Electrocardiographic Changes Associated With Ibrutinib Exposure.

Although ibrutinib-associated atrial and ventricular arrhythmias have been well described, there is little information about ibrutinib's effects on other electrocardiographic parameters, particularly the QT interval. Using our database of 137 patients treated with ibrutinib, we retrospectively identified 21 patients in whom an electrocardiogram (ECG) was obtained both prior to and after ibrutinib exposure. All traditional ECG parameters as well as QT dispersion were manually measured by an electrophysiologist. Compared to baseline ECGs, post ibrutinib ECGs demonstrated QT interval shortening from 386 ms to 356 ms (P = .007), corrected QT interval shortening using Bazett's formula from 446 ms to 437 ms (P = .04), and corrected QT interval shortening using Fridericia's formula from 425 ms to 407 ms (P = .003). QT dispersion also increased post ibrutinib exposure compared to baseline (39.8 ms vs 57.3 ms, P = .002). There was no significant change in other ECG parameters. In conclusion, both the absolute and corrected QT intervals significantly shortened after ibrutinib exposure, while there was a significant increase in QT dispersion. These findings may point to a common underlying electrophysiologic mechanism of ibrutinib-associated arrhythmias.

Arrhythmias and Other Electrophysiology Issues in Cancer Patients Receiving Chemotherapy or Radiation.

Enhanced understanding of cancer biology has significantly increased treatment options and dramatically improved outcomes for patients with malignancies. Despite these advances, many therapies have cardiovascular toxicities which can affect morbidity and mortality independent of the oncologic prognosis. Arrhythmias and other electrophysiology issues are increasingly identified as common complications of cancer therapy. Atrial fibrillation and other supraventricular arrhythmias are frequently observed in cancer patients receiving chemotherapy, often due to their effects on intracellular signaling pathways. Similarly, many oncologic pharmaceuticals can lead to QT prolongation and possible ventricular arrhythmias including torsades do pointes. Management of these arrhythmias can be challenging as typical treatment strategies may not be feasible in cancer patients. Finally, a proportion of individuals with cancer will present with an implantable cardiac device (pacemaker or defibrillator) which poses unique challenges should radiation be necessary in the region of the device. Given the frequency of electrophysiology complications in cancer patients, it is essential for cardio-oncologists to possess knowledge of these issues in order to provide optimal care.

Association between ibrutinib treatment and hypertension.

BACKGROUND: Ibrutinib is a tyrosine kinase inhibitor most commonly associated with atrial fibrillation. However, additional cardiotoxicities have been identified, including accelerated hypertension. The incidence and risk factors of new or worsening hypertension following ibrutinib treatment are not as well known. METHODS: We conducted a retrospective study of 144 patients diagnosed with B cell malignancies treated with ibrutinib (n=93) versus conventional chemoimmunotherapy (n=51) and evaluated their effects on blood pressure at 1, 2, 3 and 6 months after treatment initiation. Descriptive statistics were used to compare baseline characteristics for each treatment group. Fisher's exact test was used to identify covariates significantly associated with the development of hypertension. Repeated measures analyses were conducted to analyse longitudinal blood pressure changes. RESULTS: Both treatments had similar prevalence of baseline hypertension at 63.4% and 66.7%, respectively. There were no differences between treatments by age, sex and baseline cardiac comorbidities. Both systolic and diastolic blood pressure significantly increased over time with ibrutinib compared with baseline, whereas conventional chemoimmunotherapy was not associated with significant changes in blood pressure. Baseline hypertensive status did not affect the degree of blood pressure change over time. A significant increase in systolic blood pressure (defined as more than 10 mm Hg) was noted for ibrutinib (36.6%) compared with conventional chemoimmunotherapy (7.9%) at 1 month after treatment initiation. Despite being hypertensive at follow-up, 61.2% of patients who were treated with ibrutinib did not receive adequate blood pressure management (increase or addition of blood pressure medications). Within the ibrutinib group, of patients who developed more than 20 mm Hg increase in systolic blood pressure, only 52.9% had hypertension management changes. CONCLUSIONS: Ibrutinib is associated with the development of hypertension and worsening of blood pressure. Cardiologists and oncologists must be aware of this cardiotoxicity to allow timely management of blood pressure elevations.

