Factors associated with coronary angiography performed within 6 months of randomization to the conservative strategy in the ISCHEMIA Trial

BACKGROUND: ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) did not find an overall reduction in cardiovascular events with an initial invasive versus conservative management strategy in chronic coronary disease; however, there were conservative strategy participants who underwent invasive coronary angiography early postrandomization (within 6 months). Identifying factors associated with angiography in conservative strategy participants will inform clinical decision-making in patients with chronic coronary disease. METHODS: Factors independently associated with angiography performed within 6 months of randomization were identified using Fine and Gray proportional subdistribution hazard models, including demographics, region of randomization, medical history, risk factor control, symptoms, ischemia severity, coronary anatomy based on protocol-mandated coronary computed tomography angiography, and medication use. RESULTS: Among 2591 conservative strategy participants, angiography within 6 months of randomization occurred in 8.7% (4.7% for a suspected primary end point event, 1.6% for persistent symptoms, and 2.6% due to protocol nonadherence) and was associated with the following baseline characteristics: enrollment in Europe versus Asia (hazard ratio [HR], 1.81 [95% CI, 1.14­2.86]), daily and weekly versus no angina (HR, 5.97 [95% CI, 2.78­12.86] and 2.63 [95% CI, 1.51­4.58], respectively), poor to fair versus good to excellent health status (HR, 2.02 [95% CI, 1.23­3.32]) assessed with Seattle Angina Questionnaire, and new/more frequent angina prerandomization (HR, 1.80 [95% CI, 1.34­2.40]). Baseline low-density lipoprotein cholesterol <70 mg/dL was associated with a lower risk of angiography (HR, 0.65 [95% CI, 0.46­0.91) but not baseline ischemia severity nor the presence of multivessel or proximal left anterior descending artery stenosis >70% on coronary computed tomography angiography. CONCLUSIONS: Among ISCHEMIA participants randomized to the conservative strategy, angiography within 6 months of randomization was performed in <10% of patients. It was associated with frequent or increasing baseline angina and poor quality of life but not with objective markers of disease severity. Well-controlled baseline low-density lipoprotein cholesterol was associated with a reduced likelihood of angiography. These findings point to the importance of a comprehensive assessment of symptoms and a review of guideline-directed medical therapy goals when deciding the initial treatment strategy for chronic coronary disease.

Impact of complete revascularization in the IschemiaTrial

BACKGROUND: Anatomic complete revascularization (ACR) and functional complete revascularization (FCR) have been associated with reduced death and myocardial infarction (MI) in some prior studies. The impact of complete revascularization (CR) in patients undergoing an invasive (INV) compared with a conservative (CON) management strategy has not been reported. OBJECTIVES: Among patients with chronic coronary disease without prior coronary artery bypass grafting randomized to INV vs CON management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, we examined the following: 1) the outcomes of ACR and FCR compared with incomplete revascularization; and 2) the potential impact of achieving CR in all INV patients compared with CON management. METHODS: ACR and FCR in the INV group were assessed at an independent core laboratory. Multivariable-adjusted outcomes of CR were examined in INV patients. Inverse probability weighted modeling was then performed to estimate the treatment effect had CR been achieved in all INV patients compared with CON management. RESULTS: ACR and FCR were achieved in 43.4% and 58.4% of 1,824 INV patients. ACR was associated with reduced 4-year rates of cardiovascular death or MI compared with incomplete revascularization. By inverse probability weighted modeling, ACR in all 2,296 INV patients compared with 2,498 CON patients was associated with a lower 4-year rate of cardiovascular death or MI (difference -3.5; 95% CI: -7.2% to 0.0%). In comparison, the event rate difference of cardiovascular death or MI for INV minus CON in the overall ISCHEMIA trial was -2.4%. Results were similar but less pronounced with FCR. CONCLUSIONS: The outcomes of an INV strategy may be improved if CR (especially ACR) is achieved. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Health status and clinical outcomes in older adults with chronic coronary disease: the ISCHEMIA trial

