Interim analysis in long-term clinical trials

The purpose of this dissertation is to evaluate the usefulness of both stopping rules and estimation methods in long-term clinical trials with interim analyses. The ASPECT trial, a long-term clinical trial to assess the effect of anticoagulant therapy on mortality in patients after myocardial infarction which is currently conducted in the Netherlands, serves as a major example throughout this dissertation. In the final stage of the development of a new therapy usually a large-scale comparative clinical trial is used. In many clinical trials the effect of a treatment can only be assessed over a long period of time, or the length of time that is needed to recruit the required number of patients for the trial is long. During the course of such long-term clinical trials it is desirable to evaluate the accumulating results at regular time intervals. The interim results might indicate that continuation of the trial is meaningful, superfluous, or ethically unjustified. This dissertation describes statistical methods for the design and the analysis of long-term clinical trials with interim analyses within the classical statistical framework. The usefulness of these methods is investigated. The ASPECT trial, a trial that is currently being conducted in the Netherlands of the effect of anticoagulant therapy on mortality in patients after myocardial infarction, serves as a major example throughout this dissertation

The percutaneous assessment of regional and acute coronary hot unstable plaques by thermographic evaluation (PARACHUTE) study: A prospective reproducibility and prognostic clinical study using thermography to predict future ischemic cardiac events

Intravascular thermography is currently being considered as a valuable tool in assessing macrophage-rich plaques. Since it is unknown what the prognostic value is of non-obstructive atherosclerotic plaques showing temperature heterogeneity, we designed the PARACHUTE study, a prospective, reproducibility, and prognostic clinical study using thermography in patients presenting with an unstable coronary syndrome. The primary endpoint of the study is the predictive value of temperature heterogeneity towards the occurrence of ischemic coronary events and hospitalization for ischemia and/or angina. The secondary endpoints are the predictive value of high-risk plaques associated with the development of future cardiac events, assessmen

Inter- and intra-observer variability in the qualitative categorization of coronary angiograms.

The ABC classification of the American College of Cardiology and the American Heart Association is a commonly used categorization to estimate the risk and success of intracoronary intervention, as well as the probability of restenosis. To evaluate the reliability of qualitative angiogram readings, we randomly selected 200 films from single lesion angioplasty procedures. A repeated visual assessment (> or = 2 months interval) by two independent observers resulted in kappa values of inter and intra-observer variability for the ABC lesion classification and for all separate items that compile it. Variability in assessment is expressed in percentage of total agreement, and in kappa value, which is a parameter of the agreement between two or more observations in excess of the chance agreement. Percentage of total agreement and kappa value was 67.8% and 0.33 respectively for the ABC classification, indicating a poor agreement. Probably this is due to the deficiency of strict definitions. Further investigation has to demonstrate whether improvement can be achieved using complete and detailed definitions without ambiguity, and consensus after panel assessment

Comparison of usefulness of computer assisted continuous 48-h 3-lead with 12-lead ECG ischaemia monitoring for detection and quantitation of ischaemia in patients with unstable angina

AIMS: The selection of ECG leads used for ST monitoring may influence detection and quantitation of ischaemia. METHODS: We compared on-line continuous 48-h 12-lead against 3-lead ST monitoring in 130 unstable angina patients (Mortara. ELI-100). Onset and offset of ST episodes were defined by the lead with the first > or = 100 microV ST change relative to baseline and the lead with the latest return to baseline ST level, respectively. ST episodes were calculated for 12 leads and 3 leads (V2, V5, III) separately. RESULTS: ST episodes were detected in 88 patients (77%) by 12-lead and in 71 patients (62%) by 3-lead ST monitoring (P < 0.02). The median number (25.75%) of episodes/patient was 1 (0.3) for 3-lead and 2 (1.6) for 12-lead (P < 0.0001). The total duration of ischaemia detected during 12-lead far exceeded 3-lead monitoring: 12.3 (1, 58.2) and 1.7 (0, 23.3) min respectively (P < 0.0001). The probability of recurrent ischaemia declined most during the first 24 h of monitoring. After a period without ST changes of 1, 12, 24 and 36 h, the probabilities of recurrent ischaemia were 63, 31, 14 and 9%, respectively. CONCLUSIONS: Continuous 12-lead ST monitoring increases detection rate and duration of ST episodes compared to 3-lead ST monitoring. The use of continuous 12-lead ECG monitoring devices on emergency wards and coronary care units is recommended

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

Long-Term Clinical Outcomes With Sirolimus-Eluting Coronary Stents Five-Year Results of the RAVEL Trial

ObjectivesThis study examined the clinical outcomes at 5 years in RAVEL (A Randomized Comparison of a Sirolimus-Eluting Stent With a Standard Stent for Coronary Revascularization), the first controlled trial of drug-eluting stents.BackgroundThe 6-month rate of angiographic coronary restenosis has been markedly lowered by sirolimus-eluting stents (SES). The long-term performance of drug-eluting stents, however, is under close scrutiny.MethodsThe trial included 238 patients (mean age 60.7 ± 10.4 years, 76% men) with a single, de novo native coronary artery lesion, randomly assigned to treatment with SES versus bare-metal stents (BMS). Rates of major adverse cardiac events (MACE), defined as all-cause mortality, myocardial infarction, and percutaneous or surgical revascularization up to 5 years of follow-up, and rates of stent thrombosis were compared between the 2 treatment groups.ResultsComplete datasets were available in 92.5% of patients treated with SES and 89.1% of patients assigned to BMS. The 1-, 3-, and 5-year rates of survival free from target lesion revascularization (TLR) were, respectively, 99.2%, 93.8%, and 89.7% in the SES group versus 75.9%, 75.0%, and 74.0% in the control group (p < 0.001; log-rank). Rates of all MACE at 5 years were 25.8% in patients treated with SES versus 35.2% in patients assigned to BMS (p = 0.03; log-rank). Rates of stent thrombosis, per protocol or by the Academic Research Consortium definitions, were similar in both groups.ConclusionsThe 5-year rate of TLR associated with SES was significantly lower than that with BMS. There was no apparent adverse effect associated with the use of SES, although the trial was not powered to examine uncommon complications

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 addit