A systematic, concept-based method of developing the exposure measure for drug safety and effectiveness studies.

PURPOSE: In drug safety and effectiveness studies based on secondary data, the choice of an appropriate exposure measure for a given outcome can be challenging. Different measures of exposure can yield different estimates of treatment effect and safety. There is a knowledge gap with respect to developing and refining measures of drug exposure, to ensure that the exposure measure addresses the study question and is suitable for statistical analysis. METHODS: We present a transparent, step-by-step approach to the development of drug exposure measures involving secondary data. This approach would be of interest to students and investigators with initial training in pharmacoepidemiology. We illustrate the approach using a study about Parkinson's disease. RESULTS: We described the exposure specifications according to the study question. Next, we refined the exposure measure by linking it to knowledge about four major concepts in drug safety and effectiveness studies: drug use patterns, duration, timing, and dose. We then used this knowledge to guide the ultimate choice of exposure measure: time-varying, cumulative 6-month exposure to tamsulosin (a drug used to treat prostate hyperplasia). CONCLUSIONS: The proposed approach links exposure specifications to four major concepts in drug safety and effectiveness studies. Formulating subject-matter knowledge about these major concepts provides an avenue to develop the rationale and specifications for the exposure measure.

Mammographic non-dense area and breast cancer risk in postmenopausal women: a causal inference approach in a case-control study.

PURPOSE: The association between high mammographic density (MD) and elevated breast cancer risk is well established. However, the role of absolute non-dense area remains unclear. We estimated the effect of the mammographic non-dense area and other density parameters on the risk of breast cancer. METHODS: This study utilizes data from a population-based case-control study conducted in Greater Vancouver, British Columbia, with 477 female postmenopausal breast cancer cases and 588 female postmenopausal controls. MD measures were determined from digitized screening mammograms using computer-assisted software (Cumulus). Marginal odds ratios were estimated by inverse-probability weighting using a causal diagram for confounder selection. Akaike information criteria and receiver operating characteristic curves were used to assess the goodness of fit and predictive power of unconditional logistic models containing MD parameters. RESULTS: The risk of breast cancer is 60% lower for the highest quartile compared to the lowest quartile of mammographic non-dense area (marginal OR 0.40, 95% CI 0.26-0.61, p-trend < 0.001). The cancer risk almost doubles for the highest quartile compared to the lowest quartile of dense area (marginal OR 1.81, 95% CI 1.19-2.43, p-trend < 0.001). For the highest quartile of percent density, breast cancer risk was more than three times higher than for the lowest quartile (marginal OR 3.15, 95% CI 1.90-4.40, p-trend < 0.001). No difference was seen in predictive accuracy between models using percent density alone, dense area alone, or non-dense area plus dense area. CONCLUSIONS: In this study, non-dense area is an independent risk factor after adjustment for dense area and other covariates, inversely related with the risk of breast cancer. However, non-dense area does not improve prediction over that offered by percent density or dense area alone.

An observational study to evaluate 2 target times for elective coronary bypass surgery.

BACKGROUND: Guidelines for timing of elective bypass surgery were established by expert opinion; yet, there is little evidence to support the recommended target times. OBJECTIVES: To estimate the effect of timing of the procedure on in-hospital mortality by comparing groups of patients that differ in the duration of time between decision to operate and performed procedure. RESEARCH DESIGN: We used a population-based registry to identify patients who underwent surgical coronary revascularization and their hospital discharge summaries to identify in-hospital death. SUBJECTS: We studied 9593 patients who underwent surgical revascularization between 1992 and 2006 after registration on a wait list for first-time isolated coronary artery bypass grafting on an elective basis. MEASURES: The outcome was postoperative in-hospital death. The study variable was the timing of surgery, categorized as short, prolonged, and excessive delays according to the guidelines. METHODS: The probability of in-hospital death in relation to timing of surgery was modeled by logistic regression that included a precalculated risk score for in-hospital death, with weighting observations by inverse propensity scores for the 3 surgery timing groups. RESULTS: In-hospital death among patients with short delays was one third as likely as among those with excessive delays: adjusted odds ratio=0.32 (95% confidence interval 0.20-0.51). The protective effect was smaller and not significant for patients with prolonged delays; odds ratio=0.78 (95% confidence interval, 0.38-1.63). CONCLUSIONS: Our findings suggest a survival benefit from performing elective surgical revascularization within the time frame recommended by the stricter of the 2 guidelines. Our results have implications for health systems that provide universal coverage and that budget the annual number of procedures.

