Generalized pairwise comparison methods to analyze (non)prioritized composite endpoints.

In the analysis of composite endpoints in a clinical trial, time to first event analysis techniques such as the logrank test and Cox proportional hazard test do not take into account the multiplicity, importance, and the severity of events in the composite endpoint. Several generalized pairwise comparison analysis methods have been described recently that do allow to take these aspects into account. These methods have the additional benefit that all types of outcomes can be included, such as longitudinal quantitative outcomes, to evaluate the full treatment effect. Four of the generalized pairwise comparison methods, ie, the Finkelstein-Schoenfeld, the Buyse, unmatched Pocock, and adapted O'Brien test, are summarized. They are compared to each other and to the logrank test by means of simulations while specifically evaluating the effect of correlation between components of the composite endpoint on the power to detect a treatment difference. These simulations show that prioritized generalized pairwise comparison methods perform very similarly, are sensitive to the priority rank of the components in the composite endpoint, and do not measure the true treatment effect from the second priority-ranked component onward. The nonprioritized pairwise comparison test does not suffer from these limitations and correlation affects only its variance.

Clinical and angiographic factors associated with asymptomatic restenosis after percutaneous coronary intervention.

BACKGROUND: Angiographic restenosis after percutaneous coronary interventional procedures is more common than recurrent angina. Clinical and angiographic factors associated with asymptomatic versus symptomatic restenosis after percutaneous coronary intervention were compared. METHODS AND RESULTS: All patients with angiographic restenosis from the BENESTENT I, BENESTENT II pilot, BENESTENT II, MUSIC, WEST 1, DUET, FINESS 2, FLARE, SOPHOS, and ROSE studies were analyzed. Multivariate analysis evaluated 46 clinical and angiographic variables, comparing those with and without angina. The 10 studies recruited 2690 patients who underwent percutaneous revascularization and 6-month follow-up angiography (86% of those eligible). Restenosis (>/=50% diameter stenosis) occurred in 607 patients and was clinically silent in 335 (55%). Male sex (P=0.008), absence of antianginal therapy with nitrates (P=0.0002) and calcium channel blockers (P=0.02) at 6 months, greater reference diameter after the procedure (P=0.04), greater reference diameter at follow-up (P=0.004), and lesser lesion severity (percent stenosis) at 6 months (P=0.0004) were univariate predictors of asymptomatic restenosis. By multivariate analysis, only male sex (P=0.04), greater reference diameter at follow-up (P=0.002), and lesser lesion severity at 6 months (P=0.0001) were associated with restenosis without angina. CONCLUSIONS: Approximately half of patients with angiographic restenosis have no symptoms. The only multivariate predictors of silent restenosis at 6 months were male sex, greater reference diameter at follow-up, and lesser lesion severity on follow-up angiography.

Randomized comparison of primary stenting and provisional balloon angioplasty guided by flow velocity measurement. Doppler Endpoints Balloon Angioplasty Trial Europe (DEBATE) II Study Group.

BACKGROUND: Coronary stenting improves outcomes compared with balloon angioplasty, but it is costly and may have other disadvantages. Limiting stent use to patients with a suboptimal result after angioplasty (provisional angioplasty) may be as effective and less expensive. METHODS AND RESULTS: To analyze the cost-effectiveness of provisional angioplasty, patients scheduled for single-vessel angioplasty were first randomized to receive primary stenting (97 patients) or balloon angioplasty guided by Doppler flow velocity and angiography (523 patients). Patients in the latter group were further randomized after optimization to either additional stenting or termination of the procedure to further investigate what is "optimal." An optimal result was defined as a flow reserve >2.5 and a diameter stenosis <36%. Bailout stenting was needed in 129 patients (25%) who were randomized to balloon angioplasty, and an optimal result was obtained in 184 of the 523 patients (35%). There was no significant difference in event-free survival at 1 year between primary stenting (86.6%) and provisional angioplasty (85.6%). Costs after 1 year were significantly higher for provisional angioplasty (EUR 6573 versus EUR 5885; P:=0.014). Results after the second randomization showed that stenting was also more effective after optimal balloon angioplasty (1-year event free survival, 93.5% versus 84.1%; P:=0. 066). CONCLUSIONS: After 1 year of follow-up, provisional angioplasty was more expensive and without clinical benefit. The beneficial value of stenting is not limited to patients with a suboptimal result after balloon angioplasty.

