Safety and Efficacy of Reduced-Dose Versus Full-Dose Alteplase for Acute Pulmonary Embolism: A Multicenter Observational Comparative Effectiveness Study.

OBJECTIVES: Systemic thrombolysis improves outcomes in patients with pulmonary embolism (PE) but is associated with the risk of hemorrhage. The data on efficacy and safety of reduced-dose alteplase are limited. The study objective was to compare the characteristics, outcomes, and complications of patients with PE treated with full- or reduced-dose alteplase regimens. DESIGN: Multicenter retrospective observational study. SETTING: Tertiary care hospital and 15 community and academic centers of a large healthcare system. PATIENTS: Hospitalized patients with PE treated with systemic alteplase. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pre- and post-alteplase hemodynamic and respiratory variables, patient outcomes, and complications were compared. Propensity score (PS) weighting was used to adjust for imbalances of baseline characteristics between reduced- and full-dose patients. Separate analyses were performed using the unweighted and weighted cohorts. Ninety-eight patients were treated with full-dose (100 mg) and 186 with reduced-dose (50 mg) regimens. Following alteplase, significant improvements in shock index, blood pressure, heart rate, respiratory rate, and supplemental oxygen requirements were observed in both groups. Hemorrhagic complications were lower with the reduced-dose compared with the full-dose regimen (13% vs. 24.5%, p = 0.014), and most were minor. Major extracranial hemorrhage occurred in 1.1% versus 6.1%, respectively ( p = 0.022). Complications were associated with supratherapeutic levels of heparin anticoagulation in 37.5% of cases and invasive procedures in 31.3% of cases. The differences in complications persisted after PS weighting (15.4% vs. 24.7%, p = 0.12 and 1.3% vs. 7.1%, p = 0.067), but did not reach statistical significance. There were no significant differences in mortality, discharge destination, ICU or hospital length of stay, or readmission after PS weighting. CONCLUSIONS: In a retrospective, PS-weighted observational study, when compared with the full-dose, reduced-dose alteplase results in similar outcomes but fewer hemorrhagic complications. Avoidance of excessive levels of anticoagulation or invasive procedures should be considered to further reduce complications.

Post-thrombolytic coagulopathy and complications in patients with pulmonary embolism treated with fixed-dose systemic alteplase.

BACKGROUND: Alteplase treatment can cause a systemic coagulopathy although the incidence and contributory factors are unknown in pulmonary embolism (PE). Fixed-dosing of alteplase for PE may lead to interpatient variability in drug exposure and influence post-thrombolytic coagulopathy (PTC). While changes in fibrinogen and INR have been used to describe PTC, no universal PTC definition is available. OBJECTIVES: Evaluate the incidence of PTC after alteplase treatment for PE, the effect of patient weight and blood/plasma volume and the association with bleeding complications. METHODS: We conducted a retrospective cohort study of patients treated with alteplase for massive or high-risk submassive PE. Demographics, alteplase dosing, laboratory assessment of coagulopathy, and bleeding events were collected. The primary endpoint was incidence of PTC defined as an international normalized ratio (INR) > 1.5 or fibrinogen < 170 mg/dL. Secondary outcomes included correlation between coagulopathies and alteplase dose normalized to actual body weight (ABW), ideal body weight (IBW), plasma volume (PV), and estimated blood volume (EBV). Bleeding events in patients with and without PTC were compared. RESULTS: 125 patients met criteria for inclusion in the study. PTC occurred in 35.3% of patients, with INR >1.5 in 21.8% and fibrinogen <170 mg/dL in 26%. Alteplase dose >50 mg was associated with increased odds of PTC (OR 6.5, CI 2.1-19.9). Dose normalized to ABW and EBV correlated weakly with absolute increase in post-alteplase INR (r =0.20, p =0.06 and r =0.21, p =0.057 respectively) and to percent change in INR (r =0.20, p = 0.058 and r =0.21, p =0.048 respectively). Dose/ABW, dose/PV, and dose/EBV each correlated moderately with absolute decrease in fibrinogen (r =-0.53, -0.49, and -0.47 respectively, p <0.001 for each) and percent change in fibrinogen (r = -0.55, -0.49, and -0.49 respectively, p < 0.001 for each). Dose/IBW correlated weakly with absolute and percent decrease in fibrinogen (r = -0.32, p =0.013 and r =-0.33, p =0.011). Patients with bleeding were more likely to have PTC (58.3% vs. 28.6%, p= 0.05) and a bleeding event was predictive of PTC (OR 5.33, 1.32-23.99). CONCLUSIONS: PTC is prevalent in patients with PE. PTC is influenced by alteplase dose and exposure parameters (ABW, IBW, PV, EBV) and may contribute to the bleeding risk.

