Economic assessment of troglitazone as an adjunct to sulfonylurea therapy in the treatment of type 2 diabetes.

OBJECTIVE: To assess the economic efficiency of adding troglitazone to sulfonylurea therapy to improve glycemic control. BACKGROUND: Despite the high prevalence of type 2 diabetes, existing treatment strategies often fail. New oral agents give a wider segment of the population with type 2 diabetes hope of achieving near-normal blood-glucose levels. Troglitazone, a novel chemical entity, is one promising new agent. METHODS: We conducted an economic analysis based on glycemic-control data from a randomized clinical trial comparing troglitazone with placebo, each added to glyburide. A patient simulation model was used to translate these data to long-term outcomes associated with diabetes. Patients had poorly controlled type 2 diabetes mellitus despite glyburide therapy. Risk functions of developing and progressing through nephropathy, retinopathy, neuropathy, hypoglycemia, and macrovascular disease were developed from the Diabetes Control and Complications Trial and large epidemiologic studies. Cost estimates were based on data from 5 states, all payor databases, surveys, and literature. The main outcomes of the model were cost-consequences, number of patients developing each type of complication, mean time to development of the complication, cost per life-year gained (LYG), and cost per quality-adjusted life-year. RESULTS: The model predicts that for every 1000 patients treated with troglitazone, the improved glycemic control could mean that 95 to 140 fewer patients would experience one of the most severe diabetic complications (eg, blindness, end-stage renal disease, amputation), which may increase life expectancy by 2.0 years. These benefits are obtained at an additional $2100 per LYG (undiscounted). The ratio remains <$50,000 per LYG for most variations in input. CONCLUSIONS: The clinical trial demonstrated that troglitazone + glyburide improves glycemic control compared with glyburide alone. Based on these results, the model estimates fewer diabetic complications at a cost well below accepted cost-effective thresholds.

Identifying subgroups of the general population that may be susceptible to short-term increases in particulate air pollution: a time-series study in Montreal, Quebec.

This study was undertaken in order to shed light on which groups of the general population may be susceptible to the effects of ambient particles. The objectives of the study were (1) to determine whether concentrations of particles in the ambient air of Montreal, Quebec, were associated with daily all-cause and cause-specific mortality in the period 1984 to 1993, and (2) to determine whether groups of the population had higher than average risks of death from exposure to particles. From the network of fixed-site air pollution monitors in Montreal we obtained daily mean levels of various measures of particles, gaseous pollutants, and weather variables measured at Dorval International Airport. We also used measurements of sulfate from an acid rain monitoring station 150 km southeast of the city (Sutton, Quebec). We estimated associations for particulate matter (PM) with an aerodynamic diameter of 10 microns or smaller (PM10), or 2.5 microns or smaller (PM2.5), total suspended particles (TSP), coefficient of haze (COH), an extinction coefficient, and sulfate. Because substantial data for fine particles were missing, we developed a regression model to predict PM2.5 and to predict sulfate from PM2.5. In the main body of the report, we present results for COH, predicted PM2.5, and sulfate. Detailed results for all pollutants are included in Appendices H through O, which are available on request from Health Effects Institute and from the HEI web site at www.healtheffects.org. To address the first objective, we made use of the underlying causes of death among all 140,939 residents of Montreal who died between 1984 and 1993. We regressed the logarithm of daily counts of cause-specific mortality on the daily mean levels for a variety of measures of particles, accounting for seasonal and subseasonal fluctuations in the mortality time series, overdispersion, and weather factors. To address the second objective, we developed algorithms to define conditions that subjects had prior to death, with the focus on cardiopulmonary diseases. These algorithms were based on information retained on the databases of the universal Quebec Health Insurance Plan (QHIP). The databases include records of all procedures (e.g., type of surgery), physician visits, and consultations carried out by all physicians in Quebec. For persons > or = 65 years and for all recipients of social assistance the prescription database contains records of all pharmaceuticals dispensed (type of medication, dose, quantity). For each group of conditions defined, we used the same statistical model that was used in the analyses of all nonaccidental causes of death. In the analyses of cause-specific mortality, we found evidence of associations for all nonaccidental causes of death and specific causes of death--cancer, coronary artery disease, respiratory diseases, and diabetes--that were consistent across most metrics of ambient air particle concentrations, evaluated as the 3-day mean of particle concentrations measured on the day of death (lag 0) and on each of the two days before death (lag 1, lag 2). Associations for all cardiovascular diseases combined were found only with sulfate. As well, we generally found increased daily mortality for persons 65 years of age and over. The results for all nonaccidental causes of death are similar to findings from other studies; the mean percent increase in mortality for a 100 micrograms/m3 increase in daily TSP at lag 0 was 6.7%. In the analyses of the groups defined from the QHIP data, there was little evidence of associations with air pollutants among persons who before death were classified as having acute or chronic upper respiratory diseases, airways diseases, hypertension, acute coronary artery diseases, and cerebrovascular diseases. On the other hand, we found consistent increases across most types of ambient particles for persons who had cancer, acute lower respiratory diseases, any form of cardiovascular disease, chronic coronary artery diseases, and congestive heart failure. As well, we found an association for individuals who did not have any cardiovascular disease, lower respiratory diseases, and cancer. This latter group consisted of persons who had no interactions with the health care system one year before death (12%) and individuals with a wide variety of potentially fatal diseases (52%), including neurological conditions (12%), diabetes (8%), cardiac dysrhythmias (8%), dementia (6%), organic psychotic disorders (6%), and anemias (4%). As statistical power was reduced in the analyses presented above, differences between groups (e.g., < 65 and > or = 65 year age groups) were not usually statistically significant. The association with diabetes has not been reported previously, and this needs to be replicated in other studies. (ABSTRACT TRUNCATED)