Increased serum levels of fibrinogen degradation products due to treatment with recombinant tissue-type plasminogen activator for acute myocardial infarction are related to bleeding complications, but not to coronary patency. European Co-operative Study Groups for rt-PA.

The association of increasing serum levels of fibrinogen degradation products after recombinant tissue-type plasminogen activator (rt-PA) therapy with bleeding and early coronary patency was assessed in 242 patients with acute myocardial infarction. After administration of 5,000 IU heparin, a median of 40 mg (range 35 to 60) of double chain rt-PA was given intravenously in 90 min. Bleeding occurred in 62 patients; in 73% of patients it was observed within the 1st 24 h and 84% of events consisted of hematoma or prolonged bleeding, or both, at puncture sites. Bleeding events occurred 2.12 times as often in patients with serum levels of fibrinogen degradation products greater than 85 mg/liter as in patients with serum levels less than 22 mg/liter (95% confidence interval 1.01 to 4.43). The infarct-related coronary vessel was patent in 65% of patients at 90 min after the start of rt-PA infusion. In patients with high serum levels of fibrin(ogen) degradation products, coronary patency at 90 min after the start of rt-PA infusion was not better (13% less, 95% confidence interval - 33%, 13%) than in patients with low serum levels. This uncoupling of thrombolytic effect in terms of coronary patency and systemic fibrinogenolysis confirms the experimentally demonstrated fibrin specificity of double chain rt-PA in human subjects. Because fibrin specificity of single chain rt-PA is at least similar to that of double chain rt-PA, the observations in this analysis most likely hold also for single chain rt-PA.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and quantitative coronary angiographic predictors of coronary restenosis: a comparative analysis from the balloon-to-stent era.

OBJECTIVES: We sought to assess whether coronary stents have modified the predictive value of demographic, clinical and quantitative coronary angiographic (QCA) predictors of coronary restenosis. BACKGROUND: A systematic analysis in a large cohort of registries and randomized trials of the percutaneous transluminal coronary angioplasty (PTCA) and stent era has never been performed. METHODS: A total of 9,120 treated lesions in 8,156 patients included in nine randomized trials and 10 registries, with baseline, post-procedural and six-month follow-up QCA analyses, were included in this study. Predictors of restenosis were identified with univariate and multivariate logistic regression analyses. Interaction terms were introduced in the regression equation to evaluate whether the predictors of restenosis were common to both eras or specific for either one of the revascularization techniques. RESULTS: The restenosis rate was 35% after PTCA and 19% after angioplasty with additional stenting. In the univariate analysis, favorable predictors were previous coronary artery bypass graft surgery (CABG), stent use, stent length and a large pre-procedural minimal lumen diameter (pre-MLD); unfavorable predictors were weight, body mass index, diabetes mellitus, multi-vessel disease, lesion length and a high residual post-procedural diameter stenosis (post-DS). Predictors specific for the PTCA population were a large post-procedural MLD (post-MLD) as favorable and a severe pre-procedural DS (pre-DS) as unfavorable. Favorable predictors specific for the stent population were a large post-MLD and a large pre-procedural reference diameter (pre-RD). In the multivariate analysis, the best model included the following favorable predictors: stent use, a large post-MLD, previous CABG and the interaction term between stent use and a large post-MLD; unfavorable predictors were lesion length and diabetes mellitus. CONCLUSIONS: There are no major differences in demographic and clinical predictors of coronary restenosis between PTCA and stent populations. In the modern (stent) era, a severe pre-DS is no longer an unfavorable predictor of restenosis. Still important, but more so in the stent population, is a large post-MLD (optimal result). Finally, a larger pre-RD became a favorable predictor with the advent of stenting.

Myocardial protection by intravenous diltiazem during angioplasty of single-vessel coronary artery disease.