Evaluation of supply-side initiatives to improve access to coronary bypass surgery.

BACKGROUND: Guided by the evidence that delaying coronary revascularization may lead to symptom worsening and poorer clinical outcomes, expansion in cardiac surgery capacity has been recommended in Canada. Provincial governments started providing one-time and recurring increases in budgets for additional open heart surgeries to reduce waiting times. We sought to determine whether the year of decision to proceed with non-emergency coronary bypass surgery had an effect on time to surgery. METHODS: Using records from a population-based registry, we studied times between decision to operate and the procedure itself. We estimated changes in the length of time that patients had to wait for non-emergency operation over 14 calendar periods that included several years when supplementary funding was available. We studied waiting times separately for patients who access surgery through a wait list and through direct admission. RESULTS: During two periods when supplementary funding was available, 1998-1999 and 2004-2005, the weekly rate of undergoing surgery from a wait list was, respectively, 50% and 90% higher than in 1996-1997, the period with the longest waiting times. We also observed a reduction in the difference between 90th and 50th percentiles of the waiting-time distributions. Forty percent of patients in the 1998, 1999, 2004 and 2005 cohorts (years when supplementary funding was provided) underwent surgery within 16 to 20 weeks following the median waiting time, while it took between 27 and 37 weeks for the cohorts registered in the years when supplementary funding was not available. Times between decision and surgery were shorter for direct admissions than for wait-listed patients. Among patients who were directly admitted to hospital, time between decision and surgery was longest in 1992-1993 and then has been steadily decreasing through the late nineties. The rate of surgery among these patients was the highest in 1998-1999, and has not changed afterwards, even for years when supplementary funding was provided. CONCLUSIONS: Waiting times for non-emergency coronary bypass surgery shortened after supplementary funding was granted to increase volume of cardiac surgical care in a health system with publicly-funded universal coverage for the procedure. The effect of the supplementary funding was not uniform for patients that access the services through wait lists and through direct admission.

Constructing treatment episodes from concomitant medication logs: a prospective observational study.

OBJECTIVES: To describe an approach using concomitant medication log records for the construction of treatment episodes. Concomitant medication log records are routinely collected in clinical studies. Unlike prescription and dispensing records, concomitant medication logs collect utilisation data. Logs can provide information about drug safety and drug repurposing. DESIGN: A prospective multicentre, multicohort observational study. SETTING: Twenty-one clinical sites in the USA, Europe, Israel and Australia. PARTICIPANTS: 415 subjects from the de novo cohort of the Parkinson's Progression Markers Initiative. METHODS: We construct treatment episodes of concomitant medication use. The proposed approach treats temporal gaps as a stoppage of medication and temporal overlaps as simultaneous use or changes in dose. Log records with no temporal gaps were combined into a single treatment episode. RESULTS: 5723 concomitant medication log records were used to construct 3655 treatment episodes for 65 medications. There were 405 temporal gaps representing a stoppage of medication; 985 temporal overlaps representing simultaneous regimens of the same medication and 2696 temporal overlaps representing a change in dose regimen. The median episode duration was 37 months (IQ interval: 11-73 months). CONCLUSIONS: The proposed approach for constructing treatment episodes offers a method of estimating duration and dose of treatment from concomitant medication log records. The accompanying recommendations guide log data collection to improve their quality for drug safety and drug repurposing.

Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole.

