Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone.

BACKGROUND AND PURPOSE: Inhibition of cholesteryl ester transfer protein (CETP) with torcetrapib in humans increases plasma high density lipoprotein (HDL) cholesterol levels but is associated with increased blood pressure. In a phase 3 clinical study, evaluating the effects of torcetrapib in atherosclerosis, there was an excess of deaths and adverse cardiovascular events in patients taking torcetrapib. The studies reported herein sought to evaluate off-target effects of torcetrapib. EXPERIMENTAL APPROACH: Cardiovascular effects of the CETP inhibitors torcetrapib and anacetrapib were evaluated in animal models. KEY RESULTS: Torcetrapib evoked an acute increase in blood pressure in all species evaluated whereas no increase was observed with anacetrapib. The pressor effect of torcetrapib was not diminished in the presence of adrenoceptor, angiotensin II or endothelin receptor antagonists. Torcetrapib did not have a contractile effect on vascular smooth muscle suggesting its effects in vivo are via the release of a secondary mediator. Treatment with torcetrapib was associated with an increase in plasma levels of aldosterone and corticosterone and, in vitro, was shown to release aldosterone from adrenocortical cells. Increased adrenal steroid levels were not observed with anacetrapib. Inhibition of adrenal steroid synthesis did not inhibit the pressor response to torcetrapib whereas adrenalectomy prevented the ability of torcetrapib to increase blood pressure in rats. CONCLUSIONS AND IMPLICATIONS: Torcetrapib evoked an acute increase in blood pressure and an acute increase in plasma adrenal steroids. The acute pressor response to torcetrapib was not mediated by adrenal steroids but was dependent on intact adrenal glands.

Revascularization in the rabbit hindlimb: dissociation between capillary sprouting and arteriogenesis.

OBJECTIVE: Animal models of hindlimb ischemia are critical to our understanding of peripheral vascular disease and allow us to evaluate therapeutic strategies aimed to improve peripheral collateral circulation. To further elucidate the processes involved in revascularization following ischemia, we evaluated the temporal association between tissue ischemia, vascular endothelial cell growth factor (VEGF) release, angiogenesis (capillary sprouting), arteriogenesis (growth of the larger muscular arteries), and reserve blood flow (functional collateral flow). METHODS: New Zealand White rabbits (male 3-4 kg) were evaluated at specific days (0, 5, 10, 20 or 40) following femoral artery removal for measurement of hindlimb blood flow, skeletal muscle lactate production and VEGF content, capillary density (a marker of angiogenesis), and angiographic score (a marker of arteriogenesis). RESULTS: Maximal capillary sprouting occurred within 5 days of femoral artery removal and was temporally associated with reduced resting hindlimb blood flow, increased lactate release and detectable levels of skeletal muscle VEGF. The growth of larger angiographically visible collateral vessels occurred after 10 days and was not temporally associated with ischemia or skeletal muscle VEGF content, but did coincide with a large functional improvement in the reserve blood flow capacity of the limb. CONCLUSIONS: Following femoral artery removal in the rabbit, the time course of angiogenesis and arteriogenesis were clearly distinct. Tissue ischemia and/or VEGF may stimulate capillary sprouting, but this response does not translate to a significant improvement in collateral flow. The growth and development of the larger collateral vessels was correlated with a large functional improvement in collateral flow, and occurred at a time when VEGF levels were undetectable.

Measuring the economic impact of perioperative total parenteral nutrition: principles and design.

Although the use of total parenteral nutrition (TPN) has been increasing in recent years, few studies have been performed on both its costs and its effectiveness or benefits. This paper provides a general review of the methods of cost-effectiveness and cost-benefit analysis, summarizes briefly the existing cost-analysis studies of TPN, and outlines the authors' proposed study design for their economic assessment of TPN.

The influence of sympathoadrenal activation on skeletal muscle oxygen extraction during endotoxemia.

