Better governance in academic health sciences centres: moving beyond the Olivieri/Apotex Affair in Toronto.

The Toronto experience suggests that there may be several general lessons for academic health sciences complexes to learn from the Olivieri/Apotex affair (OAA) regarding the ethics, independence, and integrity of clinical research sponsored by for profit enterprises. From a local perspective, the OAA occurred when there already was a focus on the complex and changing relationships among the University of Toronto, its medical school, the fully affiliated teaching hospitals, and off campus faculty because of intertwined interests and responsibilities. The OAA became a catalyst that accelerated various systemic reforms, particularly concerning academic/industry relations. In this article, the evolving governance framework for the Toronto academic health sciences complex is reviewed and these policy and process reforms discussed. These reforms have created collaborative activity among research ethics boards and contract research offices of the partner institutions, and allowed the joint university/hospital ethics centre to play a role in governance and policy, while respecting the missions and mandates of the involved institutions. Although few of the policies are dramatically innovative, what is arguably novel is the elaboration of an overarching governance framework that aims to move ethics to a central focus in the academic complex. Time alone will tell how sustainable and effective these changes are.

Parkinsonism in Ontario: physician utilization.

BACKGROUND: Patients with Parkinsonism have a progressive disorder requiring substantial expertise to manage effectively. METHODS: Over a six-year period we evaluated physician utilization and related costs for a large, unselected cohort of 15,304 Parkinsonian patients from the general population, comparing them to 30,608 age- and sex-matched controls within a universal health care system in Ontario, Canada. RESULTS: On average, 45% of Parkinsonian patients saw neurologists annually. The cumulative rate of at least one neurological consultation was only 59.5% over the six years. Patients aged < 65 had a much greater likelihood of consulting a neurologist (73.3%) compared to those > or = 65 (37.2%). Most Parkinsonian patients (97.2%), regardless of age, saw family physicians/general practitioners each year; 50.4% saw internal medicine consultants. CONCLUSIONS: Parkinsonian patients had increased likelihood of utilizing neurologists, primary care physicians and internists compared to controls; related costs of physicians' services were higher. Further research is necessary to evaluate differences in outcomes and costs between neurologists and other physician service providers.

Biology or bias: practice patterns and long-term outcomes for men and women with acute myocardial infarction.

OBJECTIVES: The goal of our study was to examine how age and gender affect the use of coronary angiography and the intensity of cardiac follow-up care within the first year after acute myocardial infarction (AMI). Another objective was to evaluate the association of age, gender and treatment intensity with five-year survival after AMI. BACKGROUND: Utilization rates of specialized cardiac services inversely correlate with age. Gender-specific practice patterns may also vary with age in a manner similar to known age-gender survival differences after AMI. METHODS: Using linked population-based administrative data, we examined the association of age and gender with treatment intensity and long-term survival among 25,697 patients hospitalized with AMI in Ontario between April 1, 1992, and December 31, 1993. A Cox proportional hazards model was used to adjust for socioeconomic status, illness severity, attending physician specialty and admitting hospital characteristics. RESULTS: After adjusting for baseline differences, the relative rates of angiography and follow-up specialist care for women relative to men, respectively, fell 17.5% (95% confidence interval [CI], 13.6 to 21.3, p < 0.001) and 10.2% (95% CI, 7.1 to 13.2, p < 0.001) for every 10-year increase in age. Conversely, long-term AMI survival rates in women relative to men improved with increasing age, such that the relative survival in women rose 14.2% (95% CI, 10.1 to 17.5, p < 0.001) for every 10-year age increase. CONCLUSIONS: Gender differences in the intensity of invasive testing and follow-up care are strongly age-specific. While care becomes progressively less aggressive among older women relative to men, survival advantages track in the opposite direction, with older women clearly favored. These findings suggest that biology is likely to remain the main determinant of long-term survival after AMI for women.

Long-term MI outcomes at hospitals with or without on-site revascularization.