The possible cardioprotective effect of diltiazem during ischemia caused by percutaneous transluminal coronary angioplasty was tested. Electrocardiograms and myocardial lactate, hypoxanthine and urate production were determined in 26 patients with a stenosis in the left anterior descending artery without angiographically demonstrable collaterals. Measurements took place before angioplasty, after each of 4 occlusions and 15 minutes after the last balloon inflation. Patients were randomly given placebo or DL-diltiazem (0.4 mg/kg as a bolus intravenously, followed by an infusion of 15 mg/hr). During angioplasty the ST-segment elevation for the anterior wall leads V2, V4 and V6, and the intracoronary lead was similar for both groups, as was lactate release. Diltiazem significantly reduced cardiac hypoxanthine release immediately after angioplasty from 63 to 88% (p less than 0.05). The drug diminished urate production after the last dilatation by 82% (p less than 0.05). In conclusion, intravenous infusion of diltiazem reduced cardiac adenosine triphosphate breakdown during angioplasty as shown by diminished hypoxanthine and urate production. In contrast, diltiazem was unable to attenuate ST-segment elevation and lactate release.

Reproducibility of carotid vessel wall thickness measurements. The Rotterdam Study.

We studied the reproducibility of measurement of ultrasonographically assessed common carotid intima-media thickness and assessed whether measurement error of intima-media thickness occurred randomly or was associated with potential determinants of atherosclerosis. Eighty participants of the Rotterdam Study underwent a second ultrasound scan of both carotid arteries within 3 months of the first scan. The replicate measurements involved the posterior intima-media thickness of the distal common carotid artery. Mean differences (SD) in intima-media thickness of the right common carotid artery between paired measurements of sonographers, readers and visits were -0.004 mm (0.10), 0.066 mm (0.07), and -0.013 mm (0.13), respectively. Similar results were obtained for the left common carotid artery. Measurement error of intima-media thickness, i.e. the absolute difference in measurements between two subsequent visits, increased significantly with increasing common carotid intima-media thickness. This association disappeared after logarithmical transformation of the intima-media thickness data. Age, sex, smoking, body mass index, serum lipids, fibrinogen, and systolic and diastolic blood pressure were not significantly associated with the measurement error of intima-media thickness. Our findings indicate that measurements of common carotid intima-media thickness are highly reproducible. Measurement error of intima-media thickness is small and appears to be proportional with the level of intima-media thickness and is not significantly associated with most risk factors for atherosclerotic vessel wall disease.

Efficiency optimization of the selection period in therapeutic trials.

To determine eligibility for a (randomized) clinical trial, measuring the inclusion and exclusion criteria can be extended over a period of time. During this period, known as the selection period, a patient is repeatedly examined at certain time intervals. This study describes an approach for optimizing the efficiency of the selection period. Efficiency is defined as the costs of randomizing one patient. The objective is to construct prediction models based on data obtained early in the selection period to predict subsequent exclusions. A prediction model increases the efficiency if after its application the costs per randomization are lower. The approach is illustrated using data from the selection period of the Rotterdam Cardiovascular Risk Intervention (ROCARI) trial which was composed of five consecutive patient visits. At each visit, data to determine eligibility was obtained. We found that logistic regression models based on data of the first and second visit could predict exclusions during the third visit. Application of the prediction models suggested that in this particular trial the costs per randomization would decrease by $52. As the initial costs per randomization were $1444, there would be a 3.6% (52/1444) savings in recruitment costs under the prediction models, accounting for a savings of more than $450,000. We conclude that the use of data obtained early in a selection period can predict subsequent exclusions, and therefore could increase the efficiency of such a period. The approach could be applied to data obtained in a pilot study as well as data obtained in the beginning of a prolonged intake period.

Effect of acadesine on myocardial ischaemia in patients with coronary artery disease.

