Interim Analysis of the Phase II Study: Noninferiority Study of Doxorubicin with Upfront Dexrazoxane plus Olaratumab for Advanced or Metastatic Soft-Tissue Sarcoma.

PURPOSE: To report the interim analysis of the phase II single-arm noninferiority trial, testing the upfront use of dexrazoxane with doxorubicin on progression-free survival (PFS) and cardiac function in soft-tissue sarcoma (STS). PATIENTS AND METHODS: Patients with metastatic or unresectable STS who were candidates for first-line treatment with doxorubicin were deemed eligible. An interim analysis was initiated after 33 of 65 patients were enrolled. Using the historical control of 4.6 months PFS for doxorubicin in the front-line setting, we tested whether the addition of dexrazoxane affected the efficacy of doxorubicin in STS. The study was powered so that a decrease of PFS to 3.7 months would be considered noninferior. Secondary aims included cardiac-related mortality, incidence of heart failure/cardiomyopathy, and expansion of cardiac monitoring parameters including three-dimensional echocardiography. Patients were allowed to continue on doxorubicin beyond 600 mg/m2 if they were deriving benefit and were not demonstrating evidence of symptomatic cardiac dysfunction. RESULTS: At interim analysis, upfront use of dexrazoxane with doxorubicin demonstrated a PFS of 8.4 months (95% confidence interval: 5.1-11.2 months). Only 3 patients were removed from study for cardiotoxicity, all on > 600 mg/m2 doxorubicin. No patients required cardiac hospitalization or had new, persistent cardiac dysfunction with left ventricular ejection fraction remaining below 50%. The median administered doxorubicin dose was 450 mg/m2 (interquartile range, 300-750 mg/m2). CONCLUSIONS: At interim analysis, dexrazoxane did not reduce PFS in patients with STS treated with doxorubicin. Involvement of cardio-oncologists is beneficial for the monitoring and safe use of high-dose anthracyclines in STS.See related commentary by Benjamin and Minotti, p. 3809.

Cardiac Amyloidosis for the Primary Care Provider: A Practical Review to Promote Earlier Recognition of Disease.

Cardiac amyloidosis is increasingly recognized as an underdiagnosed cause of heart failure. Diagnostic delays of up to 3 years from symptom onset may occur, and patients may be evaluated by more than 5 specialists prior to receiving the correct diagnosis. Newly available therapies improve clinical outcomes by preventing amyloid fibril deposition and are usually more effective in early stages of disease, making early diagnosis essential. Better awareness among primary care providers of the clinical presentation and modern treatment landscape is essential to improve timely diagnosis and early treatment of this disease. In this review, we provide practical guidance on the epidemiology, clinical manifestations, diagnostic evaluation, and treatment of transthyretin and light chain cardiac amyloidosis to promote earlier disease recognition among primary care providers.

Autonomic dysfunction in early breast cancer: Incidence, clinical importance, and underlying mechanisms.

Autonomic dysfunction represents a loss of normal autonomic control of the cardiovascular system associated with both sympathetic nervous system overdrive and reduced efficacy of the parasympathetic nervous system. Autonomic dysfunction is a strong predictor of future coronary heart disease, vascular disease, and sudden cardiac death. In the current review, we will discuss the clinical importance of autonomic dysfunction as a cardiovascular risk marker among breast cancer patients. We will review the effects of antineoplastic therapy on autonomic function, as well as discuss secondary exposures, such as psychological stress, sleep disturbances, weight gain/metabolic derangements, and loss of cardiorespiratory fitness, which may negatively impact autonomic function in breast cancer patients. Lastly, we review potential strategies to improve autonomic function in this population. The perspective can help guide new therapeutic interventions to promote longevity and cardiovascular health among breast cancer survivors.

Risk factors and the effect of cardiac resynchronization therapy on cardiac and non-cardiac mortality in MADIT-CRT.