BACKGROUND: Whether initial invasive management in older vs younger adults with chronic coronary disease and moderate or severe ischemia improves health status or clinical outcomes is unknown. OBJECTIVES: The goal of this study was to examine the impact of age on health status and clinical outcomes with invasive vs conservative management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. METHODS: One-year angina-specific health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ) (score range 0-100; higher scores indicate better health status). Cox proportional hazards models estimated the treatment effect of invasive vs conservative management as a function of age on the composite clinical outcome of cardiovascular death, myocardial infarction, or hospitalization for resuscitated cardiac arrest, unstable angina, or heart failure. RESULTS: Among 4,617 participants, 2,239 (48.5%) were aged <65 years, 1,713 (37.1%) were aged 65 to 74 years, and 665 (14.4%) were aged ≥75 years. Baseline SAQ summary scores were lower in participants aged <65 years. Fully adjusted differences in 1-year SAQ summary scores (invasive minus conservative) were 4.90 (95% CI: 3.56-6.24) at age 55 years, 3.48 (95% CI: 2.40-4.57) at age 65 years, and 2.13 (95% CI: 0.75-3.51) at age 75 years (Pinteraction = 0.008). Improvement in SAQ Angina Frequency was less dependent on age (Pinteraction = 0.08). There were no age differences between invasive vs conservative management on the composite clinical outcome (Pinteraction = 0.29). CONCLUSIONS: Older patients with chronic coronary disease and moderate or severe ischemia had consistent improvement in angina frequency but less improvement in angina-related health status with invasive management compared with younger patients. Invasive management was not associated with improved clinical outcomes in older or younger patients. (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Validation of the Portuguese Version of the Kansas City Cardiomyopathy Questionnaire-12.

The Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) is a simple, feasible, and sensitive questionnaire developed in English for assessing the health status (symptoms, function, and quality of life) of patients with heart failure (HF). We aimed to assess the internal consistency and construct validity of the Portuguese version of KCCQ-12. We administered the KCCQ-12, the Minnesota Living Heart Failure (MLHFQ), and the New York Heart Association (NYHA) classification by telephone. Internal consistency was assessed with Cronbach's Alpha (α-Cronbach) and construct validity with correlations to the MLHFQ and NYHA. Internal consistency was high (α-Cronbach = 0.92 for the Overall Summary score and 0.77-0.85 for the subdomains). Construct validity was supported by finding high correlations between the KCCQ-12 Physical Limitation and the Symptom Frequency domains with the physical domain of the MLHFQ (r = -0.70 and r = -0.76, p < 0.001 for both) and the Overall Summary scale with NYHA classifications (r = -0.72, p < 0.001). The Portuguese version of KCCQ-12 has high internal consistency and shows a convergent construct validity with other measures quantifying the health status of patients with chronic HF and can be used confidently in Brazil for research and clinical care.

Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity

BACKGROUND: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) postulated that patients with stable coronary artery disease (CAD) and moderate or severe ischemia would benefit from revascularization. We investigated the relationship between severity of CAD and ischemia and trial outcomes, overall and by management strategy. METHODS: In total, 5179 patients with moderate or severe ischemia were randomized to an initial invasive or conservative management strategy. Blinded, core laboratory­interpreted coronary computed tomographic angiography was used to assess anatomic eligibility for randomization. Extent and severity of CAD were classified with the modified Duke Prognostic Index (n=2475, 48%). Ischemia severity was interpreted by independent core laboratories (nuclear, echocardiography, magnetic resonance imaging, exercise tolerance testing, n=5105, 99%). We compared 4-year event rates across subgroups defined by severity of ischemia and CAD. The primary end point for this analysis was all-cause mortality. Secondary end points were myocardial infarction (MI), cardiovascular death or MI, and the trial primary end point (cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest). RESULTS: Relative to mild/no ischemia, neither moderate ischemia nor severe ischemia was associated with increased mortality (moderate ischemia hazard ratio [HR], 0.89 [95% CI, 0.61­1.30]; severe ischemia HR, 0.83 [95% CI, 0.57­1.21]; P=0.33). Nonfatal MI rates increased with worsening ischemia severity (HR for moderate ischemia, 1.20 [95% CI, 0.86­1.69] versus mild/no ischemia; HR for severe ischemia, 1.37 [95% CI, 0.98­1.91]; P=0.04 for trend, P=NS after adjustment for CAD). Increasing CAD severity was associated with death (HR, 2.72 [95% CI, 1.06­6.98]) and MI (HR, 3.78 [95% CI, 1.63­8.78]) for the most versus least severe CAD subgroup. Ischemia severity did not identify a subgroup with treatment benefit on mortality, MI, the trial primary end point, or cardiovascular death or MI. In the most severe CAD subgroup (n=659), the 4-year rate of cardiovascular death or MI was lower in the invasive strategy group (difference, 6.3% [95% CI, 0.2%­12.4%]), but 4-year all-cause mortality was similar. CONCLUSIONS: Ischemia severity was not associated with increased risk after adjustment for CAD severity. More severe CAD was associated with increased risk. Invasive management did not lower all-cause mortality at 4 years in any ischemia or CAD subgroup.

Machine Learning Prediction of Mortality and Hospitalization in Heart Failure With Preserved Ejection Fraction.

OBJECTIVES: This study sought to develop models for predicting mortality and heart failure (HF) hospitalization for outpatients with HF with preserved ejection fraction (HFpEF) in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. BACKGROUND: Although risk assessment models are available for patients with HF with reduced ejection fraction, few have assessed the risks of death and hospitalization in patients with HFpEF. METHODS: The following 5 methods: logistic regression with a forward selection of variables; logistic regression with a lasso regularization for variable selection; random forest (RF); gradient descent boosting; and support vector machine, were used to train models for assessing risks of mortality and HF hospitalization through 3 years of follow-up and were validated using 5-fold cross-validation. Model discrimination and calibration were estimated using receiver-operating characteristic curves and Brier scores, respectively. The top prediction variables were assessed by using the best performing models, using the incremental improvement of each variable in 5-fold cross-validation. RESULTS: The RF was the best performing model with a mean C-statistic of 0.72 (95% confidence interval [CI]: 0.69 to 0.75) for predicting mortality (Brier score: 0.17), and 0.76 (95% CI: 0.71 to 0.81) for HF hospitalization (Brier score: 0.19). Blood urea nitrogen levels, body mass index, and Kansas City Cardiomyopathy Questionnaire (KCCQ) subscale scores were strongly associated with mortality, whereas hemoglobin level, blood urea nitrogen, time since previous HF hospitalization, and KCCQ scores were the most significant predictors of HF hospitalization. CONCLUSIONS: These models predict the risks of mortality and HF hospitalization in patients with HFpEF and emphasize the importance of health status data in determining prognosis. (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist [TOPCAT]; NCT00094302).

Impact of Spironolactone on Longitudinal Changes in Health-Related Quality of Life in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial.

BACKGROUND: Heart failure (HF) with preserved ejection fraction patients have equally impaired health-related quality of life (HRQL) compared with those with HF with reduced ejection fraction, but limited studies have evaluated the impact of therapies on changes in HRQL. METHODS AND RESULTS: Patients ≥50 years of age, with symptomatic HF and left ventricular ejection fraction ≥45%, were enrolled in Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) and randomized to spironolactone or placebo. Patients completed the Kansas City Cardiomyopathy Questionnaire (KCCQ), which was the primary HRQL instrument, and EQ5D visual analog scale at baseline, 4 months, 12 months, and annually thereafter. McMaster Overall Treatment Evaluation was assessed at 4 and 12 months to assess global change scores. Change scores (+SD) were calculated to determine between-group differences, and multivariable repeated-measures models were created to identify other factors associated with change scores. Paired KCCQ data were available for 91.7% of 3445 TOPCAT patients. By 4 months, the mean change in KCCQ was 7.7±16 and mean change in EQ5D visual analog scale was 4.7±16. Adjusted mean changes in KCCQ for the spironolactone group were significantly better than those for the placebo group at 4-month (1.54 better; P=0.002), 12-month (1.35 better; P=0.02), and 36-month (1.86 better; P=0.02) visits. No between-group differences in EQ5D visual analog scale change scores or McMaster Overall Treatment Evaluation were noted. Older age, obesity, current smoking, New York Heart Association class III/IV, and comorbid illnesses were associated with declines in KCCQ scores. Use of spironolactone was an independent predictor of improved KCCQ scores. CONCLUSIONS: In symptomatic HF with preserved ejection fraction patients, use of spironolactone was associated with an improvement in HF-specific HRQL. Several modifiable risk factors were associated with HRQL deterioration. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Optimal medical therapy with or without percutaneous coronary intervention in women with stable coronary disease: A pre-specified subset analysis of the Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation (COURAGE) trial.