Anticoagulant prophylaxis against stroke in atrial fibrillation: effectiveness in actual practice.

BACKGROUND: Randomized trials have shown a beneficial effect of anticoagulation with warfarin to prevent stroke in atrial fibrillation. It is not known whether the same effect will be obtained in actual practice. The authors conducted a prospective observational study to evaluate the effect of preventive anticoagulation in patients with atrial fibrillation in 2 practice settings in Montreal. METHODS: Of the 1725 outpatients screened between October 1990 and September 1993 at a community hospital and a university-affiliated hospital, 221 with documented atrial fibrillation were enrolled and followed up for a mean of 27 months. Most (75%) of the patients excluded did not meet the inclusion criteria (because of, for example, an artificial heart valve, mitral stenosis, cardiac transplantation or transient atrial fibrillation); the remainder had not completed enrollment before the end of the study. Following the baseline visit, patients were interviewed by telephone every 6 months, and reported events were confirmed through review of the patients' charts. Hazards for stroke and for stroke and transient ischemic attack (TIA) combined were calculated for each of 4 treatment groups: ASA, warfarin, blended treatment and no treatment, based on the type of anticoagulation therapy patients received during the entire observation period. The blended-treatment group consisted of patients who started on one active therapy and switched to the other or who switched treatments more than once. Corresponding rate ratios (RRs) and 95% confidence intervals (CIs) were calculated with reference to the no-treatment group. Cox proportional hazards analysis was used to adjust for differences in patient characteristics. The rates of bleeding episodes were also analysed. RESULTS: On average, the study patients were older (71.6 [standard deviation 9.3] years) and had a higher prevalence of underlying heart disease (52.0%) than those in the randomized trials. Nineteen patients had a first stroke: 4 in the ASA group, 4 in the warfarin group, 4 in the blended-treatment group and 7 in the no-treatment group, for rates of 5.2, 1.8, 5.3 and 5.9 per 100 person-years, respectively. Only warfarin was associated with a significantly lower risk of stroke compared with no anticoagulant therapy (RR 0.31, 95% CI 0.09-1.00). A similar protective effect of warfarin was found for stroke and TIA combined (2.3 v. 6.7 per 100 person-years; RR 0.34, 95% CI 0.12-0.99); the effect of ASA and blended treatment was not significantly different from no treatment. The rate per 100 person-years of any bleeding was not significantly higher for any treatment group (ASA 2.5, warfarin 3.4 and blended treatment 3.5) compared with the no-treatment group (1.9). Patients receiving warfarin had a significantly greater risk of any bleeding event than patients not receiving anticoagulant therapy (RR 1.79, 95% CI 1.07-3.00). INTERPRETATION: The relative effect of anticoagulant therapy with warfarin in preventing stroke in these practice settings was equivalent to that in the randomized trials, although these patients were older and sicker. This preventive treatment is likely to confer additional benefit as it is more widely prescribed.

A physician-centred intervention to shorten hospital stay: a pilot study.

