Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial

  • Eileen O’Meara10,

    Affiliated with

    • Lisa M Mielniczuk10, 11Email author,

      Affiliated with

      • George A Wells10, 11,

        Affiliated with

        • Robert A deKemp10, 11,

          Affiliated with

          • Ran Klein10, 11,

            Affiliated with

            • Doug Coyle11,

              Affiliated with

              • Brian Mc Ardle10, 11,

                Affiliated with

                • Ian Paterson10,

                  Affiliated with

                  • James A White11,

                    Affiliated with

                    • Malcolm Arnold11,

                      Affiliated with

                      • Matthias G Friedrich10,

                        Affiliated with

                        • Eric Larose11,

                          Affiliated with

                          • Alexander Dick10, 11, 12,

                            Affiliated with

                            • Benjamin Chow10, 11, 12,

                              Affiliated with

                              • Carole Dennie10, 11, 12,

                                Affiliated with

                                • Haissam Haddad10, 11,

                                  Affiliated with

                                  • Terrence Ruddy10, 11,

                                    Affiliated with

                                    • Heikki Ukkonen12,

                                      Affiliated with

                                      • Gerald Wisenberg11,

                                        Affiliated with

                                        • Bernard Cantin11,

                                          Affiliated with

                                          • Philippe Pibarot11,

                                            Affiliated with

                                            • Michael Freeman12,

                                              Affiliated with

                                              • Eric Turcotte10,

                                                Affiliated with

                                                • Kim Connelly12, 11,

                                                  Affiliated with

                                                  • James Clarke12,

                                                    Affiliated with

                                                    • Kathryn Williams10, 11,

                                                      Affiliated with

                                                      • Normand Racine10,

                                                        Affiliated with

                                                        • Linda Garrard10, 11,

                                                          Affiliated with

                                                          • Jean-Claude Tardif10,

                                                            Affiliated with

                                                            • Jean DaSilva10, 11,

                                                              Affiliated with

                                                              • Juhani Knuuti12,

                                                                Affiliated with

                                                                • Rob Beanlands10, 11, 12 and

                                                                  Affiliated with

                                                                  • the IMAGE HF investigators

                                                                    Affiliated with

                                                                    Trials201314:218

                                                                    DOI: 10.1186/1745-6215-14-218

                                                                    Received: 4 January 2013

                                                                    Accepted: 28 May 2013

                                                                    Published: 16 July 2013

                                                                    Abstract

                                                                    Background

                                                                    Ischemic heart disease (IHD) is the most common cause of heart failure (HF); however, the role of revascularization in these patients is still unclear. Consensus on proper use of cardiac imaging to help determine which candidates should be considered for revascularization has been hindered by the absence of clinical studies that objectively and prospectively compare the prognostic information of each test obtained using both standard and advanced imaging.

                                                                    Methods/Design

                                                                    This paper describes the design and methods to be used in the Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) multi-center trial. The primary objective is to compare the effect of HF imaging strategies on the composite clinical endpoint of cardiac death, myocardial infarction (MI), cardiac arrest and re-hospitalization for cardiac causes.

                                                                    In AIMI-HF, patients with HF of ischemic etiology (n = 1,261) will follow HF imaging strategy algorithms according to the question(s) asked by the physicians (for example, Is there ischemia and/or viability?), in agreement with local practices. Patients will be randomized to either standard (SPECT, Single photon emission computed tomography) imaging modalities for ischemia and/or viability or advanced imaging modalities: cardiac magnetic resonance imaging (CMR) or positron emission tomography (PET). In addition, eligible and consenting patients who could not be randomized, but were allocated to standard or advanced imaging based on clinical decisions, will be included in a registry.

                                                                    Discussion

                                                                    AIMI-HF will be the largest randomized trial evaluating the role of standard and advanced imaging modalities in the management of ischemic cardiomyopathy and heart failure. This trial will complement the results of the Surgical Treatment for Ischemic Heart Failure (STICH) viability substudy and the PET and Recovery Following Revascularization (PARR-2) trial. The results will provide policy makers with data to support (or not) further investment in and wider dissemination of alternative ‘advanced’ imaging technologies.

                                                                    Trial registration

                                                                    NCT01288560

                                                                    Background

                                                                    The multifaceted Canada-Finland collaborative research program, Imaging Modalities to Assist with Guiding Therapy and the Evaluation of Patients with Heart Failure (IMAGE-HF), is designed with the following overall objectives: 1) to determine the impact of emerging imaging strategies on relevant clinical outcomes and decision making in patients with HF; 2) to establish standardized quality assurance (QA) measures and central databases in order to achieve reliable outcome driven research; and 3) to apply this as a platform for evaluation of new and emerging imaging and serum biomarkers in HF. The program consists of three separate randomized controlled trials. Project 1A is designed to compare the effect of HF imaging strategies in the evaluation and diagnosis of ischemic heart disease (IHD). Project 1B evaluates the utility of cardiac magnetic resonance (CMR) imaging in addition to standard echocardiography in the evaluation and diagnosis of non-ischemic HF (with either preserved or reduced ejection fraction) in comparison to the standard echocardiography alone. Project 1C is comparing two imaging modalities for the detection of coronary artery disease (standard coronary angiography versus cardiac computerized tomography scans).

                                                                    Project 1A is the focus of this publication

                                                                    Despite multiple advances in cardiovascular disease, the morbidity and mortality of patients with heart failure (HF) in the setting of IHD remains high. Although it is believed that most patients with symptoms of significant ischemia may benefit from revascularization, decisions regarding revascularization in those with advanced ventricular dysfunction and no significant ischemia are complex, and the applicability of current clinical trial data is often challenged by limited patient selection. Over the past three decades, information describing cardiac structure, function, perfusion, hemodynamics, and metabolism obtained from noninvasive cardiac imaging studies has been used to guide management decisions for patients with HF. Although this anatomic and physiologic information adds value to clinical care, an accepted strategy is still debated regarding the optimal testing sequence approach to efficiently identify the treatment strategy most likely to improve outcomes. Consensus on proper use of cardiac imaging studies has been hindered by absence of clinical studies that objectively compare the independent treatment-related prognostic information of each test obtained using standardized methods. Uniformity of reporting formats also needs to be improved in order to provide a clearer working scheme for clinicians.

                                                                    Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) (Project I-A of the Imaging Modalities to Assist with Guiding Therapy and the Evaluation of Patients with Heart Failure, IMAGE-HF program) is a multicenter trial with the primary objective of comparing the effect of HF imaging strategies on the composite clinical endpoint of cardiac death, myocardial infarction (MI), resuscitated cardiac arrest and cardiac re-hospitalization (worsening heart failure, acute coronary syndrome, arrhythmia). Patients with an ischemic heart disease (IHD) etiology will follow HF imaging strategy algorithms according to the question(s) asked by the physicians (for example, is there ischemia and/or viability?), in agreement with their local clinical practices for standard and alternative imaging. Patients will be randomized to either standard imaging modalities for ischemia and/or viability (SPECT) or advanced imaging modalities, namely cardiac magnetic resonance imaging (CMR) or positron emission tomography (PET). Secondary objectives include the effect of HF imaging strategies on the incidence of revascularization procedures, left ventricular remodeling, HF symptoms and quality of life, as well as a health economic evaluation. A biomarker substudy (on renal function, left ventricular remodeling and a selected set of biomarkers), assessing mechanisms underlying specific cardiovascular events, is also planned (see Additional file 1).