STUDY OBJECTIVE: We investigate adverse drug events associated with antidotes ethanol and fomepizole in methanol or ethylene glycol poisonings. An "adverse drug event" is harm associated with normal or incorrect drug use. We describe type, frequency, severity, seriousness, and onset time of adverse drug events and test the hypothesis that fomepizole results in fewer adverse drug events than ethanol. METHODS: This cohort study included patients aged 13 years or older, hospitalized between 1996 and 2005 for methanol or ethylene glycol poisoning (identified by International Classification of Diseases, Ninth Revision or 10th Revision codes) and treated with at least 1 dose of ethanol or fomepizole. Two abstractors separately reviewed each chart, identifying new clinical events during antidote treatment. Three toxicologists determined, by consensus, which events were adverse drug events. The primary outcome was at least 1 adverse drug event, expressed as adverse drug event rate per person-day of antidote treatment. Association between time to first adverse drug event and antidote type was modeled by Cox regression, adjusted for confounders. RESULTS: Two hundred twenty-three charts were reviewed and 172 analyzed. Toxicologists identified at least 1 adverse drug event in 74 of 130 (57%) ethanol-treated and 5 of 42 (12%) fomepizole-treated cases. Central nervous system symptoms accounted for most adverse drug events (48% ethanol-treated, 2% fomepizole-treated). Severe adverse drug events occurred in 26 of 130 (20%) ethanol-treated (coma, extreme agitation, cardiovascular) and 2 of 42 (5%) fomepizole-treated (coma, cardiovascular). Serious (life-threatening) adverse drug events occurred in 11 of 130 (8%) ethanol-treated (respiratory depression, hypotension) and 1 of 42 (2%) fomepizole-treated (hypotension, bradycardia) cases. Median adverse drug event onset was within 3 hours after the start of either antidote. Ethanol and fomepizole adverse drug event rates were 0.93 and 0.13 adverse drug events per treatment-day, respectively. Adjusted hazard ratio was 0.16 (95% confidence interval 0.06, 0.40). CONCLUSION: Given observational study limitations, results suggest lower occurrence of adverse drug events with fomepizole than ethanol.

On reporting results from randomized controlled trials with recurrent events.

BACKGROUND: Evidence-based medicine has been advanced by the use of standards for reporting the design and methodology of randomized controlled trials (RCT). Indeed, without this information it is difficult to assess the quality of evidence from an RCT. Although a variety of statistical methods are available for the analysis of recurrent events, reporting the effect of an intervention on outcomes that recur is an area that remains poorly understood in clinical research. The purpose of this paper is to outline guidelines for reporting results from RCTs where the outcome of interest is a recurrent event. METHODS: We used a simulation study to relate an event process and results from analyses of the gamma-Poisson, independent-increment, conditional, and marginal Cox models. We reviewed the utility of regression models for the rate of a recurrent event by articulating the associated study questions, preenting the risk sets, and interpreting the regression coefficients. RESULTS: Based on a single data set produced by simulation, we reported and contrasted results from statistical methods for evaluating treatment effect from an RCT with a recurrent outcome. We showed that each model has different study questions, assumptions, risk sets, and rate ratio interpretation, and so inferences should consider the appropriateness of the model for the RCT. CONCLUSION: Our guidelines for reporting results from an RCT involving a recurrent event suggest that the study question and the objectives of the trial, such as assessing comparable groups and estimating effect size, should determine the statistical methods. The guidelines should allow clinical researchers to report appropriate measures from an RCT for understanding the effect of intervention on the occurrence of a recurrent event.

Delay in admission for elective coronary-artery bypass grafting is associated with increased in-hospital mortality.

