Evaluation of adjusted international normalized ratio goal in patients with HeartMate 3 left ventricular assist devices.

BACKGROUND: The HeartMate3 left ventricular assist device (HM3 LVAD) has shown a low incidence of thrombosis, but bleeding risk is as high as 43%. We aim to describe the impact of lower international normalization ratio (INR) goal on clinical outcomes. METHODS: In February 2019, our tertiary care institution lowered INR goal in HM3 patients from manufacturer recommendations to 1.8-2.2 and retrospectively analyzed the data. Two cohorts were compared: patients with lower INR goal upon implant (De novo) and those with subsequently lowered INR goal (Adjusted). The Adjusted group also served as its own historical control. Both groups continued aspirin 81 milligrams daily per manufacturer recommendations. The primary outcomes were incidences of bleed and thrombosis events within 12 months. Secondary outcomes included survival free of disabling stroke or reoperation to remove or replace the device and Rosendaal time in therapeutic range (TTR) over 12 months. RESULTS: Thirty-one patients were evaluated for inclusion with 26 meeting criteria. Within 12 months, incidence of bleeding events was 25% and 28.6% in the De novo and Adjusted groups, respectively. Incidence of thrombotic events within 12 months was 0% in the De novo group and 7.1% in the Adjusted group. Twelve-month survival free of disabling stroke or reoperation to remove or replace the device was higher over 12 months for patients in the De novo group (91.7% vs. 78.6%). Median 12-month TTR was 36%, which was primarily attributable to subtherapeutic deviations. CONCLUSIONS: A lower INR goal may be safe when initiated De novo following implantation of the HM3. This study informs the need for larger prospective studies.

Overview of Pharmacological Considerations in Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation has become more widely used in recent years. Although this technology has proven to be lifesaving, it is not devoid of complications contributing to significant morbidity and mortality. Nurses who care for patients receiving extracorporeal membrane oxygenation should further their understanding of changes in medication profiles due to complex interactions with the extracorporeal membrane oxygenation circuitry. The aim of this comprehensive review is to give nurses a better understanding of analgesic, sedative, anti-infective, and anticoagulation medications that are frequently used to treat patients receiving extracorporeal membrane oxygenation.

Bivalirudin for left ventricular assist device thrombosis.

Pump thrombosis remains a serious complication of implantable ventricular assist device therapy and is associated with increased risk of morbidity and mortality. Optimal management strategies remain controversial and are guided largely by limited literature and expert opinion. Medical management of pump thrombosis, including the use of direct thrombin inhibitors, has been associated with mixed results. The purpose of this study is to report the outcomes associated with bivalirudin therapy in LVAD patients with suspected pump thrombosis. A single-center, retrospective observational study of 15 patients with suspected pump thrombosis that were all treated with bivalirudin therapy was conducted. The majority of subjects' initial treatment courses were unsuccessful [9/15 (60%)]; however, 6/15 (40%) achieved an initial improvement in serum lactate dehydrogenase (LDH) levels and were stabilized to be successfully discharged from the hospital. Of the subjects discharged, there was a high rate of recurrence of pump thrombosis within 6 months [5/6 (83.3%)]. Bivalirudin therapy was not associated with a consistent reduction in LDH among all subjects studied, and clinical responses to therapy appear to be associated with high rates of thrombosis recurrence. This study analyzes the largest cohort to date of LVAD patients with pump thrombosis treated with bivalirudin therapy, and suggests that alternative therapies should be considered in management.

Factor VIIa administration in orthotopic heart transplant recipients and its impact on thromboembolic events and post-transplant outcomes.

Recombinant, activated factor VIIa (rFVIIa) is used during cardiac surgeries to mitigate refractory coagulopathic bleeding. The purpose of this study was to examine whether rFVIIa use in orthotopic heart transplant (OHT) recipients was associated with a higher incidence of thromboembolic (TE) events compared to patients who did not. A single-center, retrospective, cohort study was performed on OHT recipients who received rFVIIa for refractory coagulopathic bleeding from January 2013 to December 2015. Patients were evaluated for up to 6 months after transplantation and assessed for TE events, rejection, readmissions, graft survival, and patient survival. Categorical variables were analyzed using the Chi square test while student's t or ANOVA testing was utilized for continuous variables. Of the 62 patients who met inclusion criteria, 27 patients received rFVIIa, and 35 patients were selected for the control group. The overall incidence of TE events was not significantly different between patients who received rFVIIa compared to patients in the control group (14.8% vs 11.4%) (p = 0.69). Within 14 days, 14.81% of rFVIIa patients suffered a TE event compared to 5.7% of the control group (p = 0.23). Rejection, readmissions, graft survival, and patient survival were not significantly different at any time points. Use of rFVIIa in heart transplantation showed no difference in the overall rate of TE events, however, there was a nonsignificant trend toward higher risk of early TE development in the rFVIIa group compared to the control group.

