Miroslaw Rajda

The 2012 Canadian Cardiovascular Society heart failure management guidelines update: focus on acute and chronic heart failure.

The 2012 Canadian Cardiovascular Society Heart Failure (HF) Guidelines Update provides management recommendations for acute and chronic HF. In 2006, the Canadian Cardiovascular Society HF Guidelines committee first published an overview of HF management. Since then, significant additions to and changes in many of these recommendations have become apparent. With this in mind and in response to stakeholder feedback, the Guidelines Committee in 2012 has updated the overview of both acute and chronic heart failure diagnosis and management. The 2012 Update also includes recommendations, values and preferences, and practical tips to assist the medical practitioner manage their patients with HF.

The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: Anemia, Biomarkers, and Recent Therapeutic Trial Implications

The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Update provides discussion on the management recommendations on 3 focused areas: (1) anemia; (2) biomarkers, especially natriuretic peptides; and (3) clinical trials that might change practice in the management of patients with heart failure. First, all patients with heart failure and anemia should be investigated for reversible causes of anemia. Second, patients with chronic stable heart failure should undergo natriuretic peptide testing. Third, considerations should be given to treat selected patients with heart failure and preserved systolic function with a mineralocorticoid receptor antagonist and to treat patients with heart failure and reduced ejection fraction with an angiotensin receptor/neprilysin inhibitor, when the drug is approved. As with updates in previous years, the topics were chosen in response to stakeholder feedback. The 2014 Update includes recommendations, values and preferences, and practical tips to assist the clinicians and health care workers to best manage patients with heart failure.

The Canadian Cardiovascular Society Heart Failure Companion: Bridging Guidelines to Your Practice

The Canadian Cardiovascular Society Heart Failure (HF) Guidelines Program has generated annual HF updates, including formal recommendations and supporting Practical Tips since 2006. Many clinicians indicate they routinely use the Canadian Cardiovascular Society HF Guidelines in their daily practice. However, many questions surrounding the actual implementation of the Guidelines into their daily practice remain. A consensus-based approach was used, including feedback from the Primary and Secondary HF Panels. This companion is intended to answer several key questions brought forth by HF practitioners such as appropriate timelines for initial assessments and subsequent reassessments of patients, the order in which medications should be added, how newer medications should be included in treatment algorithms, and when left ventricular function should be reassessed. A new treatment algorithm for HF with reduced ejection fraction is included. Several other practical issues are addressed such as an approach to management of hyperkalemia/hypokalemia, treatment of gout, when medications can be stopped, and whether a target blood pressure or heart rate is suggested. Finally, elements and teaching of self-care are described. This tool will hopefully function to allow better integration of the HF Guidelines into clinical practice.

The 2013 Canadian Cardiovascular Society Heart Failure Management Guidelines Update: Focus on Rehabilitation and Exercise and Surgical Coronary Revascularization

The 2013 Canadian Cardiovascular Society Heart Failure Management Guidelines Update provides focused discussions on the management recommendations on 2 topics: (1) exercise and rehabilitation; and (2) surgical coronary revascularization in patients with heart failure. First, all patients with stable New York Heart Association class I-III symptoms should be considered for enrollment in a tailored exercise training program, to improve exercise tolerance and quality of life. Second, selected patients with suitable coronary anatomy should be considered for bypass graft surgery. As in previous updates, the topics were chosen in response to stakeholder feedback. The 2013 Update also includes recommendations, values and preferences, and practical tips to assist the clinicians and health care workers manage their patients with heart failure.

Quality-of-Life Outcomes With Coronary Artery Bypass Graft Surgery in Ischemic Left Ventricular Dysfunction: A Randomized Trial

