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Sample sizes for treatment trials with categorical outcomes are conventionally derived by balancing three elements: a difference between alternative treatments in the event rates for the outcomes of interest (commonly termed the clinically important difference), the alpha error tolerance (false positive risk) and the beta error tolerance (false negative risk). Clinically important differences used to plan trials are chosen in part based on earlier experience with similar interventions (i.e. biological or clinical plausibility). Methodological conventions and clinicians' perceptions will also affect choices. Lastly, practical concerns about the feasibility of accruing large numbers of subjects may drive trialists to specify bigger differences as clinically important, with a view to containing sample size requirements. We suggest that patients or other members of the public be given an active role in determining the magnitude of the clinically important treatment effect for trial planning. Probability trade-offs could be constructed to enable patients and/or healthy volunteers to indicate the degree of benefit they would want from a "new" treatment, given the potential side-effects of the same treatment. This method has the advantage of respecting patient autonomy and principles of informed consent. It provides an additional consideration when plausible effect sizes and error tolerances on hypothesis tests are balanced against feasibility of accruing various sample sizes. Its primary disadvantage is inconvenience, as it adds another step to trial design. On the other hand, if patient-based clinically important differences are generated for a variety of disease states and types of treatments, specific trade-off exercises may be needed only for unusual trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Unexplained variation in length of stay (LOS) following acute myocardial infarction (AMI) has been observed among American hospitals. We explored this phenomenon in the universal hospital care system of Ontario, Canada's largest province, analyzing general hospital discharge abstracts for all patients with a primary diagnosis of AMI. Case homogeneity was increased by excluding inter-hospital transfers, in-hospital deaths, patients with revascularization during the index admission and patients with severe comorbid conditions. This left 11,411 records of patients in 187 hospitals from April 1, 1990 to March 31, 1991. The mean length of stay was 9.9 days with standard deviation of 3.8. Available patient and hospital characteristics explained only 12% of the individual variation in LOS. Interinstitutional variation remained highly significant after controlling for patients' characteristics within the 87 hospitals admitting more than 50 cases per annum; these hospitals accounted for 84% of the eligible provincial admissions. The grand mean length of stay for 87 hospitals was 10 days, ranging from 6.6 to 12.9 days. Stepwise multiple linear regression analyses showed that lower caseload was associated with an increased length of hospitalization. Thus, despite Ontario's uniform system of hospital funding and medical insurance, a large amount of unexplained variation in length of stay exists for patients hospitalized with AMI, affecting thousands of bed-days per annum.

The growing burden of prescription drug costs has focused attention on factors which influence physicians' prescribing decisions. We hypothesised that third party coverage of prescription costs would elicit selection of expensive drugs, but that this tendency could be moderated by price reminders. In a mailed survey, primary care physicians throughout Ontario (n = 1072) were provided with the clinical scenario of a patient with an infectious exacerbation of chronic obstructive pulmonary disease, and asked to select diagnostic tests as well as 1 of 6 antibiotics. Two antibiotics were expensive (ciprofloxacin and cefaclor; average price $Can52.23), and 4 inexpensive {amoxicillin, cotrimoxazole (trimethoprim/sulfamethoxazole), erythromycin and tetracycline; average price $Can2.80}. Neither expensive drug is considered first line therapy for the condition described. Questionnaires differed in the presence or absence of drug benefit coverage and price information. The response rate was 71%. With third party cost coverage and prices shown, 18% of respondents selected an expensive antibiotic. This increased to 38% when the prices were omitted {odds ratio 2.72; 95% confidence interval (CI) 1.61, 4.60; p less than 0.001}, and decreased to 8% when the patient was said to have no drug benefits coverage (odds ratio 0.40; 95% CI 0.19, 0.84; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To determine whether physician willingness to prescribe drugs for primary prevention of cardiovascular disease is influenced by information about the resultant life-expectancy gains (presented in one of two formats) and about drug costs., Materials and Methods: Mailed survey (four versions randomly allocated) asking physicians to assess hypothetical preventive interventions with outcomes expressed either as averaged or as stratified gains in life expectancy (e.g., average gain of 15 weeks, versus 5% of treated patients gain 2 to 6 years, 10% gain up to 2 years, and 85% remain unchanged). Both costs and gains were varied to high and low values. The subjects rated their willingness to prescribe treatments on an 11-point scale from "strongly oppose" to "strongly favor.", Participants: Internists randomly selected from two Canadian academic centers (n = 330)., Results: 231 usable responses were received (76% of the deliverable questionnaires). For low-yield scenarios typical of very effective primary prevention strategies, the physicians gave significantly higher ratings in response to stratified life-expectancy data than to equivalent averaged data (p < 0.0001). The same trend was not observed for high-yield scenarios (p = NS). The ratings were strongly influenced by cost: 34% of the physicians reversed their treatment decisions in response to a tenfold price increase. Despite this, the rankings of the treatments differed from those expected on the basis of cost-effectiveness criteria (p < 0.0001)., Conclusions: Physician enthusiasm for a therapy designed to prolong life expectancy may be influenced by the format in which that life-expectancy gain is presented. Knowledge of drug cost also affects physicians' choices, but their greater focus on treatment effects causes their rankings to depart from those expected with cost-effectiveness criteria.