BACKGROUND: Many health care systems now use priority wait lists for scheduling elective coronary artery bypass grafting (CABG) surgery, but there have not yet been any direct estimates of reductions in in-hospital mortality rate afforded by ensuring that the operation is performed within recommended time periods. METHODS: We used a population-based registry to identify patients with established coronary artery disease who underwent isolated CABG in British Columbia, Canada. We studied whether postoperative survival during hospital admission for CABG differed significantly among patients who waited for surgery longer than the recommended time, 6 weeks for patients needing semi-urgent surgery and 12 weeks for those needing non-urgent surgery. RESULTS: Among 7316 patients who underwent CABG, 97 died during the same hospital admission, for a province-wide death rate at discharge of 1.3%. The observed proportion of patients who died during the same admission was 1.0% (27 deaths among 2675 patients) for patients treated within the recommended time and 1.5% (70 among 4641) for whom CABG was delayed. After adjustment for age, sex, anatomy, comorbidity, calendar period, hospital, and mode of admission, patients with early CABG were only 2/3 as likely as those for whom CABG was delayed to experience in-hospital death (odds ratio 0.61; 95% confidence interval [CI] 0.39 to 0.96). There was a linear trend of 5% increase in the odds of in-hospital death for every additional month of delay before surgery, adjusted OR = 1.05 (95% CI 1.00 to 1.11). CONCLUSION: We found a significant survival benefit from performing surgical revascularization within the time deemed acceptable to consultant surgeons for patients requiring the treatment on a semi-urgent or non-urgent basis.

Do women spend longer on wait lists for coronary bypass surgery? Analysis of a population-based registry in British Columbia, Canada.

BACKGROUND: Studies have shown patients who are delayed for surgical cardiac revascularization are faced with increased risks of symptom deterioration and death. This could explain the observation that operative mortality among persons undergoing coronary artery bypass surgery (CABG) is higher among women than men. However, in jurisdictions that employ priority wait lists to manage access to elective cardiac surgery, there is little information on whether women wait longer than men for CABG. It is therefore difficult to ascertain whether higher operative mortality among women is due to biological differences or to delayed access to elective CABG. METHODS: Using records from a population-based registry, we compared the wait-list time between women and men in British Columbia (BC) between 1990 and 2000. We compared the number of weeks from registration to surgery for equal proportions of women and men, after adjusting for priority, comorbidity and age. RESULTS: In BC in the 1990 s, 9,167 patients aged 40 years and over were registered on wait lists for CABG and spent a total of 136,071 person-weeks waiting. At the time of registration for CABG, women were more likely to have a comorbid condition than men. We found little evidence to suggest that women waited longer than men for CABG after registration, after adjusting for comorbidity and age, either overall or within three priority groups. CONCLUSION: Our findings support the hypothesis that higher operative mortality during elective CABG operations observed among women is not due to longer delays for the procedure.

The risk of death associated with delayed coronary artery bypass surgery.

BACKGROUND: The detrimental effect of delaying surgical revascularization has been estimated in randomized trials and observational studies. It has been argued that the Kaplan-Meier method used in quantifying the hazard of delayed treatment is not appropriate for summarizing the probability of competing outcomes. Therefore, we sought to improve the estimates of the risk of death associated with delayed surgical treatment of coronary artery disease. METHODS: Population-based prospective study of 8,325 patients registered to undergo first time isolated coronary artery bypass grafting (CABG) in any of the four tertiary hospitals that provide cardiac care to adult residents of British Columbia, Canada. The cumulative incidence of pre-operative death, the cumulative incidence of surgery, and the probability that a patient, who may die or undergo surgery, dies if not operated by certain times over the 52-week period after the decision for CABG were estimated. The risks were quantified separately in two groups: high-severity at presentation were patients with either persistent unstable angina or stable angina and extensive coronary artery disease, and low-severity at presentation were stable symptomatic patients with limited disease. RESULTS: The median waiting time for surgery was 10 weeks (interquartile range [IQR] 15 weeks) in the high-severity group and 21 weeks (IQR 30 weeks) in the low-severity group. One percent of patients died before surgery: 54 in the high-severity and 26 in the low-severity group. For 58 (72.5%) patients, death was related to CVD (acute coronary syndrome, 33; chronic CVD, 16; other CVD, 4; and sudden deaths, 5). The overall death rate from all causes was 0.61 (95% CI 0.48-0.74) per 1,000 patient-weeks, varying from 0.62 (95% CI 0.45-0.78) in the high-severity group to 0.59 (95% CI 0.37-0.82) in the low-severity group. After adjustment for age, sex, and comorbidity, the all-cause death rate in the low-severity group was similar to the high-severity group (OR = 1.02, 95% CI 0.64-1.62). The conditional probability of death was greater in the high-severity group than in the low-severity group both for all-cause mortality (p = 0.002) and cardiovascular deaths (p <0.001). CONCLUSION: The probability of death conditional on not having undergone a required CABG increases with time spent on wait lists.