AIMS: To understand modes of death and factors associated with the risk for cardiac and non-cardiac deaths in patients with cardiac resynchronization therapy with implantable cardioverter-defibrillator (CRT-D) vs. implantable cardioverter-defibrillator (ICD) therapy, which may help clarify the action and limitations of cardiac resynchronization therapy (CRT) in relieving myocardial dysfunction. METHODS AND RESULTS: In Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), during 4 years of follow-up, 169 (9.3%) of 1820 patients died of known causes, 108 (63.9%) deemed cardiac, and 61 (36.1%) non-cardiac. In multivariate analysis, increased baseline creatinine was significantly associated with both cardiac and non-cardiac deaths [hazard ratio (HR) 2.97, P < 0.001; HR 1.80, P = 0.035, respectively], as was diabetes (HR 1.79, P = 0.006; HR 1.73, P = 0.038, respectively), and the worst New York Heart Association Class > II more than 3 months prior to enrolment (HR 1.90, P = 0.012; HR 2.46, P = 0.010, respectively). Baseline left atrial volume index was significantly associated only with cardiac mortality (HR 1.28 per 5 unit increase, P < 0.001). Ischaemic cardiomyopathy was associated only with non-cardiac death (HR 3.54, P = 0.001). CRT-D vs. an ICD-only was associated with a reduced risk for cardiac death in patients with left bundle branch block (LBBB) (HR 0.56, P = 0.029) but was associated with an increased risk for non-cardiac death in non-LBBB patients (HR 3.48, P = 0.048). CONCLUSIONS: In MADIT-CRT, two-thirds of the deaths were cardiac and one-third non-cardiac. Many of the same risk factors were associated with both cardiac and non-cardiac mortalities. CRT-D was associated with a reduced risk for cardiac death in LBBB but an increased risk for non-cardiac death in non-LBBB. CLINICAL TRIAL REGISTRATION: Information for the MADIT-CRT main study http://www.clinicaltrials.gov, NCT00180271.

Improving clinical practice guidelines for practicing cardiologists.

Cardiac-related clinical practice guidelines have become an integral part of the practice of cardiology. Unfortunately, these guidelines are often long, complex, and difficult for practicing cardiologists to use. Guidelines should be condensed and their format upgraded, so that the key messages are easier to comprehend and can be applied more readily by those involved in patient care. After presenting the historical background and describing the guideline structure, we make several recommendations to make clinical practice guidelines more user-friendly for clinical cardiologists. Our most important recommendations are that the clinical cardiology guidelines should focus exclusively on (1) class I recommendations with established benefits that are supported by randomized clinical trials and (2) class III recommendations for diagnostic or therapeutic approaches in which quality studies show no benefit or possible harm. Class II recommendations are not evidence based but reflect expert opinions related to published clinical studies, with potential for personal bias by members of the guideline committee. Class II recommendations should be published separately as "Expert Consensus Statements" or "Task Force Committee Opinions," so that both majority and minority expert opinions can be presented in a less dogmatic form than the way these recommendations currently appear in clinical practice guidelines.

Identification of hospital outliers in bleeding complications after percutaneous coronary intervention.

BACKGROUND: Post-percutaneous coronary intervention (PCI) bleeding complications are an important quality metric. We sought to characterize site-level variation in post-PCI bleeding and explore the influence of patient and procedural factors on hospital bleeding performance. METHODS AND RESULTS: Hospital-level bleeding performance was compared pre- and postadjustment using the newly revised CathPCI Registry(®) bleeding risk model (c-index, 0.77) among 1292 National Cardiovascular Data Registry(®) hospitals performing >50 PCIs from 7/2009 to 9/2012 (n=1,984,998 procedures). Using random effects models, outlier sites were identified based on 95% confidence intervals around the hospital's random intercept. Bleeding 72 hours post-PCI was defined as: arterial access site, retroperitoneal, gastrointestinal, or genitourinary bleeding; intracranial hemorrhage; cardiac tamponade; nonbypass surgery-related blood transfusion with preprocedure hemoglobin ≥ 8 g/dL; or absolute decrease in hemoglobin value ≥ 3 g/dL with preprocedure hemoglobin ≤ 16 g/dL. Overall, the median unadjusted post-PCI bleeding rate was 5.2% and varied among hospitals from 2.6% to 10.4% (5th, 95th percentiles). Center-level bleeding variation persisted after case-mix adjustment (2.8%-9.5%; 5th, 95th percentiles). Although hospitals' observed and risk-adjusted bleeding ranks were correlated (Spearman ρ: 0.88), individual rankings shifted after risk-adjustment (median Δ rank order: ± 91.5; interquartile range: 37.0, 185.5). Outlier classification changed postadjustment for 29.3%, 16.1%, and 26.5% of low-, non-, and high-outlier sites, respectively. Hospital use of bleeding avoidance strategies (bivalirudin, radial access, or vascular closure device) was associated with risk-adjusted bleeding rates. CONCLUSIONS: Despite adjustment for patient case-mix, there is wide variation in rates of hospital PCI-related bleeding in the United States. Opportunities may exist for best performers to share practices with other sites.