Objective: To assess the effect of a single randomized clinical trial, the National Surgical Adjuvant Breast Project (NSABP) B-06, on the surgical management of breast cancer in women., Design: Retrospective cohort study., Setting: All hospitals in Ontario., Patients: A consecutive sample of 37,447 women with breast cancer newly diagnosed from Jan. 1, 1980, to Dec. 31, 1989, linked to a surgical procedure record in the Ontario Cancer Registry., Main Outcome Measure: The most invasive surgical procedure used within 90 days of diagnosis., Results: Unilateral breast-ablative surgery (BAS) was performed in 57.3% of the women and breast-conserving surgery (BCS) in 31.6%. The annual rate of BAS declined from 77.5% in 1980 to 44.2% in 1989 and the rate of BCS rose from 12.5% in 1980 to 43.5% in 1989. The decline was linear from 1980 to 1984 and then accelerated significantly in 1985 (p < 0.0001), after the results of the NSABP B-06 trial were published., Conclusion: One randomized clinical trial can have an immediate and profound effect on medical practice.

Objective: To determine whether sex differences exist in the use of coronary angiography, coronary artery bypass surgery (CABS) or percutaneous transluminal coronary angioplasty (PTCA) among persons recently diagnosed with an acute myocardial infarction (AMI) in Canada., Background: A growing body of literature suggests that coronary artery disease in males is treated differently from females. Specifically, recent studies have indicated that sex may influence decisions about the use of invasive diagnostic and therapeutic coronary procedures in patients with suspected or proven coronary artery disease., Patients and Methods: The study design is a population-based inception cohort study. The data source is hospital discharges from all acute care hospitals in Ontario. The study population consisted of 6949 men and women discharged with a principal diagnosis of AMI between April 1 and September 30, 1990, and followed through record linkage until March 31, 1991 to determine whether any invasive coronary procedures were performed after their AMI. Odds ratio estimates (OR) and 95% confidence intervals (95% CI) for use of coronary angiography, CABS and PTCA in men were compared with those in women., Results: The adjusted OR for coronary angiography was 1.4 (95% CI 1.2 to 1.6), indicating that males were more likely to undergo angiography than females. A similar finding was seen for CABS (OR = 1.6, 95% CI 1.2 to 2.1), but for PTCA, the sex difference was less pronounced (OR = 1.3, 95% CI 1.0 to 1.7). Cox proportional hazards regression also was used to test the hypothesis and showed similar results., Conclusions: Women suffering AMI undergo coronary angiography and CABS at a significantly lower rate than men in Ontario, with similar trends evident in use of PTCA.

Objectives: To analyse the extent of variation by county and hospital in the use of breast-conserving surgery in the initial management of breast cancer and to assess some factors that might explain the observed variation., Design: Population-based retrospective cohort study., Setting: Ontario., Patients: All women with breast cancer newly diagnosed from Jan. 1, 1989, to Dec. 31, 1991., Main Outcome Measure: Proportion of women undergoing unilateral breast cancer surgery who had breast-conserving surgery in each hospital and county., Results: Of the 14,570 women with newly diagnosed breast cancer 12,815 (88.0%) underwent unilateral breast cancer surgery. The mean proportion of breast-conserving procedures by county was 52% and ranged from 11% to 84%. The proportion of breast-conserving procedures in individual hospitals with one or more cases of breast cancer per month ranged from 6% to 84%. The variations in the rates between hospitals was greater than that expected by chance alone (p < 0.0001)., Conclusions: There was marked variation at the hospital and county level in the use of breast-conserving surgery in the initial management of breast cancer. This variation was strongly associated with the hospital where the surgery was performed.

Objectives: To summarize the process and extent of interphysician agreement within two panels convened to derive indications for the appropriate use of coronary angiography and for coronary revascularization procedures., Participants: Two panels, each with nine practitioners., Methods: Panelists rated the appropriateness of intervention for a comprehensive set of indications for each procedure. Indications were brief profiles created by combining and permuting clinical characteristics pertinent to case selection for intervention. Ratings were first made at home, with a second round at the panel meeting following open discussion. Final rankings of indications as 'appropriate', 'uncertain' or 'inappropriate' were based on the pattern of panelists' responses on a nine-point scale, including the median rating and extent of agreement among panelists. Agreement was defined as at least seven panelists' ratings within the three-point region containing the median rating. Panelists were later mailed a much-reduced list of indications for which there was agreement on appropriateness. These were re-rated on a necessity scale. A procedure was rated 'necessary' only if a physician was ethically obligated to recommend it as the preferred treatment option., Results: For appropriateness of angiography, agreement occurred in 38.2% of indications in round 1 and 64.4% in round 2 (P < 0.0001). For coronary artery bypass graft (CABG) versus medical therapy, the corresponding increase was from 43.5 to 54.0% (P < 0.0001). Agreement on necessity of angiography occurred for 44.3% of scenarios. For indications where CABG alone was appropriate, agreement on necessity was 56%. However, for indications where percutaneous transluminal coronary angioplasty (PTCA) could be regarded as the first-line intervention, agreement on necessity was only 5%., Conclusions: A two-step panel process permitted considerable convergence of panelists' ratings, highlighting the importance of formal panel methods in setting utilization management criteria. However, the extent of continuing disagreement on ratings underscores the need to avoid a forced consensus; instead, divergent opinions should be taken as indicative of uncertainty about the appropriateness of intervention. Interpanelist agreement on necessity ratings was modest, but may help in setting benchmarks to assess possible underprovision of invasive cardiac services in Canada.