Chances of late surgery in relation to length of wait lists.

BACKGROUND: The proportion of patients who undergo surgery within a clinically safe time is an important performance indicator in health systems that use wait lists to manage access to care. However, little is known about chances of on-time surgery according to variations in existing demand. We sought to determine what proportion of patients have had late coronary bypass surgery after registration on wait lists of different size in a network of hospitals with uniform standards for timing of surgery. METHODS: Using records from a population-based registry, we studied wait-list times prospectively collected in a cohort of patients registered on wait lists for coronary artery bypass grafting procedures. We compared the number of weeks from registration to surgery against target access times established for three urgency groups. The chances of undergoing surgery within target time have been evaluated in relation to wait-list size at registration and the number of surgeries performed without registration on a wait list. RESULTS: In 1991-2001, two in three patients were at risk of late surgery when registered on wait lists for isolated coronary bypass procedures in British Columbia, Canada. Although urgent patients had never seen a wait list with clearance time exceeding one week, the odds of on-time surgery were reduced by 25%, odds ratio [OR] = 0.75 (95% confidence interval [CI] 0.65-0.87) for every additional operation performed without registration on a list. When the wait list at registration required a clearance time of over one month, semi-urgent patients had 51% lower odds of on-time surgery as compared to lists with clearance time less than one week, OR = 0.49 (95%CI 0.41-0.60), after adjustment for age, sex, comorbidity, calendar period, hospital and week on the list. In the non-urgent group, the odds were 69% lower, OR = 0.31 (95%CI 0.20-0.47). Every time an operation in the same hospital was performed without registration on a wait list, the odds of on-time surgery for listed patients were reduced by 7%, OR = 0.93 (95%CI 0.91-0.95) in the semi-urgent group, and by 10%, OR = 0.90 (95%CI 0.87-0.94), in the non-urgent group. CONCLUSION: Chances of late surgery increase with the wait-list size for semi-urgent and non-urgent patients needing coronary bypass surgery. The weekly number of patients who move immediately from angiography to the operation without registration on a wait list reduced chances of surgery within target time in all urgency groups of listed patients. When advising patients who will be placed on the wait list about the expected time to treatment, hospital managers should take into account the current list size as well as the weekly number of patients who require CABG immediately after undergoing coronary angiography.

Time on wait lists for coronary bypass surgery in British Columbia, Canada, 1991-2000.

BACKGROUND: In British Columbia, Canada, all necessary medical services are funded publicly. Concerned with growing wait lists in the mid-1990s, the provincial government started providing extra funding for coronary artery bypass grafting (CABG) operations annually. Although aimed at improving access, it is not known whether supplementary funding changed the time that patients spent on wait lists for CABG. We sought to determine whether the period of registration on wait lists had an effect on time to isolated CABG and whether the period effect was similar across priority groups. METHODS: Using records from a population-based registry, we studied the wait-list time before and after supplementary funding became available. We compared the number of weeks from registration to surgery for equal proportions of patients in synthetic cohorts defined by five registration periods in the 1990s. RESULTS: Overall, 9,231 patients spent a total of 137,126 person-weeks on the wait lists. The time to surgery increased by the middle of the decade, and decreased toward the end of the decade. Relative to the 1991-92 registration period, the conditional weekly probabilities of undergoing surgery were 30% lower among patients registered on the wait lists in 1995-96, hazard ratio (HR) = 0.70 (0.65-0.76), and 23% lower in 1997-98 patients, HR = 0.77 (0.71-0.83), while there were no differences with 1999-2000 patients, HR = 0.94 (0.88-1.02), after adjusting for priority group at registration, comorbidity, age and sex. We found that the effect of registration period was different across priority groups. CONCLUSION: Our results provide evidence that time to CABG shortened after supplementary funding was provided on an annual basis to tertiary care hospitals within a single publicly funded health system. One plausible explanation is that these hospitals had capacity to increase the number of operations. At the same time, the effect was not uniform across priority groups indicating that changes in clinical practice should be considered when adding extra funding to reduce wait lists.