                                                                    Coronary revascularization and ischemic heart failure

                                                                    Among patients with coronary artery disease (CAD) and heart failure, mortality rates range from 10 to 60% at 1 year [111]. CAD is the most common cause of HF, however the role of revascularization in these patients is often unclear. Significant concerns remain about perioperative morbidity and mortality [8, 1014]. The recent Surgical Treatment for Ischemic Heart Failure (STICH) trial [15] did not demonstrate a significant benefit for coronary artery bypass graphing (CABG) surgery compared to medical therapy, for the primary endpoint of all-cause mortality in patients with LV dysfunction (ejection fraction {“EF”} ≤ 35%) and coronary disease eligible for CABG; although there was benefit for secondary endpoints of cardiovascular death and cardiovascular endpoints. STICH focused on IHD rather than on chronic HF with systolic dysfunction, and the outcomes of the many patients who were screened but did not undergo revascularization remain unknown [16]. Unfortunately, the STICH trial has not provided the final answer on the role of revascularization for patients with chronic HF; nor did it evaluate the role of advanced imaging in decision making for revascularization in this patient population.

                                                                    Imaging in ischemic heart failure

                                                                    Increasingly over the past three decades, information describing cardiac structure, function, perfusion, hemodynamics, and metabolism obtained from noninvasive cardiac imaging studies has been used to guide management decisions for patients with HF. Although this anatomic and physiologic information adds value to clinical care, an accepted imaging strategy has not evolved that tailors the testing sequence to specific presenting features of individual patients to efficiently identify the treatment strategy most likely to improve outcomes. Consensus on proper use of cardiac imaging studies has been hindered by the absence of clinical studies that objectively compare the independent treatment-related prognostic information of each test obtained using standardized methods.

                                                                    Observational data has demonstrated that methods to define ischemia, viability and scar can identify high risk patients likely to benefit (or not) from revascularization [1722].

                                                                    The long-term impact of newer or alternative imaging strategies used for the revascularization decision processes has not been evaluated prospectively in HF. Revascularization has the potential to restore function to dysfunctional viable myocardium but not scar. Our group and others have shown that patients with dysfunctional but viable hibernating myocardium are at high risk for cardiac events if they do not undergo timely revascularization [20, 23].

                                                                    Until recently, data from predominantly observational studies had shown that when viability is present, patients have better outcomes with revascularization [2426]. The PET and Recovery Following Revascularization (PARR-2) trial [27] represents the largest randomized study to evaluate viability imaging in patients with severe LV dysfunction. Overall, there was a trend for benefit for Fluorodeoxyglucose (18F) positron emission tomgoraphy scan (FDG PET) assisted management over standard care. When the adherence to imaging recommendations was considered, there was a significant outcome benefit. A high risk subgroup demonstrated a significant mortality benefit [20, 27]. Recently, in a post-hoc analysis a significant reduction in events was observed in a subset of patients at the Ottawa site (Ottawa-FIVE) [28]. The results suggest outcome benefits can be achieved using FDG PET in an experienced center with ready access to FDG and interactions with HF and revascularization teams.

                                                                    Although PARR2 was unique as a randomized controlled trial for imaging viability, it was underpowered for the primary outcome. Larger prospective randomized studies are needed, although undertaking such studies can be challenging [16, 29, 30]. The STICH viability study [29] did not include a comparison to late gadolinium enhanced CMR, other modalities, nor evaluate the role of stress induced ischemia. Finally, although care was taken to standardize imaging acquisition and transfer of data, standardization was not as rigorous as has recently been achieved in the CADRE Ontario provincial registry [31].

                                                                    Results from the STICH Viability substudy [29] suggest that identification of viable myocardium by single photon emission computed tomography (SPECT) or dobutamine stress echocardiography (DSE) do not add value in patients selected for surgical revascularization. The STICH Viability substudy results may be explained by a patient population that was at lower risk, with patients already acceptable for revascularization, having more single vessel disease, infrequent previous CABG, low incidence of renal dysfunction and predominantly without heart failure. For such patients, it may be argued that viability imaging is not needed. This is in contrast to sicker populations in studies such as PARR2 [20, 27], where physicians were uncertain about revascularization decisions and, therefore, needed viability assessment. Viability testing was not randomized in STICH [15, 16, 29]. The authors acknowledged the potential for selection bias [29]. Furthermore, only 19% of patients in the substudy were considered to have nonviable myocardium, which is far less than in most previous studies [29, 32, 33]. Analyses combining DSE and SPECT results were performed. Ischemia and hibernation imaging were not reported. More advanced (or alternative) ischemia and viability imaging modalities (that is, using PET and CMR) were not evaluated.

                                                                    Thus the STICH results need to be interpreted cautiously [16, 30], and the limitations along with the other observational and randomized data, justify the need for a prospective randomized trial to evaluate imaging strategies in patients with heart failure.

                                                                    AIMI-HF is a large randomized controlled trial, comparing ‘advanced imaging technologies’ (PET and CMR) to standard imaging (SPECT). The findings will provide policy makers with data to support (or not) further investment in and dissemination of alternative or advanced technologies.

                                                                    Study hypotheses and objectives

                                                                    Primary hypothesis

                                                                    In patients with HF due to IHD with left ventricular ejection fraction (LVEF) ≤ 45%, a management algorithm that applies alternative imaging strategies (PET or CMR) achieves a better clinical outcome measured as the composite clinical endpoint of cardiac death, MI, resuscitated cardiac arrest and cardiac re-hospitalization (hospitalization due to heart failure, acute coronary syndrome or arrhythmia) than an approach with standard care using SPECT imaging.

                                                                    Secondary hypotheses
                                                                    1. 1)

                                                                      Compared to standard care, in patients with HF due to IHD with LVEF ≤45% a management algorithm that applies alternative imaging modalities (PET or CMR) achieves: a) more efficient use of revascularization procedures with similar complication rates than standard care imaging strategies; b) better HF and angina symptom reduction; c) better quality of life (QoL), measured using MLHFQ and EQ5D; and d) is cost-effective.

                                                                       
                                                                    2. 2)

                                                                      In patients with HF due to IHD with LVEF ≤45%, a HF management algorithm that applies PET achieves a better primary (composite clinical endpoint) and secondary outcomes (revascularizations, remodeling, QoL, cost effectiveness) compared to one that applies CMR.

                                                                       

                                                                    Primary objective

                                                                    The primary objective of AIMI-HF is to compare the effect of HF imaging strategies on the composite clinical endpoint of cardiac death, MI, resuscitated cardiac arrest and cardiac re-hospitalization (WHF, ACS, and arrhythmia). Patients with HF due to an ischemic heart disease (IHD) etiology of LV dysfunction will follow HF imaging strategy algorithms according to the question(s) asked by the physicians (Is there ischemia and/or viability?), in agreement with their local practices for standard and alternative imaging.

                                                                    Secondary objectives

                                                                    To compare the effect of HF imaging strategies on:
                                                                    1. 1.