Appropriate revascularization in stable angina: lessons from the BARI 2D trial.

BACKGROUND: The 2012 Guidelines for Diagnosis and Management of Patients with Stable Ischemic Heart Disease recommend intensive antianginal and risk factor treatment (optimal medical management [OMT]) before considering revascularization to relieve symptoms. The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial randomized patients with ischemic heart disease and anatomy suitable to revascularization to (1) initial OMT with revascularization if needed or (2) initial revascularization plus OMT and found no difference in major cardiovascular events. Ultimately, however, 37.9% of the OMT group was revascularized during the 5-year follow-up period. METHODS: Data from the 1192 patients randomized to OMT were analyzed to identify subgroups in which the incidence of revascularization was so high that direct revascularization without a trial period could be justified. Multivariate logistic analysis, Cox regression models of baseline data, and a landmark analysis of participants who did not undergo revascularization at 6 months were constructed. RESULTS: The models that used only data available at the time of study entry had limited predictive value for revascularization by 6 months or by 5 years; however, the model incorporating severity of angina during the first 6 months could better predict revascularization (C statistic = 0.789). CONCLUSIONS: With the possible exception of patients with severe angina and proximal left anterior descending artery disease, this analysis supports the recommendation of the 2012 guidelines for a trial of OMT before revascularization. Patients could not be identified at the time of catheterization, but a short period of close follow-up during OMT identified the nearly 40% of patients who underwent revascularization.

An updated bleeding model to predict the risk of post-procedure bleeding among patients undergoing percutaneous coronary intervention: a report using an expanded bleeding definition from the National Cardiovascular Data Registry CathPCI Registry.

OBJECTIVES: This study sought to develop a model that predicts bleeding complications using an expanded bleeding definition among patients undergoing percutaneous coronary intervention (PCI) in contemporary clinical practice. BACKGROUND: New knowledge about the importance of periprocedural bleeding combined with techniques to mitigate its occurrence and the inclusion of new data in the updated CathPCI Registry data collection forms encouraged us to develop a new bleeding definition and risk model to improve the monitoring and safety of PCI. METHODS: Detailed clinical data from 1,043,759 PCI procedures at 1,142 centers from February 2008 through April 2011 participating in the CathPCI Registry were used to identify factors associated with major bleeding complications occurring within 72 h post-PCI. Risk models (full and simplified risk scores) were developed in 80% of the cohort and validated in the remaining 20%. Model discrimination and calibration were assessed in the overall population and among the following pre-specified patient subgroups: females, those older than 70 years of age, those with diabetes mellitus, those with ST-segment elevation myocardial infarction, and those who did not undergo in-hospital coronary artery bypass grafting. RESULTS: Using the updated definition, the rate of bleeding was 5.8%. The full model included 31 variables, and the risk score had 10. The full model had similar discriminatory value across pre-specified subgroups and was well calibrated across the PCI risk spectrum. CONCLUSIONS: The updated bleeding definition identifies important post-PCI bleeding events. Risk models that use this expanded definition provide accurate estimates of post-PCI bleeding risk, thereby better informing clinical decision making and facilitating risk-adjusted provider feedback to support quality improvement.