CONTEXT: Many studies have found that patients with acute myocardial infarction (AMI) who are admitted to hospitals with on-site revascularization facilities have higher rates of invasive cardiac procedures and better outcomes than patients in hospitals without such facilities. Whether such differences are due to invasive procedure rates alone or to other patient, physician, and hospital characteristics is unknown. OBJECTIVE: To determine whether invasive procedural rate variations alone account for outcome differences in patients with AMI admitted to hospitals with or without on-site revascularization facilities. DESIGN: Retrospective, observational cohort study using linked population-based administrative data from a universal health insurance system. SETTING: One hundred ninety acute care hospitals in Ontario, 9 of which offered invasive procedures. PATIENTS: A total of 25 697 patients hospitalized with AMI between April 1, 1992, and December 31, 1993, of whom 2832 (11%) were in invasive hospitals. MAIN OUTCOME MEASURES: Mortality, recurrent cardiac hospitalizations, and emergency department visits in the 5 years following the index admission, adjusted for patient age, sex, socioeconomic status, illness severity, and index revascularization procedures; attending physician specialty; and hospital volume, teaching status, and geographical proximity to invasive-procedure centers and compared by hospital type. RESULTS: Patients admitted to invasive-procedure hospitals were much more likely to undergo revascularization (11.4% vs 3.2% at other hospitals; P<.001). However, many other clinical and process-related factors differed between the 2 groups. Although mortality rates were similar between the 2 institution types, the nonfatal composite 5-year event rate (ie, recurrent cardiac hospitalization and emergency department visits) was lower for patients initially admitted to invasive-procedure hospitals (71.3% vs 80.4%; unadjusted odds ratio [OR], 0.65; 95% confidence interval [CI], 0.52-0.82; P<.001). This advantage persisted after adjustment for sociodemographic and clinical factors and procedure utilization (adjusted OR, 0.68; 95% CI, 0.53-0.89; P<.001). However, the nonfatal outcome advantages of invasive-procedure hospitals were explained by their teaching status (adjusted OR, 0.98; 95% CI, 0.73-1.30; P =.87). CONCLUSIONS: In this sample of patients admitted with AMI, the differing outcomes of apparently similar patients treated in 2 different practice settings were explained by multiple competing factors. Researchers conducting observational studies should be cautious about attributing patient outcome differences to any single factor.

Major trauma in elderly adults receiving lipid-lowering medications.

BACKGROUND: Some clinical trials, laboratory experiments, and in vitro studies suggest that lipid-lowering medications predispose a person to traumatic injury. METHODS: We used population-based administrative database analysis to study adults age 65 years or more over a 5-year interval (n = 1,348,259). RESULTS: About 12% of the cohort received a prescription for a lipid-lowering medication and about 88% did not. The two groups had similar distributions of age, gender, and income. Overall, 2,557 (0.2%) were hospitalized for major trauma. Those who received a lipid-lowering medication were 39% less likely to sustain a major trauma than those who did not receive such medication (95% confidence interval, 29 to 47). Similar results were observed after adjustment for age, gender, and income; cardiac and neurologic medications; and lethality. No other cardiac or neurologic medication was associated with an apparent safety advantage. CONCLUSION: Lipid-lowering medications do not lead to a clinically important increase in the absolute risk of major trauma for elderly patients in the community.

A comparison of a Bayesian vs. a frequentist method for profiling hospital performance.

The objective of this study was to compare the classification of hospitals as outcomes outliers using a commonly implemented frequentist statistical approach vs. an implementation of Bayesian hierarchical statistical models, using 30-day hospital-level mortality rates for a cohort of acute myocardial infarction patients as a test case. For the frequentist approach, a logistic regression model was constructed to predict mortality. For each hospital, a risk-adj usted mortality rate was computed. Those hospitals whose 95% confidence interval, around the risk-adjusted mortality rate, excludes the mean mortality rate were classified as outliers. With the Bayesian hierarchical models, three factors could vary: the profile of the typical patient (low, medium or high risk), the extent to which the mortality rate for the typical patient departed from average, and the probability that the mortality rate was indeed different by the specified amount. The agreement between the two methods was compared for different patient profiles, threshold differences from the average and probabilities. Only marginal agreement was shown between the Bayesian and frequentist approaches. In only five of the 27 comparisons was the kappa statistic at least 0.40. The remaining 22 comparisons demonstrated only marginal agreement between the two methods. Within the Bayesian framework, hospital classification clearly depended on patient profile, threshold and probability of exceeding the threshold. These inconsistencies raise questions about the validity of current methods for classifying hospital performance, and suggest a need for urgent research into which methods are most meaningful to clinicians, managers and the general public.

