An integrated clinical approach to predicting the benefit of tirofiban in non-ST elevation acute coronary syndromes. Application of the TIMI Risk Score for UA/NSTEMI in PRISM-PLUS.

AIMS: We evaluated the TIMI Risk Score for Unstable Angina and Non-ST Elevation Myocardial Infarction for predicting clinical outcomes and the efficacy of tirofiban in non-ST elevation acute coronary syndromes. METHODS AND RESULTS: Developed in TIMI 11B, the risk score is calculated as the sum of seven presenting characteristics (age > or =65 years, > or =3 cardiac risk factors, documented coronary disease, recent severe angina, ST deviation > or =0.5 mm, elevated cardiac markers, prior aspirin use). The risk score was validated in the PRISM-PLUS database (n=1915) and tested for interaction with the efficacy of tirofiban+heparin vs heparin alone. The risk score revealed an increasing gradient of risk for death, myocardial infarction or recurrent ischaemia at 14 days ranging from 7.7-30.5% (P<0.001). Dichotomized at the median, patients with a score > or =4 derived a greater relative risk reduction with tirofiban (P((Interaction))=0.025). Among patients with normal creatine kinase myocardial bands, the risk score showed a 3.5-fold gradient of risk (P<0.001) and identified a population that derived significant benefit from tirofiban (RR 0.73, P=0.027). CONCLUSION: The TIMI Risk Score is a simple clinical tool for risk assessment that may aid in the early identification of patients who should be considered for treatment with potent antiplatelet therapy.

[Effect of losartan on renal and cardiovascular complications of patients with type 2 diabetes and nephropathy]. / Effekt af losartan på nyre- og kardiovaskulaere komplikationer hos patienter med type 2-diabetes og nefropati.

INTRODUCTION: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in type 1 diabetic patients, but similar data are not available for type 2, the most common form of diabetes. We assessed the role of the angiotensin II receptor antagonist, losartan, in type 2 diabetic patients with nephropathy. MATERIAL AND METHODS: One thousand five hundred and thirteen patients were enrolled in this randomised, placebo-controlled study of losartan (50 to 100 mg, once daily) or placebo, in addition to conventional antihypertensive treatment (calcium antagonists, diuretics, alpha- and beta-blockers, centrally acting agents) for a mean of 3.4 years. The primary outcome was the composite of doubling of baseline serum creatinine, end-stage renal disease, or death. Secondary end points included a composite of cardiovascular morbidity and mortality, proteinuria, and the progression rate of renal disease. RESULTS: Baseline demographics in the two groups were similar. Three hundred and twenty-seven patients receiving losartan reached the primary end point, as compared with 359 on placebo (risk reduction = 16 per cent, p = 0.02). Losartan reduced the incidence of doubling of serum creatinine (risk reduction = 25 per cent, p = 0.006) and end-stage renal disease (risk reduction = 28 per cent, p = 0.002), but had no effect on death. Benefits exceeded that attributable to changes in blood pressure. The composite of cardiovascular morbidity and mortality was similar in the two groups, except hospitalisation for heart failure, which was reduced with losartan (risk reduction = 32 per cent, p = 0.005). Proteinuria declined by 35 per cent with losartan (p < 0.001). DISCUSSION: Losartan conferred significant renal benefits in type 2 diabetic patients with nephropathy and was generally well tolerated.

Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.

BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy. METHODS: A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease. RESULTS: A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo). CONCLUSIONS: Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.

Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in unstable angina or non-Q-wave myocardial infarction. Angiographic results from the PRISM-PLUS trial (Platelet receptor inhibition for ischemic syndrome management in patients limited by unstable signs and symptoms). PRISM-PLUS Investigators.

BACKGROUND: The present study describes the effects of tirofiban, a nonpeptide platelet glycoprotein (GP) IIb/IIIa receptor blocker, on the characteristics of culprit lesions in patients with unstable angina (UA) or non-Q-wave myocardial infarction (NQWMI). METHODS AND RESULTS: Of 1915 patients enrolled in PRISM-PLUS, 1491 had a readable film obtained a median of 65 hours after randomization. A core laboratory examined the culprit lesions for intracoronary thrombus burden (primary end point) and for TIMI flow grade distribution and severity of the obstruction and of underlying coronary artery disease (secondary end points). The combination of tirofiban plus heparin compared with heparin alone significantly reduced the intracoronary thrombus burden of the culprit lesions (OR=0.77, P=0.022), improved the perfusion grade (OR=0.65, P=0.002), and decreased the severity of the obstruction (P=0.037), but it did not influence the severity of the underlying plaque. Persistence of a thrombus in 45% of patients was associated with a 2.4-fold increase in the odds of death at 30 days (P=0.005) and a 2-fold increase in the odds of myocardial infarction (P=0.002). CONCLUSIONS: The addition of tirofiban to heparin reduced the thrombus burden of the culprit lesion and improved distal perfusion in patients with UA or NQWMI, which supports the clinical benefit observed with the combination treatment.