BACKGROUND: Studies of length of stay (LOS) in hospital usually focus on physician-independent factors. In this study, the authors identified physician-dependent factors and tested an intervention aimed at them to determine its effect on LOS. METHODS: A prospective comparison of LOS on 2 general medical wards in a tertiary care teaching hospital before and after the intervention. The pre-intervention (control) period and the intervention period were each 4 weeks. The intervention consisted of a checklist for planning management and discharge. RESULTS: Overall, the mean LOS was shorter during the intervention period than during the control period, but the difference was not statistically significant (12.0 and 14.4 days respectively, p = 0.13). The difference was significant on ward A (11.0 v. 14.7 days respectively, p = 0.02) but not on ward B (13.0 and 14.0 days respectively, p = 0.90). INTERPRETATION: An intervention at the level of the admitting physician may help to shorten LOS on a general medical ward.

Nonvalvular atrial fibrillation: evidence for a prothrombotic state.

OBJECTIVE: To determine whether patients with nonvalvular atrial fibrillation (NVAF) have prothrombotic changes compared with patients in sinus rhythm. DESIGN: Cross-sectional study. Hemostatic function compared in NVAF patients without prior embolic event (transient ischemic attack or embolic stroke) and control subjects without prior thrombotic stroke, and in NVAF patients with prior embolic event and control subjects with prior thrombotic stroke. SETTING: Internal medicine outpatient group practice and anticoagulation clinic in 2 teaching hospitals. PATIENTS: A total of 75 NVAF patients (50 without and 25 with prior embolic event) and 42 control patients (31 without and 11 with prior thrombotic stroke) recruited concurrently over 18 months during 1990-91. OUTCOME MEASURES: Platelet count, prothrombin time (PT), partial thromboplastin time (PTT), and plasma levels of hemoglobin, fibrinogen, von Willebrand factor antigen, factor VIII, fibrin D-dimer, antithrombin III, protein C, protein S, fibrinopeptide A and prothrombin fragment F1+2. All statistical analyses were performed after adjustments for age and sex. RESULTS: The NVAF patients without a prior embolic event had significantly higher mean hemoglobin and fibrinogen levels (p < 0.001 and p = 0.05, respectively) than the control subjects without prior thrombotic stroke. The 29 NVAF patients not taking warfarin (none had had an embolic event) had significantly lower mean protein C and protein S levels (p = 0.012 and p < 0.001, respectively) and a significantly higher fibrinopeptide A level (p = 0.03, after exclusion of outliers) than the control subjects without prior stroke. The NVAF patients with a prior embolic event had alterations in the hemostatic variables similar to those seen in the control patients with a prior thrombotic stroke. The latter had significantly higher fibrinogen, von Willebrand factor antigen and factor VIII levels (p = 0.04, 0.002 and 0.002, respectively) and significantly lower protein S levels (p = 0.02) than the control subjects without prior stroke. CONCLUSIONS: NVAF patients without a history of an embolic event show evidence of a prothrombotic state compared with patients in sinus rhythm who have not had a thrombotic stroke. NVAF patients with a history of an embolic event show evidence of a prothrombotic state similar to that of patients in sinus rhythm who have had a thrombotic stroke. Prospective studies are needed to determine whether these abnormalities predict higher risk of stroke in individual NVAF patients.

Increased tissue plasminogen activator levels in patients with nonvalvular atrial fibrillation.

OBJECTIVE: To determine whether plasma tissue plasminogen activator (tPA) levels (a) are higher in patients with novalvular atrial fibrillation (NVAF) than in control subjects in sinus rhythm; (b) differ between NVAF patients with and without a history of an embolic event (transient ischemic attack or embolic stroke); and (c) differ in control subjects with and without a history of thrombotic stroke. DESIGN: Cross-sectional study. SETTING: Internal medicine outpatient group practice and anticoagulation clinic in 2 teaching hospitals. PATIENTS: Seventy-four NVAF patients (24 with and 50 without a history of an embolic event), separated into 3 groups: no prior embolic event and no warfarin use (group 1), no prior embolic event and warfarin use (group 2), and prior embolic event and warfarin use (group 3). Forty control subjects in sinus rhythm (29 without and 11 with prior thrombotic stroke). OUTCOME MEASURES: Plasma tPA levels. RESULTS: The age-adjusted mean tPA levels exceeded the upper limit of normal in all 3 NVAF groups but not in the control groups. The NVAF patients had significantly higher mean tPA levels than the control subjects (p = 0.015). The levels did not differ significantly between the NVAF patients with a history of an embolic event and those without such a history. The control subjects with a history of thrombotic stroke had significantly higher mean tPA levels than the other control subjects (p = 0.03). CONCLUSIONS: NVAF patients, regardless of their history of embolic events, and control patients with a history of thrombotic stroke have higher tPA levels than subjects in sinus rhythm without a history of stroke. A prospective, longitudinal study involving NVAF patients is required to determine whether high baseline tPA levels are associated with, and perhaps causally related to, an increased risk of stroke.