                                                                      The incidence of revascularization procedures (percutaneous coronary intervention {PCI}, CABG).

                                                                       
                                                                    2. 2.

                                                                      LVEF,

                                                                       
                                                                    3. 3.

                                                                      HF symptoms and New York Heart Association Functional Class (NYHA) class.

                                                                       
                                                                    4. 4.

                                                                      QOL (Minnesota Living with Heart Failure questionnaire (MLHFQ), the EQ5D).

                                                                       
                                                                    5. 5.

                                                                      Health economics. Costs will be estimated through regression analysis and cost effectiveness will be assessed through decision modeling.

                                                                       
                                                                    6. 6.

                                                                      The safety of imaging tests measured by cumulative radiation, adverse reactions to imaging contrast agents and stress testing agents will also be determined.

                                                                       

                                                                    Methods/Design

                                                                    The AIMI-HF is a randomized controlled trial to compare the effectiveness of HF imaging strategies in patients with HF due to IHD. Patients enrolled will have LV systolic dysfunction due to IHD where evaluation of ischemia and viability is relevant. Patients will be allocated in a concealed fashion to standard (SPECT) versus advanced (PET or CMR) imaging. In addition, a registry will be maintained of patients undergoing standard or advanced imaging based on clinical decisions.

                                                                    A survey sent to participating centers revealed that most of them could not provide stress echocardiography consistently within the requested timeframe as per the research protocol. This was especially true for dobutamine stress-echo (DSE) and viability protocols. The decision not to include this method was mainly due to statistical considerations; since if only a few centers elected to use this standard method, there may not be enough patients to adequately compare it with other methods (and site bias might also be involved).

                                                                    Study participants

                                                                    Patients with clinical HF (see Table 1 for definition) or severe LV systolic dysfunction who need further definition of ischemia, viability or scar and meet the following inclusion and exclusion criteria, will be considered for entry into this trial. Patients will be prospectively randomized to standard (SPECT) versus advanced (PET or CMR) imaging. Patients who meet inclusion criteria but cannot be randomized due to clinical management decisions, yet undergo standard or advanced imaging, will be entered into a registry.
                                                                    Table 1

                                                                    Criteria for the clinical diagnosis of heart failure

                                                                    At least one of each of the following symptoms and signs in the last 12 months:a

                                                                    Symptoms

                                                                    Signs

                                                                    ▪ Paroxysmal nocturnal dyspnea

                                                                    ▪ Pulmonary rales (post cough)

                                                                    ▪ Orthopnea

                                                                    ▪ Jugular venous pressure (JVP) ≥5 cm above sternal angle

                                                                    ▪ Dyspnea upon mild or moderate exertion

                                                                    ▪ Lower extremity oedema

                                                                     

                                                                    ▪ Chest x-ray demonstrating pleural effusion, pulmonary congestion, or cardiomegaly

                                                                    aIf LVEF is 30% or less, no signs or symptoms of HF are required for eligibility.

                                                                    Inclusion criteria:

                                                                    •  Age >18 years

                                                                    and

                                                                    •  Known or highly suspected coronary artery disease (CAD) documented by coronary angiography or by history of previous MI or evidence of moderate ischemia or scar based on prior imaging.

                                                                    and

                                                                    •  LV dysfunction most likely attributable to ischemic heart disease with EF ≤45% measured by any acceptable means (echo, nuclear RNA, PET or SPECT perfusion, angiography, CMR) within the previous 6 months and NYHA class II to IV symptoms within the past 12 months or

                                                                    •  LV dysfunction most likely attributable to ischemic heart disease with EF ≤30% measured by any acceptable means (echo, nuclear RNA, PET or SPECT perfusion, angiography, CMR) within the previous 6 months AND NYHA class I within the past 12 months.

                                                                    Exclusion criteria:

                                                                    •  Severe medical conditions that significantly affect the patient's recommended management (for example, severe COPD, active metastatic malignancy) and would preclude revascularization.

                                                                    •  <4 weeks post-ST segment elevation myocardial infarction (STEMI)

                                                                    •  Already identified as not suitable for revascularization

                                                                    •  Emergency revascularization indicated

                                                                    •  Severe valvular heart disease requiring valve surgery

                                                                    •  Pregnancy, breast feeding

                                                                    •  Potential for non-compliance to tests involved in this protocol

                                                                    •  Incapacity to provide informed consent

                                                                    Randomization

                                                                    Patients will be randomized according to a pre-defined randomization scheme and availability of imaging procedures at individual participating centers. All eligible patients will be randomized to either standard or advanced imaging modalities for ischemia and/or viability testing. Participating sites with the capability for two advanced imaging modalities will then be further randomized between each modality. If randomization is not possible due to local site factors, the patient can be entered into the registry (Figure 1). The ratio of advanced to standard imaging will be 2:1.
                                                                    http://static-content.springer.com/image/art%3A10.1186%2F1745-6215-14-218/MediaObjects/13063_2013_1426_Fig1_HTML.jpg
                                                                    Figure 1

                                                                    Overall randomization scheme for patients enrolled in Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF).

                                                                    Blinding

                                                                    The study is not blinded given the nature and purpose of the interventions. Knowledge of imaging results and potential gained from the intervention will need to be considered to implement the appropriate treatment strategy. Therefore, performance bias (that is, systematic differences between groups in the care provided or exposure to factors other than the interventions of interest) and attrition bias (that is, systematic differences between groups in withdrawals from the study) may occur. Detection bias is still a potential concern, but an independent assessor will evaluate the objectively defined primary outcome and an adjudication committee will independently review and adjudicate each clinical event blinded to treatment randomization.

                                                                    Measurements

                                                                    Standard imaging protocols have been defined by the IMAGE-HF Standardization team, using nationally recognized protocols (Additional file 2) GFR will be estimated (eGFR) using the Modified Diet in Renal Disease (MDRD) equations based on current recommendations [3437]. CBC, electrolytes, urea, creatinine will be measured locally on randomization. This creatinine measurement will serve for local eGFR assessment (to ensure CMR eligibility). Further laboratory analyses will be collected and stored for future biomarkers analyses (at baseline and at 1 year in a subgroup of patients; Additional file 1).

                                                                    Subject evaluation

                                                                    At baseline, demographic and clinical data will be collected from all participants on standardized case report forms. These data will be collected from the most recent, routine history and physical examination that has been completed by the treating physician. Quality of life questionnaires (EuroQol and Minnesota Living with Heart Failure) will be administered. In addition, the above-mentioned laboratory samples will be collected. To address a secondary objective, whenever possible, an echocardiogram will be performed if LV ejection fraction has not been determined by echocardiography within 6 months prior to randomization. As much as possible, imaging procedures will be performed within 4 weeks after entry into the trial. Subsequent telephone follow-up and repeat blood work will be performed on a predetermined schedule (Table 2). If the patient cannot be reached by telephone for their final assessment, a query will be made at government or national health care resources to verify if any corresponding events have occurred since the last visit (search of corresponding codes for cardiac death, MI, cardiac arrest and cardiac re-hospitalization for WHF, ACS, or arrhythmia). A follow-up echocardiogram will be requested at one year (LV remodeling, LVEF). Within 3 months of the baseline scan the treating physician will be asked to record the HF management plan.
                                                                    Table 2

                                                                    Patient assessment schedule

                                                                     

                                                                    Baseline

                                                                    3 months

                                                                    6 months

                                                                    12 months

                                                                    18 months

                                                                    24 months

                                                                    36 months

                                                                    48 months

                                                                    Imaging (SPECT, PET or CMR)

                                                                    x

                                                                           

                                                                    Blood work

                                                                    x

                                                                      

                                                                    x

                                                                        

                                                                    Demographic and history

                                                                    x

                                                                           

                                                                    Clinical data collected

                                                                    x

                                                                      

                                                                    x

                                                                        

                                                                    EuroQol questionnaire

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    MLWHF questionnaire

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    Telephone follow-up

                                                                     

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    x

                                                                    CMR cardiac magnetic resonance, MLWHF Minnesota Living with Heart Failure, PET positron emission tomography, SPECT single photon emission computed tomography.