A discriminant analysis extension to mixed models.

Discriminant analysis is commonly used to classify an observation into one of two (or more) populations on the basis of correlated measurements. Classical discriminant analysis approaches require complete data for all observations. Our extension enables the use of all available longitudinal data, regardless of completeness. Traditionally a linear discriminant function assumes a common unstructured covariance matrix for both populations, which may be taken from a multivariate model. Here, we can model the correlated measurements and use a structured covariance in the discriminant function. We illustrate cases in which the estimated covariance structure is either compound symmetric, heterogeneous compound symmetric or heterogeneous autoregressive. Thus a structured covariance is incorporated into the discrimination process in contrast to standard discriminant analysis methodology. Simulations are performed to obtain a true measure of the effect of structure on the error rate. In addition, the usual multivariate expected value structure is altered. The impact on the discrimination process is contrasted when using the multivariate and random-effects covariance structures and expected values. The random-effects covariance structure leads to an improvement in the error rate in small samples. To illustrate the procedure we consider repeated measurements data from a clinical trial comparing two active treatments; the goal is to determine if the treatment could be unblinded based on repeated anxiety score measurements.

Power considerations when a continuous outcome variable is dichotomized.

An investigator can compare two groups with respect to a continuous outcome variable, Y, by comparing the means of Y or by collapsing that variable into categories. For example, antihypertensive treatments can be compared on the basis of blood pressure measurements, or on the basis of the proportions of patients with blood pressure in prespecified ranges. This report is concerned with the loss of power when inherently continuous variables are dichotomized. The report will focus on the power loss when a normally distributed variable with a known, common variance in each of two groups is dichotomized. Power is shown to depend on the relationship between the means of the two groups and the cutoff point, and it varies from negligible to substantial. The results will be applied to data from the Lovastatin Restenosis Trial. Initially the trial considered a dichotomous outcome (proportion of patients with elevated percent diameter stenosis), but the endpoint was later changed to the mean percent diameter stenosis. The modification in the design of the trial was well justified because the power loss was considerable when comparing proportions.

Survival analysis with uncertain endpoints.

In some survival analysis applications, the endpoint of interest has a degree of uncertainty associated with it. These events are typically classified by the investigator or by an endpoint committee as true or false according to some decision rule, and the analysis proceeds using only the true endpoints. This procedure has two drawbacks: The cut point for the decision rule is somewhat arbitrary, and the information contained in the level of certainty is lost. This paper introduces a modification of the Cox regression model that allows all potential endpoints to be included in the analysis along with the level of certainty of each. Simulation results show this procedure to considerably increase the power of the standard procedure in a wide range of situations.

A note on assessing the superiority of a combination drug with a specific alternative.

This paper describes a new statistical test for evaluating the efficacy of a combination therapy. This procedure is conservative and makes use of prior information in an attempt to improve power for a specific prespecified alternative. The power of this procedure is substantially greater than that of the min test when the effects of the components are equal or nearly equal and are accurately predicted. This procedure could be of value for evaluating combinations of well-studied drugs.

Benefit of converting enzyme inhibition on left ventricular volumes and ejection fraction in patients receiving beta-blockade after myocardial infarction. CONSENSUS II multiecho study group.

Beta-blockers reduce infarct size and improve survival after acute myocardial infarction (MI). Post-MI angiotensin-converting enzyme inhibition also improves survival and may attenuate left ventricular (LV) dilatation. We evaluated the effect of early enalapril treatment on LV volumes and ejection fraction (EF) in patients on concomitant beta-blockade after MI. Intravenous enalaprilat or placebo was administered <24 hours after MI and was continued orally for 6 months. LV volumes were assessed by echocardiography 3 +/- 2 days, 1 and 6 months after MI. Change in LV diastolic volume during the first month was attenuated with enalapril (2.7 vs placebo 6.5 ml/m2 change; p < 0.05), and significantly lower LV diastolic and systolic volumes were observed with enalapril treatment compared with placebo at 1 month (enalapril 47.21 23.9 vs placebo 53.1/29.2 ml/m2; p < 0.05) and at 6 months (enalapril 47.9/24.8 vs placebo 53.8/29.6 ml/m2; p < 0.05). EF was also significantly higher 1 month after MI in these patients (enalapril 50.4% vs placebo 46.4%; p < 0.05). Our date demonstrate that early enalapril treatment attenuates LV volume expansion and maintains lower LV volumes and higher EF in patients receiving concurrent beta-blockade after MI. A possible additive effect of combined therapy should be evaluated prospectively.