Context A randomized, controlled trial of patients with high-risk coronary artery disease and heart failure previously reported no significant difference between medical therapy alone and medical therapy plus coronary artery bypass grafting when the outcome was death from any cause. Contribution This study from the same trial reports that medical therapy plus coronary artery bypass grafting is better than medical therapy alone when the outcome is quality of life. Caution The type of therapy was not concealed from patients or investigators. Implication This is the first study to examine how these therapies affect quality of life in patients who have coronary artery disease and heart failure. The Editors Clinical trials performed during the 1970s and 1980s defined several major coronary artery disease (CAD) subgroups for which coronary artery bypass grafting (CABG) provided incremental survival, angina relief, or both relative to medical therapy. These early trials formed the foundation for current practice patterns and guideline recommendations on the use of CABG (13). However, patients with severe left ventricular dysfunction (ejection fraction 0.35) were not represented. Thus, management decisions for these patients have largely relied on clinical judgment to extrapolate from those trials and a small group of observational studies(4, 5). The challenges in using this evidence to select treatment for contemporary patients is further complicated by the substantial improvement in medical therapies for both CAD and heart failure over those used in the earlier trials. The STICH (Surgical Treatment for Ischemic Heart Failure) trial was funded by the National Heart, Lung, and Blood Institute in 2002 to provide a comprehensive evaluation of the incremental therapeutic benefits of routine CABG over contemporary guideline-based medical therapy in patients with severe systolic dysfunction due to CAD (6). A major prespecified secondary end point of the trial was health-related quality of life (QOL), which is an outcome that complements the major clinical end points by assessing the patients experience of, and satisfaction with, the 2 therapeutic strategies compared (7, 8). Methods Patient Population and Primary Clinical Results To test the STICH trials surgical revascularization hypothesis, we randomly assigned 1212 patients with site-defined left ventricular ejection fraction of 0.35 or less and CAD suitable for revascularization to CABG or medical therapy (6). Rationale, trial design, and complete inclusion and exclusion criteria have been described previously (7). Patients were enrolled at 99 clinical sites in 22 countries between July 2002 and May 2007. All patients provided informed consent, and study protocol was approved by each sites institutional review board or ethics committee. Median follow-up was 56 months. The primary intention-to-treat comparison showed that 35.7% of patients assigned to CABG and 40.5% of those assigned to medical therapy died (primary analysis: unadjusted hazard ratio for all-cause mortality, 0.86 [95% CI, 0.72 to 1.04]; P= 0.123; secondary analysis: adjusted hazard ratio for all-cause mortality, 0.82 [CI, 0.68 to 0.99]; P= 0.039). Patients assigned to CABG had lower rates of the 2 major secondary clinical end points: death from cardiovascular causes (hazard ratio, 0.81; P= 0.050) and the composite of all-cause mortality and hospitalization for cardiovascular causes (hazard ratio, 0.74; P< 0.001). Health-Related QOL Data Collection We collected QOL data using structured interviews at baseline and 4, 12, 24, and 36 months after randomization. Site coordinators were specially trained by the Duke Clinical Research Institute Outcomes Research Group to conduct baseline interviews. The original research plan called for all patients to be enrolled in North America and all English- and Spanish-language follow-up QOL interviews to be completed via telephone by the Duke Clinical Research Institute. The few patients expected to require French-language interviews were to be interviewed by site coordinators. When enrollment was expanded outside of North America, the plan was modified to have those site coordinators do all QOL interviews in the patients native language. For nonEnglish-speaking participants, translations of the QOL instruments were obtained from the instrument developers or a translation service was used to create validated translations. The New York Heart Association (NYHA) class and Canadian Cardiovascular Society (CCS) angina class were collected on the clinical case report form at baseline and each follow-up interval. QOL Measures A battery of validated measures was used to provide a comprehensive but efficient assessment of QOL. The principal prespecified QOL measure was the Kansas City Cardiomyopathy Questionnaire (KCCQ), which is a 23-item instrument that measures the effect of heart failure symptoms on QOL (9). We used 3 scales from the Seattle Angina Questionnaire to assess the effect of angina symptoms on QOL outcomes (10), the Short Form-12 Survey to provide a brief overall generic measure of health status (11), and 5 individual scales from the Short Form-36 Health Survey to provide a more detailed assessment of areas of functioning and well-being from a generic perspective (12). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (13). The Cardiac Self-Efficacy Questionnaire was used to measure patient confidence in controlling disease symptoms and maintaining physical functioning (14). Finally, we used the EuroQol-5D, which is a generic instrument consisting of a 5-dimension single summary health status index and a self-rated visual analogue scale (0 to 100) of current health-related QOL (15). Statistical Analysis All primary comparisons were performed with the treatment group defined according to the intention-to-treat principle. Descriptive statistics included percentages for discrete variables and medians with 25th to 75th percentiles plus means with SDs for continuous variables. The chi-square test was used for discrete variable comparisons. Treatment comparisons of continuous variables were done by using a linear mixed model to account for repeated measures within a patient. The baseline QOL measure was used as one of the repeated measures. In PROC MIXED in SAS, version 9.2 (SAS Institute), the baseline, 4-, 12-, 24-, and 36-month measurements within a patient were fitted using maximum likelihood methods with unstructured covariance matrix (16). At each time point, estimated treatment differences, 95% CIs, and P values were obtained using the model estimates. Finally, the proportion of patients who achieved a clinically important improvement of 5 points or more in KCCQ overall summary scores were compared by treatment group using the chi-square test (17). All analyses were conducted using SAS, version 8 or higher. All reported P values were 2-sided. No adjustment was made in significance levels for multiple comparisons. Benchmarks for clinically significant changes in QOL scores for individual patients were used informally to assess the magnitude of the mean difference between the 2 groups. However, a QOL difference between groups at or exceeding the benchmark was not used as a formal decision rule to define clinical significance. Subgroup Analysis Regional effects were tested as interactions between the 5 regions used in the clinical analyses (Asia, Australia and New Zealand, Europe, North America, and South America) and the KCCQ overall summary score. Other interactions tested from those prespecified in the clinical analysis plan included age, sex, race, current NYHA class, left ventricular ejection fraction, baseline diabetes, CCS angina class, and myocardium viability. Sensitivity Analysis Some QOL data were missing because a small proportion of living patients did not complete a scheduled QOL assessment and a larger proportion of patients died before 1 or more of the scheduled assessments could be done. Almost all cases of missing data among living patients were attributed to administrative reasons rather than their state of health (Supplement 1), which supports the assumption of missing at random and the use of multiple imputation techniques. Supplement 1. Data Collection in the Surgical Treatment of Ischemic Heart Disease (STICH) Trial Quality of Life Substudy The STICH trial had a high overall mortality rate and a treatment-related mortality difference, as noted previously. These deaths produced a nonrandom group of survivors who provided the follow-up QOL data. No consensus exists in the statistical literature about how best to analyze intermediate end points, such as QOL, when death prevents complete data collection. The primary concern this issue raises in a treatment comparison is that a therapy more effective at preventing death may also preserve more patients with poor QOL than the comparison therapy. Thus, when comparing QOL in such a situation using all survivors, the therapy with the worse survival might have an artifactual improvement in QOL measurements. Rubin has proposed that because QOL data that are censored due to death do not exist even in theory and should be regarded as undefined, the most meaningful analysis is to compare QOL for patients in the 2 treatment groups who would have survived with either therapy (18). To accomplish this, we performed a survival average causal effect (SACE) analysis (1821). The SACE estimates of QOL are calculated from weighted averages of the QOL data multiplied by survival probability estimates (from survival models developed in the parent STICH study cohort) specific to the study group. The 95% CIs for the SACE were calculated using 200 repetitions of a nonparametric bootstrap procedure (22). These sensitivity analyses are helpful as supplements to the primary analysis but have their own difficulties, not the least of which are the important but untestable assumptioClinical trials performed during the 1970s and 1980s defined several major coronary artery disease (CAD) subgroups for which coronary artery bypass grafting (CABG) provided incremental survival, angina relief, or both relative to medical therapy, which formed the foundation for current practice patterns and guideline recommendations on the use of CABG (1-3). However, patients with severe left ventricular dysfunction (ejection fraction ≤0.35) were not represented in these early trials. Thus, management decisions for these patients have largely relied on clinical judgment to extrapolate from those trials and a small group of observational studies (4, 5). The challenges in using this evidence to select treatment for contemporary patients is further complicated in that medical therapies for both CAD and heart failure have improved substantially over those used in the earlier trials. The STICH (Surgical Treatment for Ischemic Heart Failure) trial was funded by the National Heart, Lung, and Blood Institute in 2002 to provide a comprehensive evaluation of the incremental therapeutic benefits of routine CABG over contemporary guideline-based medical therapy in patients with severe systolic dysfunction due to CAD (6). A major prespecified secondary end point of the trial was health-related quality of life (QOL), which is an outcome that complements the major clinical end points by assessing the patient’s experience of, and satisfaction with, the 2 therapeutic strategies compared (7, 8).