Enhanced mortality risk prediction with a focus on high-risk percutaneous coronary intervention: results from 1,208,137 procedures in the NCDR (National Cardiovascular Data Registry).

OBJECTIVES: This study sought to update and validate a contemporary model for inpatient mortality following percutaneous coronary intervention (PCI), including variables indicating high clinical risk. BACKGROUND: Recently, new variables were added to the CathPCI Registry data collection form. This modification allowed us to better characterize the risk of death, including recent cardiac arrest and duration of cardiogenic shock. METHODS: Data from 1,208,137 PCI procedures performed between July 2009 and June 2011 at 1,252 CathPCI Registry sites were used to develop both a "full" and pre-catheterization PCI in-hospital mortality risk model using logistic regression. To support prospective implementation, a simplified bedside risk score was derived from the pre-catheterization risk model. Model performance was assessed by discrimination and calibration metrics in a separate split sample. RESULTS: In-hospital mortality was 1.4%, ranging from 0.2% among elective cases (45.1% of total cases) to 65.9% among patients with shock and recent cardiac arrest (0.2% of total cases). Cardiogenic shock and procedure urgency were the most predictive of inpatient mortality, whereas the presence of a chronic total occlusion, subacute stent thrombosis, and left main lesion location were significant angiographic predictors. The full, pre-catheterization, and bedside risk prediction models performed well in the overall validation sample (C-indexes 0.930, 0.928, 0.925, respectively) and among pre-specified patient subgroups. The model was well calibrated across the risk spectrum, although slightly overestimating risk in the highest risk patients. CONCLUSIONS: Clinical acuity is a strong predictor of PCI procedural mortality. With inclusion of variables that further characterize clinical stability, the updated CathPCI Registry mortality models remain well-calibrated across the spectrum of PCI risk.

Quality of life in patients with non-CAD chest pain: associations to fear of pain and psychiatric disorder severity.

Chest pain in the absence of identified cardiac cause, or non-cardiac chest pain (NCCP), is a common condition that may result in impaired quality of life. Theories of NCCP put forward that patients who react to cardiopulmonary sensations with fear may avoid activities that elicit cardiac sensations. Co-morbid psychiatric disorders, which are prevalent in this population, may predispose individuals to be more vigilant to physiological sensations, including cardiac-related symptoms. The daily impact of avoiding cardiopulmonary cues may limit quality of life. This study examined psychiatric disorders, fear of pain, and quality of life in 30 non-coronary artery disease (CAD) chest pain patients. Psychiatric disorder severity was independently associated with mental health related quality of life and fear of pain was independently associated with physical health related quality of life. This research adds understanding to contributory factors to impaired quality of life among patients with non-CAD chest pain.

Differing effects of cardiac resynchronization therapy on long-term mortality in patient subgroups of MADIT-CRT defined by baseline conduction and 1-year post-treatment left ventricular remodeling.

BACKGROUND: Long-term mortality data after cardiac resynchronization therapy with implanted defibrillator (CRT-D) in minimally symptomatic patients are limited. OBJECTIVE: To clarify influences on long-term mortality after CRT-D, we assessed MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy) patient outcomes by baseline conduction abnormality and 1-year posttreatment remodeling. METHODS: MADIT-CRT followed 1820 patients assigned to CRT-D or implanted cardioverter-defibrillator (ICD) only. Using Cox proportional hazards regression analysis, treatment effects (CRT-D vs ICD only) on mortality were evaluated in patients with left bundle branch block (LBBB) and non-LBBB. Among 1196 patients with echocardiography repeated at 1 year, effect of CRT-D on later mortality (landmark analysis) was analyzed by baseline conduction and 1-year change in left ventricular end-systolic volume (LVESV). RESULTS: Overall mortality was not reduced by CRT-D (hazard ratio [HR] for CRT-D/ICD only 0.94; P = .72). Among 761 patients with LBBB and CRT-D, mortality trended lower (HR 0.71; P = .10) after adjustment for clinical covariates. The effect of CRT-D on mortality was further evaluated in patients who did (responders) and did not (hypo-responders) have reduction in LVESV by ≥ 30%. LBBB responders (n = 323) had significantly reduced mortality with CRT-D (HR 0.36; P = .027), and LBBB hypo-responders (n = 182) did not (HR 0.99). By contrast, non-LBBB responders (n = 89) trended toward more deaths with CRT-D (HR 2.11; P = .22). Non-LBBB hypo-responders (n = 118) had significantly worsened mortality (HR 3.72; P =.011). CONCLUSIONS: In MADIT-CRT, late mortality with CRT-D varied markedly with baseline conduction defect and remodeling response. Patients with both LBBB and substantially reduced LVESV had improved mortality. Those with non-LBBB or with LBBB and less-reduced LVESV had unchanged or worsened mortality after CRT-D.