Objective: To compare the appropriateness of use of coronary angiography (CA) and bypass surgery (CABS) in the early 1980s in one Canadian hospital and several American hospitals using explicit case-based criteria. Procedure rates were much lower in Canada during this period., Subjects: Canadian subjects, 502 Manitoba residents undergoing CA at one hospital in 1981-82 were tracked forward to determine whether and when they underwent CABS. CA comparisons were made with 351 Canadian patients aged 55 years or older; 1677 American CA patients aged 65 years or older and were drawn in 1981 from three hospitals. Two hundred and forty-five patients undergoing CABS within 12 months of CA made up the Canadian sample. American CABS patients were sampled from three hospitals during 1979-82. Manitoba patients assigned to medical treatment after CA were also appraised., Methods: Criteria were derived by an American panel of clinicians following a Delphi process; indications were rated appropriate, equivocal and inappropriate. A trained abstractor reviewed charts and assigned ratings. Results of exercise electrocardiograms were not available in the Manitoba data set, hence sensitivity analyses were performed to determine how differing proportions of positive exercise electrocardiograms might affect the Manitoba results., Results: Even assuming only 50% of treadmill tests were positive in the Manitoba sample, the proportion of inappropriate CA was lower in Manitoba than for the American hospitals: 9% versus 15 to 18%. For CABS, only one of the three comparison American hospitals approached the Manitoba hospital level of appropriateness., Conclusions: In the early 1980s, there was more appropriate use of CA and CABS in a Manitoba hospital compared with several American hospitals. Many Canadian patients undergoing CA and treated medically met American indications for appropriate use of CABS. Whether this represents underprovision of necessary care remains uncertain.

Objectives: To determine the frequency of major adverse events among patients awaiting coronary revascularization; to assess the match between referring physicians' estimates of urgency, a computer-generated multifactorial urgency rating score and actual waiting times; to determine the changes in waiting times as capacity for bypass surgery increased; and to evaluate the influence of choice of procedure or operator on waiting times., Design: Consecutive case series., Setting: Greater Toronto region., Subjects: All 571 patients referred to an organized referral office by cardiologists at hospitals without on-site revascularization facilities between Jan. 3, 1989, and June 30, 1991., Main Outcome Measures: Preoperative fatal or nonfatal myocardial infarction; proportions of patients waiting longer than the maximum period recommended for their urgency rating; mean waiting times for various subgroups; and correlations among referring physicians' urgency ratings, computer-generated multifactorial urgency scores and waiting times., Results: Of the 496 patients accepted for a procedure 5 had fatal cardiac events and 3 nonfatal myocardial infarction. Events occurred three times more often in patients with left mainstem disease than in those in other anatomic categories (relative risk [RR] 3.05, 95% confidence interval [CI] 1.48 to 6.27, p = 0.03). Both the computer-generated scores and the referring physicians' scores were correlated with the actual waiting time (r = 0.46 and 0.57 respectively). Waiting times and the proportion of patients with excessive waiting times fell during the study period (p < 0.0001). However, urgent cases were much less likely to be done "on time" than those with a recommended waiting time of more than 2 weeks (RR 0.16, 95% CI 0.11 to 0.25, p < 0.0001). The mean wait for coronary artery bypass grafting (CABG) was 22.73 days if the referral office was allowed to find a surgeon or interventional cardiologist and 35.31 days if one was requested (p = 0.002 after adjustment for urgency scores)., Conclusions: Death of a patient on the waiting list is uncommon in an organized referral system. Patients with left main-stem disease are at higher risk of death than those in other anatomic categories. There were significant correlations between referring physicians' ratings of urgency, multifactorial urgency scores and actual waiting times. Expansion of capacity for CABG led to shorter waiting times, but patients with unstable symptoms continued to wait longer than recommended. Requests for a specific surgeon caused significantly longer delays.

Objective: To assess sex-related differences in coronary revascularization practices in a Canadian setting., Design: Prospective analytic cohort study., Setting: Regional referral office in Toronto., Patients: A selected but consecutive group of 131 women and 440 men referred by cardiologists for revascularization procedures between Jan. 3, 1989, and June 30, 1991., Interventions: Coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA). Nurse-coordinators placed the referral with a surgeon or interventional cardiologist at one of three hospitals, who then communicated directly with the referring cardiologist., Main Outcome Measures: Symptom status at referral, procedures requested and performed, and time from referral to procedure., Results: Although the women were more likely than the men to have unstable angina at the time of referral (odds ratio [OR] 2.28, 95% confidence interval [CI] 1.38 to 3.79, p = 0.0006), more women than men (16.8% v. 12.1%) were turned down for a procedure. Significant sex-related differences in practice patterns (p < 0.001) persisted after controlling for age or for the referring cardiologists' perception of expected procedural risk. A stepwise multivariate model showed that anatomy was the main determinant of case management; sex was the only other significant variable (p = 0.016). The referring physicians requested CABG more often for men than for women (p = 0.009), and the men accepted for a procedure were much more likely to undergo CABG than the women (OR 2.40, CI 1.47 to 3.93, p = 0.0002). Although the women undergoing CABG waited shorter periods than the men (p = 0.0035), this difference was attributable to their more severe symptoms., Conclusions: In this selected group women had more serious symptoms before referral but were turned down for revascularization more often than men. Reduced use of CABG rather than PTCA largely accounted for the sex-related differences in revascularization. Once accepted for a procedure women had shorter waiting times, which was appropriate given their more severe symptoms.

Purpose: To determine whether alpha-interferon is effective in terminating viral replication and in eradicating the carrier state in patients with chronic hepatitis B virus (HBV) infection., Data Sources: Randomized controlled studies published in the English literature between January 1966 and June 1992 were identified through a MEDLINE computer search., Study Selection: Fifteen randomized controlled studies with a total of 837 adult chronic HBV carriers who were positive for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were identified. Studies were included if patients were treated for at least 3 months and followed for at least 6 months after cessation of therapy., Results: Overall, the loss of HBsAg occurred 6% more often in interferon-treated patients than the natural seroconversion seen in controls (7.8% compared with 1.8%, P = 0.001), and the loss of viral replication occurred approximately 20% more often in treated patients than in controls (33% compared with 12% for loss of HBeAg and 37% compared with 17% for the loss of HBV DNA, P = 0.0001) if patients received interferon for 3 to 6 months and were followed for 6 to 12 months. Interferon also had a significant treatment effect on the development of antibodies to HBsAg (anti-HBs), antibodies to HBeAg (anti-HBe), and on the normalization of alanine aminotransferase levels., Conclusions: Alpha-interferon is effective in terminating viral replication and in eradicating the carrier state in patients with chronic HBV infection who are HBeAg positive when these patients are treated for 3 to 6 months and followed for 6 to 12 months after cessation of therapy. Follow-up studies are required to determine whether interferon reduces the risk for developing cirrhosis or hepatocellular carcinoma.