OBJECTIVES: To determine whether sex-based differences exist in clinical effectiveness of percutaneous coronary intervention (PCI) when added to optimal medical therapy (OMT) in patients with stable coronary artery disease. BACKGROUND: A prior pre-specified unadjusted analysis from COURAGE showed that women randomized to PCI had a lower rate of death or myocardial infarction during a median 4.6-year follow-up with a trend for interaction with respect to sex. METHODS: We analyzed outcomes in 338 women (15%) and 1949 men (85%) randomized to PCI plus OMT versus OMT alone after adjustment for relevant baseline characteristics. RESULTS: There was no difference in treatment effect by sex for the primary end point (death or myocardial infarction; HR, 0.89; 95% CI, 0.77-1.03 for women and HR, 1.02, 95% CI 0.96-1.10 for men; P for interaction = .07). Although the event rate was low, a trend for interaction by sex was nonetheless noted for hospitalization for heart failure, with only women, but not men, assigned to PCI experiencing significantly fewer events as compared to their counterparts receiving OMT alone (HR, 0.59; 95% CI, 0.40-0.84, P < .001 for women and HR, 0.86; 95% CI, 0.74-1.01, P = .47 for men; P for interaction = .02). Both sexes randomized to PCI experienced significantly reduced need for subsequent revascularization (HR, 0.72; 95% CI, 0.62-0.83, P < .001 for women; HR, 0.84; 95% CI, 0.79-0.89, P < .001 for men; P for interaction = .02) with evidence of a sex-based differential treatment effect. CONCLUSION: In this adjusted analysis of the COURAGE trial, there were no significant differences in treatment effect on major outcomes between men and women. However, women assigned to PCI demonstrated a greater benefit as compared to men, with a reduction in heart failure hospitalization and need for future revascularization. These exploratory observations require further prospective study.

Use of Heart Failure Medical Therapies Among Patients With Left Ventricular Assist Devices: Insights From INTERMACS.

BACKGROUND: Use of left ventricular assist devices (LVADs) for treatment of advanced heart failure has expanded significantly over the past decade. However, concomitant use of heart failure medical therapies after implant is poorly characterized. METHODS AND RESULTS: We examined the use of heart failure medications before and after LVAD implant in adult patients enrolled in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) between 2008 and 2013 (N = 9359). Using logistic regression, we examined relationships between patient characteristics and medication use at 3 months after implant. Baseline rates of heart failure therapies before implant were 38% for angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), 55% for ß-blockers, 40% for mineralocorticoid receptor antagonists (MRAs), 87% for loop diuretics, 54% for amiodarone, 11% for phosphodiesterase inhibitors, 22% for warfarin, and 54% for antiplatelet agents. By 3 months after implant, the rates were 50% for ACE inhibitors or ARBs, 68% for ß-blockers, 33% for MRAs, 68% for loop diuretics, 42% for amiodarone, 21% for phosphodiesterase inhibitors, 92% for warfarin, and 84% for antiplatelet agents. In general, age, preimplant INTERMACS profile, and prior medication use were associated with medication use at 3 months. CONCLUSIONS: Overall use of neurohormonal antagonists was low after LVAD implant, whereas use of loop diuretics and amiodarone remained high. Heart failure medication use is highly variable, but appears to generally increase after LVAD implantation. Low neurohormonal antagonist use may reflect practice uncertainty in the clinical utility of these medications post-LVAD.