Dual Angiotensin Receptor and Neprilysin Inhibition with Sacubitril/Valsartan in Chronic Systolic Heart Failure: Understanding the New PARADIGM.

OBJECTIVE: To evaluate the clinical role of sacubitril/valsartan, a novel angiotensin-neprilysin inhibitor, for the treatment of chronic heart failure with a reduced ejection fraction (HFrEF). DATA SOURCES: A search of PubMed was conducted using a combination of the search terms sacubitril, valsartan, LCZ696, neprilysin inhibition, natriuretic peptide system, renin-angiotensin system, and heart failure with reduced ejection fraction. Bibliographies of all retrieved articles were reviewed for relevant literature. All references included were published between 1980 and May 2015. STUDY SELECTION/DATA EXTRACTION: All studies and review articles that contained data describing the use of sacubitril/valsartan in HFrEF were reviewed. DATA SYNTHESIS: HFrEF remains a disease of high morbidity and mortality. Natriuretic peptide (NP) augmentation has emerged as a most promising neurohormonal target in HFrEF. NPs provide vasodilatory, natriuretic, diuretic, and antiproliferative actions to help support the failing heart. Neprilysin, a neutral endopeptidase, is a primary pathway for NP metabolism. Combined inhibition of the renin angiotensin aldosterone system and neprilysin augments the beneficial natriuretic peptide pathway while providing direct antagonism to increases in angiotensin II. In the landmark PARADIGM HF trial, the neprilysin inhibitor sacubitril added to valsartan significantly improved morbidity and mortality over enalapril, a standard of care in HFrEF. Application of these results to clinical practice requires careful considerations of trial design, study patient population, and clinical monitoring. CONCLUSIONS: Sacubitril/valsartan significantly improved morbidity and mortality in patients with chronic HFrEF but will require careful application to "real-world" populations of HFrEF.

Retrospective Analysis of Direct-Acting Oral Anticoagulants (DOACs) Initiation Timing and Outcomes After Thrombolysis in High- and Intermediate-Risk Pulmonary Embolism.

Direct-acting oral anticoagulants (DOACs) are prescribed in the treatment of venous thromboembolism, including pulmonary embolism (PE). Evidence is limited regarding the outcomes and optimal timing of DOACs in patients with intermediate- or high-risk PE treated with thrombolysis. We conducted a retrospective analysis of outcomes among patients with intermediate- and high-risk PE who received thrombolysis, by choice of long-term anticoagulant agent. Outcomes of interest included hospital length of stay (LOS), intensive care unit LOS, bleeding, stroke, readmission, and mortality. Descriptive statistics were used to examine characteristics and outcomes among patients, by anticoagulation group. Patients receiving a DOAC (n = 53) had shorter hospital LOS compared to those in warfarin (n = 39) and enoxaparin (n = 10) groups (mean LOS 3.6, 6.3 and 4.5 days, respectively; P < .0001). This single institution retrospective study suggests DOAC initiation <48 h from thrombolysis may result in shorter hospital LOS compared to DOAC initiation ≥48 h (P < .0001). Further larger studies with more robust research methodology are needed to address this important clinical question.

COVID-19 and venous thromboembolism: Known and unknown for imaging decisions.

As we continue to fight against the current coronavirus disease-2019 (COVID-19) pandemic, healthcare professionals across the globe are trying to answer questions surrounding how to best help patients with the up-to-date available science while awaiting the development of new therapies and mass vaccination. Since early in the pandemic, studies indicated a heightened risk of venous thromboembolism (VTE) in COVID-19 infected patients. There have been differing expert opinions about how to assess pretest probability of VTE in this patient population. This has been partly due to the high prevalence of respiratory failure in this patient population and the use of D-dimer as a prognostic test which is also frequently elevated in patients with COVID-19 in absence of VTE. Some experts have argued for an approach similar to usual care with testing if clinical suspicion is high enough. Some have argued for more routine screening at different points of care. Others have even suggested empiric therapeutic anti-coagulation in moderate to severely ill COVID-19 patients. In the following article, we review and summarize the most current literature in hopes of assisting clinicians in decision making and guidance for when to be concerned for VTE in COVID-19 patients. We also discuss research gaps and share pathways currently being used within our institution.

