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.

Glycoprotein IIb/IIIa receptor blockade improves outcomes in diabetic patients presenting with unstable angina/non-ST-elevation myocardial infarction: results from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study.

BACKGROUND: Diabetic patients who present with unstable angina or non-ST-elevation myocardial infarction suffer a substantially greater incidence of subsequent infarction or death compared with nondiabetic patients. The present study was undertaken to examine whether diabetic patients in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study appeared to benefit from platelet glycoprotein IIb/IIIa receptor-mediated inhibition of platelet aggregation by tirofiban. METHODS AND RESULTS: Of the 1570 PRISM-PLUS patients treated with either tirofiban plus heparin (n=773) or heparin alone (n=797), approximately 23% in each treatment group were diabetic. A comparison of treatment outcomes in the diabetic subgroup revealed that the combination therapy compared with heparin alone was associated with reductions in the incidence of the composite primary end point of death, myocardial infarction (MI), or refractory ischemia at 2, 7, 30, and 180 days (7.7% versus 8.3%, 14. 8% versus 21.8%, 20.1% versus 29.0%, and 32.0% versus 39.9%, respectively; P=NS) and in the incidence of MI or death (0.0% versus 3.1%, P:=0.03; 1.2% versus 9.3%, P:=0.005; 4.7% versus 15.5%, P:=0. 002; and 11.2% versus 19.2%, P:=0.03). Tests for quantitative interaction between tirofiban therapy and diabetic status were significant. CONCLUSIONS: The addition of tirofiban to heparin and aspirin appears effective in the prevention of major ischemic events, particularly MI or death, in diabetic patients presenting with unstable angina and non-ST-elevation MI.

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.

Effects of enalapril on long-term mortality in severe congestive heart failure. CONSENSUS Trial Group.

All surviving patients in a double-blind study comparing the effects of enalapril and placebo on survival in severe congestive heart failure were recommended to be treated with active drug after stopping the trial. Two-year follow-up from the end of the blinded trial demonstrated that among 77 survivors of 127 patients originally allocated to the group with enalapril, 38 were still alive. Of 126 patients allocated to the group with placebo 58 survived the blinded study, and after 2-year follow-up 26 were still alive. Thus, the difference between the original treatment groups remained, despite that treatment with enalapril was made available to all surviving patients and that those in the group with enalapril were sicker at baseline than those in the group with placebo. If enalapril was prescribed, the mortality was 47% compared with 75% if it was not. Life-table analysis suggests a marked carry-over effect of treatment in the group with enalapril that lasted for up to 15 months before mortality rates became comparable in the 2 treatment groups. This strongly suggests that enalapril confers structural protection to the failing myocardium.

Effects of enalapril and neuroendocrine activation on prognosis in severe congestive heart failure (follow-up of the CONSENSUS trial). CONSENSUS Trial Study Group.

This study enrolled 253 patients with severe heart failure (New York Heart Association functional class IV) from 35 centers in Scandinavia, randomly assigned to treatment with placebo or enalapril, in addition to their usual treatment for heart failure. After an initial titration period, the daily doses of enalapril ranged from 2.5 to 40 mg. At the end of the trial, 46% of the placebo-treated patients and 61% of the enalapril-treated patients were alive (p = 0.003); the survival figures at 8 months after completion of the trial were 32 and 48%, respectively (p = 0.001); and 21 and 30%, respectively (p = 0.006) at the 2-year follow-up. In the placebo group, there was a significant positive association between mortality and baseline levels of norepinephrine, epinephrine, angiotensin II, aldosterone and atrial natriuretic peptide; no such association was found in the enalapril-treated patients. The results suggest that the effects of enalapril on mortality are related to a counteraction of the neuroendocrine activation in general and to the renin-angiotensin system in particular.

Validation of a computerized technique for detection of the gas exchange anaerobic threshold in cardiac disease.

Respiratory gas exchange data were collected from 77 men greater than 6 months after acute myocardial infarction. Maximal exercise was performed on an ergometer cycle programmed for a ramp protocol of 15 W/min. The gas exchange anaerobic threshold (ATge) was determined by analysis of the carbon dioxide elimination (VCO2) vs oxygen consumption (VO2) curve below a respiratory exchange ratio of 1.00 using a computerized algorithm. This value was estimated at the inflection of VCO2 from a line with a slope of 1 which intersects the VCO2 vs VO2 curve. The relation of the ATge to the lactate acidosis threshold was studied in 29 patients. The reproducibility of the ATge method was studied in 77 patients. Mean (+/- standard deviation) VO2 for the ATge was 905 +/- 220 vs 866 +/- 299 ml/min for the lactate acidosis threshold (r = 0.86, p less than 0.001). Mean VO2 at the ATge for test 1 was 968 +/- 225 vs 952 +/- 217 ml/min for test 2 (r = 0.71, p less than 0.001). Mean peak VO2 was 1,392 +/- 379 vs 912 +/- 202 ml/min at the ATge (r = 0.76, p less than 0.001). Results demonstrate that this ATge method correlates well with the lactate acidosis threshold, is reproducible, and should be useful as an objective measure of submaximal exercise performance.

A risk score system for predicting adverse outcomes and magnitude of benefit with glycoprotein IIb/IIIa inhibitor therapy in patients with unstable angina pectoris.