Acadesine, an adenosine regulating agent, attenuates the adverse effects of ischaemia on ventricular function in animals. This study examined its influence on pacing-induced ischaemia in 47 patients undergoing coronary angiography. After 15 min of recovery from control pacing, an infusion of acadesine (5, 10, 20, 50 mg/kg i.v.) was commenced and after a further 15 min the protocol was repeated with the infusion continued. At higher doses, minor beneficial effects on ejection fraction and myocardial lactate metabolism were observed. Haemodynamics were unaffected. Systemic lactate rose in relation to acadesine, up to 60% (P < 0.001 versus placebo). The data may indicate that acadesine stimulates anaerobic glycolysis in man.

Application of treatment thresholds to diagnostic-test evaluation: an alternative to the comparison of areas under receiver operating characteristic curves.

Diagnostic tests are often evaluated by comparison of the areas under receiver operating characteristic (ROC) curves. In this study the authors compared this approach with a more direct method that takes into account consequences of a diagnosis. Data from a prospective study of diagnosis of pulmonary embolism were used for a motivating example. Using multivariable logistic regression analysis, three diagnostic models were built and compared based on their ROC curves. Although model 1 (0.706) and model 2 (0.702) had the same ROC-curve area, they performed differently when risks and benefits of subsequent decisions were considered by applying the treatment probability threshold. Models 1 and 3 (0.611) had substantially different ROC-curve areas but performed similarly taking into account the therapeutic consequences. This demonstrates that comparison of diagnostic tests using the areas under the ROC curves may lead to erroneous conclusions about therapeutic usefulness. To correspond to daily practice, it would be more appropriate to also consider the clinical implications in evaluating diagnostic tests. This is made feasible by explicit definition and application of a treatment threshold.

One year cost effectiveness of sirolimus eluting stents compared with bare metal stents in the treatment of single native de novo coronary lesions: an analysis from the RAVEL trial.

OBJECTIVE: To assess the balance between costs and effects of the sirolimus eluting stent in the treatment of single native de novo coronary lesions in the RAVEL (randomised study with the sirolimus eluting Bx Velocity balloon expandable stent in the treatment of patients with de novo native coronary artery lesions) study. DESIGN: Multicentre, double blind, randomised trial. SETTING: Percutaneous coronary intervention for single de novo coronary lesions. PATIENTS: 238 patients with stable or unstable angina. INTERVENTIONS: Randomisation to sirolimus eluting stent or bare stent implantation. MAIN OUTCOME MEASURES: Patients were followed up to one year and the treatment effects were expressed as one year survival free of major adverse cardiac events (MACE). Costs were estimated as the product of resource utilisation and Dutch unit costs. RESULTS: At one year, the absolute difference in MACE-free survival was 23% in favour of the sirolimus eluting stent group. At the index procedure, sirolimus eluting stent implantation had an estimated additional procedural cost of 1286. At one year, however, the estimated additional cost difference had decreased to 54 because of the reduction in the need for repeat revascularisations in the sirolimus group (0.8% v 23.6%; p < 0.01). After adjustment of actual results for the consequences of angiographic follow up (correction based on data from the BENESTENT (Belgium Netherlands stent) II study), the difference in MACE-free survival was estimated at 11.1% and the additional one year costs at 166. CONCLUSIONS: The one year data from RAVEL suggest an attractive balance between costs and effects for sirolimus eluting stents in the treatment of single native de novo coronary lesions. The cost effectiveness of drug eluting stents in more complex lesion subsets remains to be determined.

Serum potassium values in relation to the use of diuretics in patients with unstable angina pectoris.

