Cardiovascular adverse events in patients with hepatocellular carcinoma receiving vascular endothelial growth factor inhibitors.

BACKGROUND: Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs) and anti-angiogenics, are first-line therapies for advanced and metastatic hepatocellular carcinoma. Although TKIs have a greater potential for off-target adverse effects compared with bevacizumab (anti-angiogenics), a direct comparison of the risk of cardiovascular adverse events between these two types of therapies has not been performed. OBJECTIVE: To compare the incidence of and characterize cardiovascular adverse events in patients with hepatocellular carcinoma receiving TKIs versus bevacizumab. METHODS: This cohort study included adult patients with hepatocellular carcinoma who received first-line TKIs (sorafenib or lenvatinib) or bevacizumab at two academic medical centers and one community cancer center from September 2018 to August 2021. The primary outcome was risk of cardiovascular adverse events. Major secondary outcomes included the incidence of individual types of cardiovascular adverse events and risk factors associated with major adverse cardiovascular events (MACE). RESULTS: The study included 221 patients (159 TKI patients; 62 bevacizumab patients). At a median follow-up of 5 months, the probability of cardiovascular adverse events was not significantly different between the two groups (hazard ratio [HR]: 0.85; 95% confidence interval [95% CI]: 0.58-1.24; p = 0.390). The cumulative incidence of cardiovascular events was highest in patients receiving lenvatinib (sub-distribution hazard ratio [SHR]: 1.53; 95% CI: 1.02-2.30) compared with those receiving sorafenib (reference) or bevacizumab (SHR: 1.05; 95% CI: 0.68-1.64) after adjustment for comorbidities, liver transplant status, and presence of portal vein thrombosis at baseline. Cardiovascular adverse events were observed in 151 (68%) patients, and MACE were observed in 27 (12%) patients. Risk factors associated with MACE were hypertension (SHR: 3.5; 95% CI: 0.9087-15.83; p = 0.086), prior history of MACE (SHR: 2.01; 95% CI: 0.83-4.87; p = 0.124), and tobacco use (SHR: 2.85; 95% CI: 0.90-8.97; p = 0.074). CONCLUSIONS: Cardiovascular risk was not significantly different between TKIs and bevacizumab. Lenvatinib appears to have the highest risk of cardiovascular adverse events among these first-line VEGF inhibitors.

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.

Development of a risk score to identify patients with type 2 diabetes mellitus and multivessel coronary artery disease who can defer bypass surgery.

BACKGROUND: Current American College of Cardiology/American Heart Association (ACC/AHA) guidelines provide a class I recommendation for patients with type 2 diabetes mellitus and multivessel coronary artery disease (CAD) to be treated with coronary artery bypass graft surgery (CABG). However, these patients are heterogeneous in terms of the risks and benefits associated with CABG. We sought to develop a risk score to identify low-risk patients with diabetes and multivessel CAD in whom CABG can be safely deferred. METHODS: Patients in the CABG strata randomized to intensive medical therapy (IMT) in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial who experienced death, myocardial infarction (MI), or stroke were compared with those who did not. We developed a risk score for death, MI, or stroke using a Cox proportional hazards model that included the following variables: age, history of heart failure, history of hypercholesterolemia, history of stroke, transient ischemic attack, serum creatinine, insulin use, myocardial jeopardy index, and HbA1c. RESULTS: Among patients with a risk score less than the median, those randomized to IMT or prompt CABG experienced similar rates of event-free survival at 5 years (77.8% vs. 83.2%, logrank P = 0.24). Among patients with a risk score greater than the median, those randomized to IMT experienced worse rates of event-free survival at 5 years than those randomized to prompt CABG (60.3% vs 73.2%, logrank P = 0.01). CONCLUSIONS: A novel risk score identifies low-risk patients with diabetes and stable, symptomatic multivessel CAD in whom CABG can be safely deferred.

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.

Prognosis and response to therapy of first inpatient and outpatient heart failure event in a heart failure clinical trial: MADIT-CRT.

