 trials of tranexamic acid (TXA) (1,342 participants). TXA reduced the rate of RBC transfusion by a relative 34% (RR=0.66: 95%CI: 0.54 to 0.81). This represented an ARR of 17.2% (95%CI: 8.7% to 25.7%). TXA use resulted in a saving of 1.03 units of RBC (95%CI: 0.67 to 1.39) in those requiring transfusion. We found four trials of epsilon aminocaproic acid (EACA) (208 participants). EACA use resulted in a statistically non-significant reduction in RBC transfusion (RR=0.48: 95%CI: 0.19 to 1.19). Comparisons between agents Eight trials made 'head-to-head' comparisons between TXA and aprotinin. There was no significant difference between the two drugs in the rate of RBC transfusion: RR=1.21 (95%CI: 0.83 to 1.76) for TXA compared to aprotinin. Adverse Effects Aprotinin did not seem to be associated with an excess risk of adverse effects, including thrombo-embolic events (thrombosis RR=0.64: 95%CI: 0.31 to 1.31) and renal failure (RR=1.19: 95%CI: 0.79 to 1.79). Fewer data were available for TXA and EACA. REVIEWER'S CONCLUSIONS: From this review it appears that aprotinin reduces the need for red cell transfusion, and the need for re-operation due to bleeding, without serious adverse effects. However, there was significant heterogeneity in trial outcomes, and some evidence of publication bias. Similar trends were seen with TXA and EACA, although the data were rather sparse. The poor evaluation of these latter drugs is unfortunate as results suggest they may be equally as effective as aprotinin, but are significantly cheaper. The evidence reviewed here supports the use of aprotinin in cardiac surgery. Further small trials of this drug are not warranted. Future trials should be large enough to compare the efficacy and cost-effectiveness of aprotinin with that of TXA and EACA.

The Canadian C-spine rule for radiography in alert and stable trauma patients.

CONTEXT: High levels of variation and inefficiency exist in current clinical practice regarding use of cervical spine (C-spine) radiography in alert and stable trauma patients. OBJECTIVE: To derive a clinical decision rule that is highly sensitive for detecting acute C-spine injury and will allow emergency department (ED) physicians to be more selective in use of radiography in alert and stable trauma patients. DESIGN: Prospective cohort study conducted from October 1996 to April 1999, in which physicians evaluated patients for 20 standardized clinical findings prior to radiography. In some cases, a second physician performed independent interobserver assessments. SETTING: Ten EDs in large Canadian community and university hospitals. PATIENTS: Convenience sample of 8924 adults (mean age, 37 years) who presented to the ED with blunt trauma to the head/neck, stable vital signs, and a Glasgow Coma Scale score of 15. MAIN OUTCOME MEASURE: Clinically important C-spine injury, evaluated by plain radiography, computed tomography, and a structured follow-up telephone interview. The clinical decision rule was derived using the kappa coefficient, logistic regression analysis, and chi(2) recursive partitioning techniques. RESULTS: Among the study sample, 151 (1.7%) had important C-spine injury. The resultant model and final Canadian C-Spine Rule comprises 3 main questions: (1) is there any high-risk factor present that mandates radiography (ie, age >/=65 years, dangerous mechanism, or paresthesias in extremities)? (2) is there any low-risk factor present that allows safe assessment of range of motion (ie, simple rear-end motor vehicle collision, sitting position in ED, ambulatory at any time since injury, delayed onset of neck pain, or absence of midline C-spine tenderness)? and (3) is the patient able to actively rotate neck 45 degrees to the left and right? By cross-validation, this rule had 100% sensitivity (95% confidence interval [CI], 98%-100%) and 42.5% specificity (95% CI, 40%-44%) for identifying 151 clinically important C-spine injuries. The potential radiography ordering rate would be 58.2%. CONCLUSION: We have derived the Canadian C-Spine Rule, a highly sensitive decision rule for use of C-spine radiography in alert and stable trauma patients. If prospectively validated in other cohorts, this rule has the potential to significantly reduce practice variation and inefficiency in ED use of C-spine radiography.

The future of evidence-based medicine.

Evidence-based medicine (EBM) stresses the examination of evidence from clinical research as an important basis for the practice of medicine. EBM is an approach that is intuitively reasonable, and is increasingly taught in medical schools and incorporated into practice. Although it is often not feasible for busy clinicians to find and appraise original research themselves, EBM is now frequently used to develop clinical practice guidelines. However, there are often 'grey areas' in the interpretation of the evidence, some of which are discussed in this paper. Clinical medicine can be complex, and EBM will never provide easy answers to difficult problems, which means that there will always be an art to clinical medicine. As well, EBM is practised in complex, semirational, constantly changing health care systems, which sometimes actually establish barriers to the incorporation of evidence into practice.

Canadian CT head rule study for patients with minor head injury: methodology for phase II (validation and economic analysis).

Prospective validation on a new set of patients is an essential test of a new decision rule. However, many clinical decision rules are not prospectively assessed to determine their accuracy, reliability, clinical sensibility, or potential impact on practice. This validation process is important because many statistically derived rules or guidelines do not perform well when tested in a new population. The methodologic standards for a validation study are similar to those described in the article on phase I for derivation studies in the August 2001 issue of Annals of Emergency Medicine. The goal of phase II is to prospectively assess the accuracy, reliability, and acceptability of the decision rule in a new set of patients with minor head injury. This will determine the clinical utility of the rule and is essential if such a rule is to be widely adopted into clinical practice.