                                                                    Safety and ethics

                                                                    This study was approved by the University of Ottawa Heart Institute Human Research Ethics Board, protocol #2010620-01H. In addition, before study initiation at each site, this protocol, and the informed consent form, as well as any advertisement for subject recruitment, was submitted for review and approval by each local participating site’s ethics committee charged with this responsibility and will be so submitted for future sites. These ethic committees will submit written notification of the approval to the investigator. This study will be conducted according to the Declaration of Helsinki, Good Clinical Practice and the TriCouncil Policy.

                                                                    Registry

                                                                    Eligible and consenting patients that could not be randomized but undergo standard or advanced imaging based on clinical decisions, will be included in a registry. Measurement, subject evaluation and safety and ethics as outlined in the previous sections will apply to these registry patients. The registry patients for advanced imaging will be considered in the sample size calculation and data analysis (see below); however, the small number of patients expected to be part of the SPECT registry will not be considered in the primary analysis.

                                                                    Sample size

                                                                    For the sample size determination, the estimated occurrence over one year of the composite clinical endpoint of cardiac death, MI, resuscitated cardiac arrest and cardiac re-hospitalization (WHF, ACS, arrhythmia) for PET is 27% and for standard care is 40%, based on the Ottawa-FIVE substudy [28] of the PARR-2 [27] study in which the composite event rates were 19% and 41%, respectively. These estimates were considered reasonable as it reflects the outcome rates that may be achievable at a facility with expertise and access to FDG PET imaging. There are no similar data upon which to draw an estimate for CMR. Considering the Schinkel et al. publication [38], which noted sensitivity of CMR to be between PET and standard care modalities and based on expert consensus from our IMAGE-HF workshop (16 December 2008 in Toronto, Canada), we estimate the event rate for CMR directed care would lie between the above values at 34%. Hence, an overall rate for the alternative (PET, CMR) modalities would be approximately 30%. The rates are considered conservative since the mean duration of follow-up will be 2 years, whereas the PARR-2 study was 1 year.

                                                                    For the primary hypothesis, using the two-sided log-rank test for comparing advanced (PET + CMR) versus standard modalities with a 2:1 patient allocation, a sample size of 495 patients (of which 330 are allocated to the advance modality and 165 are allocated to the standard modality) would be needed in order to detect a difference after 1 year in the composite clinical endpoint of 30% for the advanced modalities (PET, CMR) compared to 40% for standard care modalities (SPECT). This is calculated with a level of significance of 0.05 and power of 80%, and assuming a uniform accrual of patients over the 2.5 year recruitment period, a 1 year minimum follow-up period and a 10% loss from each study group. The difference of 10% was considered to be a minimal clinically important difference based on a consensus of the IMAGE-HF investigators.

                                                                    For the secondary hypothesis, using the Cox regression model for comparing the advanced modalities PET versus CMR with an approximate 1:1 patient allocation, a sample size of 548 patients per modality is needed considering an anticipated rate for the composite clinical endpoint of 30% after 1 year, a level of significance of 0.05, a power of 80% and a loss to follow-up of 10%. The sample size calculation is complicated by the fact that 766 patients (383 per group) from the registry (in which patients in the registries were clinically directed to PET or CMR) will be combined in the analysis with the 330 patients (165 per group) from the randomized part of the study (in which patients in the randomized study will be randomly allocated to PET versus CMR versus standard modality) for a total of 1096 patients (548 per group). For a sample of 1096 patients, a Cox regression of the log hazard ratio of the composite clinical endpoint on the group allocation variable (PET versus CMR) with a conservative standard deviation of 0.5 (based on an approximate equal allocation to PET and CMR), achieves 80% power at a 0.05 significance level to detect a 40% increase in the hazard ratio to1.4. This increase in the hazard ratio was deemed to be the minimal clinically important difference based on a consensus among the IMAGE-HF investigators. The sample size includes an adjustment to accommodate confounding by indication for allocation patients to PET versus CMR by incorporating a multiple regression of the group allocation variable on the other covariates in the Cox regression model; a conservative estimate of this confounding was considered by taking a value of 0.25 for the multiple correlation coefficient R for the relationship between the group allocation variable and the set of covariates identified.

                                                                    The total sample size is thus 1,096 + 165 = 1,261.

                                                                    Statistical analysis

                                                                    Descriptive statistics will be used to summarize the characteristics of the patients for each imaging technology on demographic, clinical and site-related factors, and differences between these groups will be reviewed for their clinical significance.

                                                                    Analysis populations

                                                                    For the purposes of data analysis, three study populations will be considered: Intent-to-treat (ITT) Population, As-Treated Population and Per-protocol Population. The ITT population will be used for the main analysis for all primary and secondary objectives, except for the safety analysis where the as-treated population will be used. As a secondary analysis, the analyses will be repeated for the as-treated and per-protocol populations.

                                                                    Primary analysis (advanced versus standard imaging)

                                                                    For the primary analysis, the time-to-event of the composite clinical endpoint of cardiac death, MI, arrest and cardiac re-hospitalization (WHF, ACS, arrhythmia) will be compared between the advanced modality (PET or CMR) to an approach with standard care using SPECT imaging using survival analysis. Kaplan-Meier survival curves of the primary endpoint will be compared between the advanced and standard modalities with the log-rank test. Potential confounding variables of the relationship between the imaging technologies and the primary endpoint will be assessed. In particular, propensity scores based on patient factors (for example, in/outpatient, NYHA class, HF duration, diabetes, atrial fibrillation) and site factors (for example, time-to-imaging, time-to-therapy) will be used in the analysis if necessary to adjust for potential differences. A Cox proportional hazard models will be used to assess the occurrence of the endpoints between the imaging technologies (model will include a group indicator variable) adjusting for any pertinent baseline differences identified. The proportional hazards assumption underlying the Cox model will be assessed.

                                                                    Secondary outcomes

                                                                    For the secondary outcomes PCI, CABG, HF symptoms and NYHA class, chi-square tests will be used to compare the advanced and standard imaging technologies; logistic regression analysis will be used for adjusting any pertinent baseline differences identified. For the secondary outcomes LVEF, MLHFQ and EQ5D, analysis of variance will be used to compare trends over time between the advanced and standard technologies. Analysis of covariance will be used for adjusting any pertinent baseline differences identified.