An Internet-Based Counseling Intervention With Email Reminders that Promotes Self-Care in Adults With Chronic Heart Failure: Randomized Controlled Trial Protocol

Background Chronic heart failure (CHF) is a public health priority. Its age-standardized prevalence has increased over the past decade. A major challenge for the management of CHF is to promote long-term adherence to self-care behaviors without overtaxing available health care resources. Counseling by multidisciplinary health care teams helps to improve adherence to self-care behaviors and to reduce the rate of death and hospitalization. In the absence of intervention, adherence to self-care is below recommended standards. Objective This trial aims to establish and evaluate a Canadian e-platform that will provide a core, standardized protocol of behavioral counseling and education to facilitate long-term adherence to self-care among patients with CHF. Methods Canadian e-Platform to Promote Behavioral Self-Management in Chronic Heart Failure (CHF-CePPORT) is a multi-site, double blind, randomized controlled trial with a 2 parallel-group (e-Counseling + Usual Care vs e-Info Control + Usual Care) by 3 assessments (baseline, 4-, and 12-month) design. We will identify subjects with New York Heart Association Class II or III systolic heart failure from collaborating CHF clinics and then recruit them (n=278) by phone. Subjects will be randomized in blocks within each site (Toronto, Montreal, and Vancouver). The primary outcome will be improved quality of life, defined as an increased number of subjects with an improvement of ≥5 points on the summary score of the Kansas City Cardiomyopathy Questionnaire. We will also assess the following secondary outcomes: (1) diet habits, depression, anxiety, smoking history, stress level, and readiness for change using self-report questionnaires, (2) physical activity level, current smoking status, and vagal-heart rate modulation by physiological tests, and (3) exercise capacity, prognostic indicators of cardiovascular functioning, and medication adherence through medical chart review. The primary outcome will be analyzed using generalized estimation equations with repeated measures on an intention-to-treat basis. Secondary outcomes will be analyzed using repeated-measures linear mixed models with a random effects intercept. All significant main effects or interactions in the statistical models will be followed up with post hoc contrasts using a Bonferroni correction with a 2-sided statistical significance criterion of P<.05. Results This 3.5-year, proof-of-principle trial will establish the e-infrastructure for a pan-Canadian e-platform for CHF that is comprised of a standardized, evidence-based protocol of e-Counseling. Conclusions CHF-CePPORT is designed to improve long-term adherence to self-care behaviors and quality of life among patients with CHF. It will demonstrate a distinct Canadian initiative to build capacity for preventive eHealth services for patients with CHF. Trial Registration ClinicalTrials.gov NCT01864369; http://clinicaltrials.gov/ct2/show/NCT01864369 (Archived by WebCite at http://www.webcitation.org/6Iiv6so7E).

Arrhythmogenic right ventricular cardiomyopathy: use of a left ventricular assist device as a bridge to transplantation?

The principal characteristic of arrhythmogenic right ventricular cardiomyopathy (ARVC) is the tendency for ventricular arrhythmia and sudden death to occur without overt ventricular dysfunction. Current recommendations for management of patients with ARVC include insertion of an automated implantable cardioverter–defibrillator (AICD) to prevent sudden cardiac death. However, despite the use of AICD and/or anti-arrhythmic drugs some patients suffer recurrent ventricular arrhythmias unresponsive to optimum medical management. We present two cases of ARVC with refractory recurrent ventricular arrhythmias that were successfully managed by left ventricular assist device (LVAD) implantation, as a bridge to transplant (BTT). These two cases are unconventional examples of use of LVAD, given the predominant right ventricular pathology of ARVC and the arrhythmogenic nature of their presentation. The novelty of these cases should be taken in the context of increasing pressure to standardize indications for use of mechanical circulatory support.

Routine versus selective cardiac magnetic resonance in non-ischemic heart failure – OUTSMART-HF: study protocol for a randomized controlled trial (IMAGE-HF (heart failure) project 1-B)

BackgroundImaging has become a routine part of heart failure (HF) investigation. Echocardiography is a first-line test in HF given its availability and it provides valuable diagnostic and prognostic information. Cardiac magnetic resonance (CMR) is an emerging clinical tool in the management of patients with non-ischemic heart failure. Current ACC/AHA/CCS/ESC guidelines advocate its role in the detection of a variety of cardiomyopathies but there is a paucity of high quality evidence to support these recommendations.The primary objective of this study is to compare the diagnostic yield of routine cardiac magnetic resonance versus standard care (that is, echocardiography with only selective use of CMR) in patients with non-ischemic heart failure. The primary hypothesisis that the routine use of CMR will lead to a more specific diagnostic characterization of the underlying etiology of non-ischemic heart failure. This will lead to a reduction in the non-specific diagnoses of idiopathic dilated cardiomyopathy and HF with preserved ejection fraction.DesignTertiary care sites in Canada and Finland, with dedicated HF and CMR programs, will randomize consecutive patients with new or deteriorating HF to routine CMR or selective CMR. All patients will undergo a standard clinical echocardiogram and the interpreter will assign the most likely HF etiology. Those undergoing CMR will also have a standard examination and will be assigned a HF etiology based upon the findings. The treating physician’s impression about non-ischemic HF etiology will be collected following all baseline testing (including echo ± CMR). Patients will be followed annually for 4 years to ascertain clinical outcomes, quality of life and cost. The expected outcome is that the routine CMR arm will have a significantly higher rate of infiltrative, inflammatory, hypertrophic, ischemic and ‘other’ cardiomyopathy than the selective CMR group.DiscussionThis study will be the first multicenter randomized, controlled trial evaluating the role of CMR in non-ischemic HF. Non-ischemic HF patients will be randomized to routine CMR in order to determine whether there are any gains over management strategies employing selective CMR utilization. The insight gained from this study should improve appropriate CMR use in HF.Trial registrationNCT01281384.