Transient hypokalaemia may occur in acutely ill patients and is associated with an increased incidence of life-threatening arrhythmias. Therefore, we performed a retrospective analysis of the serum potassium values of 538 patients with unstable angina included in the Holland Interuniversity Nifedipine/metoprolol Trial in relation to the use of diuretics. On admission, 113 of these patients used diuretics. Potassium sparing diuretics had been used in 65 patients (group A) and non-potassium sparing diuretics in 48 patients (group B). From the 425 patients not on diuretics a random sample of 56 (group C) was drawn. Blood samples were taken routinely on admission to the coronary care unit. The serum potassium values found for group A, B and C were 3.77 +/- 0.55, 3.44 +/- 0.69 and 4.14 +/- 0.48, respectively, and the prevalence of hypokalaemia (less than 3.6 mmol) 40, 65 and 14% respectively. Rate ratio [95% confidence interval (CI)] for hypokalaemia when compared to group C was 2.6 (1.2-5.6) for group A and 4.9 (2.4-10.1) for group B. The prevalence of hypokalaemia was higher for women than for men (rate ratio, 95% CI: 1.4, 0.9-2.2). Patients already on beta-blocker therapy showed a 10% lower prevalence of hypokalaemia (rate ratio, 95% CI: 0.7, 0.5-1.1). These data were compared with serum potassium values of 104 patients with stable angina, who reported to the outpatient clinic. These patients were also divided into three groups according to the use of diuretics. Only in 15% of the patients using non-potassium sparing diuretics was hypokalaemia observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Early termination of clinical trials with prolonged observation of individual patients: a case study.

Stopping rules for a placebo controlled clinical trial of anticoagulants after acute myocardial infarction were evaluated by means of computer simulation for the case of five interim analyses. The trial will be terminated and the null hypothesis of no treatment effect rejected when the one-sided P-value (logrank test) is lower than 0.005, 0.005, 0.005, 0.014, and 0.023 at the respective interim analyses, and 0.032 at final evaluation. This implies a total size alpha = 0.05 and a power close to that of fixed sample size testing. The trial will also be terminated, without rejecting the null hypothesis, when the one-sided P-value exceeds 0.95, 0.88, 0.81, 0.74, and 0.67 at the respective interim analyses. This modification hardly affects size and power.

Quality of life after myocardial infarction: effect of long term metoprolol on mortality and morbidity.

A double blind randomised study of 154 patients with myocardial infarction assigned to metoprolol (100 mg twice daily) and 147 assigned to placebo compared the effects of treatment in relation to health state over three years. Health state was evaluated by a new method based on the average number of days spent in each of seven mutually exclusive categories of health. The scale took into account death, history of serious complications, functional state, and side effects of treatment. Of the maximum attainable 1095 days alive during the three years patients given metoprolol attained 992 days and those given placebo 964 days. During the period alive the metoprolol treated group spent an average of 278 days in an optimal functional state as compared with 176 days for the placebo treated group. This included 221 and 156 days respectively in a completely asymptomatic state (that is, without either cardiac symptoms or side effects of treatment). The time spent with a serious non-fatal complication was shortened by 56 days in the metoprolol group. The overall differences between the groups were statistically significant (p = 0.03). Aside from bringing an improved quality of life after myocardial infarction, metoprolol may add up to one month to life expectancy for three years of treatment.

Assessment of immediate and long-term functional results of percutaneous transluminal coronary angioplasty.

Assessment of the functional significance of coronary artery lesions during cardiac catheterization has recently become possible by calculating coronary flow reserve from both myocardial contrast appearance time and density in the resting and hyperemic states determined from digitized coronary cineangiograms. However, the interobserver and intraobserver variabilities, as well as the short-, medium-, and long-term variabilities of the coronary flow reserve measurements, have to be established before this technique becomes an acceptable means of assessing the immediate and long-term functional results of revascularization procedures such as percutaneous transluminal coronary angioplasty (PTCA). Variability was defined as the mean difference and standard deviation of the difference between duplicate determinations of coronary flow reserve. The intraobserver variability (mean difference +/- SD) in the measurement of coronary flow reserve was -0.01 +/- 0.07. Interobserver variability by two observers was +0.08 +/- 0.52. Short-term variability based on the analysis of two coronary cineangiograms taken 5 minutes apart was -0.02 +/- 0.26. Medium-term variability (coronary cineangiographies repeated 1-3 hours apart) was found to be -0.06 +/- 0.52. Long-term variability (coronary cineangiographies repeated 3-5 months apart) was 0.11 +/- 0.63. Having established the reproducibility of this radiographic method, we studied the prospective changes in coronary flow reserve in 25 patients undergoing PTCA for single vessel coronary artery disease. Coronary flow reserve measurements and quantitative coronary cineangiography were performed before, immediately after, and 3-5 months after PTCA. PTCA resulted in an immediate increase in coronary flow reserve from 1 +/- 0.3 to 2.3 +/- 0.6 with a concomitant increase in obstruction area from 0.9 +/- 0.3 to 3.3 +/- 0.7 mm2. Nine of the 25 patients developed restenosis defined as a diameter stenosis greater than 50% at follow-up. The other 16 patients had a coronary flow reserve of 3.3 +/- 0.6, which was measured 3-5 months after PTCA. Coronary flow reserve measurement from digitized coronary cineangiograms is a reproducible method for the assessment of the physiological importance of coronary artery obstructions. Short-, medium-, and long-term investigations of the functional results of interventions such as pharmacological therapy or revascularization can be performed reliably with this technique.