                                                                    Economic evaluation

                                                                    For secondary objective 5, a cost-effectiveness analysis of advanced versus standard modality groups will be conducted. Analysis will take the form of a cost-utility analysis with cost effectiveness assessed in terms of the incremental cost per quality life year. Analysis will incorporate data on resource use and patients utility values for the period from initiation of treatment to study termination. Resource use will be assessed through review of patient charts and patient utility values will be derived using the EQ5D and MLHF. A decision model will be created to estimate long-term costs and quality adjusted life years (QALYs) for all comparators. Uncertainty within the analysis will be assessed through Monte Carlo and other simulation techniques.

                                                                    Safety analysis

                                                                    For the secondary objective 6, safety will be evaluated by documenting all adverse events. Descriptive statistics (frequency distributions, numerical descriptors) and 95% CIs will be calculated. The as-treated population will be the main analysis population for this safety evaluation.

                                                                    Secondary analysis (PET versus CMR)

                                                                    For the secondary analysis, comparing the PET and CMR modalities, potential confounding variables of the relationship between the imaging technologies and the primary endpoint will be assessed. In particular, propensity scores based on patient factors (for example, in/outpatient, NYHA class, HF duration, diabetes, atrial fibrillation) and site factors (for example, time-to-imaging, time-to-therapy) will be used in the analysis if necessary to adjust for potential differences between PET and CMR. A Cox proportional hazard models will be used to assess the occurrence of the endpoints between the imaging technologies (the model will include a group indicator variable) adjusting for any pertinent baseline differences identified. The proportional hazards assumption underlying the Cox model will be assessed. The secondary outcomes will be analyzed in a similar fashion.

                                                                    Missing data

                                                                    ‘Missingness’ is considered to be missing at random (MAR) and mixed methods repeated measures (MMRM) and multiple imputation techniques will be used for handling missing data. In particular, for continuous outcomes at multiple time points MMRM will be used.

                                                                    Study management

                                                                    The IMAGE-HF trial is managed by an Executive Committee consisting of clinicians specialized in diagnostic imaging and/or heart failure and experts in biostatistics, physics and radiochemistry, as well as a larger Steering Committee consisting of members of the Executive Committee and representatives of all the initial study centers. (Table 3) In addition there is an events adjudication committee, which will independently review and adjudicate each clinical event blinded to treatment randomization. Since all the imaging approaches are part of standard clinical practice, no interim analysis is planned, but there will be independent data safety monitoring board (DSMB), which will review the safety data on a periodic basis; the frequency of the meetings and the charter governing the DSMB will be finalized at the first meeting of the DSMB.
                                                                    Table 3

                                                                    Imaging Modalities to Assist with Guiding Therapy and the Evaluation of Patients with Heart Failure (IMAGE-HP) participating

                                                                    IMAGE-HF Participating Sites

                                                                     

                                                                    Investigator

                                                                    Role

                                                                    University of Ottawa Heart Institute

                                                                     

                                                                    R Beanlands

                                                                    Co-Principal Investigator IMAGE-HF, Canada

                                                                    G. A. Wells

                                                                    Principal Investigator CRMC

                                                                    R. deKemp

                                                                    Principal Investigator QA Program

                                                                    D. Birnie

                                                                    Co-Principal Investigator Project IIA

                                                                    L. Mielniczuk

                                                                    Co-Principal Investigator Project IA

                                                                    K. Chan

                                                                    Site Principal Investigator

                                                                    B. Chow

                                                                    Principal Investigator Project IC

                                                                    L. Garrard

                                                                    Project Management

                                                                    R. Hessian

                                                                    Investigator

                                                                    T. Ruddy

                                                                    Investigator

                                                                    RA Davies

                                                                    Investigator

                                                                    H. Haddad

                                                                    Investigator

                                                                    A. Dick

                                                                    Investigator

                                                                    C. Dennie

                                                                    Investigator

                                                                    D. Coyle

                                                                    Investigator

                                                                    B. McArdle

                                                                    Investigator

                                                                    T. Dowsley

                                                                    Investigator

                                                                    G. Dwivedi

                                                                    Investigator

                                                                    J. DaSilva

                                                                    Investigator

                                                                    C. Kelly

                                                                    Research Coordinator

                                                                    E. Moga

                                                                    Research Coordinator

                                                                    R. Klein

                                                                    Core Lab Manager

                                                                    K. Williams

                                                                    Statistician

                                                                    R. Fleming

                                                                    Research Coordinator

                                                                    M. Boomgaardt

                                                                    Research Coordinator

                                                                    Montreal Heart Institute-Université de Montréal

                                                                     

                                                                    JC Tardif

                                                                    Investigator

                                                                    E. O'Meara

                                                                    Co-Principal Investigator Project IA

                                                                    M. Friedrich

                                                                    Investigator

                                                                    J. Rouleau

                                                                    Investigator

                                                                    T. Heinonen

                                                                    Investigator

                                                                    F. Marcotte

                                                                    Investigator

                                                                    N. Racine

                                                                    Investigator

                                                                    H. Q Ly

                                                                    Investigator

                                                                    J. Morrissette

                                                                    Research Coordinator

                                                                    H. Brown

                                                                    Research Coordinator

                                                                    University of Alberta

                                                                     

                                                                    I. Paterson

                                                                    Principal Investigator Project IB

                                                                    L. Lalonde

                                                                    Investigator

                                                                    J. Ezekowitz

                                                                    Investigator

                                                                    M. Irwin

                                                                    Research Coordinator

                                                                    University of Turku

                                                                     

                                                                    J. Knuuti

                                                                    Co-Principal Investigator IMAGE-HF, Finland

                                                                    H. Ukkonen

                                                                    Investigator

                                                                    S. Yla-Herttuala

                                                                    Investigator

                                                                    H. Leskinen

                                                                    Investigator

                                                                    A. Saraste

                                                                    Investigator

                                                                    T. Vasankari

                                                                    Research Coordinator

                                                                    K. Lahtonen

                                                                    Research Coordinator

                                                                    M. Tarkia

                                                                    Site Project Manager

                                                                    University Central Hospital, Helsinki

                                                                     

                                                                    M. Laine

                                                                    Site Principal Investigator

                                                                    H. Hanninen

                                                                    Investigator

                                                                    M. Pietila

                                                                    Research Coordinator

                                                                    University of Kuopio

                                                                     

                                                                    J. Hartikainen

                                                                    Site Principal Investigator

                                                                    S. Karkkainen

                                                                    Investigator

                                                                    I. Kaivonurmi

                                                                    Research Coordinator

                                                                    M. Sutinen

                                                                    Research Coordinator

                                                                    Sunnybrook Health Sciences Centre

                                                                     

                                                                    G. Wright

                                                                    Site Co-Principal Investigator

                                                                    K. Connelly

                                                                    Site Co-Principal Investigator

                                                                    R. Myers

                                                                    Investigator

                                                                    C. Cunningham

                                                                    Investigator

                                                                    E. Crystal

                                                                    Investigator

                                                                    A. Leber

                                                                    Investigator

                                                                    M. Mohammed

                                                                    Research Coordinator

                                                                    J. Malko

                                                                    Research Coordinator

                                                                    University of Calgary

                                                                     