From delirium cordis to atrial fibrillation: historical development of a disease concept.

In 1874, the electrical stimulation of animal hearts made known the existence of atrial fibrillation, but atrial fibrillation was not associated with its clinical counterpart, arrhythmia perpetua, until 1909, by which time simultaneous recordings of the human heartbeat, the venous and arterial pulses, and electrocardiographic activity had revealed the common origin of these events. After the electrical basis of atrial fibrillation was found and after atrial fibrillation was clearly distinguished from ventricular fibrillation, investigation into its mechanism ensued. Two contrasting theories, that of circus movement and that of tachysystole from a single focus, led to 30 years of research and debate. Pivotal to the argument was the notion of blocked conduction. Although the theory of circus movement prevailed for a long time, it appeared to be demolished by electrophysiologic experiments done between 1948 and 1950. The realization that blocked conduction could later reenter led to more recent research in animals and humans that revived the notion of circular conduction, although in a much more sophisticated form.

Atrial fibrillation and anticoagulation: from randomised trials to practice.

Randomised trials confirm that anticoagulants reduce the risk of emboli in atrial fibrillation. To apply this evidence to practice, we developed an expression relating all relevant factors. Trial-based estimates of the risks of emboli and haemorrhage, and of the effects of anticoagulants on these risks were used to derive the extent to which haemorrhage has to be seen to be more detrimental than emboli to justify not using anticoagulants. Information from other studies was used to assess the risks for the types of patients not included in the trials. Haemorrhage needs to be assessed as being at least six times more detrimental than emboli to warrant withholding anticoagulants from patients like those in the trials. Only in patients with lone atrial fibrillation and in those with features suggesting a bleeding risk six times higher than the trials' average would a perception of equal detriment risk justify not giving anticoagulation.

Factors relevant to preventing embolic stroke in patients with non-rheumatic atrial fibrillation.

Whether or not to treat patients with non-rheumatic atrial fibrillation with anticoagulants to prevent embolic stroke is a dilemma for physicians. If randomized trials, currently underway, demonstrate a beneficial effect, the dilemma will not be solved because not all of the relevant factors can be addressed by trials. We used current knowledge about non-rheumatic atrial fibrillation and a method of obtaining patient-derived weights for avoiding stroke from eight medically trained subjects, to determine the overall benefit of anticoagulants and to see what factors were relevant and what effect each might have in deciding whether to use anticoagulant therapy. Using standard assumptions, anticoagulants gave an expected benefit for all subjects. The expected benefit (expressed in terms of lives per 1000 saved due to anticoagulants) varied between 5.4 and 46.7. This benefit remained for all subjects when we did a sensitivity analysis for different rates of stroke prevented by anticoagulants and different rates of intracranial hemorrhage caused by anticoagulants. When we used different baseline rates of stroke and different impacts of major hemorrhagic complications the benefit disappeared for 3 and 4 subjects respectively. We found the factors that were most crucial to the decision will not be included in randomized trials; the weight that an individual would place on avoiding embolic stroke vs the risk of intracranial bleeding from anticoagulant therapy; and the rate of embolic stroke that could be expected for the subject at risk. Factors which will be measured in randomized trials, will change results less substantially: the increased risk of major hemorrhages; the proportion of strokes that could be prevented by treatment; the increase in risk of intracranial hemorrhage. This method of analysis suggests that for most patients anticoagulants are beneficial and that the most important factor in determining this result is the value that subjects put on different outcomes.

Risk factors for stroke and other embolic events in patients with nonrheumatic atrial fibrillation.

Factors associated with stroke and other cardiac embolic events in subjects with nonrheumatic atrial fibrillation were examined in a retrospective study of 91 patients from a teaching hospital clinic. There were 28 first strokes during 355 person-years of follow-up (7.9 per 100 person-years). Patients who had experienced one or more previous events were approximately 2.3 times more likely to have a subsequent event (hazard ratio 2.3, 95% confidence interval 1.5-3.4) than patients who had experienced no events. A univariate analysis of factors associated with a first stroke of any cause or other embolic event showed that age of greater than 75 years (hazard ratio 2.5) and systolic blood pressure of greater than 160 mm Hg (hazard ratio 6.4) were significant factors. After adjusting for the effect of age and systolic blood pressure, previous events still carried an increased risk for subsequent events. Subject with nonrheumatic atrial fibrillation who have had one or more embolic events are at high risk of further emboli. They require special consideration when treatment is being planned.