We have previously shown a direct relationship (r = .97) between the fall in arterial blood pressure and the increase in skeletal muscle oxygen extraction (MVO2) during canine endotoxemia. Since it is well known that hypotension activates the sympathetic system, the primary aim of these experiments was to determine if the increase in MVO2 during endotoxemia is a result of elevated levels of catecholamines due to increased sympathetic neural and/or humoral activity (sympathoadrenal system). Canine gracilis muscles were vascularly isolated and perfused in situ at a constant flow (6-7 ml/min/100 g). Endotoxemia was induced by a 30 min intravenous infusion of Escherichia coli endotoxin (2 mg/kg), which induced a 50% reduction in arterial pressure. Perfusion pressure, mean arterial pressure, and arteriovenous oxygen difference (a-v O2) were continuously measured. We found 1) no significant difference between the amount of O2 extracted by an innervated or a denervated muscle during endotoxemia; 2) the intra-arterial infusion of norepinephrine or epinephrine into a denervated gracilis muscle (plasma molar concentrations of; 10(-11), 10(-9), 10(-7), and 10(-5) failed to increase MVO2 to the level observed during endotoxemia; 3) pretreatment of a muscle with propranolol to block skeletal muscle beta-adrenergic receptors, did not suppress the endotoxin-induced rise in MVO2. We concluded that the increase in MVO2 seen after the administration of endotoxin is not due to either increased sympathetic nerve activity or elevated levels of circulating catecholamines. We speculate that the increased MVO2 during endotoxemia is caused by nonadrenergic mediators released by endotoxin rather than the hypotensive stimulus.

Cognitive processes and the decisions of some parents to forego pertussis vaccination for their children.

Public health analyses suggest that, in spite of the possibility that pertussis vaccine may cause rare cases of neurological injury, catastrophic risks to individual children are lower if they are vaccinated. A number of parents, however, choose not to vaccinate their children. The purpose of this study was to investigate the decision processes of some parents who choose to vaccinate and some parents who choose not to do so. Surveys were mailed to 500 randomly selected subscribers of Mothering magazine. Two hundred and ninety-four completed questionnaires were returned (59%). In addition to well-recognized factors in vaccination decisions, perceived dangers of the vaccine, and of the disease and susceptibility to the disease, several cognitive processes not previously considered in vaccination decision studies were found to be important predictors in this population of parents: perceived ability to control children's susceptibility to the disease and the outcome of the disease; ambiguity or doubts about the reliability of vaccine information; a preference for errors of omission over errors of commission; and recognition that if many other children are vaccinated, the risk to unvaccinated children may be lowered. Although perhaps most cases of undervaccination for pertussis reflect more general problems of health care access, some parents choose to forego vaccination for their children for other reasons. Traditional risk-benefit arguments alone will be unlikely to persuade these parents to reassess their decisions. Efforts to increase childhood vaccination must incorporate an understanding of the cognitive processes that help drive these decisions.

Analysis of capacity decisions for progressive patient care hospital facilities.

In this study we provide a methodology for investigating the relationships between capacity decisions and selected performance measures for a progressive patient care facility. The methodology is illustrated with published data from a coronary care facility. The facility is modeled using a simulation approach. The utilization rate of each unit, the fraction of transfers blocked in each unit, and the proportion of each unit's patient-days resulting from inappropriate use are determined for a range of capacity levels. Finally, the results of this experimentation are transformed by regression analysis into prediction equations that give insight into the sensitivity of these performance measures to capacity levels and provide a useful tool for guiding resource allocation decisions.

Comparing aggregate estimates of derived thresholds for clinical decisions.

Thresholds for medical decision making are the probabilities of disease at which clinicians choose to initiate testing or therapy. A descriptive analysis of clinicians' decision making can derive their test and test-treatment thresholds and has the potential to explain variations in test utilization. A previously described method summarizes thresholds for a group of clinicians by determining the range of probability which includes the maximum number of clinicians' individual thresholds. However, there is no statistical procedure to compare the summary measure of thresholds that is derived from the distribution of clinicians' thresholds. We describe two alternative methods of developing a summary measure of the thresholds for a group of clinicians. These alternative methods enable the analyst to apply standard statistical tests when analyzing the decision-making behavior of groups of clinicians. For the "Unweighted Mean of the Midpoints" method, confidence limits of means and standard t-tests can be used to compare different groups. For the "Weighted Mean of the Midpoints" method, a weighted standard error of the mean can be calculated to determine confidence intervals, and a weighted t-test or weighted regression can be used to compare weighted means of the midpoints of threshold ranges.