                                                                    A. Howarth

                                                                    Site Co-Principal Investigator

                                                                    T. Anderson

                                                                    Site Co-Principal Investigator

                                                                    A. Krysk

                                                                    Investigator

                                                                    S. Hutchison

                                                                    Investigator

                                                                    N. Merchant

                                                                    Investigator

                                                                    S. Weeks

                                                                    Investigator

                                                                    R. Sandonato

                                                                    Research Coordinator

                                                                    S. Rivest

                                                                    Research Coordinator

                                                                    J. Veenhuyzen

                                                                    Research Coordinator

                                                                    M. Seib

                                                                    Research Coordinator

                                                                    B. Madden

                                                                    Research Coordinator

                                                                    D. Durand

                                                                    Research Coordinator

                                                                    London Health Sciences

                                                                     

                                                                    M. Arnold

                                                                    Site Principal Investigator

                                                                    G. Wisenberg

                                                                    Investigator

                                                                    T. Lee

                                                                    Investigator

                                                                    F. Prato

                                                                    Investigator

                                                                    J. White

                                                                    Co-Principal Investigator Project IIA

                                                                    K. Carter

                                                                    Research Coordinator

                                                                    Laval University

                                                                     

                                                                    E. Larose

                                                                    Site Principal Investigator

                                                                    P. Pibarot

                                                                    Investigator

                                                                    B. Cantin

                                                                    Investigator

                                                                    J. Carange

                                                                    Research Coordinator

                                                                    K. Bibeau

                                                                    Research Coordinator

                                                                    St. Michael's Hospital

                                                                     

                                                                    M. Freeman

                                                                    Site Co-Principal Investigator

                                                                    K. Connelly

                                                                    Site Co-Principal Investigator

                                                                    H. Leong-Poi

                                                                    Investigator

                                                                    G. Moe

                                                                    Investigator

                                                                    A. Al-Hesayen

                                                                    Investigator

                                                                    J. Sloninko

                                                                    Research Coordinator

                                                                    Hamilton

                                                                     

                                                                    V. Tandon

                                                                    Site Principal Investigator

                                                                    K. Gulenchyn

                                                                    Investigator

                                                                    F. Spence

                                                                    Investigator

                                                                    A. Khoorshed

                                                                    Research Coordinator

                                                                    Sherbrooke

                                                                     

                                                                    E. Turcotte

                                                                    Site Principal Investigator

                                                                    S. Lepage

                                                                    Investigator

                                                                    Paul Farand

                                                                    Investigator

                                                                    S. Joncas

                                                                    Resident, recruitment

                                                                    E. Lavallee

                                                                    Research Coordinator

                                                                    Halifax

                                                                     

                                                                    M. Rajda

                                                                    Site Principal Investigator

                                                                    R. Stewart

                                                                    Investigator

                                                                    J. Clarke

                                                                    Investigator

                                                                    S. Burrell

                                                                    Investigator

                                                                    B. Clarke

                                                                    Investigator

                                                                    S. Yarn

                                                                    Research Coordinator

                                                                    M. MacFarlane

                                                                    Research Coordinator

                                                                    Winnipeg

                                                                     

                                                                    M. Kass

                                                                    Site Principal Investigator

                                                                    J. Tan

                                                                    Investigator

                                                                    T. Moore

                                                                    Research Coordinator

                                                                    A. Munoz

                                                                    Research Coordinator

                                                                    QA Core Labs

                                                                     

                                                                    R. Klein

                                                                    Core Lab Manager (Ottawa)

                                                                    R. deKemp

                                                                    PET, SPECT QA Core Lab Team Leader (Ottawa)

                                                                    B. McArdle

                                                                    PET, SPECT QA Core Lab (Ottawa)

                                                                    J. Renaud

                                                                    PET, SPECT QA Core Lab (Ottawa)

                                                                    K. Chan

                                                                    ECHO QA Core Lab Team Leader (Ottawa)

                                                                    J. White

                                                                    CMR QA Core Lab 1A Team Leader (London)

                                                                    I. Pauchard

                                                                    CMR QA Core Lab 1A (London)

                                                                    I. Patterson

                                                                    CMR QA Core Lab 1B Team Leader (Edmonton)

                                                                    P. L’Allier

                                                                    ICA QA Core Lab Team Leader (Montreal)

                                                                    B. Chow

                                                                    CTA QA Core Lab Team Leader (Ottawa)

                                                                    Steering Committee

                                                                     

                                                                    R. Beanlands

                                                                     

                                                                    G. A. Wells

                                                                     

                                                                    J. Knuuti

                                                                     

                                                                    M. Friedrich

                                                                     

                                                                    G. Wright

                                                                     

                                                                    M. Arnold

                                                                     

                                                                    J.C. Tardif

                                                                     

                                                                    P. Pibarot

                                                                     

                                                                    S. Ylä-Herttuala

                                                                     

                                                                    R. deKemp

                                                                     

                                                                    DSMB

                                                                     

                                                                    A. Krahn, Chair

                                                                     

                                                                    J. Fallavollita

                                                                     

                                                                    L. Thabane

                                                                     

                                                                    Events

                                                                     

                                                                    H. Haddad, Chair

                                                                     

                                                                    D.S. Beanlands

                                                                     

                                                                    L. Duchesne

                                                                     

                                                                    J. Ezekowitz

                                                                     

                                                                    R. A. Davies

                                                                     

                                                                    Blood samples for the biomarkers ancillary study will be stored at the Montreal Heart Institute central laboratory for analyses to be performed after study completion.

                                                                    Trial status

                                                                    At the time of this manuscript preparation, the IMAGE IA trial is currently in the second year of active enrollment. We have enrolled a total of 249 patients, representing 20% of anticipated total enrollment. The study is active in a total of 13 sites across Canada and Finland. We anticipate study completion of enrollment by December 2015.

                                                                    Abbreviations

                                                                    AIMI-HF: 

                                                                    Alternative Imaging Modalities in Ischemic Heart Failure

                                                                    CABG: 

                                                                    Coronary artery bypass graphing

                                                                    CAD: 

                                                                    Coronary artery disease

                                                                    CKD: 

                                                                    Chronic kidney disease

                                                                    CMR: 

                                                                    Cardiac magnetic resonance imaging

                                                                    DSE: 

                                                                    Dobutamine stress echocardiography

                                                                    DSMB: 

                                                                    Data safety monitoring board

                                                                    EF: 

                                                                    Ejection fraction

                                                                    eGFR: 

                                                                    Estimated glomerular filtration rate

                                                                    FDG PET: 

                                                                    Fluorodeoxyglucose (18F) positron emission tomgoraphy scan

                                                                    HF: 

                                                                    Heart failure

                                                                    IHD: 

                                                                    Ischemic heart disease

                                                                    IMAGE-HF: 

                                                                    Imaging Modalities to Assist with Guiding Therapy and the Evaluation of Patients with Heart Failure

                                                                    ITT: 

                                                                    Intent-to-treat

                                                                    JVP: 

                                                                    Jugular venous pressure

                                                                    LVEF: 

                                                                    Left ventricular ejection fraction

                                                                    MAR: 

                                                                    Missing at random

                                                                    MDRD: 

                                                                    Modification of Diet in Renal Disease

                                                                    MI: 

                                                                    Myocardial infarction

                                                                    MLWHF: 

                                                                    Minnesota Living with Heart Failure

                                                                    MMRM: 

                                                                    Mixed methods repeated measures

                                                                    NYHA: 

                                                                    New York Heart Assocation Functional Class

                                                                    PARR-2: 

                                                                    PET and Recovery Following Revascularization

                                                                    PCI: 

                                                                    Percutaneous coronary interventsion

                                                                    PET: 

                                                                    Positron emission tomography

                                                                    QA: 

                                                                    Quality assurance

                                                                    QALYS: 

                                                                    Quality adjusted life years

                                                                    SOPs: 

                                                                    Standard operating procedures

                                                                    SPECT: 

                                                                    Single photon emission computed tomography

                                                                    STEM: 

                                                                    Segment elevation myocardial infarction

                                                                    STICH: 

                                                                    Surgical treatment for ischemic heart failure.