Quality-of-Life Outcomes With Coronary Artery Bypass Graft Surgery in Ischemic Left Ventricular DysfunctionA Randomized TrialQuality-of-Life Outcomes in Surgical Treatment of Ischemic Heart Failure

Context A randomized, controlled trial of patients with high-risk coronary artery disease and heart failure previously reported no significant difference between medical therapy alone and medical therapy plus coronary artery bypass grafting when the outcome was death from any cause. Contribution This study from the same trial reports that medical therapy plus coronary artery bypass grafting is better than medical therapy alone when the outcome is quality of life. Caution The type of therapy was not concealed from patients or investigators. Implication This is the first study to examine how these therapies affect quality of life in patients who have coronary artery disease and heart failure. The Editors Clinical trials performed during the 1970s and 1980s defined several major coronary artery disease (CAD) subgroups for which coronary artery bypass grafting (CABG) provided incremental survival, angina relief, or both relative to medical therapy. These early trials formed the foundation for current practice patterns and guideline recommendations on the use of CABG (13). However, patients with severe left ventricular dysfunction (ejection fraction 0.35) were not represented. Thus, management decisions for these patients have largely relied on clinical judgment to extrapolate from those trials and a small group of observational studies(4, 5). The challenges in using this evidence to select treatment for contemporary patients is further complicated by the substantial improvement in medical therapies for both CAD and heart failure over those used in the earlier trials. The STICH (Surgical Treatment for Ischemic Heart Failure) trial was funded by the National Heart, Lung, and Blood Institute in 2002 to provide a comprehensive evaluation of the incremental therapeutic benefits of routine CABG over contemporary guideline-based medical therapy in patients with severe systolic dysfunction due to CAD (6). A major prespecified secondary end point of the trial was health-related quality of life (QOL), which is an outcome that complements the major clinical end points by assessing the patients experience of, and satisfaction with, the 2 therapeutic strategies compared (7, 8). Methods Patient Population and Primary Clinical Results To test the STICH trials surgical revascularization hypothesis, we randomly assigned 1212 patients with site-defined left ventricular ejection fraction of 0.35 or less and CAD suitable for revascularization to CABG or medical therapy (6). Rationale, trial design, and complete inclusion and exclusion criteria have been described previously (7). Patients were enrolled at 99 clinical sites in 22 countries between July 2002 and May 2007. All patients provided informed consent, and study protocol was approved by each sites institutional review board or ethics committee. Median follow-up was 56 months. The primary intention-to-treat comparison showed that 35.7% of patients assigned to CABG and 40.5% of those assigned to medical therapy died (primary analysis: unadjusted hazard ratio for all-cause mortality, 0.86 [95% CI, 0.72 to 1.04]; P= 0.123; secondary analysis: adjusted hazard ratio for all-cause mortality, 0.82 [CI, 0.68 to 0.99]; P= 0.039). Patients assigned to CABG had lower rates of the 2 major secondary clinical end points: death from cardiovascular causes (hazard ratio, 0.81; P= 0.050) and the composite of all-cause mortality and hospitalization for cardiovascular causes (hazard ratio, 0.74; P< 0.001). Health-Related QOL Data Collection We collected QOL data using structured interviews at baseline and 4, 12, 24, and 36 months after randomization. Site coordinators were specially trained by the Duke Clinical Research Institute Outcomes Research Group to conduct baseline interviews. The original research plan called for all patients to be enrolled in North America and all English- and Spanish-language follow-up QOL interviews to be completed via telephone by the Duke Clinical Research Institute. The few patients expected to require French-language interviews were to be interviewed by site coordinators. When enrollment was expanded outside of North America, the plan was modified to have those site coordinators do all QOL interviews in the patients native language. For nonEnglish-speaking participants, translations of the QOL instruments were obtained from the instrument developers or a translation service was used to create validated translations. The New York Heart Association (NYHA) class and Canadian Cardiovascular Society (CCS) angina class were collected on the clinical case report form at baseline and each follow-up interval. QOL Measures A battery of validated measures was used to provide a comprehensive but efficient assessment of QOL. The principal prespecified QOL measure was the Kansas City Cardiomyopathy Questionnaire (KCCQ), which is a 23-item instrument that measures the effect of heart failure symptoms on QOL (9). We used 3 scales from the Seattle Angina Questionnaire to assess the effect of angina symptoms on QOL outcomes (10), the Short Form-12 Survey to provide a brief overall generic measure of health status (11), and 5 individual scales from the Short Form-36 Health Survey to provide a more detailed assessment of areas of functioning and well-being from a generic perspective (12). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (13). The Cardiac Self-Efficacy Questionnaire was used to measure patient confidence in controlling disease symptoms and maintaining physical functioning (14). Finally, we used the EuroQol-5D, which is a generic instrument consisting of a 5-dimension single summary health status index and a self-rated visual analogue scale (0 to 100) of current health-related QOL (15). Statistical Analysis All primary comparisons were performed with the treatment group defined according to the intention-to-treat principle. Descriptive statistics included percentages for discrete variables and medians with 25th to 75th percentiles plus means with SDs for continuous variables. The chi-square test was used for discrete variable comparisons. Treatment comparisons of continuous variables were done by using a linear mixed model to account for repeated measures within a patient. The baseline QOL measure was used as one of the repeated measures. In PROC MIXED in SAS, version 9.2 (SAS Institute), the baseline, 4-, 12-, 24-, and 36-month measurements within a patient were fitted using maximum likelihood methods with unstructured covariance matrix (16). At each time point, estimated treatment differences, 95% CIs, and P values were obtained using the model estimates. Finally, the proportion of patients who achieved a clinically important improvement of 5 points or more in KCCQ overall summary scores were compared by treatment group using the chi-square test (17). All analyses were conducted using SAS, version 8 or higher. All reported P values were 2-sided. No adjustment was made in significance levels for multiple comparisons. Benchmarks for clinically significant changes in QOL scores for individual patients were used informally to assess the magnitude of the mean difference between the 2 groups. However, a QOL difference between groups at or exceeding the benchmark was not used as a formal decision rule to define clinical significance. Subgroup Analysis Regional effects were tested as interactions between the 5 regions used in the clinical analyses (Asia, Australia and New Zealand, Europe, North America, and South America) and the KCCQ overall summary score. Other interactions tested from those prespecified in the clinical analysis plan included age, sex, race, current NYHA class, left ventricular ejection fraction, baseline diabetes, CCS angina class, and myocardium viability. Sensitivity Analysis Some QOL data were missing because a small proportion of living patients did not complete a scheduled QOL assessment and a larger proportion of patients died before 1 or more of the scheduled assessments could be done. Almost all cases of missing data among living patients were attributed to administrative reasons rather than their state of health (Supplement 1), which supports the assumption of missing at random and the use of multiple imputation techniques. Supplement 1. Data Collection in the Surgical Treatment of Ischemic Heart Disease (STICH) Trial Quality of Life Substudy The STICH trial had a high overall mortality rate and a treatment-related mortality difference, as noted previously. These deaths produced a nonrandom group of survivors who provided the follow-up QOL data. No consensus exists in the statistical literature about how best to analyze intermediate end points, such as QOL, when death prevents complete data collection. The primary concern this issue raises in a treatment comparison is that a therapy more effective at preventing death may also preserve more patients with poor QOL than the comparison therapy. Thus, when comparing QOL in such a situation using all survivors, the therapy with the worse survival might have an artifactual improvement in QOL measurements. Rubin has proposed that because QOL data that are censored due to death do not exist even in theory and should be regarded as undefined, the most meaningful analysis is to compare QOL for patients in the 2 treatment groups who would have survived with either therapy (18). To accomplish this, we performed a survival average causal effect (SACE) analysis (1821). The SACE estimates of QOL are calculated from weighted averages of the QOL data multiplied by survival probability estimates (from survival models developed in the parent STICH study cohort) specific to the study group. The 95% CIs for the SACE were calculated using 200 repetitions of a nonparametric bootstrap procedure (22). These sensitivity analyses are helpful as supplements to the primary analysis but have their own difficulties, not the least of which are the important but untestable assumptioClinical trials performed during the 1970s and 1980s defined several major coronary artery disease (CAD) subgroups for which coronary artery bypass grafting (CABG) provided incremental survival, angina relief, or both relative to medical therapy, which formed the foundation for current practice patterns and guideline recommendations on the use of CABG (1-3). However, patients with severe left ventricular dysfunction (ejection fraction ≤0.35) were not represented in these early trials. Thus, management decisions for these patients have largely relied on clinical judgment to extrapolate from those trials and a small group of observational studies (4, 5). The challenges in using this evidence to select treatment for contemporary patients is further complicated in that medical therapies for both CAD and heart failure have improved substantially over those used in the earlier trials. The STICH (Surgical Treatment for Ischemic Heart Failure) trial was funded by the National Heart, Lung, and Blood Institute in 2002 to provide a comprehensive evaluation of the incremental therapeutic benefits of routine CABG over contemporary guideline-based medical therapy in patients with severe systolic dysfunction due to CAD (6). A major prespecified secondary end point of the trial was health-related quality of life (QOL), which is an outcome that complements the major clinical end points by assessing the patient’s experience of, and satisfaction with, the 2 therapeutic strategies compared (7, 8).