Outcome bias in decision evaluation.

In 5 studies, undergraduate subjects were given descriptions and outcomes of decisions made by others under conditions of uncertainty. Decisions concerned either medical matters or monetary gambles. Subjects rated the quality of thinking of the decisions, the competence of the decision maker, or their willingness to let the decision maker decide on their behalf. Subjects understood that they had all relevant information available to the decision maker. Subjects rated the thinking as better, rated the decision maker as more competent, or indicated greater willingness to yield the decision when the outcome was favorable than when it was unfavorable. In monetary gambles, subjects rated the thinking as better when the outcome of the option not chosen turned out poorly than when it turned out well. Although subjects who were asked felt that they should not consider outcomes in making these evaluations, they did so. This effect of outcome knowledge on evaluation may be explained partly in terms of its effect on the salience of arguments for each side of the choice. Implications for the theory of rationality and for practical situations are discussed.

Clinical reasoning and cognitive processes.

Expected utility theory, and the Bayesian probability theory on which it is based, form the normative basis of most work in medical decision analysis. Recent work in the psychology of judgments and decisions indicates that people do not conform to the axioms of this theory and that these deviations occur in clinical reasoning as well as in the psychology laboratory. At issue is what to do now. The authors argue that the important next steps lie at the interface between descriptive, prescriptive, and normative accounts, all of which affect each other. They point to examples in which the simplest application of supposedly normative theory seems inappropriate, and suggest ways in which the tension between normative and descriptive models may be resolved.

Derived thresholds. Determining the diagnostic probabilities at which clinicians initiate testing and treatment.

The medical decision making literature has previously considered the test and test-treatment thresholds in a normative fashion. In the normative approach, the analyst calculates the optimal threshold--the likelihood of disease at which testing or treatment should be undertaken. In contrast, we describe a method of deriving the threshold in a descriptive fashion, by determining the probabilities of disease at which clinicians actually make the decision to test or to initiate specific treatment without further testing. In applying this method, the analyst first asks clinicians to provide an estimate of the prior probability of disease, and to select one of three options: test, treat, or do neither. After receiving new information about the patient, the clinicians are asked to revise the probability estimate and to select a new option. Correlation of changes in the probability of a disease with changes in the clinicians' selections of options to test or treat enables the analyst to estimate the test and test-treatment thresholds used by the clinicians in medical decision making. Knowledge of these thresholds also enables the analyst to calculate the clinicians' ratio of the benefits to the costs of the therapy being considered, considering the risks of the test itself.

The importance of considering single testing when two tests are available.

When considering two dichotomous tests in combination for reaching a treatment decision, the choice between single and multiple testing depends, in part, on the pretest probability of disease. The authors show that two tests are never preferred to a single test for all disease probabilities, regardless of whether the two tests are performed in parallel or in series.

Clinical guidelines for using two dichotomous tests.

Building on the threshold model developed by Pauker and Kassirer for a single test, the authors describe a decision analytic model for two tests with dichotomous outcomes. The model includes ten decision strategies that differ depending on which tests are performed, whether the tests are performed together or in sequence, and the definition of a positivity criterion used to make the treatment decision when the test results disagree. Formulas derived from the model are used to compute the preferred option as a function of disease probability and to calculate test and test-treatment thresholds. General guidelines developed from the model can be used without calculation to identify relative preferences for alternative options and to predict threshold effects.

Knowing for the sake of knowing: the value of prognostic information.