Clinical outcomes of patients with unstable angina are variable. We sought to identify predictors of adverse clinical outcomes in patients with unstable angina and to investigate whether these factors would predict the magnitude of benefit achieved with platelet glycoprotein IIb/IIIa inhibition. We analyzed 20 variables in the 1,915 patients enrolled in the Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial. Five independent predictors were identified: age >65 years, prior coronary artery bypass grafting, antecedent aspirin use, antecedent beta-blocker use, and ST depressions on the presenting electrocardiogram. A risk score system was created using these predictors in which patients were assigned 1 point for the presence of each risk factor. There was a progressive increase in the rate of the composite end point of death, myocardial infarction, or refractory ischemia at 7 days with an increasing number of risk factors. For patients treated with heparin alone, the composite end point event rate was 6.5% in the group with 0 or 1 predictor, 14.6% in the group with 2 predictors, 22.7% in the group with 3 predictors, and 37.1% in the group with 4 or 5 predictors (p <0.00001). When dividing patients into low- (0 or 1 point), medium- (2 or 3 points), and high-risk (4 or 5 points) groups, the addition of tirofiban to heparin therapy was associated with no significant benefit in the low-risk group, a 5.2% absolute reduction in the medium-risk group (p = 0.05), and a 16% absolute reduction in the high-risk group (p = 0.0055). Thus, we have developed a risk score system using 5 variables that can be used to identify patients at high risk for death and cardiac ischemic events and who experience the greatest benefit from the addition of a glycoprotein IIb/IIIa inhibitor to their treatment regimen.

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.

Randomized, placebo-controlled comparison of famotidine 20 mg b.d. or 40 mg b.d. in patients with erosive oesophagitis.

METHODS: This US multicentre, randomized, double-blind, placebo-controlled, parallel group study determined the effects of two twice daily oral famotidine regimens on symptom relief and healing of erosive oesophagitis in patients with gastro-oesophageal reflux disease. Three hundred and eighteen patients were enrolled: 66 received placebo, 125 received famotidine 20 mg b.d., and 127 received famotidine 40 mg b.d. Patients maintained diaries of their symptoms. Endoscopy was performed at weeks 0 and 6, and again at week 12 if healing had not occurred. RESULTS: Healing at 6 and 12 weeks was (respectively) 48% (P < or = 0.01 vs. placebo) and 69% (P < or = 0.01 vs. placebo) for famotidine 40 mg b.d.; 32% and 54% (P < or = 0.01 vs. placebo) for famotidine 20 mg b.d., and 18% and 29% for placebo. At both 6 and 12 weeks the healing rates of famotidine 40 mg b.d. were significantly greater than placebo and famotidine 20 mg b.d. Compared to placebo, famotidine produced more frequent global symptom improvement and more rapid heartburn relief. There were no significant differences among treatment groups in the incidence of clinical or laboratory adverse events. CONCLUSIONS: Famotidine 40 mg b.d. was a better regimen than famotidine 20 mg b.d. or placebo. The clinical efficacy paralleled the previously documented effect of the famotidine regimens on decrease of oesophageal acid exposure.

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.

The plasma concentration of N-terminal proatrial natriuretic factor ANF(1-98) is related to prognosis in severe heart failure.

Due to its longer halflife, the N-terminal of ANF prohormone, ANF(1-98), has plasma concentrations that exceed those of ANF itself by a factor of 10 or more. It is also less prone to rapid changes secondary to hemodynamic alterations. To evaluate the prognostic significance of ANF(1-98) plasma levels in severe heart failure (NYHA IV), the peptide was measured by radioimmunoassay in plasma samples from patients randomized to additional treatment with enalapril (n = 78) or placebo (n = 61) (CONSENSUS study). In the placebo group there was a positive relation between mortality after 6 months and baseline ANF(1-98) level. Because of a reduced mortality, especially among patients with high ANF(1-98) levels, there was no such relation in the patients treated with enalapril. For both groups there was a positive relationship between increase in ANF(1-98) after 6 weeks of treatment and mortality, while a decrease signaled a favorable prognosis. It is concluded that the magnitude and changes of plasma ANF(1-98) provide information on prognosis and therapeutic effects with respect to mortality in patients with severe heart failure. Plasma ANF(1-98) may serve as a useful clinical biochemical parameter in the treatment of heart failure.

[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.

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.

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.

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.

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.

Long-term survival in severe heart failure in patients treated with enalapril. Ten year follow-up of CONSENSUS I.

BACKGROUND: The CONSENSUS trial was the first study to show prognostic improvement by an ACE inhibitor. Patients in NYHA class IV heart failure were treated with enalapril or placebo. After study completion (average 183 days) all patients were offered open-label enalapril therapy. This paper reports on the survival at the 10-year follow up of the patients randomized in the CONSENSUS trial. METHODS: All 35 participating centres in CONSENSUS I were asked to complete a questionnaire on the survival status at 1 November 1996 of patients randomized in CONSENSUS. RESULTS: At 10-year follow up, one patient was lost to follow-up. Five patients, all in the enalapril group, were long-term survivors (P = 0.004). Averaged over the duration of the trial (double-blind plus open-label extension) the risk reduction was 30% (P = 0.008), with a 95% confidence interval of 11% to 46%. At the end of the double-blind study period, mortality was considerably higher among patients who did not receive open ACE inhibitor therapy compared to those who did. CONCLUSION: After a treatment period of, on average, 6 months, enalapril was shown to be effective. The effect was sustained for at least 4 years i.e. for another 3.5 years. The present follow-up is the first heart failure trial where the full life-cycle has been followed from randomization. In severe heart failure, mortality is significantly reduced by enalapril. On average, the beneficial effect is maintained for several years and overall survival time is prolonged by 50% (from 521 to 781 days).

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.

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.

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.