Clinical and angiographic risk stratification and differential impact on treatment outcomes in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

BACKGROUND: The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial assigned patients with type 2 diabetes mellitus to prompt coronary revascularization plus intensive medical therapy versus intensive medical therapy alone and reported no significant difference in mortality. Among patients selected for coronary artery bypass graft surgery, prompt coronary revascularization was associated with a significant reduction in death/myocardial infarction/stroke compared with intensive medical therapy. We hypothesized that clinical and angiographic risk stratification would affect the effectiveness of the treatments overall and within revascularization strata. METHODS AND RESULTS: An angiographic risk score was developed from variables assessed at randomization; independent prognostic factors were myocardial jeopardy index, total number of coronary lesions, prior coronary revascularization, and left ventricular ejection fraction. The Framingham Risk Score for patients with coronary disease was used to summarize clinical risk. Cardiovascular event rates were compared by assigned treatment within high-risk and low-risk subgroups. Overall, no outcome differences between the intensive medical therapy and prompt coronary revascularization groups were seen in any risk stratum. The 5-year risk of death/myocardial infarction/stroke was 36.8% for intensive medical therapy compared with 24.8% for prompt coronary revascularization among the 381 coronary artery bypass graft surgery-selected patients in the highest angiographic risk tertile (P=0.005); this treatment effect was amplified in patients with both high angiographic and high Framingham risk (47.3% intensive medical therapy versus 27.1% prompt coronary revascularization; P=0.010; hazard ratio=2.10; P=0.009). Treatment group differences were not significant in other clinical-angiographic risk groups within the coronary artery bypass graft surgery stratum, or in any subgroups within the percutaneous coronary intervention stratum. CONCLUSION: Among patients with diabetes mellitus and stable ischemic heart disease, a strategy of prompt coronary artery bypass graft surgery significantly reduces the rate of death/myocardial infarction MI/stroke in those with extensive coronary artery disease or impaired left ventricular function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Appropriateness of percutaneous coronary intervention.

CONTEXT: Despite the widespread use of percutaneous coronary intervention (PCI), the appropriateness of these procedures in contemporary practice is unknown. OBJECTIVE: To assess the appropriateness of PCI in the United States. DESIGN, SETTING, AND PATIENTS: Multicenter, prospective study of patients within the National Cardiovascular Data Registry undergoing PCI between July 1, 2009, and September 30, 2010, at 1091 US hospitals. The appropriateness of PCI was adjudicated using the appropriate use criteria for coronary revascularization. Results were stratified by whether the procedure was performed for an acute (ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, or unstable angina with high-risk features) or nonacute indication. MAIN OUTCOME MEASURES: Proportion of acute and nonacute PCIs classified as appropriate, uncertain, or inappropriate; extent of hospital-level variation in inappropriate procedures. RESULTS: Of 500,154 PCIs, 355,417 (71.1%) were for acute indications (ST-segment elevation myocardial infarction, 103,245 [20.6%]; non-ST-segment elevation myocardial infarction, 105,708 [21.1%]; high-risk unstable angina, 146,464 [29.3%]), and 144,737 (28.9%) for nonacute indications. For acute indications, 350,469 PCIs (98.6%) were classified as appropriate, 1055 (0.3%) as uncertain, and 3893 (1.1%) as inappropriate. For nonacute indications, 72,911 PCIs (50.4%) were classified as appropriate, 54,988 (38.0%) as uncertain, and 16,838 (11.6%) as inappropriate. The majority of inappropriate PCIs for nonacute indications were performed in patients with no angina (53.8%), low-risk ischemia on noninvasive stress testing (71.6%), or suboptimal (≤1 medication) antianginal therapy (95.8%). Furthermore, although variation in the proportion of inappropriate PCI across hospitals was minimal for acute procedures, there was substantial hospital variation for nonacute procedures (median hospital rate for inappropriate PCI, 10.8%; interquartile range, 6.0%-16.7%). CONCLUSIONS: In this large contemporary US cohort, nearly all acute PCIs were classified as appropriate. For nonacute indications, however, 12% were classified as inappropriate, with substantial variation across hospitals.