Our objective was to determine the effects of fish oil on renal function, symptoms, and serum lipids in patients with lupus nephritis. A double-blind, randomized crossover trial of fish oil versus placebo (olive oil) was done on 26 patients with confirmed systemic lupus; 21 completed the study. Intervention was fish oil or placebo, 15 g/day, for one year followed by a 10 week wash-out period, and then the reverse treatment for one year. At baseline and six month intervals, we measured platelet membrane fatty acids, indices of renal function, a disease activity index, serum lipid levels, blood pressure, serum viscosity and red cell flexibility. We found that platelet membrane phospholipids were uniformly affected by fish oil supplementation (P < 0.001) but with significant carry-over effects despite a 10 week wash-out period. Glomerular filtration rate and serum creatinine were not affected. A non-significant reduction in mean (SE) 24-hour proteinuria occurred, from 1424.1 mg (442.7) on placebo to 896.7 mg (352.2) on fish oil (P = 0.21). Fish oil lowered serum triglycerides from 1.89 (0.25) mmol/liter to 1.02 (0.11) mmol/liter (P = 0.004). VLDL cholesterol decreased markedly whether patients initially received fish oil or placebo (P = 0.004). The size of the reduction was affected by the order of treatment (P = 0.03), but parallel comparisons were significant before the crossover (P = 0.0006). With the possible exception of bleeding time, no other treatment effects were shown with fish oil. However, treatment order effects were seen in urinary IgG excretion (P = 0.03), whole blood viscosity (P < 0.0001), red cell flexibility (P = 0.004), and bleeding time (P = 0.06). In conclusion, one year of dietary supplementation with fish oil in patients with stable lupus nephritis did not improve renal function or reduce disease activity, but did alter some lipid parameters. Hitherto unreported carry-over effects and treatment order effects caused by the olive oil created a risk of type II error, and bear methodologic consideration in the design of future studies.

Queues for in-patient surgery are commonplace in universal health care systems. Clinicians and hospitals usually manage these waiting lists with informal criteria for determining patient priority--a form of implicit rationing. To understand the workings of implicit rationing by queue, we took advantage of a natural experiment in the Canadian province of Ontario. Unprecedentedly severe supply-demand mismatch led to long waiting lists for coronary surgery [CABS] in Ontario during 1987-88. The crisis was resolved by increased funding and widespread adoption of a multifactorial clinical index for patient priority that was developed by an expert panel in 1989. Thus, we audited randomly chosen charts of patients who underwent coronary angiography at four Toronto hospitals during the crisis period, and calculated urgency scores for each case based on the multifactorial index. From 413 charts, 193 eligible patients were identified who proceeded to CABS. Waiting times did correlate with urgency ratings (r = 0.42, P < 0.0001). However, mean wait from catheterization to CABS varied among hospitals by as much as 8 weeks (P < 0.0001 after controlling for urgency scores). At the hospital with shortest queues, waiting times were twice as long for patients catheterized by cardiologists off-site vs those referred by on-site practitioners (P < 0.0001, after controlling for urgency scores); a similar form of bias was found at a second coronary surgery centre (P = 0.056, after controlling for urgency scores). Over half the patients waited longer than the maximum suggested for their category by the expert panel.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To rate the urgency of coronary angiography for patients with ischemic heart disease. Ratings were made for patients with varying degrees of symptoms and noninvasive cardiac test results., Design: A panel of 10 cardiologists rated 354 case scenarios which presented varying combinations of clinical factors that may affect urgency., Measurements: The case scenarios were rated by each panelist on a waiting time scale consisting of six categories which ranged from the requirement for emergency angiography to a delay of up to three months. A seventh category represented the lack of urgent need for angiography. The contribution of each clinical factor to urgency of coronary angiography was determined., Main Results: Symptom class as defined by a modification to the Canadian Cardiovascular Society grading scale for angina pectoris, results of exercise stress tests and results of imaging studies were the major determinants of urgency. In cases of unstable angina, rest electrocardiography is of importance. These factors explained at least 95% of the variance in the case urgency scores. There was agreement by at least five of the panelists on urgency score in 84% of cases. The assigned urgency varied from 6.7, representing no urgent need for angiography, for minimally asymptomatic angina with no positive noninvasive test results, to immediate angiography for cardiogenic shock. Other factors had minimal or negligible effects on urgency., Conclusions: The urgency of need for coronary angiography was addressed by an explicit method incorporating the judgements of a panel of expert cardiologists, permitting derivation of a scoring system for rating priority of individual patients in the face of waiting lists. These methods illustrate an approach to problems presented by procedure waiting lists.

Objectives: To determine the trends in overall and age-specific rates of coronary artery bypass grafting (CABG) in Ontario from 1981 to 1989 and to assess whether relative resource scarcity, as manifested in waiting lists, resulted in obvious age-related or sex-related changes in utilization., Design: Computerized compilation of hospital discharge abstracts from the Hospital Medical Records Institute. All separations for every other year from Apr. 1, 1981, to Mar. 31, 1990, were included. Procedures rather than patients were the unit of analysis (repeat procedures were double-counted if associated with separate hospital admissions)., Setting: Ontario acute care hospitals offering CABG., Patients: People aged 20 years and over who underwent one or more CABG procedures., Results: The overall rate of CABG increased by 31% in the study period, plateauing only between 1983 and 1985. By 1989-90 the rate was 66.03 per 100,000. The highest annual increase in the rate was among people aged 65 to 74 years, at 17.61 procedures per 100,000, as compared with 4.64 per 100,000 among people 75 years and over. In 1989-90 those aged 65 and over represented 37% of the total caseload. The overall male:female ratio did not change significantly throughout the study period., Conclusions: Since the CABG utilization rate continues to increase in Ontario, recent waiting lists must be due to a disproportionate growth in demand. There was no convincing evidence of age-related or sex-related discrimination in allocating this limited resource. Supply-demand mismatch was driven above all by the continued increase in CABG use among elderly people.

