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.

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.

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.

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.

Relationships of obesity and fat distribution with atherothrombotic risk factors: baseline results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

The impact of obesity on cardiovascular disease (CVD) outcomes in patients with type 2 diabetes mellitus (T2DM) and established coronary artery disease (CAD) is controversial; whether BMI and/or waist circumference correlate with atherothrombotic risk factors in such patients is uncertain. We sought to evaluate whether higher BMI or waist circumference are associated with specific risk factors among 2,273 Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study participants with T2DM and documented CAD (baseline data, mean age 62 years, 66% non-Hispanic white, 71% men). Multiple linear regression models were constructed after adjusting for sex, age, race/ethnicity, US vs. non-US site, diabetes duration, exercise, smoking, alcohol, and relevant medication use. First-order partial correlations of BMI with risk factors after controlling for waist circumference and of waist circumference with risk factors after controlling for BMI were also evaluated. Ninety percent of the patients were overweight (BMI > or =25 kg/m(2)); 68% of men and 89% of women had high-risk waist circumference measures (> or =102 and > or =88 cm, respectively). BMI and waist circumference, in separate models, explained significant variation in metabolic (insulin, lipids, blood pressure (BP)) and inflammatory/procoagulation (C-reactive protein, PAI-1 activity and antigen, and fibrinogen) risk factors. In partial correlation analyses BMI was independently associated with BP and inflammatory/procoagulation factors, waist circumference with lipids, and both BMI and waist circumference with insulin. We conclude that, in cross-sectional analyses, both BMI and waist circumference, independently, are associated with increased atherothrombotic risk in centrally obese cohorts such as the BARI 2D patients with T2DM and CAD.

Utilization of distal embolic protection in saphenous vein graft interventions (an analysis of 19,546 patients in the American College of Cardiology-National Cardiovascular Data Registry).

In clinical trials, the use of a distal embolic protection device (EPD) during saphenous vein graft (SVG) percutaneous intervention (PCI) decreases the incidence of major adverse events. However, the frequency of EPD use during SVG PCI in clinical practice is unknown. We evaluated 19,546 SVG PCI procedures in the American College of Cardiology-National Cardiovascular Data Registry from January 1, 2004, through March 30, 2006. EPD use was the primary outcome. Univariate and multivariable analyses were used to assess for characteristics associated with EPD use and to determine the association between EPD use and 2 outcomes: no-reflow and in-hospital mortality. EPDs were used in 22% of patients who underwent SVG PCI. Characteristics independently associated with EPD use were age (odds ratio [OR] 1.04, p = 0.03), male gender (OR 1.12, p = 0.02), older grafts (p <0.001 for the group), longer lesions (OR 1.16, p <0.001), and American College of Cardiology/American Heart Association class C lesions (OR 1.41, p <0.001). Patients were less likely to receive an EPD if they had class <3 grade flow according to Thrombolysis in Myocardial Infarction classification (p <0.001) or previously treated lesions (OR 0.55, p <0.001). There was a weak correlation between annual hospital PCI volume and EPD use (r = 0.2, p <0.001). Nineteen percent of centers did not use EPDs and 41% used them in <10% of cases. EPD use was independently associated with a lower incidence of no-reflow (OR 0.68, p = 0.032), but not in-hospital mortality (1.0% vs 0.9%, p = NS). In conclusion, in current practice, EPDs are used in <25% of SVG PCI procedures.

Prevention of contrast induced nephropathy: recommendations for the high risk patient undergoing cardiovascular procedures.

Contrast induced nephropathy (CIN) is the third leading cause of hospital acquired renal failure and is associated with significant morbidity and mortality. Chronic kidney disease is the primary predisposing factor for CIN. As estimated glomerular filtration rate<60 ml/1.73 m2 represents significant renal dysfunction and defines patients at high risk. Modifiable risk factors for CIN include hydration status, the type and amount of contrast, use of concomitant nephrotoxic agents and recent contrast administration. The cornerstone of CIN prevention, in both the high and low risk patients, is adequate parenteral volume repletion. In the patient at increased risk for CIN it is often appropriate to withhold potentially nephrotoxic medications, and consider the use of n-acetylcysteine. In patients at increased risk for CIN the use of low or iso-osomolar contrast agents should be utilized and strategies employed to minimize contrast volume. In these patients serum creatinine should be obtained forty-eight hours post procedure and it is often appropriate to continue withholding medications such as metformin or non steroidal anti-inflammatories until renal function returns to normal.

Relationship between procedure indications and outcomes of percutaneous coronary interventions by American College of Cardiology/American Heart Association Task Force Guidelines.

BACKGROUND: An American College of Cardiology/American Heart Association (ACC/AHA) Task Force periodically revises and publishes guidelines with evidence-based recommendations for appropriate use of percutaneous coronary intervention (PCI). Some studies have suggested that closer adherence to guidelines can reduce variations in care, can improve quality, and may ultimately result in better outcomes, but this finding is incompletely understood. Guidelines themselves must change to be responsive to continuously evolving clinical practice. Our goal here was to investigate whether any relationship existed between the most recent ACC/AHA recommended indications for PCI and short term in-hospital outcomes. METHODS AND RESULTS: We analyzed the ACC National Cardiovascular Data Registry for the period of January 1, 2001, through March 31, 2004. We excluded PCI procedures performed for acute myocardial infarction (ST-segment elevation myocardial infarction); all others were grouped by their indications according to the standard ACC/AHA scheme: Class I, evidence and/or agreement that PCI is useful and effective; Class IIa, conflicting evidence and/or divergent opinions, weight is in favor; Class IIb, usefulness/efficacy is less well established; and Class III, evidence and/or agreement that PCI is not useful or effective and may be harmful. Clinical success was defined as angiographic success (<20% residual stenosis) at all lesions attempted without the adverse events of myocardial infarction, same-admission bypass surgery, or death. There were 412 617 PCI procedures included in the analysis. Frequency of indications was as follows: Class I, 64%; Class IIa, 21%; Class IIb, 7%; and Class III, 8%. Clinical success declined across the indications classes (92.8%, 91.7%, 89%, and 85.5%, respectively; P<0.001), whereas adverse events increased. CONCLUSIONS: In this large survey of contemporary PCI practice, most procedures were performed for Class I indications. A significant relationship between evidence-based indications recommended by the ACC/AHA Task Force and in-hospital outcomes was noted.