Acceptance, panic, and partial recovery the pattern of usage of drug-eluting stents after introduction in the U.S. (a report from the American College of Cardiology/National Cardiovascular Data Registry).

OBJECTIVES: Review the use of drug-eluting stents (DES) to evaluate changes in use. BACKGROUND: The DES were approved after several small studies in carefully selected patients showed dramatic reduction in in-stent restenosis. The DES were then rapidly adopted into routine practice. In 2006, 3 years after introduction, serious concerns regarding long-term safety were raised. METHODS: We queried the American College of Cardiology/National Cardiovascular Data Registry (ACC/NCDR) CathPCI Registry. The percentage of DES used through mid-2009 was reviewed overall and in subgroups of patients categorized by lesion type, clinical factors, insurance, and hospital characteristics. Multivariable logistic models relating these covariates to DES usage were constructed for 3 relevant time intervals. RESULTS: A total of 2,247,647 coronary stent procedures were analyzed. By 2005 over 90% of first stents placed were DES. Safety concerns arising in 2006 reduced DES use to 64% of first stent placed. After publication of salutary outcomes data in 2008, usage increased to 76% by mid-2009. The logistic models demonstrated decreased likelihood of DES usage in patients with: 1) ST-segment elevation myocardial infarctions; and 2) no medical insurance. The DES usage increased for in-stent restenosis. Hospital characteristics were not associated with significant differences in DES usage. CONCLUSIONS: There was rapid adoption of DES into U.S. clinical practice. Concern for late stent thrombosis in 2006 significantly altered DES use with reductions seen in subgroups at risk for thrombosis and patients with no insurance. These rapid cyclic changes after DES introduction reinforce the need for continuous, timely reporting of outcomes data after the introduction of new technologies.

Managing coronary artery disease in the cancer patient.

The cancer patient with coronary disease presents particular challenges that directly impact on the management of coronary disease, both stable and acute. The frequent need for surgery in the cancer patient is an important consideration in avoiding a coronary artery stent or any percutaneous coronary intervention for management of chronic stable angina, which will delay surgery or pose of risk of stent thrombosis during surgery. Cancer surgery is considered low or intermediate cardiac risk so revascularization before surgery is needed only in exceptional circumstances. Medical treatment in most patients or coronary artery bypass graft in high risk situations may be preferable if the cancer is being actively treated. The likelihood of thrombocytopenia, either primary from bone marrow disease, or secondarily during chemotherapy causes concern about the need for continuous use of platelet suppressing agents, aspirin for all patients, or double antiplatelet therapy in all patients after receiving a coronary artery stent. Drug-eluting stents pose special problems and should be avoided. Even bare metal stents may have a higher long-term risk of stent thrombosis in the cancer patient. The increase in propensity for venous clotting, either as a result of the cancer itself, or especially with selected chemotherapeutic agents may be an issue after stenting and certainly early after coronary bypass surgery. Aggressive medical treatment to reduce risk factors, especially with statins is essential to stabilize the underlying coronary disease.