In evaluating diagnostic tests, traditional methods in decision analysis often emphasize how the results of the test will or will not affect patient management. Clinicians are advised to avoid testing if the results will not alter treatment strategy or other management plans. But patients may be interested in the prognostic information that testing provides even if it is not used to guide treatment. The authors present a model that defines this prognostic information as the expected deviation from the prior probability of disease. The model generates utility functions that are curvilinear over prior probabilities. Whereas the traditional threshold approach to medical decision making produces at most three zones of management strategy (withhold, test, and treat), the incorporation of prognostic information into threshold analysis produces two additional zones (test but withhold anyway, and test but treat anyway). Conditions under which one or both of these additional zones will appear are described. The model justifies the practice of performing tests that cannot alter management plans; it explains the unwillingness of some patients to undergo diagnostic testing when they fear unwanted results; and it provides a method for quantifying the sensitive nature of confidential tests. The model is illustrated using the antibody test for the Smith antigen. This test has a high specificity but a low sensitivity for lupus erythematosus. Clinicians may use the test because a positive result will support their prior suspicion of disease even though they may not change their management strategy if the test result is negative. The advantage of testing in this setting lies in the test's potential for establishing with virtual certainty that the disease is present. Thus, the test is valued for the prognostic information it provides apart from its effect on patient management.

Omission bias and pertussis vaccination.

BACKGROUND: Several laboratory studies have suggested that many people favor potentially harmful omissions over less harmful acts. The authors studied the role of this omission bias in parents' decisions whether to vaccinate their children against pertussis. METHODS: Two hundred mail surveys were sent to subscribers to a magazine that had published articles favoring and opposing pertussis vaccination. Subjects were asked about their beliefs about the vaccine and the disease, and whether they had vaccinated their own children or planned to, and they were given test items to identify omission bias in their reasoning. RESULTS: One hundred and three subjects (52%) responded to the survey. Respondents who reported they did not or would not allow their children to be vaccinated (n = 43; 41%) were more likely to believe that vaccinating was more dangerous than not vaccinating (p < 0.001). They were also more likely to exhibit omission bias (p = 0.004), holding constant their stated beliefs about the danger of the vaccine. CONCLUSIONS: Omission bias plays a role in decisions not to vaccinate with pertussis vaccine, beyond the role played by belief about the risk of vaccination.

Multiple test analyzer (MTA): a microcomputer program for determining preferred strategies with two diagnostic tests.

There are ten distinct management strategies in clinical situations that involve two diagnostic tests with dichotomous outcomes. The authors describe a microcomputer program, based on a previously described model, that can be used to identify test and test-treatment thresholds and to compute preferred strategies. The program provides tables and graphs of the results, which can be viewed or printed, and there is an optimization routine that facilitates comprehensive analysis. It can be used by decision-analytic researchers and policy analysts, medical educators who teach decision analysis, and clinicians who use decision analysis in their practices.

The single-cutoff trap: implications for Bayesian analysis of stress electrocardiograms.

Quantitative analysis of exercise electrocardiograms has been emphasized by many investigators. Specific problems have been found when a single cutoff is used to define a positive or a negative test: a single cutoff does not distinguish stress electrocardiography results that are slightly positive from those that are markedly positive. This may lead clinicians to underweigh strong evidence for or against coronary artery disease. This study evaluated clinicians' quantitative analysis of stress electrocardiograms. Two hundred and thirty-five physicians interpreted the results of mildly positive (1.2 mm ST-segment depression) and strongly positive (2.2 mm ST-segment depression) stress electrocardiograms. Their posttest probability estimates were too high for a mildly positive test (0.62 +/- 0.02 versus actual of 0.38; p less than 0.001) and too low for a strongly positive test (0.77 +/- 0.01 versus actual of 0.98; p less than 0.001). Physicians should understand decision aids and should use multiple rather than single cutoffs to interpret the results of stress electrocardiography.

Public preferences for prevention versus cure: what if an ounce of prevention is worth only an ounce of cure?