Vitamin B12 injections versus oral supplements. How much money could be saved by switching from injections to pills?

OBJECTIVE: To estimate savings, using a third-party payer perspective, if all elderly patients currently receiving vitamin B12 (cobalamin) injections were switched to high-dose oral therapy. DESIGN: We modeled high-dose oral B12 supplement costs to include drugs, pharmacists' fees, and one-time conversion costs consisting of two physician visits and laboratory monitoring. The number of vitamin-injection visits avoided by switching to oral therapy was predicted using a multivariate model that considered covariates for overall patient illness. SETTING: Ontario family physicians' and internists' practices. PARTICIPANTS: Population-based administrative databases for Ontario were used to identify all people between 65 and 100 years who received parenteral vitamin B12 during 1995 and 1996. MAIN OUTCOME MEASURES: The cost of parenteral vitamin B12 for each patient, including drugs, injections, pharmacists' fees, and injection-associated physician visits, was measured directly from the databases. RESULTS: The annual cost of parenteral vitamin B12 therapy averaged $145.88 per person and totaled a maximum $25 million over 5 years. Converting all patients to high-dose oral B12 and treating them for 5 years would cost $7.4 million. Depending on how many vitamin-injection visits are avoided by switching to oral therapy, between $2.9 million and $17.6 million would be saved. Switching to oral B12 administration saved costs as long as 16.3% of injection-associated visits were avoided. CONCLUSION: Switching all patients from B12 injections to oral cobalamin therapy could result in substantial savings.

Parkinsonism in Ontario: increased mortality compared with controls in a large cohort study.

BACKGROUND: PD was associated with increased mortality before levodopa therapy became available. There have been conflicting reports of PD mortality in the modern era. OBJECTIVE: To assess current mortality rates in a large unselected population receiving treatment for parkinsonism (PKM) followed for up to 6 years. METHODS: Cases were identified using linked administrative databases, including physician service and prescription drug claims, generated in Ontario's universal health insurance system. Control subjects were identified from the provincial registry of citizens and age and sex matched to cases. Comparative mortality was evaluated over the 6-year period of the study (1993/94 to 1998/99). The sensitivity of the findings was tested with differing case definitions. RESULTS: In 1993, 15,304 patients with PKM were identified and were age and sex matched to 30,608 control subjects (1:2 ratio). Over the study period, 50.8% (7,779) of the cases with PKM died compared with 29.1% (8,899) of the control subjects. The cases with PKM had an overall mortality odds ratio of 2.5 (95% CI: 2.4, 2.6) compared with the control group. Results were consistent whether cases were defined by physician diagnosis, use of anti-PD drugs, or both criteria. CONCLUSION: Despite modern drug therapy, PKM continues to confer a sharply increased mortality on unselected patients followed for several years.

Prognostic significance of diabetes as a predictor of survival after cardiac catheterization. APPROACH Investigators. Alberta Provincial Program for Outcome Assessment in Coronary Heart Disease.

PURPOSE: Diabetes is a recognized risk factor for the development of cardiac disease, but its importance as a prognostic factor among patients with known cardiovascular disease is less clear. We evaluated survival in patients with and without diabetes who underwent cardiac catheterization for presumed coronary artery disease. SUBJECTS AND METHODS: We analyzed data from a prospective cohort study that captures detailed clinical information and longitudinal outcomes for all patients who undergo cardiac catheterization in Alberta, Canada. We studied 11,468 patients, 1959 (17%) of whom had diabetes. Logistic regression was used to model predictors of 1-year mortality, and proportional hazards analysis was used to model predictors of survival up to 3 years after cardiac catheterization. RESULTS: One-year mortality was 7.6% for patients with diabetes versus 4.1% for those without diabetes (odds ratio = 1.9, 95% confidence interval [CI]: 1.6 to 2.3). After adjusting for other characteristics of the patients, including comorbid conditions, previous cardiac history, coronary anatomy, and renal function, the odds ratio for 1-year mortality was 1.1 (95% CI: 0.8 to 1.3). Similarly, the adjusted hazard ratio for longer term mortality was 1. 2 (95% CI: 1.0 to 1.4, mean follow-up of 702 days). CONCLUSIONS: These results suggest that there is little or no independent association between diabetes and mortality for up to 3 years after cardiac catheterization. Estimates of short- to intermediate-term prognosis for diabetic patients with coronary artery disease should be based on the presence of other prognostic factors associated with diabetes.