Assessment of the bradycardic and inotropic properties of ST 567 using a new scheme of administration.

In 10 patients undergoing diagnostic cardiac catheterisation a bolus of 15 mg ST 567 was administered intravenously in 1.5 min followed by a 30 min infusion of 7.5 mg. The maximal plasma level was 343 +/- 131 ng ml-1 (mean +/- s.d.) 1 min after bolus injection and stabilised around 179 ng ml-1 thereafter. Heart rate decreased from 71 +/- 10 beats min-1 at baseline to 66 +/- 10 beats min-1 at the end of the bolus injection (-7%). This decrease in heart rate persisted during the whole observation period. Also there was an 8% reduction in peak positive first derivative of LV pressure. Cardiac output measured by thermodilution during atrial pacing decreased from 5.9 +/- 1.1 l min-1 to 5.3 +/- 0.7 l min-1 (P less than 0.02). In 3 patients with the largest decrease in cardiac output, the end diastolic LV pressure at the end of the observation period decreased, which may reflect a decrease in pre-load. Only in 1 patient the decrease in end diastolic LV pressure exceeded twice the standard deviation of the random error component of duplicate measurements. Thus, although normal therapeutic plasma levels were achieved, ST 567 demonstrated negative inotropic properties independent of changes in heart rate with this scheme of administration.

ST 567 (alinidine) in stable angina: a comparison with metoprolol.

Alinidine, a drug which reduces heart rate without depressing myocardial function was compared against metoprolol, a beta-blocking drug, in the treatment of stable angina pectoris in a double-blind cross-over trial. It was found that both drugs reduced anginal attacks and nitroglycerine consumption to a comparable degree. Exercise tolerance did not appear to be improved by either drug yet chest pain at ergometry was postponed by both drugs. In the doses used metoprolol was more effective in restraining heart rate, both at rest and even more during exertion. Both drugs were well tolerated and side-effects were few. It seems probable that the optimal dose of alinidine was not used in this trial and that the dosage could have been higher.

Limitations of sensitivity, specificity, likelihood ratio, and bayes' theorem in assessing diagnostic probabilities: a clinical example.

We evaluated the extent to which the sensitivity, specificity, and likelihood ratio of the exercise test to diagnose coronary artery disease vary across subgroups of a certain patient population. Among 295 patients suspected of coronary artery disease, as independently determined by coronary angiography, we assessed variation in sensitivity and specificity according to patient history, physical examination, exercise test results, and disease severity in 207 patients with and 88 patients without coronary artery disease, respectively. The sensitivity varied substantially according to sex (women 30% and men 64%), systolic blood pressure at baseline (53% to 65%), expected workload (50% to 64%), systolic blood pressure at peak exercise (50% to 67%), relative workload (33% to 68%), and number of diseased vessels (39% to 77%). The specificity varied across subgroups of sex (men 89% and women 97%) and relative workload (85% to 98%). The likelihood ratio varied (3.8 to 17.0) across the same patient subgroups, as did the sensitivity. As each population tends to be heterogeneous with respect to patient characteristics, no single level of these parameters can be given that is adequate for all subgroups. Use of these parameters as a basis for calculating diagnostic probabilities in individual patients using Bayes' theorem has serious limitations.