Relationship between intermittent claudication, inflammation, thrombosis, and recurrent cardiac events among survivors of myocardial infarction.

BACKGROUND: Among coronary disease patients, concomitant peripheral arterial disease is a potent risk factor for future cardiac events and mortality. We sought to determine clinical and biochemical markers that might better elucidate the relationship between coronary and peripheral arterial disease. METHODS: Two months after an index myocardial infarction, 1045 patients provided detailed medical histories and underwent blood testing for selected hemostatic, lipid, and inflammatory markers. Patients were then followed up prospectively for a mean of 26 months. RESULTS: Compared with individuals without intermittent claudication (n = 966), those with claudication (n = 78) (information was unavailable for 1 individual) were significantly older and demonstrated an increased frequency of diabetes mellitus, tobacco use, prior cardiac and cerebrovascular events, and depressed left ventricular function. Individuals with claudication were less likely to receive beta-blocker therapy after the index infarction. Individuals with claudication had evidence of enhanced procoagulant and proinflammatory states manifested by relative elevations in plasma fibrinogen, D-dimer, C-reactive protein, and serum amyloid A concentrations. During follow-up, the presence of claudication was associated with an independent 2-fold increase in the combined end point of death or nonfatal cardiac event (38.5% vs 17.8%, P =.001) and a 5-fold increase in cardiac mortality (19.2% vs 3.6%, P =.001). Patients with intermittent claudication who were not treated with beta-blockers had a significant 3-fold mortality excess relative to those receiving beta-blockers. CONCLUSIONS: Following myocardial infarction, the added presence of intermittent claudication is associated with heightened procoagulant and proinflammatory states and an underuse of beta-blocker therapy and is a strong independent predictor of recurrent cardiovascular events.

A contemporary overview of percutaneous coronary interventions. The American College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR).

The American College of Cardiology (ACC) established the National Cardiovascular Data Registry (ACC-NCDR) to provide a uniform and comprehensive database for analysis of cardiovascular procedures across the country. The initial focus has been the high-volume, high-profile procedures of diagnostic cardiac catheterization and percutaneous coronary intervention (PCI). Several large-scale multicenter efforts have evaluated diagnostic catheterization and PCI, but these have been limited by lack of standard definitions and relatively nonuniform data collection and reporting methods. Both clinical and procedural data, and adverse events occurring up to hospital discharge, were collected and reported according to uniform guidelines using a standard set of 143 data elements. Datasets were transmitted quarterly to a central facility for quality-control screening, storage and analysis. This report is based on PCI data collected from January 1, 1998, through September 30, 2000.A total of 139 hospitals submitted data on 146,907 PCI procedures. Of these, 32% (46,615 procedures) were excluded because data did not pass quality-control screening. The remaining 100,292 procedures (68%) were included in the analysis set. Average age was 64 +/- 12 years; 34% were women, 26% had diabetes mellitus, 29% had histories of prior myocardial infarction (MI), 32% had prior PCI and 19% had prior coronary bypass surgery. In 10% the indication for PCI was acute MI < or =6 h from onset, while in 52% it was class II to IV or unstable angina. Only 5% of procedures did not have a class I indication by ACC criteria, but this varied by hospital from a low of 0 to a high of 38%. A coronary stent was placed in 77% of procedures, but this varied by hospital from a low of 0 to a high of 97%. The frequencies of in-hospital Q-wave MI, coronary artery bypass graft surgery and death were 0.4%, 1.9% and 1.4%, respectively. Mortality varied by hospital from a low of 0 to a high of 4.2%. This report presents the first data collected and analyzed by the ACC-NCDR. It portrays a contemporary overview of coronary interventional practices and outcomes, using uniform data collection and reporting standards. These data reconfirm overall acceptable results that are consistent with other reported data, but also confirm large variations between individual institutions.

Evaluation of the Society for Coronary Angiography and Interventions' lesion classification system in 14,133 patients with percutaneous coronary interventions in the current stent era.

We recently showed that the ACC/AHA coronary lesion classification could be simplified with no loss of predictive value (SCAI I = patent/non-C; SCAI II = patent/C; SCAI III = occluded/non-C; SCAI IV = occluded/C). We now test this system in a database reflecting current stent usage. Data from 14,133 patients with single-native-vessel interventions recorded in the Society for Coronary Angiography and Interventions (SCAI) Registry from July 1996 to July 1999 were analyzed. Stents were used in 60.2% of procedures. Logistic models predicting angiographic success suggested a slight, clinically insignificant preference for the SCAI classification (c-statistic = 0.692 vs. 0.670). Models using clinical variables to predict major complications were superior to models using only lesion classification. Lesion characteristics were related to outcomes primarily in elective (not acute myocardial infarction) patients. In the current PCI device era, the simpler SCAI classification using 7 variables predicted interventional success and complications as well as or better than the ACC/AHA system requiring 26.