Losartan and low-dose hydrochlorothiazide in patients with essential hypertension. A double-blind, placebo-controlled trial of concomitant administration compared with individual components.

BACKGROUND: Angiotensin II acts at the cellular level through specific angiotensin II subtype I, AT-1 receptors. Losartan is the first of a new class of antihypertensive agents that specifically block angiotensin II at AT-1 receptors. By acting on complementary and different pharmacologic mechanisms, the concomitant use of low doses of hydrochlorothiazide with losartan may offer an additive antihypertensive activity with fewer adverse experiences. METHODS: This double-blind study evaluated losartan concomitantly administered with hydrochlorothiazide as initial therapy in 703 patients with essential hypertension. RESULTS: The greatest reduction in blood pressure was observed in the 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide group (17.2 mm Hg in sitting systolic blood pressure and 13.2 mm Hg in sitting diastolic blood pressure [P < or = .001]), and the effects of the two components appeared to be additive. Seventy-eight percent of the patients treated with 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide had an excellent or good antihypertensive response (sitting diastolic blood pressure < 90 mm Hg or > or = 90 mm Hg with a reduction of 10 mm Hg or more). Peak (6 hours after dosing) and trough placebo-adjusted ratios for the losartan-hydrochlorothiazide groups ranged from 62% to 85%, indicating that there was a smooth reduction in sitting diastolic blood pressure that was sustained over 24 hours. The most common clinical adverse experiences (> or = 4%) that occurred with an incidence slightly greater than that reported by the placebo-treated patients were headache, asthenia or fatigue, dizziness, sinusitis, and upper respiratory infection. CONCLUSION: The concomitant administration of losartan potassium, 50 mg, with 12.5 mg of hydrochlorothiazide once daily produced an additive reduction in trough sitting systolic and diastolic blood pressure and was well tolerated.

Monitoring of clinical trials and interim analyses from a drug sponsor's point of view.

This paper illustrates aspects of data monitoring of clinical trials in the pharmaceutical industry. Formal interim analyses are performed at least in part to address the question of whether the trial should proceed or whether there should be an early termination of the trial. For formal interim analyses, frequently independent data and safety monitoring committees are utilized for monitoring clinical trials, and adjustments to nominal significance levels for test statistics are required. Various statistical methods developed during the last fifteen years are utilized. Administrative interim analyses are those analyses that are performed without any intention to stop the trial as a consequence of those analyses. For administrative interim analyses, adjustments to significance levels may not be required, but results must still be carefully interpreted. Regardless of the interim analyses performed, it is critical that the plans for interim analyses be identified in the study protocol, and the dissemination of interim results be carefully restricted. The following clinical trials sponsored by Merck Sharp and Dohme Research Laboratories (MSDRL) will illustrate these points: CONSENSUS; CONSENSUS II; 4S; Haemophilus influenza type b efficacy trial; famotidine in upper gastrointestinal haemorrhage, and a phase II analgesic study. It is anticipated that data monitoring and interim analysis activities will increase for future clinical trials due to the availability of appropriate statistical methods and improved data management systems.

Monitoring clinical trials with a conditional probability stopping rule.

Conditional probability procedures offer a flexible means of performing sequential analysis of clinical trials. Since these procedures are not based on repeated significance test, the number and schedule of the interim analyses is less important than with group sequential procedures. Their main disadvantage is that the magnitude of their effect on the significance level is difficult to assess. This paper describes a conditional probability procedure which attempts to maintain the overall significance level by balancing the probabilities of false early rejection and false early acceptance. Monte Carlo sampling results suggest that this procedure can achieve a large reduction in expected sample size without greatly affecting either the significance level or power of the trial.

Hemodynamic effects of lisinopril after long-term administration in congestive heart failure.

