Ajay Naik

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).

Profiling cardiac arrhythmia and heart failure patients in India: The Pan-arrhythmia and Heart Failure Observational Study

Background The PANARrhythMia and Heart Failure Registry (PANARM HF) characterized demographic, clinical and interventional therapy indication profiles of cardiac arrhythmia (CA) and heart failure (HF) patients in India. Methods Consulting Physicians (CP) who medically manage CA and HF patients enrolled patients with one or more of the following: syncope, pre-syncope, dyspnea, palpitation, fatigue and LV dysfunction. The CPs were trained by interventional cardiologists (IC) to identify CA/HF patients indicated for implantable device/radiofrequency ablation (RFA). 59 CP’s, 16 IC’s & 2205 patients from 12 cities participated. Demographic, clinical, device/RFA indication and referral-consultation profiles were created. IC’s provided device/RFA recommendations based on these profiles. Results The CA/HF distribution of patients was: HF – 58%, bradyarrhythmia – 15%, atrial fibrillation – 15%, other supraventricular tachyarrhythmia – 10% and ventricular tachycardia/fibrillation – 4.5%. 62% of the CA/HF population was male and 45% were below age 60. Coronary artery disease (52%), hypertension (44%), diabetes (30%) & myocardial infarction (20%) were prominent. 1011 (46%) of the CA/HF population were potential device/RFA candidates according to the IC’s. However, only 700 (69%) of these patients were referred to the IC by the CP. Of referred patients, only 177 (25%) consulted the IC and were recommended therapy. Thus, 824 (83%) of patients indicated for interventional therapy were not advised therapy or did not opt for it. Conclusion The India PANARM HF study provides new information and insights into the demographic, clinical, interventional therapy, referral and consultation pattern profiles of CA/HF patients in India.

Regional variations in baseline characteristics of cardiac rhythm device recipients: The PANORAMA observational cohort study

Background The PANORAMA study was designed to collect concurrent data on subjects from different worldwide regions implanted with CRM devices. Methods In this prospective, multi-center study, we analyzed baseline data on 8586 subjects implanted with CRM devices with no additional selection criteria (66% pacemaker (IPG), 16% implantable cardiac defibrillators (ICD), 17% cardiac resynchronization therapy (CRT) and < 1% Internal Loop Recorder) from 156 hospitals across 6 geographical regions between 2005 and 2011. Results Regardless of the device implanted, subjects from the Middle East and India often had more diabetes than other regions. Eastern and Western Europe had higher rates of atrial fibrillation reported, and men were more likely to smoke than women (46% vs 11%, p < 0.001). Within the CRT cohort there was significant variation in the proportion of males receiving a device, ranging from 55% in India to 83% in Eastern Europe. Conclusions We provide comprehensive descriptive data on patients receiving CRM devices from a range of geographies that are not typically reported in literature. We found significant variations in clinical characteristics and implant practices. Long term follow-up data will help evaluate if these variations require adjustments to outcome expectations.

Real-world geographic variations in the use of cardiac implantable electronic devices-The PANORAMA 2 observational cohort study: BASTIAN et al.

Currently, several geographies around the world remain underrepresented in medical device trials. The PANORAMA 2 study was designed to assess contemporary region‐specific differences in clinical practice patterns of patients with cardiac implantable electronic devices (CIEDs).

Cardiac resynchronization therapy is associated with improvement in clinical outcomes in Indian heart failure patients: Results of a large, long-term observational study

Background Heart failure (HF) is a common health problem in South Asia, and its incidence and prevalence are projected to rise. Cardiac resynchronization therapy (CRT) has been shown to improve mortality, reduce hospitalizations, and improve symptoms in selected patients with HF. The South Asian Systolic Heart Failure Registry (SASHFR) was designed to be a large and comprehensive registry of Indian HF patients with the purpose of enhancing the quality of care and clinical outcomes of HF patients by promoting the adoption of evidence-based, guideline-recommended therapies, in particular CRT. Methods Overall, 471 patients on optimized medical therapy and meeting CRT implantation guidelines were followed up in 12 Indian hospitals. During the 2-year follow-up period, clinical response in terms of clinical composite score, overall performance and changes in HF performance metrics, mortality and hospitalizations rates were evaluated. Results Of 471 patients, 116 (24.6%) accepted to be implanted with a CRT device, while 355 (75.4%) refused, financial constraints being the main reason for refusing a CRT device. The study met its primary outcome, as the number of patients associated with an improvement in clinical composite score at 24 months was significantly higher (69.1%) in the CRT group than in the no-CRT group (44.7%) [odds ratio = 2 (95% confidence interval 1.25–3.20), p = 0.004]. Also, changes in HF metrics, mortality and hospitalizations rates indicated a more favorable response among patients who underwent CRT. Conclusions The results from the SASHFR registry show a clear superiority of CRT over optimal pharmacological therapy in terms of improvement in clinical conditions among HF patients. The low rate of CRT acceptance, in patients indicated to this therapy, highlights the need for new health-care policies to improve awareness about HF disease and its therapies and possibly to enhance financial coverage of indicated therapies.

Under-utilization of pacemaker therapy for sinus node dysfunction – Real world data from South Asia

Objective Chronic symptomatic sinus node dysfunction (SND), the most common bradyarrhythmia, can be effectively managed by permanent cardiac pacing. Yet the care pathway and barriers to adoption of pacing therapy are not well understood – particularly in low volume implanting countries. The IMPROVE Brady study is a quality improvement initiative being conducted at centers in South Asia, Latin America, and Russia. We assessed the rates of SND diagnosis and pacemaker treatment for SND in the South Asia cohort. Methods The prospective study enrolled patients with heart rate of  ≤50 beats per minute presenting with symptoms including syncope, dizziness, and/or dyspnea from ten centers in India and Bangladesh. Patients were followed to identify the proportion diagnosed with SND and subsequently treated with pacemaker therapy. Results A total of 508 patients meeting criteria were enrolled and followed on average for 8.3 ± 8.0 months. Patients were on average 58 years of age, 77% were male, and 91% had completed at least primary education. An SND diagnosis was made in 368 (72%) of patients, with the majority (80%) of diagnoses occurring within 1 month of enrollment. Of the patients with an SND diagnosis, 63 (17%) were treated with a pacemaker. Reasons for not receiving treatment were: subject refusal or deferred decision (45%), unaffordability (34%), physician determined – not-indicated (20%), and other (1%). Older age, female gender, history of hypertension, lower resting heart rate, and syncopal or pre-syncopal symptoms were associated with a higher probability of implant. Conclusions In a care pathway assessment for the diagnosis and treatment of symptomatic SND in South Asia only 1 in 6 patients received pacemaker indicated therapy, largely due to patient refusal and physician decision. Phase II of the study will be aimed to improve this treatment rate.

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).