                                                                    Declarations

                                                                    Acknowledgements

                                                                    AIMI-HF is supported by the IMAGE HF Team Grant funded by Canadian Institute of Health Research CIHR (team grant # CIF 99470). R.B. is a Career Investigator supported by the Heart and Stroke Foundation of Ontario and Tier 1 Research Chair supported by the University of Ottawa. E.O. is sponsored by les Fonds de Rercherche en Santé du Québec (Junior 2 researcher grant 2011-2015) for research on biomarkers and imaging in heart failure and chronic kidney disease. B.M. is supported in part by the MFI HSFO Program Grant (HSFO Grant #PRG6242) and the University of Ottawa Heart Institute’s Whit & Heather Tucker Endowed Research Fellowship in Cardiology.

                                                                    Authors’ Affiliations

                                                                    (1)
                                                                    Division of Cardiology, (including Cardiac Imaging, The National Cardiac PET Centre, The Heart Failure Program, and the Cardiac Research Methods Centre), Department of Medicine, University of Ottawa Heart Institute
                                                                    (2)
                                                                    University of Ottawa
                                                                    (3)
                                                                    Department of Radiology, The Ottawa Hospital, Module S
                                                                    (4)
                                                                    Montreal Heart Institute
                                                                    (5)
                                                                    London Health Sciences Centre
                                                                    (6)
                                                                    Turku PET Centre, c/o Turku University Hospital
                                                                    (7)
                                                                    University of Alberta
                                                                    (8)
                                                                    Université de Québec
                                                                    (9)
                                                                    St. Michael’s Hospital
                                                                    (10)
                                                                    Université de Sherbrooke
                                                                    (11)
                                                                    Sunnybrook Health Sciences Centre
                                                                    (12)
                                                                    Dalhousie University

