Should there be early publication of ancillary studies prior to the first primary report of an unblinded randomized clinical trial?
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Authorship↗
Biomedical subjects
C D Naylor
Publications and source records attributed to C D Naylor.
Optimal antithrombotic therapy following aortocoronary bypass: a meta-analysis.
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.
Anticoagulants↗
Fish oil in lupus nephritis: clinical findings and methodological implications.
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.
Adult↗
Does coronary endarterectomy adversely affect the results of bypass surgery?
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.
Adult↗
Rating the urgency of coronary angiography: results of an expert panel process. Ontario Coronary Angiography Panel.
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.
Adult↗
Measured enthusiasm: does the method of reporting trial results alter perceptions of therapeutic effectiveness?
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.
Adult↗
The Canadian Cardiovascular Society grading scale for angina pectoris: is it time for refinements?
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.
Angina Pectoris↗
Central-nervous-system dysfunction after warm or hypothermic cardiopulmonary bypass.
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.
Body Temperature↗
Coronary artery bypass grafting in Canada: What is its rate of use? Which rate is right?
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.
Adult↗
The Canadian health care system: a model for American to emulate?
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.
Canada↗
Meta-analyses of the effects of thrombolysis and aspirin on clinical outcomes.
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Aspirin↗
Further thoughts on the importance of models in the assessment of clinical evidence.
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Aspirin↗
Incorporating variations in the quality of individual randomized trials into meta-analysis.
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.
Bias↗
How should health status measures be assessed? Cautionary notes on procrustean frameworks.
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Epidemiologic Methods↗
Adapting to waiting lists for coronary revascularization. Do Canadian specialists agree on which patients come first?
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.
Attitude of Health Personnel↗
The internal logic of the Canadian Cardiovascular Society scale for grading angina pectoris: a first appraisal.
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.
Adult↗
Comparison of an aggressive (U.S.) and a less aggressive (Canadian) policy for cholesterol screening and treatment.
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.
Adult↗