Serotonergic antidepressants and hospitalization for bleeding in patients supported with a continuous flow left ventricular assist device.

BACKGROUND: Continuous flow left ventricular assist devices (CF -LVAD) improve survival in patients with advanced heart failure, but confer risk of bleeding complications. Serotonergic antidepressants (SA) are commonly used in heart failure patients receiving LVADs, but their inhibitory effect on platelet function may contribute to bleeding risk. METHODS: We performed a retrospective analysis of LVAD patients at our institution from 2016 -2019 comparing patients treated with SA after LVAD to those without SA. Demographic and clinical variables related to bleeding were collected on discharge from index hospitalization for CF-LVAD implantation and on admission for any bleeding event. The primary endpoint was incidence of bleeding requiring hospitalization after discharge. Secondary endpoints included overall number of admissions for bleeding, time to first hospitalization for a bleeding event, and incidence rate of hospitalizations for bleeding per patient year. RESULTS: 100 patients met inclusion criteria for the study. A total of 5 patients without a history of SA use and 31 patients who were prescribed SA after CF -LVAD implant were readmitted for a bleeding event after initial implant hospitalization (15% vs 46%, p = 0.004). Bleeding rate per person year (0.3 vs 0.61, p = 0.01) were significantly less in patients without SA use. Age-adjusted multivariable analysis found SA use to be associated with a hospitalization for bleeding (HR 2.3, 95% CI 0.99 -5.4). The higher incidence of hospitalization for bleeding was driven by non-gastrointestinal anatomical sites (6% vs 28%, p = 0.02) with a HR 7.7 (95% CI 0.96 -62). CONCLUSIONS: SA treatment after CF-LVAD implantation was associated with an increased risk for bleeding complications requiring hospitalization, particularly non-gastrointestinal bleeding.

Clinical outcomes associated with sedation and analgesia in patients supported with venoarterial extracorporeal membrane oxygenation.

Sedatives and analgesics are frequently used in critically ill adult patients requiring mechanical ventilation in the intensive care unit, but optimal agent selection and dosing in patients supported with venoarterial extracorporeal membrane oxygenation remain poorly defined. This retrospective study evaluated whether sedative and analgesic agent selection and dosing had any impact on clinical outcomes after venoarterial extracorporeal membrane oxygenation decannulation. The primary endpoint of our study was the incidence of delirium within 48 h after venoarterial extracorporeal membrane oxygenation decannulation in patients who received an empiric ⩾50% sedation reduction of benzodiazepines (N = 22, group 2) compared to those who did not (N = 10, group 1) and those who required no sedatives within 24 h prior to venoarterial extracorporeal membrane oxygenation decannulation (N = 21, group 3). Secondary endpoints included time to extubation after decannulation, need for tracheostomy after decannulation, intensive care unit length of stay after decannulation, total hospital length of stay, and in-hospital mortality. Delirium within 48 h after decannulation was observed in 47% of all patients and did not differ between the three groups (50% vs 50% vs 43%, p = 0.9). No differences were observed in the secondary endpoints; though there was a trend toward shorter duration of mechanical ventilation and intensive care unit length of stay in patients who received an empiric ⩾50% sedation reduction. Our study suggests that we may need more than a 50% reduction in sedation but prospective studies with a larger sample size are warranted to evaluate how sedative/analgesic selection and dosing affect important clinical outcomes.

Tolvaptan for Volume Management in Heart Failure.

Volume management in acute decompensated and chronic heart failure (HF) remains a significant challenge. Although progress has been made in the development of mortality-reducing neurohormonal regimens in the reduced ejection fraction population, no clinical trial has yet demonstrated anything more than symptomatic relief or biomarker reduction with pharmacotherapeutic volume-based interventions made in the acutely decompensated individual or those with evolving outpatient congestion. As the number of patients with HF continues to grow, in addition to HF-related hospitalizations, identifying therapies that have the potential to aid in diuresis more safely and efficaciously is paramount to decreasing inpatient length of stay and preventing unnecessary admissions. More recently, a significant amount of research has been dedicated to the use of vasopressin antagonists, specifically tolvaptan, as adjunctive therapy to loop and thiazide diuretics. Although these agents do not seem to have a pervasive role in fluid management in the acute decompensated and chronic HF populations, they are effective tools to have available for specific clinical situations. This review summarizes the literature surrounding the use of tolvaptan for volume management in congestive HF, as well as offering practical guidance for use of this agent.