Impact of Global Budget Payments on Cardiovascular Care in Maryland: An Interrupted Time Series Analysis.

Background Global budget payments (GBP) are considered effective in containing health care expenditures; however, information on their impact on quality of cardiovascular care is limited. We aimed to evaluate the effects of GBP on utilization, outcomes, and costs for 3 major cardiovascular conditions. Methods We analyzed claims data of hospital admissions in Maryland from fiscal year 2013 to 2018. Using segmented regression, we evaluated temporal trends in hospitalizations, length of stay, percutaneous coronary intervention and coronary artery bypass grafting volumes, case mix-adjusted 30-day readmission rates, risk-standardized mortality rates, and hospitalization charges in patients with principal diagnosis of heart failure, acute ischemic stroke, and acute myocardial infarction (AMI) in relation to GBP implementation. Trends in global cardiovascular procedure charges/volumes were also studied. Results Hospitalization rates for congestive heart failure and AMI remained unaffected by GBP, while the gradient of ischemic stroke admissions decreased (Ptrend <0.0001). Length of stay slightly increased for patients with congestive heart failure (Ptrend=0.03). Inpatient coronary artery bypass grafting surgeries decreased (Ptrend <0.0001). We observed a significant decrease in casemix-adjusted 30-day readmission rate in the AMI cohort beyond the prepolicy trend (Ptrend=0.0069). There were no significant changes in mortality for any of the 3 conditions. Hospitalization charges increased for ischemic stroke (Ptrend <0.0001), remained constant for congestive heart failure (Ptrend=0.1), and decreased for AMI (Ptrend=0.0005). We observed a significant increase in electrocardiography rate charges (Ptrend <0.0001), coincidentally with a reduction in volumes (Ptrend=0.0003). Conclusions Introducing GBP in Maryland had no perceivable adverse effects on inpatient outcomes and quality indicators for 3 major cardiovascular conditions. Savings were observed in the AMI cohort, possibly due to reduced unnecessary readmissions, efficiency improvements, or shifts to outpatient care. Reduced cardiovascular procedure volumes were counterbalanced by a proportional rise in charges. State-level adoption of GBP with pay-for-performance incentives may be effective for cost containment without adversely impacting quality of cardiovascular care.

Rates and Risk of Atrial Arrhythmias in Patients Treated With Ibrutinib Compared With Cytotoxic Chemotherapy.

There is increasing evidence that rates of atrial arrhythmias (AA), specifically atrial fibrillation and flutter are elevated in patients treated with the tyrosine kinase inhibitor, ibrutinib; however, the exact risk of ibrutinib-associated AA is not definitively established. We conducted a retrospective study of 137 patients diagnosed with B-cell malignancies treated with ibrutinib compared with 106 patients treated with chemotherapy for the same cancers in order to quantify the rates and risk of AA in a "real-world" sample of cancer patients. Fisher's exact test was used to evaluate for any statistically significant differences between groups. Logistic regression was used to generate odds ratios, adjusting for potential confounders. Incidence of AA was 14% (n = 17) in ibrutinib-treated patients compared with 3% (n = 3) in patients treated with chemotherapy (p = 0.009). Ibrutinib-treated patients were significantly older (mean age 67 vs 63 years, p = 0.003); however, there were no other significant differences in baseline characteristics. Ibrutinib use, age, hypertension, and previous use of ACE inhibitors, angiotensin receptor blocker use, ß blocker use, and aspirin use were independently associated with incident arrhythmias. In multivariable analysis, patients treated with ibrutinib were associated with a 5-fold increased risk of developing AA (odds ratio = 5.18, 95% confidence interval 1.42 to 18.89). In conclusion, the rates and risk of AA are higher in patients treated with ibrutinib compared with chemotherapy, and this study provides strong evidence that ibrutinib itself is an independent risk factor for the development of incident AA.