Rate of heart failure and 1-year survival for older people receiving low-dose beta-blocker therapy after myocardial infarction.

BACKGROUND: Many older people do not receive beta-blocker therapy after myocardial infarction or receive doses lower than those tested in trials, perhaps because physicians fear that beta-blockers may precipitate heart failure. We examined the relation between use of beta-blockers, the dose used, and hospital admission for heart failure and 1-year survival in a cohort of all older patients surviving myocardial infarction in Ontario, Canada. METHODS: We collected data on a cohort of 13,623 patients aged 66 years or older who were discharged from hospital after a myocardial infarction and who did not receive beta-blocker therapy or received low, standard, or high doses. We used Cox's proportional-hazards models to study the association of dose with admission for heart failure and survival with adjustment for factors including age, sex, and comorbidity. FINDINGS: Among 8232 patients with no previous history of heart failure, dispensing of beta-blocker therapy was associated with a 43% reduction in subsequent admission for heart failure (adjusted risk ratio 0.57 [95% CI 0.48-0.69]) compared with patients not dispensed this therapy. Among the 4681 patients prescribed beta-blockers, the risk of admission was greater in the high-dose than in the low-dose group (1.53 [1.01-2.31]). Among all 13,623 patients in the cohort, 2326 (17.1%) died by 1 year. Compared with those not dispensed beta-blocker therapy, the adjusted risk ratio for mortality was lower for all three doses (low 0.40 [0.34-0.47], standard 0.36 [0.31-0.42], high 0.43 [0.33-0.56]). INTERPRETATION: Compared with high-dose beta-blocker therapy, low-dose treatment is associated with a lower rate of hospital admission for heart failure and has a similar 1-year survival benefit. Our findings support the need for a randomised controlled trial comparing doses of beta-blocker therapy in elderly patients.

Users' Guides to the Medical Literature: XXV. Evidence-based medicine: principles for applying the Users' Guides to patient care. Evidence-Based Medicine Working Group.

This series provides clinicians with strategies and tools to interpret and integrate evidence from published research in their care of patients. The 2 key principles for applying all the articles in this series to patient care relate to the value-laden nature of clinical decisions and to the hierarchy of evidence postulated by evidence-based medicine. Clinicians need to be able to distinguish high from low quality in primary studies, systematic reviews, practice guidelines, and other integrative research focused on management recommendations. An evidence-based practitioner must also understand the patient's circumstances or predicament; identify knowledge gaps and frame questions to fill those gaps; conduct an efficient literature search; critically appraise the research evidence; and apply that evidence to patient care. However, treatment judgments often reflect clinician or societal values concerning whether intervention benefits are worth the cost. Many unanswered questions concerning how to elicit preferences and how to incorporate them in clinical encounters constitute an enormously challenging frontier for evidence-based medicine. Time limitation remains the biggest obstacle to evidence-based practice but clinicians should seek evidence from as high in the appropriate hierarchy of evidence as possible, and every clinical decision should be geared toward the particular circumstances of the patient.

Predictive accuracy study: comparing a statistical model to clinicians' estimates of outcomes after coronary bypass surgery.

BACKGROUND: The purpose of this study was to compare clinicians' prior probability estimates of operative mortality (OM) and prolonged intensive care unit stay (ICU) length of stay greater than 48 hours after coronary artery bypass graft surgery (CABG) with estimates derived from statistical models alone. METHODS: Nine clinicians estimated the predicted probability of OM and ICU stay greater than 48 hours from an abstract of information for each of 100 patients selected from the 1996 to 1997 database of 1,904 patients who underwent isolated CABG. Logistic regression models were used to calculate the predicted probability of OM and ICU stay greater than 48 hours for each patient. The study sample was split into two parts; clinicians were randomly given access to a predictive rule to guide their judgements for one part of the study. RESULTS: Clinicians' estimates were similar with or without access to the rule, and both parts of the study were therefore pooled. Clinicians significantly overestimated the probability of OM (model 6.3% +/- 1%, clinicians 7.6% +/- 3%, p = 0.0001) and ICU stay greater than 48 hours (model 25% +/- 2%, clinicians 28% +/- 1%, p = 0.0012). Clinicians' estimates of OM were not significantly higher than the model's for nonsurvivors (0.8% +/- 0.7%, p = 0.2), but were significantly higher for survivors (1.4% +/- 0.3%, p = 0.039). CONCLUSIONS: Clinicians trusted their own empiric estimates rather than a predictive rule and overestimated the probability of OM and ICU stay greater than 48 hours.