BACKGROUND: The belief that small preventive efforts bring large benefits may explain why many people say they value prevention above all other types of health care. However, it often takes a great deal of preventive medicine to prevent a bad outcome. This study explores whether people value prevention or cure more when each brings the same magnitude of benefit and examines whether preferences for prevention or cure vary according to the severity of the disability of the patients who can receive the preventive or curative intervention. METHODS: 289 prospective jurors were presented with a policy dilemma involving how best to allocate funds to benefit people with varying levels of disability. Each project was said to influence the functional ability of 100 nursing home residents, either by improving their level of function or by preventing their level of function from declining. RESULTS: When given a choice between preventive and curative interventions, more subjects preferred the preventive intervention (37% vs 21%, p=0.002). However, when the strength of people's preferences was taken into account, the preference for preventive interventions was not statistically significant (p=0.135). With both preventive and curative interventions, the subjects preferred helping patients with more severe disabilities (p < 0.005 for both comparisons). This preference for helping more severely disabled patients did not differ for prevention and cure (p=0.663). CONCLUSION: When the magnitude of benefit was held constant, the subjects slightly preferred prevention over cure. In addition, they preferred directing limited resources toward those with greater disabilities, regardless of whether those resources were targeted toward prevention or cure. These findings suggest that previously stated preferences for prevention over cure may result from a belief that small efforts at prevention will be repaid by large reductions in the later need for cure.

Assessing physicians' estimates of the probability of coronary artery disease: the influence of patient characteristics.

The authors assessed physicians' probability estimates of coronary artery disease (CAD) in 250 patients undergoing a screening exercise stress test. True likelihood of disease (prevalence) was derived from the literature. Discrimination and calibration were assessed by comparing physicians' probability estimates and prevalence using pairwise comparisons, rank correlation, and linear regression. There were differences in the discriminative abilities of the physicians based on patient characteristics. For example, the physicians had better discriminative ability for patients with typical cardiac chest pain compared with atypical chest pain. The physicians were able to predict the prevalence of CAD in broad groups of patients. However, they overestimated probabilities for patients with low prevalence of disease and underestimated probabilities for patients with high prevalence of disease. The authors conclude that physicians make consistent errors in the use of probability estimates. The quality of these estimates depends on patient characteristics such as type of chest pain and true likelihood of disease.

Further explorations of medical decisions for individuals and for groups.

BACKGROUND: Important discrepancies between clinical practice and health policy may be related to the ways in which physicians and others make decisions about individuals and groups. Previous research has found that physicians and laypersons asked to consider an individual patient generally make different decisions than those asked to consider a group of comparable patients, but this discrepancy has not been observed in more recent studies. This study was designed to explore possible reasons for these findings. METHODS: Prospective jurors (N = 1,013) each made a recommendation regarding a risky treatment for an incurable blood condition. Perspective (individual vs group) was crossed with uncertainty frame (probability vs frequency) and response wording (original vs revised) in a 2 x 2 x 2 between-participants design. RESULTS: When the strength of participants' recommendations was considered, the effects of perspective, uncertainty frame, and response wording were not statistically significant. When recommendations were dichotomized, participants in the revised-response-wording conditions were more likely to recommend treatment to the group than to the individual. CONCLUSIONS: These results conflict with previous findings for this scenario and suggest that reported differences between decisions for individuals and decisions for groups are not robust.

Carrier screening for cystic fibrosis: costs and clinical outcomes.

OBJECTIVES: To evaluate the costs and clinical effects of 16 alternative strategies for cystic fibrosis (CF) carrier screening in the reproductive setting; and to test the sensitivity of the results to assumptions about cost and detection rate, stakeholder perspective, DNA test specificity, chance of nonpaternity, and couples' reproductive plans. METHOD: Cost-effectiveness analysis. RESULTS: A sequential screening strategy had the lowest cost per CF birth avoided. In this strategy, the first partner was screened with a standard test that identifies 85% of carriers. The second partner was screened with an expanded test if the first partner's screen was positive. This strategy identified 75% of anticipated CF births at a cost of $367,000 each. This figure does not include the lifetime medical costs of caring for a patient with CF, and it assumes that couples who identify a pregnancy at risk will choose to have prenatal diagnosis and termination of affected pregnancies. The cost per CF birth identified is approximately half this figure when couples plan two children. CONCLUSIONS: The cost-effectiveness of CF carrier screening depends greatly on couples' reproductive plans. CF carrier screening is most cost-effective when it is performed sequentially, when the information is used for more than one pregnancy, and when the intention of the couple is to identify and terminate affected pregnancies. These conclusions are important for policy considerations regarding population-based screening for CF, and may also have important implications for screening for less common diseases.