To evaluate the role of antithrombotic therapy, on preserving graft patency, we performed a meta-analysis of randomized clinical trials involving aspirin (ASA), dipyridamole (D), anticoagulants (AC) and placebo or nontreatment controls (P). Manual literature searches were performed supplemented by computerized MEDLINE listings complete to July 1991. Saphenous vein graft occlusion was determined by angiography (patients with > or = 1 distal anastomotic occlusion). The trial data were aggregated with the methods of Mantel and Haenszel. The results are reported as odds ratios (OR) +/- 95% confidence intervals (CI). Seventeen trials were evaluated. Aspirin strongly influenced graft occlusion [ASA +/- D vs P: OR 0.60, 95% CI 0.51, 0.71, P < 0.0001], but dipyridamole provided no additional benefit [ASA+D vs ASA: OR 0.94, 95% CI 0.72, 1.24, P = 0.71]. Anticoagulants reduced graft occlusion [AC vs P: OR 0.56, 95% CI 0.33, 0.93, P = 0.025] and the results were similar to that achieved with aspirin [ASA vs AC: OR 0.95, 95% CI 0.62, 1.44, P = 0.87]. The combination of aspirin and anticoagulants was superior to anticoagulants alone in two limited trials [ASA+AC vs AC: OR 0.55, 95% CI 0.33, 0.88, P = 0.01]. A low (100 mg) to medium (325 mg) daily aspirin dosage was more effective than a high dose (975 mg). Early postoperative treatment (< or = 6 h) strongly influenced graft occlusion while preoperative administration provided no additional benefit. No mortality advantage was identified for any antithrombotic therapy. Aspirin or anticoagulants enhance saphenous vein graft patency following aortocoronary bypass surgery, and a combination thereof deserves further investigation in a trial large enough to detect the effects of these treatments with respect to clinical events.

Coronary endarterectomy (TEA) is performed infrequently during coronary artery bypass graft (CABG) surgery due to the impression that it results in higher rates of myocardial infarction (MI), operative mortality (OM), and poor long-term outcome. To assess the effectiveness of TEA, 1,228 patients undergoing isolated CABG between 1982 and 1989 were evaluated. The incidence of OM (3.2%) and MI (6.0%) following TEA was similar to conventional CABG (OM = 3.8%, MI = 5.5%, p = NS). The incidence of low output syndrome (LOS, 15.1%) and intraaortic balloon pump insertion (IABP, 4.5%) following TEA was similar to conventional CABG (LOS = 12.6%, IABP = 6.0%, p = NS). The highest level of the cardiac specific isoenzyme (CK-MB) released following surgery was similar for the TEA group (46 +/- 49) and conventional CABG group (42 +/- 44, p = NS). Ventricular dysfunction, urgent surgery, left main stenosis, advanced age, and reoperative surgery were similar in the TEA and conventional CABG groups. At a mean follow-up of 4.2 years, 65.6% of all TEA patients were free of angina, 44.4% were gainfully employed, and 62% were in New York Heart Association Class I. The incidence of late myocardial infarction was 5.4%. The 5-year actuarial survival was 90%. Patients with double TEA and limited TEA ( < or = 3 cm TEA specimens) tended to have a lower 5-year survival. With strict criteria for selection of TEA patients and with significant technical experience, the short- and long-term results of TEA are comparable to conventional CABG.

Objective: To compare clinicians' ratings of therapeutic effectiveness when different trial end points were presented as percent reductions in relative compared with absolute risk and as numbers of patients treated to avoid one adverse outcome., Design: Survey, with random allocation of two questionnaires., Setting: Toronto teaching hospitals., Respondents: Convenience sample of 100 faculty and housestaff in internal medicine and family medicine., Intervention: One questionnaire presented results for three end points of the Helsinki Heart Study as separate drug trials using only absolute differences in events; the other showed the same end points as relative differences. Both questionnaires included a fourth "trial," showing person-years of treatment needed to prevent one myocardial infarction., Main Outcome Measure: The "trials" were each rated on an 11-point scale, from treatment "harmful" to "very effective.", Results: Respondents' ratings of effectiveness varied with the end point. Controlling for end point, ratings of effectiveness by the 50 participants receiving absolute event data were lower than those by 50 participants responding to relative risk reductions (P < 0.001); however, no end-point difference was more than 0.6 scale points. For a "trial" reporting that 77 persons were treated for 5 years to prevent one myocardial infarction, mean ratings were 2.3 or 1.8 scale points lower, respectively (both P < 0.001), than when the same data were shown as relative or absolute risk reductions., Conclusions: Clinicians' views of drug therapies are affected by the common use of relative risk reductions in both trial reports and advertisements, by end-point emphasis, and, above all, by underuse of summary measures that relate treatment burden to therapeutic yields in a clinically relevant manner.