The occurrence of adverse events in relation to time after registration for coronary artery bypass surgery: a population-based observational study.

BACKGROUND: Our objective was to evaluate the effect of delays on adverse events while waiting for coronary artery bypass grafting (CABG). METHODS: An observational study that prospectively followed patients from registration on a wait list to removal for planned surgery, death while waiting, or unplanned emergency surgery. The population-based registry provided data on 12,030 patients with a record of registration on a wait list for first-time isolated CABG surgery between 1992 and 2005. RESULTS: In total, 104 patients died and 382 patients underwent an emergency surgery before planned CABG. The death rate was 0.5 per 1000 patient-weeks in the semiurgent group and 0.6 per 1000 patient-weeks the nonurgent group, adjusted OR = 1.07 (95% confidence interval [CI] 0.69-1.65). The emergency surgery rate of 1.2 per 1000 patient-weeks in the nonurgent group was lower compared to 2.1 per 1000 patient-weeks in the semiurgent group (adjusted OR = 0.72, 95% CI 0.54-0.97). However, the nonurgent group had a greater cumulative incidence of preoperative death than the semiurgent group for almost all weeks on the wait list, adjusted OR = 1.92 (95% CI 1.25-2.95). The surgery rate was 1.2 per 1000 patient-weeks in the nonurgent group and 2.1 per 1000 patient-weeks in the semiurgent group, adjusted OR = 0.72 (95% CI 0.54-0.97). The cumulative incidence of emergency surgery before planned CABG was similar in the semiurgent and nonurgent groups, adjusted OR = 0.88, (95% CI 0.64-1.20). CONCLUSION: Despite similar death rates in the semiurgent and nonurgent groups, the longer waiting times in the nonurgent group result in a greater cumulative incidence of death on the wait list compared to that in the semiurgent group. These longer waiting times also offset the lower rate of emergency surgery before planned admission in the nonurgent group so that the cumulative incidence of the emergency surgery was similar in both groups.

The effect of waiting time on pain intensity after elective surgical lumbar discectomy.

BACKGROUND CONTEXT: Waitlists are commonly used in Canada to manage access to surgical procedures such as elective surgical lumbar discectomy (ESLD). The timing of enrollment onto the waitlist is important as this is a proxy measure for the concordance of preferences for surgery between a patient and surgeon. After enrollment, the waiting time to actual surgery extends the duration of preoperative symptoms, which possibly affects the outcome of ESLD. Waiting time also specifically reflects the delay in service delivery imposed by the limited capacity of the health-care system. PURPOSE: To determine if a system-imposed delay in treatment, that is, longer waiting time, for ESLD is associated with a higher odds of experiencing residual postoperative pain. STUDY DESIGN/SETTING: Ambidirectional cohort study with 2-year retrospective and 3-year prospective components, conducted at a major tertiary care center serving a metropolitan area in Canada. PATIENT SAMPLE: Patients aged 16 years or older with sciatica because of herniated lumbar disc, confirmed on advanced imaging, were recruited at the time of waitlist enrollment for ESLD. Patients with significant comorbidity or emergency indications for surgery were excluded. Of 391 participants, 291 had complete follow-up information at 6 months postoperatively. OUTCOME MEASURE: Intensity of the predominant symptom (worse of either back or leg pain) was assessed on the 11-point numerical rating scale at waitlist enrollment and 6 months postoperatively. Pain scores were highly skewed and therefore categorized into four ordinal levels defined by quartiles. METHODS: For the primary analysis, time to surgery from waitlist enrollment was dichotomized based on a predetermined clinically meaningful cut-point of 12 weeks. Ordinal logistic regression was used to compare the odds of experiencing higher pain intensity between wait groups. Control of confounders was achieved using both propensity scores and conventional multivariable modeling. RESULTS: In unadjusted analyses, long-wait patients were 80% more likely than short-wait patients to experience higher ordinal pain intensity at 6 months; unadjusted proportional odds ratio (POR)=1.8 (95% confidence interval [CI], 1.2-2.8). The association held after controlling for all imbalances in measured confounders, with long-wait patients still being 70% more likely to report worse pain; adjusted POR=1.7 (95% CI, 1.0-2.8). CONCLUSIONS: A waiting time of 12 weeks or more after waitlist enrollment for ESLD is associated with a modest likelihood of experiencing worse pain at 6 months postoperatively. This result was not because of differences in measured confounders. Future studies are encouraged to identify other, as-of-yet unmeasured, variables that might be associated with both longer waiting times and worse outcomes among ESLD patients. Until then, in jurisdictions where highly constrained access to ESLD is managed through waitlists, the expected waiting time for the operation could be an informative deciding criterion for patients with otherwise unresolved preferences for operative treatment.