                                                                    References

                                                                    1. Arnold JM, Liu P, Demers C, Dorian P, Giannetti N, Haddad H, Heckman GA, Howlett JG, Ignaszewski A, Johnstone DE, Jong P, McKelvie RS, Moe GW, Parker JD, Rao V, Ross HJ, Sequeira EJ, Svendsen AM, Teo K, Tsuyuki RT, White M: Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management. Can J Cardiol 2006, 22:23–45.PubMedView Article
                                                                    2. McKee PA, Castelli WP, McNamara PM, Kannel WB: The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971, 285:1441–1446.PubMedView Article
                                                                    3. Yatteau RF, Peter RH, Behar VS, Bartel AG, Rosati RA, Kong Y: Ischemic cardiomyopathy: the myopathy of coronary artery disease. Natural history and results of medical versus surgical treatment. Am J Cardiol 1974, 34:520–525.PubMedView Article
                                                                    4. Alderman EL, Fisher LD, Litwin P, Kaiser GC, Myers WO, Maynard C, Levine F, Schloss M: Results of coronary artery surgery in patients with poor left ventricular function (CASS). Circulation 1983, 68:785–795.PubMedView Article
                                                                    5. Alderman EL, Bourassa MG, Cohen LS, Davis KB, Kaiser GG, Killip T, Mock MB, Pettinger M, Robertson TL: Ten-year follow-up of survival and myocardial infarction in the randomized Coronary Artery Surgery Study. Circulation 1990, 82:1629–1646.PubMedView Article
                                                                    6. Franciosa JA, Wilen M, Ziesche S, Cohn JN: Survival in men with severe chronic left ventricular failure due to either coronary heart disease or idiopathic dilated cardiomyopathy. Am J Cardiol 1983, 51:831–836.PubMedView Article
                                                                    7. Tu JV, Austin PC, Walld R, Roos L, Agras J, McDonald KM: Development and validation of the Ontario acute myocardial infarction mortality prediction rules. J Am Coll Cardiol 2001, 37:992–997.PubMedView Article
                                                                    8. Tjan TD, Kondruweit M, Scheld HH, Roeder N, Borggrefe M, Schmidt C, Schober O, Deng MC: The bad ventricle revascularization versus transplantation. Thorac Cardiovasc Surg 2000, 48:9–14.PubMedView Article
                                                                    9. Passamani E, Davis KB, Gillespie MJ, Killip T: A randomized trial of coronary artery bypass surgery. Survival of patients with a low ejection fraction. N Engl J Med 1985, 312:1665–1671.PubMedView Article
                                                                    10. Jones RH: Is it time for a randomized trial of surgical treatment of ischemic heart failure? J Am Coll Cardiol 2001, 37:1210–1213.PubMedView Article
                                                                    11. Doenst T, Velazquez EJ, Beyersdorf F, Michler R, Menicanti L, Di Donato M, Gradinac S, Sun B, Rao V: To STICH or not to STICH: we know the answer, but do we understand the question? J Thorac Cardiovasc Surg 2005, 129:246–249.PubMedView Article
                                                                    12. Louie HW, Laks H, Milgalter E, Drinkwater DC Jr, Hamilton MA, Brunken RC, Stevenson LW: Ischemic cardiomyopathy. Criteria for coronary revascularization and cardiac transplantation. Circulation 1991,84(5 Suppl):III290-III295.PubMed
                                                                    13. Kron IL, Flanagan TL, Blackbourne LH, Schroeder RA, Nolan SP: Coronary revascularization rather than cardiac transplantation for chronic ischemic cardiomyopathy. Ann Surg 1989, 210:348–352. discussion 352–344PubMedView Article
                                                                    14. Hochberg MS, Parsonnet V, Gielchinsky I, Hussain SM: Coronary artery bypass grafting in patients with ejection fractions below forty percent. Early and late results in 466 patients. J Thorac Cardiovasc Surg 1983, 86:519–527.PubMed
                                                                    15. Velazquez EJ, Lee KL, Deja MA, Jain A, Sopko G, Marchenko A, Ali IS, Pohost G, Gradinac S, Abraham WT, Yii M, Prabhakaran D, Szwed H, Ferrazzi P, Petrie MC, O'Connor CM, Panchavinnin P, She L, Bonow RO, Rankin GR, Jones RH, Rouleau JL, STICH Investigators: Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011, 364:1607–1616.PubMedView Article
                                                                    16. Fang JC: Underestimating medical therapy for coronary artery disease… Again. N Engl J Med 2011, 364:1671–1673.PubMedView Article
                                                                    17. Beanlands RS, Chow BJ, Dick A, Friedrich MG, Gulenchyn KY, Kiess M, Leong-Poi H, Miller RM, Nichol G, Freeman M, Bogaty P, Honos G, Hudon G, Wisenberg G, Van Berkom J, Williams K, Yoshinaga K, Graham J: CCS/CAR/CANM/CNCS/CanSCMR joint position statement on advanced noninvasive cardiac imaging using positron emission tomography, magnetic resonance imaging and multidetector computed tomographic angiography in the diagnosis and evaluation of ischemic heart disease--executive summa. Can J Cardiol 2007, 23:107–119.PubMedView Article
                                                                    18. Schinkel AF, Bax JJ, Poldermans D, Elhendy A, Ferrari R, Rahimtoola SH: Hibernating myocardium: diagnosis and patient outcomes. Curr Probl Cardiol 2007, 32:375–410.PubMedView Article
                                                                    19. Di Carli MF, Davidson M, Little R, Khanna S, Mody FV, Brunken RC, Czernin J, Rokhsar S, Stevenson LW, Laks H, Hawkins R, Schelbert HR, Phelps ME, Maddahi J: Value of metabolic imaging with positron emission tomography for evaluating prognosis in patients with coronary artery disease and left ventricular dysfunction. Am J Cardiol 1994, 73:527–533.PubMedView Article
                                                                    20. D’Égiodio G, Nichol G, Williams KA, Guo A, Garrard L, deKemp R, Ruddy TD, DaSilva J, Humen D, Gulenchyn KY, Freeman M, Racine N, Benard F, Hendry P, Beanlands RS, PARR-2 Investigators: Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial. JACC Cardiovasc Imaging 2009, 2:1060–1068.View Article
                                                                    21. Tillisch J, Brunken R, Marshall R, Schwaiger M, Mandelkern M, Phelps M, Schelbert H: Reversibility of cardiac wall-motion abnormalities predicted by positron tomography. N Engl J Med 1986, 314:884–888.PubMedView Article
                                                                    22. Kwon DH, Halley CM, Carrigan TP, Zysek V, Popovic ZB, Setser R, Schoenhagen P, Starling RC, Flamm SD, Desai MY: Extent of left ventricular scar predicts outcomes in ischemic cardiomyopathy patients with significantly reduced systolic function: a delayed hyperenhancement cardiac magnetic resonance study. JACC Cardiovasc Imaging 2009, 2:34–44.PubMedView Article
                                                                    23. Beanlands RS, Hendry PJ, Masters RG, deKemp RA, Woodend K, Ruddy TD: Delay in revascularization is associated with increased mortality rate in patients with severe left ventricular dysfunction and viable myocardium on fluorine 18-fluorodeoxyglucose positron emission tomography imaging. Circulation 1998,98(19 Suppl):II51-II56.PubMed
                                                                    24. Lee KS, Marwick TH, Cook SA, Go RT, Fix JS, James KB, Sapp SK, MacIntyre WJ, Thomas JD: Prognosis of patients with left ventricular dysfunction, with and without viable myocardium after myocardial infarction. Relative efficacy of medical therapy and revascularization. Circulation 1994, 90:2687–2694.PubMedView Article
                                                                    25. Yoshida K, Gould KL: Quantitative relation of myocardial infarct size and myocardial viability by positron emission tomography to left ventricular ejection fraction and 3-year mortality with and without revascularization. J Am Coll Cardiol 1993, 22:984–997.PubMedView Article
                                                                    26. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE: Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2002, 39:1151–1158.PubMedView Article
                                                                    27. Beanlands RS, Nichol G, Huszti E, Humen D, Racine N, Freeman M, Gulenchyn KY, Garrard L, deKemp R, Guo A, Ruddy TD, Benard F, Lamy A, Iwanochko RM: F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2). J Am Coll Cardiol 2007, 50:2002–2012.PubMedView Article
                                                                    28. Abraham A, Nichol G, Williams K, Garrard L, Guo A, de Kemp RA, Davies RA, Duchesne L, Haddad H, Ruddy TD, Chow B, DaSilva J, Hendry P, Masters R, Higginson L, Beanlands RS: Ottawa-FIVE: FDG in viability evaluation at an experienced center with ready Access to FDG and integration with management teams. J Nucl Med 2010, 51:567–574.PubMedView Article
                                                                    29. Bonow RO, Maurer G, Lee KL, Holly TA, Binkley PF, Desvigne-Nickens P, Drozdz J, Farsky PS, Feldman AM, Doenst T, Michler RE, Berman DS, Nicolau JC, Pellikka PA, Wrobel K, Alotti N, Asch FM, Favaloro LE, She L, Velazquez EJ, Jones RH, Panza JA, STICH Trial Investigators: Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med 2011, 364:1617–1625.PubMedView Article
                                                                    30. Mielniczuk L, Beanlands R: Imaging-guided selection of patients with ischemic heart failure for high risk revascularization improves identification of those with the highest clinical benefit. Circ Cardiovasc Imaging 2012, 5:262–270.PubMedView Article
                                                                    31. Ziadi MC, Garrard L, Beanlands R, Chow B, Hessian R, Ruddy T, Guo A, Williams K, Davies RA, Renaud J, Etele J, DaSilva JN, Ficaro FP, Wisenberg G, Iwanachko M, Marriott C: FDG PET impacts positively management direction and predicts outcomes in a multicentre ‘real world’ setting. Circulation 2009, 120:S349. [abstract]
                                                                    32. Liao L, Cabell CH, Jollis JG, Velazquez EJ, Smith WT 4th, Anstrom KJ, Pappas PA, Ryan T, Kisslo JA, Landolfo CK: Usefulness of myocardial viability or ischemia in predicting long-term survival for patients with severe left ventricular dysfunction undergoing revascularization. Am J Cardiol 2004, 93:1275–1279.PubMedView Article
                                                                    33. Sawada SG, Dasgupta S, Nguyen J, Lane KA, Gradus-Pizlo I, Mahenthiran J, Feigenbaum H: Effect of revascularization on longterm survival in patients with ischemic left ventricular dysfunction and a wide range of viability. Am J Cardiol 2010, 106:187–192.PubMedView Article
                                                                    34. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification Am J Kidney Dis 2002, 39:S1-S266.
                                                                    35. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, Hogg RJ, Perrone RD, Lau J, Eknoyan G, National Kidney Foundation: National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003, 139:137–147.PubMedView Article
                                                                    36. O’Meara E, Chong KS, Gardner RS, Jardine AG, Neilly JB, McDonagh TA: The Modification of Diet in Renal Disease (MDRD) equations provide valid estimations of glomerular filtration rates in patients with advanced heart failure. Eur J Heart Fail 2006, 8:63–67.PubMedView Article
                                                                    37. Earley A, Miskulin D, Lamb EJ, Levey AS, Uhlig K: Estimating equations for glomerular filtration rate in the era of creatinine standardization: A systematic review. Ann Intern Med 2012, 156:785–795.PubMedView Article
                                                                    38. Schinkel AF, Poldermans D, Elhendy A, Bax JJ: Assessment of myocardial viability in patients with heart failure. J Nucl Med 2007, 48:1135–1146.PubMedView Article

                                                                    Copyright

                                                                    © O'Meara et al.; licensee BioMed Central Ltd. 2013

                                                                    This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.