Practice-level variation in use of recommended medications among outpatients with heart failure: Insights from the NCDR PINNACLE program.

BACKGROUND: The objective of this study is to examine practice-level variation in rates of guideline-recommended treatment for outpatients with heart failure and reduced ejection fraction, and to examine the association between treatment variation and practice site, independent of patient factors. METHODS AND RESULTS: Cardiology practices participating in the National Cardiovascular Disease Registry Practice Innovation and Clinical Excellence registry from July 2008 to December 2010 were evaluated. Practice rates of treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and ß-blockers and an optimal combined treatment measure were determined for patients with heart failure and reduced ejection fraction and no documented contraindications. Multivariable hierarchical regression models were adjusted for demographics, insurance status, and comorbidities. A median rate ratio was calculated for each therapy, which describes the likelihood that the treatment of a patient with given comorbidities would differ at 2 randomly selected practices. We identified 12 556 patients from 45 practices. The unadjusted practice-level prescription rates ranged from 44% to 100% for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (median, 85%; interquartile range, 75%-89%), from 49% to 100% for ß-blockers (median, 92%; interquartile range, 83%-95%), and from 37% to 100% for optimal combined treatment (median, 79%; interquartile range, 66%-85%). The adjusted median rate ratio was 1.11 (95% confidence interval, 1.08-1.18) for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers therapy, 1.08 (95% confidence interval, 1.05-1.15) for ß-blockers therapy, and 1.17 (1.13-1.26) for optimal combined treatment. CONCLUSIONS: Variation in the use of guideline-recommended medications for patients with heart failure and reduced ejection fraction exists in the outpatient setting. Addressing practice-level differences may be an important component of improving quality of care for patients with heart failure and reduced ejection fraction.

Six-month results of the NEVO RES-ELUTION I (NEVO RES-I) trial: randomized, multicenter comparison of the NEVO Sirolimus-Eluting coronary stent vith the TAXUS libert paclitaxel-eluting stent in de novo native coronary artery lesions

Background—Drug-eluting stents reduce restenosis and reintervention rates but are complicated by stent thrombosis,which may be related to polymer coating. The NEVO sirolimus-eluting coronary stent (NEVO SES) is designed to improve long-term percutaneous coronary intervention safety by combining sirolimus release from reservoirs withbioabsorbable polymer to reduce spatial and temporal polymer exposure.Methods and Results—NEVO ResElution-I was a prospective randomized study in 394 patients with coronary arterydisease comparing the NEVO SES with the TAXUS Liberte´ paclitaxel-eluting coronary stent (TAXUS Liberte´ PES)stent. The primary end point was in-stent angiographic late loss at 6 months. Six months after percutaneous coronaryintervention (PCI), the primary end point favored NEVO SES (0.13 0.31 mm versus 0.36 0.48 mm, P 0.001 fornoninferiority and superiority). The study was not powered for clinical end points and showed no significant differencefor NEVO SES versus TAXUS Liberte´ PES: death: 0.5 versus 1.6%, P 0.36; myocardial infarction: 2.0 versus 2.6%,P 0.75; target lesion revascularization: 1.5 versus 3.2%, P 0.33; major adverse cardiac events: 4.0 versus 7.4%, P 0.19.No stent thrombosis was observed with NEVO SES, whereas 2 cases occurred in TAXUS Liberte´ PES. Intravascularultrasound showed lower percent volume obstruction for NEVO SES (5.5 11% versus 11.5 9.7%, P 0.016).Conclusions—This trial proved the superiority of NEVO SES over TAXUS Liberte´ PES for the primary angiographic endpoint of in-stent late loss. No stent thrombosis occurred in the NEVO SES group.