Systematic review of the use of computer simulation modeling of patient flow in surgical care.

Computer simulation has been employed to evaluate proposed changes in the delivery of health care. However, little is known about the utility of simulation approaches for analysis of changes in the delivery of surgical care. We searched eight bibliographic databases for this comprehensive review of the literature published over the past five decades, and found 34 publications that reported on simulation models for the flow of surgical patients. The majority of these publications presented a description of the simulation approach: 91% outlined the underlying assumptions for modeling, 88% presented the system requirements, and 91% described the input and output data. However, only half of the publications reported that models were constructed to address the needs of policy-makers, and only 26% reported some involvement of health system managers and policy-makers in the simulation study. In addition, we found a wide variation in the presentation of assumptions, system requirements, input and output data, and results of simulation-based policy analysis.

Medication errors associated with the use of ethanol and fomepizole as antidotes for methanol and ethylene glycol poisoning.

INTRODUCTION: Little is known about medication errors which occur with the antidotes ethanol and fomepizole, used for treatment of methanol and ethylene glycol poisoning. Study objectives were to describe and compare the frequency, type, outcome and underlying causes of medication errors associated with ethanol and fomepizole. METHODS: Patients aged ≥13 years were included if they were hospitalized in 1996-2005 for methanol or ethylene glycol poisoning and treated with ethanol or fomepizole. Charts from 10 hospitals were separately reviewed by two abstracters who recorded case details. A consensus panel of clinicians used the abstracted data to identify medication errors and classify error outcome. Fisher's exact test determined significant differences in the proportion of ethanol and fomepizole-treated cases with medication error and univariate logistic regression identified risk factors associated with harmful dosage errors. RESULTS: There were 145 ethanol- and 44 fomepizole-treated cases. There was ≥1 medication error in 113/145 (78%) ethanol- and 20/44 (45%) fomepizole-treated cases (p = 0.0001) with more ethanol-related errors involving excessive dose, inadequate monitoring and inappropriate antidote duration. Harmful errors occurred in 19% of ethanol- and 7% of fomepizole-treated cases (p = 0.06) and were largely due to excessive antidote dose or delayed antidote initiation. Occurrence of harmful dosage error was reduced in cases with Poison Control Centre consultation, odds ratio (95% confidence interval) 0.39 (0.17, 0.91), hemodialysis 0.37 (0.16, 0.88), or fomepizole versus ethanol 0.24 (0.06, 1.04). CONCLUSION: Fomepizole was less prone to medication error than ethanol. Error-related harm was most commonly due to excessive antidote dose or delayed antidote initiation.

Survival benefit of coronary-artery bypass grafting accounted for deaths in those who remained untreated.