Developing a Comprehensive Cardio-Oncology Program at a Cancer Institute: The Moffitt Cancer Center Experience.

Cardio-oncology is a multidisciplinary field focusing on the management and prevention of cardiovascular complications in cancer patients and survivors. While the initial focus of this specialty was on heart failure associated with anthracycline use, novel anticancer agents are increasingly utilized and are associated with many other cardiotoxicities including hypertension, arrhythmias and vascular disease. Since its inception, the field has developed at a rapid pace with the establishment of programs at many major academic institutions and community practices. Given the complexities of this patient population, it is important for providers to possess knowledge of not only cardiovascular disease but also cancer subtypes and their specific therapeutics. Developing a cardio-oncology program at a stand-alone cancer center can present unique opportunities and challenges when compared to those affiliated with other institutions including resource allocation, cardiovascular testing availability and provider education. In this review, we present our experiences establishing the cardio-oncology program at Moffitt Cancer Center and provide guidance to those individuals interested in developing a program at a similar independent cancer institution.

Rates and risk of arrhythmias in cancer survivors with chemotherapy-induced cardiomyopathy compared with patients with other cardiomyopathies.

Objectives: There is little information about arrhythmia burden in cancer survivors with chemotherapy-induced cardiomyopathy (CIC). We hypothesise that the rates and risk of arrhythmias will be similar in CIC when compared with other non-ischaemic cardiomyopathy (NICMO) aetiologies. Methods: We retrospectively identified nine patients with CIC and an implantable defibrillator and 18 age and sex-matched control patients (nine patients with NICMO and nine patients with ischaemic cardiomyopathy (ICMO)). Rates and odds of arrhythmias were calculated by type of cardiomyopathy, adjusting for days since implantable cardioverter defibrillator implantation, history of atrial fibrillation and length of follow-up using logistic regression analysis. Results: Compared with patients with NICMO, rates and adjusted odds were similar for patients with CIC for atrial arrhythmias (44.4% vs 33.3%; adjusted OR=1.89; 95% CI0.17 to 21.03; P=0.61), non-sustained ventricular tachycardia (NSVT) (44.4% vs 33.3%; OR=2.10; 95% CI 0.21 to 20.56; P=0.53), and the combined outcome of NSVT, sustained ventricular tachycardia and/or ventricular fibrillation (44.4% vs 44.4%; OR=2.70; 95% CI 0.25 to 29.48; P=0.42). Conversely, compared with patients with NICMO, patients with ICMO demonstrated higher rates and adjusted odds of the combined outcome (88.9% vs 44.4%; OR=28.60; 95% CI 1.26 to 648.2; P=0.04) and NSVT (77.8% vs 33.3%; OR=8.95; 95% CI 0.90 to 88.94; P=0.06). Conclusions: While tentative based on sample size, rates of arrhythmias in patients with CIC appear to be similar to those experienced by patients with other forms of NICMO.

Anti-VEGF-Induced Hypertension: a Review of Pathophysiology and Treatment Options.

OPINION STATEMENT: Abnormal intracellular signaling has been implicated in the development of many different types of cancer. Therapies targeting these abnormal pathways have revolutionized the treatment of many malignancies leading to significantly improved outcomes and survival. Despite these advances, cardiovascular toxicity is a frequently reported complication. Angiogenesis is the physiologic process of new blood vessel development and can be dysregulated in some forms of cancer. VEGF inhibitors are the pharmaceutical agents targeting this pathway; however hypertension is a commonly observed toxicity which can have significant adverse consequences including premature cessation of therapy if adequate blood pressure control cannot be achieved. This review will provide a comprehensive discussion about hypertension due to VEGF inhibition, focusing on pathophysiology, frequently used agents, and available treatment options for VEGF-induced hypertension.

Anti-carbonic anhydrase II antibodies in systemic sclerosis: association with lung involvement.