To determine whether acute effects of the angiotensin converting enzyme inhibitor lisinopril are maintained during long-term therapy, 19 patients were studied using right-sided heart catheterization before an initial randomized dose of lisinopril and again after 12 weeks of maintenance lisinopril therapy. During initial evaluation, lisinopril produced significant decreases in mean systemic arterial pressure, pulmonary artery wedge pressure, systemic vascular resistance, mean pulmonary arterial pressure, mean right atrial pressure and pulmonary vascular resistance, and concomitant increases in cardiac index and stroke volume index. After 12 weeks of therapy with lisinopril, the dosage of which was titrated to produce optimal relief of symptoms of congestive heart failure (CHF), repeat hemodynamic studies revealed persistent significant reductions in baseline systemic arterial pressure, pulmonary artery wedge pressure, mean pulmonary arterial pressure and systemic vascular resistance. However, the increases in cardiac index and stroke volume index were not statistically significant. To determine if further acute hemodynamic changes occur during long-term therapy, the patients were readministered a dose of lisinopril. This caused further decreases in systemic arterial pressure, mean pulmonary arterial pressure, pulmonary artery wedge pressure, systemic vascular resistance and mean right atrial pressure, and an increase in cardiac index. Lisinopril did not change stroke work index at either initial or rechallenge study. This study indicates that in patients with CHF treated with lisinopril, acute hemodynamic effects persist after 12 weeks of therapy, and acute hemodynamic response continues to occur upon drug readministration.

Estimation of error rates in discriminant analysis with selection of variables.

Accurate estimation of misclassification rates in discriminant analysis with selection of variables by, for example, a stepwise algorithm, is complicated by the large optimistic bias inherent in standard estimators such as those obtained by the resubstitution method. Application of a bootstrap adjustment can reduce the bias of the resubstitution method; however, the bootstrap technique requires the variable selection procedure to be repeated many times and is therefore difficult to compute. In this paper we propose a smoothed estimator that requires relatively little computation and which, on the basis of a Monte Carlo sampling study, is found to perform generally at least as well as the bootstrap method.

Evaluating the efficacy of a combination therapy.

Standard multiple comparison techniques do not adequately address the situation in which one must demonstrate a combination therapy's superiority to both of its components. This paper proposes several alternative tests to deal with this situation, and evaluates the tests with a Monte Carlo sampling experiment that compares the actual with the nominal significance levels of the tests. Data from a clinical trial that compares the efficacy of a combination analgesic/muscle relaxant to its components and placebo in the treatment of low back pain and spasm illustrate the tests.

Tests of significance using regression models for ordered categorical data.

Regression models of the type proposed by McCullagh (1980, Journal of the Royal Statistical Society, Series B 42, 109-142) are a general and powerful method of analyzing ordered categorical responses, assuming categorization of an (unknown) continuous response of a specified distribution type. Tests of significance with these models are generally based on likelihood-ratio statistics that have asymptotic chi 2 distributions; therefore, investigators with small data sets may be concerned with the small-sample behavior of these tests. In a Monte Carlo sampling study, significance tests based on the ordinal model are found to be powerful, but a modified test procedure (using an F distribution with a finite number of degrees of freedom for the denominator) is suggested such that the empirical significance level agrees more closely with the nominal significance level in small-sample situations. We also discuss the parallels between an ordinal regression model assuming underlying normality and conventional multiple regression. We illustrate the model with two data sets: one from a study investigating the relationship between phosphorus in soil and plant-available phosphorus in corn grown in that soil, and the other from a clinical trial comparing analgesic drugs.

A method for constructing case-mix indexes, with application to hospital length of stay.

This article presents the methodological development of an index for case-mix adjustment of hospital data exemplified by our construction of an index for studying length of stay. We describe the development and evaluation of this index, including internal and external validation procedures, and show an example of its use in a policy-relevant context by applying it to the analysis of length-of-stay differences between investor-owned and voluntary hospitals. Some advantages of this approach to adjusting for case mix are applicability to many hospital or patient output measurements/diagnostic scheme situations; usefulness in reducing heterogeneity in other case-mix adjustments, e.g., the Diagnosis-Related Group (DRG) approach; interpretation possibilities; production of a single score for each patient/hospital; statistical approach allowing more accurate and reliable interpretation of hospital and patient output measurements, ability to deal with hospital deaths; and consideration of the complete set of secondary diagnoses. We also suggest other possible uses of this approach.

Inlet and intrachamber concentration distributions in tracer studies of the canine central circulation and their relation to the isotope dilution residue function.

We analyzed the isotope dilution residue function from a single cardiac chamber for an arbitrary inlet distribution of tracer and arbitrary mixing within the chamber, and established a general relationship between cardiac output and the chamber residue function. In our experiments, we made simultaneous temperature measurements in three left ventricular chamber subregions of the dog subjected to left and right atrial injections of chilled saline. Flow-proportional tracer labeling always occurred at the left ventricular inlet when injection was into the right atrium. This state almost never obtained, however, with direct left atrial injection, although it was approximated most closely when multiple side hole cathers were used. We also demonstrated that imperfect tracer mixing in the normal ventricle can lead to significant regional temperature inequalities during tracer passage. These inequalities are more pronounced in the ventricle with compromised function, but in both normal and compromised ventricles they are minimal several beats after tracer concentration peaks if injection is into the right atrium.