Objective: To assess the internal logic (content validity) of the Canadian Cardiovascular Society (CCS) scale for grading angina pectoris., Patients: Forty-one consenting patients with stable angina of at least two months duration, admitted to a tertiary centre for coronary angiography., Methods: Patients completed a supervised questionnaire with closed-ended questions. Key questions included: usual numbers of blocks walked on the level or flights of stairs climbed before onset of chest pain; frequency with which chest pain occurred at the usual threshold distance; presence of rest pain; and influence of modifiers suggested for class II of the scale such as walking uphill and into the wind., Results: Agreement of four questionnaire-defined 'stair-climbing grades' and 'walking grades' was statistically significant (P < 0.001) but only 37% better than expected by chance alone (weighted kappa). Frequency of angina at a patient's self-defined exercise threshold varied; only 22 of 41 patients (54%) had symptoms always or often. Higher classes of angina were more likely to be associated with frequent symptoms at threshold, eg, class I/II, six of 23 versus class III/IV, 16 of 17; 2P = 0.00002). Pain at rest was reported as 'definitely' present by 23 of 41 patients, and was similar in incidence across angina classes. All suggested modifiers reduced distances walked in a significant majority of patients (P values uniformly < 0.01) except for walking in the first few hours after awakening. However, the proportions of subjects for whom these factors were relevant were statistically similar for all angina grades, rather than for class II patients alone., Conclusions: These findings suggest that internal inconsistencies in the CCS scale are identifiable with simple validity checks. Further research appears warranted to improve this popular and useful clinical tool.

Objective: To appraise the measurement properties of the Canadian Cardiovascular Society (CCS) classification of stable angina pectoris., Data Sources: Relevant articles were identified through a MEDLINE search (1976 to November 1991). Bibliographies of retrieved articles were also reviewed., Study Selection: Studies chosen directly addressed the validity and reliability of the CCS scale. Recent studies and reviews of related topics (for example, silent ischemia) are selectively cited., Data Synthesis: No data address the scale's applicability, that is, how clinicians typically assign angina grades in practice. Comprehensiveness would be improved by coverage of the patient's perceptions of symptom burden; mixed exertional and rest symptoms; episodic or changing symptoms; and modifying factors. Reliability was assessed in one study with two clinicians; the interobserver, chance-corrected agreement on patient grading was 60%. Content validity (the ability of the scale to measure what it claims) is threatened by the unproven assumption of symptomatic or physiologic equivalence among diverse levels of different activities within any given grade of angina. Construct validity is uncertain, given weak relations between angina grade and noninvasive markers of ischemia, anatomical disease, or prognosis. The scale's responsiveness (the ability to detect the smallest clinically important changes) is limited by the reliance on four coarse gradations based on only ambulation or stair-climbing., Conclusions: The CCS scale for stable angina might be made more useful by developing measurements for patients' self-rated symptom burden and the changes they deem important; by adding items on clinical instability (that is, progressive symptoms or pain at rest); and by empirically testing the current scale to eliminate redundant or inconsistent elements.

Objective: To determine the effects of age and work status on whether and where cardiovascular specialists would place hypothetical patients in the queue for coronary surgery., Materials and Methods: Mailed survey presenting a set of clinical scenarios either to be rated on a scale with 7 time frames for urgency of need or to be designated as questionable/inappropriate for intervention. The basic scenario was a patient with mild-moderate stable angina, good left ventricular function, and limited coronary disease; operative risks and stress test results were varied. Three identifiers were used: "45-year-old civil servant gainfully employed"; "45-year-old laborer disabled by angina, faces job loss"; and "75-year-old retiree, angina limits golf.", Participants: Cardiologists and cardiac surgeons practicing in five Ontario medical centers (n = 120)., Results: There was a 59% response rate (120 usable responses). Large shifts in willingness to intervene occurred in favor of the disabled laborer (p less than 0.0001) and against the retiree (p-value ranges from 0.04 to less than 0.0001, depending on operative risk and stress test results), but not for the employed civil servant. Striking effects (p less than 0.0001) were also evident in ratings of waiting time, with the order of priority being the disabled laborer first, the civil servant second, and the retiree last. The overall mean shift due to work status or age was equal to, or larger than, the mean shift due to clinical factors, such as stress test results, changes in severity of stable angina, and extent of coronary disease., Conclusion: Cardiovascular specialists may place considerable weight on age and work status in determining urgency and appropriateness of coronary revascularization. Risk-benefit concerns may partly explain shifting thresholds for intervention, but not differential waiting times. The influence of these factors should be sought in utilization audits and addressed from an ethical perspective.

The increasing popularity of warm heart surgery led us to assess the effect of temperature during cardiopulmonary bypass (CPB) on neuropsychological function after coronary surgery. 34 patients enrolled in a randomised trial of normothermic versus hypothermic CPB were subjected to a battery of psychomotor and memory tests before and after their operations. The mean nasopharyngeal temperature for warm CPB was 34.7 (SD 0.5) degrees C and that for hypothermic CPB was 27.8 (2.0) degrees C. In all seven neuropsychological tests the postoperative scores were better in the warm CPB than in the hypothermic group, although only one difference achieved significance (trial-making test A; p less than 0.023). Thus, neurological function after normothermic CPB seems to be no worse than that after hypothermic procedures.

The American health care system has the world's highest per capita costs and over 30 million citizens uninsured. The neighbouring Canadian system provides coverage for all basic medical and hospital services, at costs per capita that are about US$700 lower. Single-agency public funding allows tighter control of Canadian expenditures, and reduces administrative overheads. Hospitals are run as non-profit private corporations, funded primarily by a fixed annual allocation for operating costs. Most physicians are in private fee-for-service practice, but cannot charge more than the insured tariff negotiated between their provincial government and medical association. This approach, while attractive in its decentralization, tends to separate the funding and management of clinical services. Thus, hospital information systems lag a decade behind the USA, managed care initiatives are few, health maintenance organisations do not exist, and experimentation with alternative funding or delivery systems has been sporadic. Strengths of the system compared to the USA include: higher patient satisfaction, universal coverage, slightly better cost containment, higher hospital occupancy rates, and reduction in income-related rationing with more equitable distribution of services. Weaknesses in common with the United States are: cost escalation consistently outstripping the consumer price index with costs per capita second highest in the world, ever rising consumption of services per capita, inadequate manpower planning and physician maldistribution, poor regional co-ordination of services, inadequate quality assurance and provider frustration. Additional weaknesses include: an emerging funding crisis caused by the massive federal deficit, less innovation in management and delivery of care as compared to the USA, implicit rationing with long waiting lists for some services, and recurrent provider-government conflicts that have reduced goodwill among stakeholders. Thus, while the Canadian model has important advantages, it does not offer a panacea for American health care woes.