Users' guides to the medical literature: XXIV. How to use an article on the clinical manifestations of disease. Evidence-Based Medicine Working Group.

Clinicians rely on knowledge about the clinical manifestations of disease to make clinical diagnoses. Before using research on the frequency of clinical features found in patients with a disease, clinicians should appraise the evidence for its validity, results, and applicability. For validity, 4 issues are important-how the diagnoses were verified, how the study sample relates to all patients with the disease, how the clinical findings were sought, and how the clinical findings were characterized. Ideally, investigators will verify the presence of disease in study patients using credible criteria that are independent of the clinical manifestations under study. Also, ideally the study patients will represent the full spectrum of the disease, undergo a thorough and consistent search for clinical findings, and these findings will be well characterized in nature and timing. The main results of these studies are expressed as the number and percentages of patients with each manifestation. Confidence intervals can describe the precision of these frequencies. Most clinical findings occur with only intermediate frequency, and since these frequencies are equivalent to diagnostic sensitivities, this means that the absence of a single finding is rarely powerful enough to exclude the disease. Before acting on the evidence, clinicians should consider whether it applies to their own patients and whether it has been superseded by new developments. Detailed knowledge of the clinical manifestations of disease should increase clinicians' ability to raise diagnostic hypotheses, select differential diagnoses, and verify final diagnoses. JAMA. 2000;284:869-875

Postmenopausal estrogen replacement therapy and increased rates of cholecystectomy and appendectomy.

BACKGROUND: Several studies have indicated that estrogen may prime inflammatory and nociceptive pathways, leading to symptoms that mimic cholecystitis. We set out to confirm the relation between recent estrogen use and cholecystectomy in postmenopausal women and to test the novel hypothesis that a similar relation exists for appendectomy. METHODS: We developed a retrospective cohort using prescribing and surgical procedure information from health administrative databases for approximately 800,000 female residents of Ontario who were over 65 years of age between July 1, 1993, and Mar. 31, 1998. We compared the incidence of cholecystectomy and appendectomy among women recently prescribed estrogen replacement therapy, levothyroxine and dihydropyridine calcium-channel antagonists (DCCA) using age-adjusted Cox proportional hazards models. Patients were followed for a mean of 540 (standard deviation [SD] 449) days. RESULTS: Compared with women taking DCCA, those who had recently begun taking estrogen were significantly more likely to undergo cholecystectomy (age-adjusted risk ratio [aRR] 1.9, 95% confidence interval [CI] 1.6-2.2) and appendectomy (aRR 1.8, 95% CI 1.1-3.0). No significant difference in either outcome measure was found between the levothyroxine users and the DCCA users. INTERPRETATION: This study identifies an increased risk of cholecystectomy and appendectomy among postmenopausal women who have recently begun estrogen replacement therapy.

Users' guides to the medical literature: XXII: how to use articles about clinical decision rules. Evidence-Based Medicine Working Group.