Carbonic anhydrase II (CAII) is expressed on alveolar epithelium and participates to CO2 elimination, fluid secretion and post-capillary pH regulation. CAII is overexpressed in animal models of lung fibrosis in sites of epithelial injury. Autoantibodies directed against CAII (anti-CAII) have been described in sera from patients affected by systemic sclerosis (SSc), but no study focused on their clinical associations in this disease. The aim of this study was to assess the presence of anti-CAII in sera of SSc patients and to investigate their association with lung involvement. We performed ELISA to detect anti-CAII in 34 SSc patients who underwent pulmonary function tests (PFT) and Doppler echocardiography. We found increased prevalence and significantly elevated serum levels of anti-CAII in SSc patients affected by restrictive lung disease (RLD) compared to SSc patients without lung involvement and healthy controls. These findings suggest both a possible pathogenic role of anti-CAII in the development of lung damage and a potential clinical utility as serological marker of pulmonary involvement in SSc patients.

Effect of early diagnosis and treatment with percutaneous lead extraction on survival in patients with cardiac device infections.

Cardiac device infections (CDIs) represent a serious complication after the implantation of pacemakers and defibrillators. In addition to antimicrobials, complete hardware removal, mostly with percutaneous lead extraction (PLE), is necessary to limit recurrences. However, CDI diagnosis is often difficult and is sometimes delayed, and scarce data exist on how the timing of PLE may affect clinical outcomes. In this study, the in-hospital outcomes of 52 consecutive patients with CDIs who underwent PLE were retrospectively analyze. Co-morbidities such as diabetes mellitus, congestive heart failure, renal insufficiency, and end-stage renal disease were highly prevalent in the study cohort. Patients were divided into group A (bacteremia or device endocarditis) and group B (localized pocket infection). In-hospital mortality was 29% in group A and 5% in group B (p = 0.02) and was due mostly to sepsis. Hospital stays were shorter in group B patients (5.7 vs 21.7 days, p <0.001). Presentation with hypotension was more commonly observed in group A patients and was associated with higher in-hospital mortality, whereas pocket findings correlated with better survival. Postoperative courses after PLE were uneventful in most patients, and no fatal complications were observed. PLE was performed significantly earlier in group B patients (hospitalization day 1.3 vs 7.6, p <0.001). PLE performed within 3 hospitalization days was associated with lower in-hospital mortality (p = 0.01). In conclusion, PLE performed within 3 days from admission is associated with shorter hospitalization and better survival. A timely diagnosis is crucial, particularly in the absence of local findings, because early treatment with PLE is likely to prevent the catastrophic outcomes of unrelenting CDIs.

Endovascular recanalization of central venous access to allow for pacemaker implantation or upgrade.

BACKGROUND: Several patients undergoing permanent pacemaker (PPM) implantation/upgrade present with difficult access due to sub- or total central vein occlusion. Our institution has used the endovascular approach to recanalize central veins to allow for subsequent PPM implantation. Here we aim to describe the feasibility and safety of using this approach to allow for PPM implantation/upgrade. METHODS: From October 2006 to November 2010, 50 consecutive patients who underwent central vein recanalization prior to PPM implantation were included in this analysis. RESULTS: The population's mean age was 70 years, with a high rate of comorbidities including chronic renal failure (52.0%), congestive heart failure (64.0%), diabetes (33.3%) and peripheral vascular disease (36.0%). The endovascular recanalization procedure was performed via femoral access in all patients; however adjuvant brachial access was required in 13 cases and subclavian vein in one. Subclavian vein (74.5%) followed by innominate vein (21.6%) were the most common locations/target for recanalization. Successful vein recanalization followed by successful PPM implantation/upgrade was achieved in 48 patients (96.0%) without peri-procedural complications. Two patients died during the hospitalization, one due to severe respiratory failure and a second due to complicated end-stage renal disease, although neither was related to the endovascular procedure. No other event, including myocardial infarction, cerebral-vascular accident, bleeding/transfusion, or renal failure was identified. CONCLUSIONS: This study proved the feasibility and safety of the endovascular approach to recanalize central veins in patients with poor vascular access to allow for further PPM implantation/upgrade.