AIMS: Hospitalization for worsening heart failure (HF) is known to increase mortality and morbidity risk and has been frequently used as an endpoint in randomized clinical trials. Whether outpatient management of HF exacerbation carries similar prognostic and therapeutic information is less well known, but could be important for the design of trials that use HF hospitalization as an endpoint. METHODS AND RESULTS: MADIT-CRT randomized patients with mild HF symptoms to resynchronization therapy vs. control with an average follow-up of 3.3 years and a total of 191 deaths. HF events were centrally adjudicated for receiving i.v. decongestive therapy in an outpatient setting, or an augmented HF regimen during a hospital stay. Patients were compared according to whether their first HF was an out- or inpatient event. The first primary event was non-fatal outpatient HF, non-fatal inpatient HF, and death in 52, 331, and 78 patients, respectively. Patients with inpatient HF tended to be older and more likely to have HF of ischaemic aetiology than subjects who developed outpatient HF events. The risk of death following either type of non-fatal HF events was extremely high [hazard ratio (HR) 12.4, 95% confidence interval (CI) 9.1-16.9 for inpatient HF; HR 10.7, 95% CI 6.1-18.7 for outpatient HF] compared with subjects without non-fatal HF events. Allocation to CRT-D was associated with significant reduction in both types of HF. CONCLUSION: Outpatient management of worsening HF portends a high risk of death, similar to inpatient HF events, and may be equally sensitive to the effects of therapy. These findings suggest that outpatient HF events should be considered in publicly reported outcomes measures and future HF clinical trials. TRIAL REGISTRATION: NCT01294449.

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.

In-hospital outcomes of percutaneous coronary interventions in extremely obese and normal-weight patients: findings from the NCDR (National Cardiovascular Data Registry).

OBJECTIVES: The purpose of this study was to compare in-hospital outcomes of percutaneous coronary intervention (PCI) in extreme obesity (EO) (body mass index [BMI] ≥ 40 kg/m²) with those of normal-weight (NW) patients and to examine the influence of access site on outcomes. BACKGROUND: Little is known about the outcomes of PCI in EO patients. METHODS: We analyzed CathPCI Registry data from patients who underwent radial or femoral PCI and were discharged between July 2009 and June 2011 and compared in-hospital outcomes of EO (N = 83,861) with those of NW patients (BMI 20 to 25 kg/m²; N = 217,616). Outcomes included in-hospital mortality and procedural and bleeding complications. Multivariable logistic regression models were used to assess the independent association of EO with outcomes, using previously validated risk models derived from the CathPCI Registry. The role of access site was specifically examined. RESULTS: Compared with NW patients, EO patients were younger (median age 60 vs. 69 years), more likely female (47% vs. 37%), and more likely African American (12% vs. 7%). EO patients had lower unadjusted mortality (1.2% vs. 2.0%); however, after multivariable adjustment, EO was independently associated with increased risk of in-hospital mortality (odds ratio: 1.22; 95% CI: 1.08 to 1.39) in those presenting with ST-segment elevation myocardial infarction (STEMI). Access site had no effect on bleeding or outcome. CONCLUSIONS: EO patients who underwent PCI were younger and had less bleeding compared with NW patients. After multivariable adjustment for risk, EO was independently associated with higher in-hospital mortality overall and particularly in the patients undergoing STEMI.

Evaluation of coronary steal in myocardium supplied by coronary collaterals: the role of speckle tracking analysis in resting and stress echocardiography.

Coronary steal could develop in patients with chronic coronary artery disease (CAD) with collateral circulation, and adversely affect ventricular function and long-term clinical outcome. Poorly developed collaterals are more prone than well-developed collaterals to withdrawing their blood support to the collateralized myocardium due to higher collateral pathway resistance and lower vasodilatory reserve of the collateral bed. Even with well-developed coronary collaterals, coronary steal could still occur when perfusion pressure in the donor artery becomes low, or the recipient microvasculature is maximally dilated with exhaustion of vasodilatory reserve. The evaluation of distinctive coronary collateral function with or without steal provides important therapeutic and prognostic information in patients with chronic CAD. However, due to lack of reliable assessment methods, the detection and quantitative measurement of coronary steal remains a challenge. In this article, we present typical clinical scenarios to illustrate the major mechanisms underlying coronary steal in patients with chronic CAD and coronary collateral circulation, and review invasive and noninvasive methods currently available to assess coronary steal in myocardium supplied by coronary collaterals. We specifically focus on recent advances in the resting and stress echocardiography with speckle tracking techniques.

Senior academic physicians and retirement considerations.

An increasing number of academic senior physicians are approaching their potential retirement in good health with accumulated clinical and research experience that can be a valuable asset to an academic institution. Considering the need to let the next generation ascend to leadership roles, when and how should a medical career be brought to a close? We explore the roles for academic medical faculty as they move into their senior years and approach various retirement options. The individual and institutional considerations require a frank dialogue among the interested parties to optimize the benefits while minimizing the risks for both. In the United States there is no fixed age for retirement as there is in Europe, but European physicians are initiating changes. What is certain is that careful planning, innovative thinking, and the incorporation of new patterns of medical practice are all part of this complex transition and timing of senior academic physicians into retirement.

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.