Clinical experience provides clinicians with an intuitive sense of which findings on history, physical examination, and investigation are critical in making an accurate diagnosis, or an accurate assessment of a patient's fate. A clinical decision rule (CDR) is a clinical tool that quantifies the individual contributions that various components of the history, physical examination, and basic laboratory results make toward the diagnosis, prognosis, or likely response to treatment in a patient. Clinical decision rules attempt to formally test, simplify, and increase the accuracy of clinicians' diagnostic and prognostic assessments. Existing CDRs guide clinicians, establish pretest probability, provide screening tests for common problems, and estimate risk. Three steps are involved in the development and testing of a CDR: creation of the rule, testing or validating the rule, and assessing the impact of the rule on clinical behavior. Clinicians evaluating CDRs for possible clinical use should assess the following components: the method of derivation; the validation of the CDR to ensure that its repeated use leads to the same results; and its predictive power. We consider CDRs that have been validated in a new clinical setting to be level 1 CDRs and most appropriate for implementation. Level 1 CDRs have the potential to inform clinical judgment, to change clinical behavior, and to reduce unnecessary costs, while maintaining quality of care and patient satisfaction. JAMA. 2000;284:79-84

Subgroups, treatment effects, and baseline risks: some lessons from major cardiovascular trials.

BACKGROUND: The objective of this study was to determine how subgroup analyses are performed in large randomized trials of cardiovascular pharmacotherapy. METHODS AND RESULTS: We reviewed 67 randomized, double-blind, controlled trials involving pharmacotherapy in at least 1000 patients with unstable angina, myocardial infarction, left ventricular dysfunction, or heart failure with clinical outcomes as primary end points, published between 1980 and 1997. Nine had no subgroup analyses but 43 reported on 5 or more subgroups and 31 reported subgroups without formal statistical tests for treatment-subgroup interactions. In most trials, a rationale for subgroup selection was missing. All but 6 focused on single-factor subgroups. CONCLUSIONS: Trial subgroups should ideally be defined a priori on 2 bases: single-factor subgroups with a strong rationale for biological response modification and multifactorial prognostic subgroups defined from baseline risks. However, single-factor subgroup analyses are often reported without a supporting rationale or formal statistical tests for interactions. We suggest that clinicians should interpret published subgroup-specific variations in treatment effects skeptically unless there is a prespecified rationale and a significant treatment-subgroup interaction.

Dealing with missing data in observational health care outcome analyses.

Observational outcome analyses appear frequently in the health research literature. For such analyses, clinical registries are preferred to administrative databases. Missing data are a common problem in any clinical registry, and pose a threat to the validity of observational outcomes analyses. Faced with missing data in a new clinical registry, we compared three possible responses: exclude cases with missing data; assume that the missing data indicated absence of risk; or merge the clinical database with an existing administrative database. The predictive model derived using the merged data showed a higher C statistic (C = 0.770), better model goodness-of-fit as measured in a decile-of-risk analysis, the largest gradient of risk across deciles (46.3), and the largest decrease in deviance (-2 log likelihood = 406.2). The superior performance of the enhanced data model supports the use of this "enhancement" methodology and bears consideration when researchers are faced with nonrandom missing data.

Benchmarking the vital risk of waiting for coronary artery bypass surgery in Ontario.

BACKGROUND: Deaths among patients awaiting coronary artery bypass grafting (CABG) are a source of private grief and public concern in Canada. However, some deaths are expected over time among patients with coronary artery disease. Methods of benchmarking the burden of delayed care may be useful in understanding and managing waiting lists for CABG and other health services. The authors therefore determined the vital risk among people waiting for CABG in Ontario and compared it with the risk in the general population and among people living with coronary artery disease. METHODS: Patients registered to undergo CABG in Ontario between 1991 and 1995 were followed to ascertain numbers and dates of preoperative deaths or completed operations. Linking hospital discharge abstract data to vital statistics for 1991 to 1994, the authors defined a cohort of people who had survived 6 months after an acute myocardial infarction (AMI) and followed them for an additional 6 months to determine numbers and dates of deaths. They matched patients by age and sex and then calculated the standardized mortality ratio for each cohort (i.e., the ratio of observed deaths to those expected based on age- and sex-specific daily probabilities of death for the provincial population). RESULTS: Among 21,220 patients awaiting CABG, there were 82 preoperative deaths over a median follow-up of 18 days; the standardized mortality ratio was 2.92 (95% confidence limit [CL] 2.29-3.55). Among 21,220 matched 6-month survivors of an AMI, there were 663 deaths over a median follow up of 185 days; the standardized mortality ratio was 3.84 (95% CI 3.54-4.14). INTERPRETATION: Patients awaiting CABG in Ontario are at a much greater risk of death than the general population. However, when compared with thousands of other patients living with coronary artery disease, they are at similar or decreased vital risk.