Staphylococcus lugdunensis endocarditis following lower extremity revascularization.

We describe a fatal case of Staphylococcus lugdunensis aortic valve endocarditis that was diagnosed in a 75-year-old man approximately 6 months following a lower extremity by-pass surgery. A relatively indolent clinical course in the early phase following the suspicious exposure may have contributed to a delay in the diagnosis. At the time of presentation the patient had evidence of rapidly progressive congestive heart failure with anasarca, dyspnea and low grade fevers. Blood cultures were positive for coagulase-negative staphylococci and a transthoracic echocardiogram was not clearly suggestive of infective endocarditis. Despite intense medical treatment the patient expired on day four of hospitalization. On post-mortem examination, multiple vegetations were observed on the aortic valve and culture identification showed S. lugdunensis. Early detection of coagulase-negative bacteremia from multiple blood culture samples in this clinical setting is critical and should give rise to a suspicion of this rare but often fatal form of infective endocarditis. Besides appropriate antibiotic treatment, early surgical referral for valve replacement should be considered since it appears to be the only treatment positively affecting survival. Finally, further studies are needed to establish the efficacy of antibiotic prophylaxis in patients undergoing angiograms with a femoral approach.

High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study.

More effective therapeutic strategies are required for patients with poor-prognosis systemic sclerosis (SSc). A phase 2 single-arm study of high-dose immunosuppressive therapy (HDIT) and autologous CD34-selected hematopoietic cell transplantation (HCT) was conducted in 34 patients with diffuse cutaneous SSc. HDIT included total body irradiation (800 cGy) with lung shielding, cyclophosphamide (120 mg/kg), and equine antithymocyte globulin (90 mg/kg). Neutrophil and platelet counts were recovered by 9 (range, 7 to 13) and 11 (range, 7 to 25) days after HCT, respectively. Seventeen of 27 (63%) evaluable patients who survived at least 1 year after HDIT had sustained responses at a median follow-up of 4 (range, 1 to 8) years. There was a major improvement in skin (modified Rodnan skin score, -22.08; P < .001) and overall function (modified Health Assessment Questionnaire Disability Index, -1.03; P < .001) at final evaluation. Importantly, for the first time, biopsies confirmed a statistically significant decrease of dermal fibrosis compared with baseline (P < .001). Lung, heart, and kidney function, in general, remained clinically stable. There were 12 deaths during the study (transplantation-related, 8; SSc-related, 4). The estimated progression-free survival was 64% at 5 years. Sustained responses including a decrease in dermal fibrosis were observed exceeding those previously reported with other therapies. HDIT and autologous HCT for SSc should be evaluated in a randomized clinical trial.

Factors affecting antibody levels after allogeneic hematopoietic cell transplantation.

To obtain insight into the mechanism(s) of posttransplantation humoral immunodeficiency, we evaluated factors affecting serum antibody levels against polio, tetanus, Haemophilus influenzae, and Streptococcus pneumoniae in 87 patients. Patients with hematologic malignancies were randomized to receive marrow versus blood stem cells, which contain approximately 10 times more lymphocytes than marrow. Blood stem cell recipients did not have higher antibody levels than marrow recipients. Recipient pretransplantation antibody levels were correlated with the posttransplantation levels, especially in the first 6 months after transplantation when the correlation coefficients typically exceeded 0.6. Donor pretransplantation antibody levels had less of a correlation with posttransplantation levels in the recipient. Patient or donor age, total body irradiation, and graft-versus-host disease or its treatment appeared to have no effect. In conclusion, antibody levels in the first year after transplantation are affected primarily by pretransplantation antibody levels in the recipient and, to a lesser degree, in the donor. These findings suggest that immunization of the recipient and the donor before transplantation may be more effective in improving antibody immunity after transplantation than manipulating graft-versus-host disease, changing conditioning, or increasing the number of lymphocytes in the graft.