Lacosamide-Induced Recurrent Ventricular Tachycardia in the Acute Care Setting.

Lacosamide is a new-generation antiepileptic drug (AED) most commonly used adjunctively in the setting of partial-onset seizures refractory to traditional therapy. We describe the first case report, to our knowledge, of a patient who developed recurrent, sustained ventricular tachycardia with multiple administrations of lacosamide in an acute setting. A 70-year-old woman with a history significant for valvular heart disease was admitted to the inpatient cardiology service for worsening heart failure. On hospital day 7, she received a bioprosthetic aortic valve. Prior to surgery and immediately after, the patient's electrocardiogram (ECG) was normal. After developing multiple generalized tonic-clonic seizures refractory to levetiracetam, fosphenytoin, and valproic acid, the decision was made to initiate lacosamide. Two hours following the second lacosamide dose, the patient developed a wide complex QRS that transitioned into sustained ventricular tachycardia requiring electrical cardioversion. Sustained ventricular tachycardia occurred again, just hours after the third dose of lacosamide was given. Following cessation of lacosamide, the patient's QRS interval normalized and has since had no documented episodes of ventricular tachycardia. Clinicians should be aware of the potential for life-threatening rhythmic disturbances in patients initiated on lacosamide and the need for vigilant ECG, electrolyte, and drug-drug monitoring.

Aminophylline for Preventing Bradyarrhythmias During Orbital or Rotational Atherectomy of the Right Coronary Artery.

BACKGROUND: Coronary atherectomy, orbital or rotational, is frequently used for plaque modification in patients with heavily calcified lesions. Atherectomy can be associated with clinically significant bradyarrhythmias or transient atrioventricular block requiring temporary pacemaker insertion, mainly in lesions involving the right coronary artery or a dominant left circumflex artery. Bradyarrhythmias may be mediated by endogenous release of adenosine from red blood cell breakdown. Aminophylline, an adenosine antagonist, can prevent adenosine-mediated bradyarrhythmias. METHODS: This retrospective analysis examined 7 patients in whom aminophylline (250-300 mg intravenously over 10 min) was administered before coronary atherectomy. The study endpoint was the occurrence of any bradyarrhythmia. RESULTS: Orbital atherectomy was used in 3 cases, rotational atherectomy was used in 3 cases, and both systems were used in 1 case. Technical success was 100% and all patients had Thrombolysis in Myocardial Infarction 3 flow at the end of the procedure. Preprocedural aminophylline administration successfully prevented bradyarrhythmias or atrioventricular block in all cases. CONCLUSIONS: Intravenous aminophylline represents a simple, safe, widely available, and low-cost intervention for preventing bradyarrhythmias during atherectomy of the right coronary artery or a dominant circumflex artery.

Evaluation of Systemic Heparin Versus Bivalirudin in Adult Patients Supported by Extracorporeal Membrane Oxygenation.

Systemic anticoagulation is a standard of care in adult patients supported by extracorporeal membrane oxygenation (ECMO) to prevent circuit thrombosis and subsequent thromboembolic events. Unfractionated heparin has long been considered the anticoagulant of choice, but emerging evidence reports successful ECMO runs with direct thrombin inhibitors. This retrospective study sought to determine whether bivalirudin offers distinct clinical benefits as the anticoagulant of choice in ECMO. Primary end points included thrombotic events during the initial 96 hours of anticoagulation, over the course of their entire ECMO run, and at any time during the admission, as well as in-hospital and 30-day mortality. Secondary end points included percent time within therapeutic range for each anticoagulant, neurologic events, vascular complications, and bleeding. Compared with patients receiving heparin, patients receiving bivalirudin show similar rates of thrombotic events across the three time points (17.9% vs. 9.1%; p = 0.47, 21.4% vs. 11.4%; p = 0.41, and 25% vs. 22.7%; p = 1.00, respectively). In-hospital (32.1% vs. 36.4%; p = 0.91) and 30-day mortality (32.1% vs. 36.4%; p = 0.91) were no different. Similarly, no differences were observed in percent time within therapeutic range (83.0% vs. 87.7%, p = 0.34), neurological events (7.1% vs. 11.4%, p = 0.99), vascular complications (57.1% vs. 38.6%, p = 0.20), or major (25.0% vs. 45.5%, p = 0.13) and minor (25.0% vs. 22.7%, p = 1.00) bleeding. These results suggest that bivalirudin is a viable alternative to heparin for anticoagulation in ECMO but may not offer a clinically significant advantage as the anticoagulant of choice.