Elsevier

Controlled Clinical Trials

Volume 24, Issue 6, December 2003, Pages 776-794
Controlled Clinical Trials

Original article
Evaluation of outcome and cost-effectiveness using an FDG PET-guided approach to management of patients with coronary disease and severe left ventricular dysfunction (PARR-2): rationale, design, and methods

https://doi.org/10.1016/S0197-2456(03)00106-5Get rights and content

Abstract

Patients with severe ventricular dysfunction and coronary disease have high morbidity and mortality. They may benefit from revascularization but have significant perioperative morbidity and mortality. Positron emission tomography (PET) imaging with F-18-fluorodeoxyglucose (FDG) can detect viable myocardium that may recover from revascularization in such patients. It is unclear whether use of FDG PET in this population improves outcome or is cost-effective. The principal aim of this study is to determine whether FDG PET-guided therapy improves clinical outcome compared to standard care. Secondary objectives are to determine whether FDG PET-guided therapy improves left ventricular (LV) function, improves quality of life, and provides a cost benefit versus standard care. Included in this multicenter randomized controlled trial are patients with coronary artery disease and severe LV dysfunction who are referred for revascularization, heart failure, or cardiac transplantation or in whom FDG PET is potentially useful. Consenting subjects will be randomized to therapy directed by FDG PET or standard care. The primary outcome is the composite cardiovascular endpoint of cardiac death, myocardial infarction, transplantation, or rehospitalization for unstable angina or heart failure. Secondary outcomes include health-related quality of life, costs, mortality, cardiovascular events, and LV function. Assuming two-sided alpha = 0.05, power = 80%, a sample size of 206 patients per group is required to detect a 15% absolute difference in the primary outcome between PET-directed therapy compared to standard care. Analyses will be conducted on an intention-to-treat basis. To our knowledge, this is the first large trial to evaluate whether FDG PET-directed therapy is effective and provides a cost benefit in patients with severe LV dysfunction. If so, thousands of such patients can be risk-stratified to select who is likely to benefit from revascularization.

Section snippets

Statement of problem

Reduced left ventricular (LV) function is associated with significant morbidity and mortality [1], [2], [3], [4]. Among patients with coronary artery disease and severe ventricular dysfunction, mortality rates range from 15–60% at 1 year [5], [6], [7], [8], [9]. In addition, ventricular function correlates inversely with mortality [7]. Although medical therapies have improved survival in patients with poor ventricular function, mortality and morbidity remain high [1], [2], [3], [4]. As a

Objectives

The primary objective is to determine whether therapy directed by FDG PET imaging (used to define ischemic viable myocardium or scar tissue) improves clinical outcome compared to standard care for patients with severe LV dysfunction.

Secondary objectives are to determine whether FDG PET-guided therapy in patients with severe LV dysfunction is cost-effective and to determine whether therapy directed by FDG PET is associated with better health-related quality of life, clinical outcomes, or

Hypotheses

The principal null hypothesis is that compared to standard care FDG PET-guided therapy is identically distributed with respect to the composite cardiovascular endpoint of cardiac death, myocardial infarction (MI), transplantation, or rehospitalization for unstable angina or heart failure. The secondary null hypotheses are that compared to standard care, FDG PET-directed therapy is identically distributed with respect to costs, quality of life, LV function, and clinical outcomes.

Design

This multicenter randomized controlled study will compare FDG PET-directed therapy to standard care in patients with severe LV dysfunction. Eligible patients are those being considered for (1) revascularization; (2) transplantation workup; (3) referred for heart failure workup; or (4) any patient where FDG PET might be considered useful by the attending physician. Eligibility criteria are listed in Table 1.

Block randomization will be performed with sealed opaque envelopes using a previously

FDG PET-directed therapy

Patients randomized to this group will undergo perfusion and FDG PET within 2 weeks of randomization. An automated method of image analysis was used in the final analysis of the PARR phase 1 data to yield quantified measures of the extent of scar tissue and mismatch. These PET parameters are included with clinical parameters in a model that is used to predict LV function recovery developed from PARR phase 1 [28]. This model yields a point estimate and 95% confidence interval for predicted

Study variable definition and measurement

The primary outcome of the trial is the occurrence of the composite clinical endpoint at 1 year. Secondary outcomes include quality of life, costs, and cost-effectiveness of PET-directed therapy versus control; time to occurrence of the composite endpoint; individual components of the composite endpoint; and EF. Clinical follow-up will occur at baseline and annual follow-up. Economic outcomes will be assessed by telephone interview every 3 months. The definitions of each variable and the timing

Ejection fraction (baseline, 1 year, and 2 year)

All patients will undergo radionuclide angiogram (RNA) imaging. RNAs will be acquired using a standard electrocardiogram-gated equilibrium technetium-99m-red blood cell blood pool imaging protocol [27], [29], [33], [34], [35], [36]. The EF will be measured from the left anterior oblique 45° acquisition. RNA analysis will be performed in a central core laboratory, blinded to any clinical or imaging data [37], [38].