BACKGROUND: Currently there are no direct estimates of mortality reduction afforded by coronary-artery bypass grafting (CABG) that take into account the deaths among patients for whom coronary revascularization was indicated but who did not undergo the treatment. The objective of this analysis was to compare survival after the treatment decision between patients who underwent CABG and those who remained untreated. METHODS: We used a population-based registry to identify patients with established coronary artery disease who were to undergo first-time isolated CABG. We measured the effect of surgical revascularization on survival after the treatment decision in two cohorts of patients categorized by symptoms, coronary anatomy, and left ventricular function. RESULTS: One in 10 patients died during the five years after treatment decision. The hazard of death among patients who underwent CABG was 51 percent of that for the untreated group, the adjusted hazard ratio was 0.51 (95 percent confidence interval, 0.43 to 0.61). The effect was stronger when CABG was performed within the recommended time: adjusted hazard ratios were 0.43 (95 percent confidence interval, 0.35 to 0.53) and 0.58 (95 percent confidence interval, 0.48 to 0.70) for early and late intervention, respectively; chi-square for the difference between hazard ratios was 12.2 (P < 0.001). CONCLUSION: Estimates that account for patients who died before they could undergo a required CABG indicate a significant survival benefit of performing early surgical revascularization even for patients registered to undergo the operation on the non-urgent basis.

Evaluation of booking systems for elective surgery using simulation experiments.

OBJECTIVE: This study compared two methods of booking elective surgery - booking from wait lists and pre-booking surgery dates at the time of decision to operate - in terms of cancellations of elective procedures and time to surgery. METHODS: The authors conducted simulation experiments with group randomized design, in which the unit of allocation was the hospital and the units of analysis were both the hospital and the patient. RESULTS: In the case of pre-booking, cancellation of high-priority elective procedures was only one-third as likely as it was in the case of booking from wait lists (odds ratio 0.35; 95% confidence interval 0.18-0.68). After adjustment for hospital and patient factors, the weekly likelihood that patients on the wait list had their operation was about 20% higher for medium-priority procedures (OR 1.21; CI 1.18-1.24) after pre-booking surgery dates. CONCLUSION: The findings suggest that redesigning booking processes may improve the performance of surgical services.

Cumulative incidence for wait-list death in relation to length of queue for coronary-artery bypass grafting: a cohort study.

BACKGROUND: In deciding where to undergo coronary-artery bypass grafting, the length of surgical wait lists is often the only information available to cardiologists and their patients. Our objective was to compare the cumulative incidence for death on the wait list according to the length of wait lists at the time of registration for the operation. METHODS: The study cohort included 8966 patients who registered to undergo isolated coronary-artery bypass grafting (82.4% men; 71.9% semi-urgent; 22.4% non-urgent). The patients were categorized according to wait-list clearance time at registration: either "1 month or less" or "more than 1 month". Cumulative incidence for wait-list death was compared between the groups, and the significance of difference was tested by means of regression models. RESULTS: Urgent patients never registered on a wait list with a clearance time of more than 1 month. Semi-urgent patients registered on shorter wait lists more often than non-urgent patients (79.1% vs. 44.7%). In semi-urgent and non-urgent patients, the observed proportion of wait-list deaths by 52 weeks was lower in category "1 month or less" than in category "more than 1 month" (0.8% [49 deaths] vs. 1.6% [39 deaths], P < 0.005). After adjustment, the odds of death before surgery were 64% higher in patients on longer lists, odds ratio [OR] = 1.64 (95% confidence interval [CI] 1.02-2.63). The observed death rate was higher in category "more than 1 month" than in category "1 month or less", 0.79 (95%CI 0.54-1.04) vs. 0.58 (95% CI 0.42-0.74) per 1000 patient-weeks, the adjusted OR = 1.60 (95%CI 1.01-2.53). Longer wait times (log-rank test = 266.4, P < 0.001) and higher death rates contributed to a higher cumulative incidence for death on the wait list with a clearance time of more than 1 month. CONCLUSION: Long wait lists for coronary-artery bypass grafting are associated with increased probability that a patient dies before surgery. Physicians who advise patients where to undergo cardiac revascularization should consider the risk of pre-surgical death that is associated with the length of a surgical wait list.