We reviewed recent reports from administrative databases and clinical registries addressing the utilization of coronary artery bypass grafting (CABG) in Canada. The Canadian CABG rate per 100,000 people increased from 31.1 to 43.2 between 1981-82 and 1986-87. Between 1981 and 1986 the rate in the United States increased from 69.9 to 95.3 per 100,000, consistently about two times the Canadian rate. Provincial data have shown particular growth in utilization among elderly people. However, in the United States the 1985 CABG rate was twice as high as the aggregated age-specific rates for Ontario and Manitoba among people 65 to 74 years of age and four times higher among those 75 years or more. Limited registry data suggest that the Canadian CABG case mix is similar to the case mix in major US centres and that, utilization growth notwithstanding, the procedure is largely applied to patients who should, in theory, benefit (i.e., those with severe angina, impaired left ventricular function and left main-stem or triple-vessel disease). However, chart audits and registry evaluations using explicit criteria are needed to compare the use of CABG in Canada and the United States. In addition, Canadian data show moderate regional and municipal variations, the 1986-87 rates per 100,000 population in major census metropolitan areas varying from 19.5 to 46.9. Areas with consistently low rates raise particular concerns about impaired access to CABG. Reasons for variations should therefore be a research priority.

Meta-analysis is a method of synthesizing evidence from multiple sources. It has been increasingly applied to combine results from randomized trials of therapeutic strategies. Unfortunately there is often variation in the quality of the trials that are included in meta-analyses, limiting the value of combining the results in an overview. This variation in quality can lead to both bias and reduction in precision of the estimate of the therapy's effectiveness. There are a number of methods for quantifying the quality of trials including the detailed Chalmers system and simple scales. The nature of the relationship between these quality scores and the true estimate of effectiveness is unknown at this time. We discuss four methods of incorporating quality into meta-analysis: threshold score as inclusion/exclusion criterion, use of quality score as a weight in statistical pooling, visual plot of effect size against quality score and sequential combination of trial results based on quality score. The last method permits an examination of the relation between quality and both bias and precision on the pooled estimates. We conclude that while it is possible to incorporate the effect of variation of quality of individual trials into overviews, this issue requires more study.

Study Objectives: To assess specialists' adaptation to long waiting lists for coronary revascularization, and their acceptance of a formal queue-ordering schema proposed by an expert panel., Design: Mail survey of practitioners in referral centers using 49 hypothetical case scenarios. Scenarios were rated for maximum acceptable delay prior to coronary surgery, on a scale with seven interventional time frames graded from emergency to three to six months' permissible delay. The survey included the proposed schema and rating system; respondents were invited to differ as they saw fit. HYPOTHETICAL PATIENTS: Assumed uniformly to be middle aged with typical angina, but clinical factors varied, eg, severity and stability of angina, response to medical therapy, coronary anatomy, and noninvasive test results. PHYSICIAN SUBJECTS: There were 122 respondents, for a 60 percent response rate, including a majority of cardiac surgeons and invasive cardiologists on staff in Ontario teaching hospitals., Measurements and Results: Fifty-seven percent rated some scenarios for acceptable waiting times of three to six months; another 39 percent rated their least urgent scenarios to wait six weeks to three months. Interpractitioner agreement was high: for 48/49 scenarios, at least 75 percent of urgency ratings fell within two contiguous points on the scale. Symptom status was the dominant determinant of waiting time, with mean maximum acceptable wait of 74 days for patients with mild-moderate stable angina but three days for those receiving parenteral nitroglycerin (p less than 0.00001). About half the ratings matched those predicted based on the original panel's consensus criteria; 90 percent were within one scale point., Conclusions: Specialist practitioners in Ontario have adapted to waiting lists for coronary artery bypass surgery/percutaneous transluminal coronary angioplasty, and assess the priority of hypothetical patients in similar ways and in reasonable accord with formal queue-ordering criteria. This behavior may help mitigate the impact of resource constraints, allowing delay of services for those with less acute need--a potential contrast to delayed access in America based on low income or lack of insurance.

Objective: An economic evaluation of the potential incremental benefits of intravenous tissue plasminogen activator (tPA) versus streptokinase (SK) for treatment of acute myocardial infarction., Design: Cost effectiveness analysis from a third-party payer perspective (Ontario Ministry of Health). ECONOMIC INPUTS: Fully allocated costs for cardiovascular procedures and hospitalization for myocardial infarction were obtained anonymously for four Ontario teaching hospitals and converted to 1988 Canadian dollars. Professional charges were taken from the provincial health insurance fee schedule and drug costs obtained from the manufacturers. CLINICAL INPUTS: The baseline analysis was for nonelderly patients with uncomplicated myocardial infarctions; sensitivity analyses allowed extrapolation to higher risk subgroups. Short and longer term mortality and short term invasive procedure rates were estimated using data from clinical trials., Main Results: If tPA achieves a 1% short term mortality advantage over SK with no advantages for other survivors, cost per life-year gained can be comparable to other cardiovascular interventions at $58,600. In the absence of immediate survival advantages, but assuming greater left ventricular preservation, the constant annual hazard rate advantage must be about 0.5% per year for competitive cost effectiveness ratios., Conclusions: A full range of projections is presented to help guide the policy decisions that will arise in the wake of the Global Utilization of SK and tPA for Occluded Coronary Arteries (GUSTO) trial. The analysis also illustrates the general importance of considering longer term effects of in-hospital therapies for acute myocardial infarction.