Disease-specific

The Minnesota Living with Heart Failure Questionnaire will be used [39], [40], [41].

Generic

The health-related quality of life of all patients will be measured as utilities, since the relative cost-effectiveness of some cardiac therapies is sensitive to the magnitude of the difference between the utilities associated with either treatment [42]. The interview instrument, the Health Utilities Index Mark 3, is self-administered and requires about 10 minutes to complete [43], [44]. It is known to be both

Sampling frame

Identification of the resources associated with each patient is not feasible because certain costs (namely emergency medical services costs) are not currently attributed to individual patients, and most of the study centers do not have fully allocated cost models to identify the cost of hospitalization. Therefore, we will use the combined primary and secondary data by using cost functions to estimate the cost associated with either intervention [48].

Cost methodology

We will calculate the cost of care as

Sample size

Calculations for estimated sample size are based on the uncorrected chi-square test procedure for comparing two proportions. For two-sided alpha = 0.05, power = 80%, standard care event rate of 50%, the required sample size per group is estimated at 169 patients to detect a 15% absolute difference (i.e., 30% relative risk reduction) in the composite clinical endpoint between patients receiving PET-directed therapy compared to standard care. Considering a crossover rate of 2.5% based on previous

Interim analysis

One interim analysis will be performed once 50% of the patients have been accrued to determine if the PET-directed approach is beneficial or hazardous. Should the event rate be less than expected, the sample size will be adjusted. O'Brien-Fleming group sequential stopping rules were chosen to maintain an overall significance level of 0.05. Significance boundaries will be symmetrical with alpha = 0.019 for the interim analysis and alpha = 0.043 for the final analysis.

Primary

Baseline characteristics of patients in the two approach groups will be compared by using univariate descriptive statistics. An uncorrected chi-square test will be used to compare the proportion of events in each study group. A logistic regression procedure will be employed to adjust the comparison of these event rates using significant covariates that predict outcome.

Secondary

Categorical variables including the components of the composite endpoints will be analyzed by using an uncorrected chi-square test followed by using multiple logistic regression analysis. Survival analyses will be used to compare event-free survival. Kaplan-Meier survival curves will be compared using the log-rank test. Proportional hazards methods will be used as appropriate. Continuous outcome measures including EF and quality of life will be analyzed by using either parametric procedures

Economic analyses

We will evaluate the cost-effectiveness of control versus intervention as follows: (1) estimate the incremental survival benefit based on PARR-2 effectiveness data, (2) cost the components of care, and (3) pool the effectiveness and cost data in a decision model. A societal perspective will be adopted. Future costs and effects will be discounted at a rate of 3%.

The incremental cost-effectiveness ratio (ICER) will be calculated as the ratio of the difference in costs divided by the difference in

Decision modeling

Decision modeling will be used to project the costs and effects beyond the duration of the study, since adoption of a shorter time horizon may bias the analysis against PET-directed therapy. Long-term costs and effects will be modeled using a Markov model with a cycle length of 3 months [57].

Uncertainty analysis

The impact of uncertainty in clinical and economic data will be assessed. First, Monte-Carlo simulation will be used to assess variability in the long-term costs and effects [57], [58], [59]. Second, one-way sensitivity analyses will evaluate the robustness of the results by substituting the upper and lower 95% confidence limits of the value of each variable [60]. Threshold analyses will identify the value of each variable, if any, at which one should be indifferent between control (standard

Organizational structure and governance

The study is jointly coordinated by persons at the University of Ottawa Heart Institute and the Clinical Epidemiology Program of the Ottawa Hospital. Collectively, they are responsible for adjudication of clinical issues, maintaining adequate enrollment at study sites, and data entry and verification.

The executive committee is composed of the principal investigator for each site including the coordinating center and will meet biannually to review study progress.

The steering committee is

Data collection and transmission

All patient data will be collected on data collection forms and audited by using standard procedures. Security procedures will be enforced to guard patient confidentiality and prevent loss of data.

Discussion

To our knowledge, this will be the first large prospective randomized study to evaluate whether FDG PET-directed therapy has a beneficial effect on clinical outcome and is cost-effective in patients with severe LV dysfunction. One previous study randomized patients to FDG PET-guided therapy or technetium-99m-sestamibi–guided therapy [19]. This study did not show a significant difference in outcome. However, the study did not focus on patients with severe LV dysfunction as two-thirds of the

Acknowledgements

Rob Beanlands is a Research Scientist supported by the Canadian Institutes for Health Research and a Premier's Research Excellence Award. Graham Nichol is a Career Scientist supported by the Ontario Ministry of Health Career Scientist Award and a Premier's Research Excellence Award. The study is supported in part by the Canadian Institutes for Health Research (CIHR grant no. MCT 37412) and the Heart and Stroke Foundation of Ontario (HSFO grant no. NA 4007) and a government/university/industry

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