Quality-of-Life Outcomes in Surgical Treatment of Ischemic Heart Failure Quality-of-Life Outcomes With Coronary Artery Bypass Graft Surgery in Ischemic Left Ventricular Dysfunction: A Randomized Trial

Context A randomized, controlled trial of patients with high-risk coronary artery disease and heart failure previously reported no significant difference between medical therapy alone and medical therapy plus coronary artery bypass grafting when the outcome was death from any cause. Contribution This study from the same trial reports that medical therapy plus coronary artery bypass grafting is better than medical therapy alone when the outcome is quality of life. Caution The type of therapy was not concealed from patients or investigators. Implication This is the first study to examine how these therapies affect quality of life in patients who have coronary artery disease and heart failure. The Editors Clinical trials performed during the 1970s and 1980s defined several major coronary artery disease (CAD) subgroups for which coronary artery bypass grafting (CABG) provided incremental survival, angina relief, or both relative to medical therapy. These early trials formed the foundation for current practice patterns and guideline recommendations on the use of CABG (13). However, patients with severe left ventricular dysfunction (ejection fraction 0.35) were not represented. Thus, management decisions for these patients have largely relied on clinical judgment to extrapolate from those trials and a small group of observational studies(4, 5). The challenges in using this evidence to select treatment for contemporary patients is further complicated by the substantial improvement in medical therapies for both CAD and heart failure over those used in the earlier trials. The STICH (Surgical Treatment for Ischemic Heart Failure) trial was funded by the National Heart, Lung, and Blood Institute in 2002 to provide a comprehensive evaluation of the incremental therapeutic benefits of routine CABG over contemporary guideline-based medical therapy in patients with severe systolic dysfunction due to CAD (6). A major prespecified secondary end point of the trial was health-related quality of life (QOL), which is an outcome that complements the major clinical end points by assessing the patients experience of, and satisfaction with, the 2 therapeutic strategies compared (7, 8). Methods Patient Population and Primary Clinical Results To test the STICH trials surgical revascularization hypothesis, we randomly assigned 1212 patients with site-defined left ventricular ejection fraction of 0.35 or less and CAD suitable for revascularization to CABG or medical therapy (6). Rationale, trial design, and complete inclusion and exclusion criteria have been described previously (7). Patients were enrolled at 99 clinical sites in 22 countries between July 2002 and May 2007. All patients provided informed consent, and study protocol was approved by each sites institutional review board or ethics committee. Median follow-up was 56 months. The primary intention-to-treat comparison showed that 35.7% of patients assigned to CABG and 40.5% of those assigned to medical therapy died (primary analysis: unadjusted hazard ratio for all-cause mortality, 0.86 [95% CI, 0.72 to 1.04]; P= 0.123; secondary analysis: adjusted hazard ratio for all-cause mortality, 0.82 [CI, 0.68 to 0.99]; P= 0.039). Patients assigned to CABG had lower rates of the 2 major secondary clinical end points: death from cardiovascular causes (hazard ratio, 0.81; P= 0.050) and the composite of all-cause mortality and hospitalization for cardiovascular causes (hazard ratio, 0.74; P< 0.001). Health-Related QOL Data Collection We collected QOL data using structured interviews at baseline and 4, 12, 24, and 36 months after randomization. Site coordinators were specially trained by the Duke Clinical Research Institute Outcomes Research Group to conduct baseline interviews. The original research plan called for all patients to be enrolled in North America and all English- and Spanish-language follow-up QOL interviews to be completed via telephone by the Duke Clinical Research Institute. The few patients expected to require French-language interviews were to be interviewed by site coordinators. When enrollment was expanded outside of North America, the plan was modified to have those site coordinators do all QOL interviews in the patients native language. For nonEnglish-speaking participants, translations of the QOL instruments were obtained from the instrument developers or a translation service was used to create validated translations. The New York Heart Association (NYHA) class and Canadian Cardiovascular Society (CCS) angina class were collected on the clinical case report form at baseline and each follow-up interval. QOL Measures A battery of validated measures was used to provide a comprehensive but efficient assessment of QOL. The principal prespecified QOL measure was the Kansas City Cardiomyopathy Questionnaire (KCCQ), which is a 23-item instrument that measures the effect of heart failure symptoms on QOL (9). We used 3 scales from the Seattle Angina Questionnaire to assess the effect of angina symptoms on QOL outcomes (10), the Short Form-12 Survey to provide a brief overall generic measure of health status (11), and 5 individual scales from the Short Form-36 Health Survey to provide a more detailed assessment of areas of functioning and well-being from a generic perspective (12). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (13). The Cardiac Self-Efficacy Questionnaire was used to measure patient confidence in controlling disease symptoms and maintaining physical functioning (14). Finally, we used the EuroQol-5D, which is a generic instrument consisting of a 5-dimension single summary health status index and a self-rated visual analogue scale (0 to 100) of current health-related QOL (15). Statistical Analysis All primary comparisons were performed with the treatment group defined according to the intention-to-treat principle. Descriptive statistics included percentages for discrete variables and medians with 25th to 75th percentiles plus means with SDs for continuous variables. The chi-square test was used for discrete variable comparisons. Treatment comparisons of continuous variables were done by using a linear mixed model to account for repeated measures within a patient. The baseline QOL measure was used as one of the repeated measures. In PROC MIXED in SAS, version 9.2 (SAS Institute), the baseline, 4-, 12-, 24-, and 36-month measurements within a patient were fitted using maximum likelihood methods with unstructured covariance matrix (16). At each time point, estimated treatment differences, 95% CIs, and P values were obtained using the model estimates. Finally, the proportion of patients who achieved a clinically important improvement of 5 points or more in KCCQ overall summary scores were compared by treatment group using the chi-square test (17). All analyses were conducted using SAS, version 8 or higher. All reported P values were 2-sided. No adjustment was made in significance levels for multiple comparisons. Benchmarks for clinically significant changes in QOL scores for individual patients were used informally to assess the magnitude of the mean difference between the 2 groups. However, a QOL difference between groups at or exceeding the benchmark was not used as a formal decision rule to define clinical significance. Subgroup Analysis Regional effects were tested as interactions between the 5 regions used in the clinical analyses (Asia, Australia and New Zealand, Europe, North America, and South America) and the KCCQ overall summary score. Other interactions tested from those prespecified in the clinical analysis plan included age, sex, race, current NYHA class, left ventricular ejection fraction, baseline diabetes, CCS angina class, and myocardium viability. Sensitivity Analysis Some QOL data were missing because a small proportion of living patients did not complete a scheduled QOL assessment and a larger proportion of patients died before 1 or more of the scheduled assessments could be done. Almost all cases of missing data among living patients were attributed to administrative reasons rather than their state of health (Supplement 1), which supports the assumption of missing at random and the use of multiple imputation techniques. Supplement 1. Data Collection in the Surgical Treatment of Ischemic Heart Disease (STICH) Trial Quality of Life Substudy The STICH trial had a high overall mortality rate and a treatment-related mortality difference, as noted previously. These deaths produced a nonrandom group of survivors who provided the follow-up QOL data. No consensus exists in the statistical literature about how best to analyze intermediate end points, such as QOL, when death prevents complete data collection. The primary concern this issue raises in a treatment comparison is that a therapy more effective at preventing death may also preserve more patients with poor QOL than the comparison therapy. Thus, when comparing QOL in such a situation using all survivors, the therapy with the worse survival might have an artifactual improvement in QOL measurements. Rubin has proposed that because QOL data that are censored due to death do not exist even in theory and should be regarded as undefined, the most meaningful analysis is to compare QOL for patients in the 2 treatment groups who would have survived with either therapy (18). To accomplish this, we performed a survival average causal effect (SACE) analysis (1821). The SACE estimates of QOL are calculated from weighted averages of the QOL data multiplied by survival probability estimates (from survival models developed in the parent STICH study cohort) specific to the study group. The 95% CIs for the SACE were calculated using 200 repetitions of a nonparametric bootstrap procedure (22). These sensitivity analyses are helpful as supplements to the primary analysis but have their own difficulties, not the least of which are the important but untestable assumptioClinical trials performed during the 1970s and 1980s defined several major coronary artery disease (CAD) subgroups for which coronary artery bypass grafting (CABG) provided incremental survival, angina relief, or both relative to medical therapy, which formed the foundation for current practice patterns and guideline recommendations on the use of CABG (1-3). However, patients with severe left ventricular dysfunction (ejection fraction ≤0.35) were not represented in these early trials. Thus, management decisions for these patients have largely relied on clinical judgment to extrapolate from those trials and a small group of observational studies (4, 5). The challenges in using this evidence to select treatment for contemporary patients is further complicated in that medical therapies for both CAD and heart failure have improved substantially over those used in the earlier trials. The STICH (Surgical Treatment for Ischemic Heart Failure) trial was funded by the National Heart, Lung, and Blood Institute in 2002 to provide a comprehensive evaluation of the incremental therapeutic benefits of routine CABG over contemporary guideline-based medical therapy in patients with severe systolic dysfunction due to CAD (6). A major prespecified secondary end point of the trial was health-related quality of life (QOL), which is an outcome that complements the major clinical end points by assessing the patient’s experience of, and satisfaction with, the 2 therapeutic strategies compared (7, 8).