Objective: To assess the match between multifactorial risk of coronary heart disease (CHD) and treatment intensity under the National Cholesterol Education Program (NCEP) guidelines for primary prevention of CHD., Methods: The multiple logistic regression equation from the Framingham Study was used to derive predicted risks for development of CHD over eight years of follow-up for different age-gender groupings, with serum total cholesterol (TC) values chosen in light of the NCEP cutoff points for both TC and low-density-lipoprotein cholesterol levels. Additional risk factors--hypertension, glucose intolerance, and smoking--were considered in combination for each of these values., Results: Controlling for the effects of age and gender, there is little difference in the ranges of absolute CHD risks for persons who would receive interventions of differing intensities (i.e., general dietary advice, dietary treatment, or drug therapy). Those who are candidates for drug treatment because of serum lipids alone are often at low levels of risk for the development of CHD when compared with those of the same age with lower TC values who have other risk factors. Discrepancies in CHD risk are wider still when age is also allowed to vary. Furthermore, in every age grouping, women with high TC levels (e.g., 6.9 mmol/L) and two other risk factors are eligible for drug treatment but have a CHD risk that is no higher, and often much lower, than that of males with one other risk factor and TC levels of 4.8 mmol/L or 5.7 mmol/L who are candidates for dietary advice or dietary therapy, respectively., Conclusions: Inconsistencies exist in the NCEP guidelines such that persons at low risk for the development of CHD are offered more intensive interventions than are other who actually are at much higher risks, and vice versa. Women in particular tend to be overtreated, relative to men. These findings point out the difficulties of promulgating guidelines that will appropriately match risk to preventive interventions in a complex multifactorial disease.

Objective: To determine the point at which adverse quality-of-life effects engendered by an aggressive cholesterol-lowering strategy dictate the use of a less aggressive approach., Design: Decision analysis was used to compare the effects of the National Cholesterol Education Program (NCEP) guidelines, an aggressive program, with those of the Canadian Task Force on the Periodic Health Examination (CTF) guidelines, a more conservative program. Quality-adjusted life expectancy was calculated for a theoretical cohort of middle-aged men treated according to each program using Markov cohort analysis., Measurements: Guidelines were applied to the population of the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), under the assumption that cholesterol levels had the distribution of the age- and sex-matched general population. Outcomes were calculated using a three-state (health, coronary heart disease, and death) Markov model. State transition probabilities were calculated using bivariate (age and cholesterol) proportional hazards and logistic regression functions., Main Results: The result was a "toss-up"; the number of expected quality-adjusted life years was similar for both programs at all time intervals, although the conservative program was consistently slightly favored. The result was very sensitive to the disutility of dietary therapy (threshold value, 0.0014 compared with the baseline estimate of 0.02) but was also affected by the time frame of the analysis and the rate at which adverse effects of treatment decline., Conclusions: Even small disutilities associated with treatment may outweight the benefits of aggressive cholesterol-lowering strategies. Research should be directed toward measuring these disutilities and finding ways to reduce their size. Incorporation of the disutility of treatment into policy formulation may result in less interventionist and less costly policies.

In light of lengthy waiting lists for coronary surgery in Canada, a panel of 16 cardiologists and cardiac surgeons was convened to derive guiding principles for ranking how urgently diverse patients with angiographically proven coronary disease require revascularization. Factors likely to affect urgency were agreed upon by the panelists and incorporated into a case scenario questionnaire. Each panelist then rated 438 case scenarios with respect to maximum acceptable waiting time on a scale with seven time frames ranging from emergency surgery ('level 1') to delays of up to six months ('level 7'). The scenario rating process facilitated attainment of a panel consensus. The purpose of the principles is to assist in assigning priorities to patients according to both symptoms and risk of death or additional morbidity from ischemic events. The pattern or severity of the patient's anginal symptoms and the response of those symptoms to medical therapy emerged as the single most important determinant of the level of urgency. Anatomy and noninvasive tests of ischemic risk were the other key determinants of priority. All other factors were less important, and operated largely within a given level of urgency on the seven-point scale. The principles, including explicit ranking criteria divided according to angina class, are outlined in this final report. The panel specifically cautioned that adoption of such principles is not designed to countenance delays in treatment, but if necessary, should help form more rational queues for coronary revascularization.

A meta-analysis of randomized clinical trials of fibrinolysis was performed, examining the interaction between aspirin and fibrinolysis in treating patients with acute myocardial infarction. Reductions in the odds of death up to 35 days were assessed for patients receiving tissue plasminogen activator or streptokinase up to 6 hours after the onset of symptoms. No significant difference in effectiveness between tissue plasminogen activator and streptokinase was demonstrated. The overall reduction in odds of death due to fibrinolytic therapy was 28%. However, there was a significant difference between the odds reduction of 24% when fibrinolysis is compared to placebo, and 40% when fibrinolysis and aspirin combined are compared to aspirin alone (p = 0.02). This difference indicates that there exists a synergistic interaction between coronary fibrinolysis and aspirin rather than independence of their beneficial effects, as is generally believed. These results illustrate the perils of assessing drug efficacy, even in an overview of all relevant trials, without consideration of identifiable sources of heterogeneity such as the interaction between the treatment of interest and co-interventions. They also demonstrate the potential application of logistic regression diagnostic techniques to meta-analyses.