Bivalirudin Medication Use Evaluation and Cost Savings Initiative.

Bivalirudin is a parenteral anticoagulant that elicits its effect through inhibition of both free and clot bound-thrombin. Inhibition of thrombin serves as a unique mechanism for anticoagulation when compared to heparin as thrombin serves as the final common pathway for the intrinsic and extrinsic coagulation cascades. Due to unclear benefit over heparin, concerns regarding reversibility, and most importantly cost its use as a parenteral anticoagulant varies by institution. A recent drug expenditure review within our institution noted a significant increase in the contribution bivalirudin had on the overall drug budget. In an effort to establish the rationale for the cost increase, a medication use evaluation was performed. While it was discovered that 625 out of 1364 days of bivalirudin therapy were potentially avoidable, an equally important discovery was the amount of waste that was associated with bivalirudin therapy. Calculating daily requirements for bivalirudin indicated that 60% of patients required less than 100 mg per day. Within this article, we describe a cost-savings initiative to reduce bivalirudin waste and the resulting cost-avoidance following implementation.

Pharmacotherapeutic Management of Gastrointestinal Bleeding in Patients with Continuous-Flow Left Ventricular Assist Devices.

Continuous-flow left ventricular assist devices (CF-LVADs) have become an integral component of the management in patients with advanced heart failure, serving as destination therapy or as a bridge to heart transplantation. Despite significant advances in the design and longevity of the device, the ongoing risk for bleeding remains a significant concern. The genesis of gastrointestinal bleeding (GIB) in patients with CF-LVADs is likely multifactorial and may include components of acquired von Willebrand disease, angiodysplasia, and gastrointestinal arteriovenous malformations, as well as additional risk factors such as history of GIB and increased age. Several pharmacotherapy options have been used, but the data surrounding their overall efficacy remain sparse. The necessity for larger prospective studies is essential to further advance the management of this devastating complication. Within this review, we discuss the known pathophysiologic process of CF-LVAD-related GIB and highlight the therapeutic options discussed within the literature. In addition, we discuss potential therapeutic options based on mechanisms of action as they correlate to known pathophysiologic processes of CF-LVAD-related GIB. Finally, we provide recommendations for constructing drug therapy regimens in patients with CF-LVADs who develop GIB.

Evaluation of Altered Drug Pharmacokinetics in Critically Ill Adults Receiving Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a life-support modality used in patients with refractory cardiac and/or respiratory failure. A significant resurgence in the use ECMO has been seen in recent years as a result of substantial improvements in technology and survival benefit. With expanding ECMO use, a better understanding of how ECMO affects drug pharmacokinetics (PK) is necessary. The vast majority of PK studies in patients receiving ECMO have been conducted within neonatal or pediatric populations or within a controlled environment (e.g., in vitro or ex vivo). Because of significant differences in absorption, distribution, metabolism, and excretion, it may be inappropriate to extrapolate these PK data to adults. Thus, the aims of this review are to evaluate the changes in drug PK during ECMO and to summarize the available PK data for common drugs used in the adult critically ill patients during ECMO support. A search of the PubMed (1965-July 2016), EMBASE (1965-July 2016), and Cochrane Controlled Trial Register databases was performed. All relevant studies describing PK alterations during ECMO in ex vivo experiments and in adults were included. Evaluation of the data indicated that drug PK in adults receiving ECMO support may be significantly altered. Factors influencing these alterations are numerous and have intricate relationships with each other but can generally be classified as ECMO circuit factors, drug factors, and patient factors. Commonly used drugs in these patients include antimicrobials, sedatives, and analgesics. PK data for most of these drugs are generally lacking; however, recent research efforts in this patient population have provided some limited guidance in drug dosing. With an improved understanding of altered drug PK secondary to ECMO therapy, optimization of pharmacotherapy within this critically ill population continues to move forward.

Safety and Efficacy of High-Dose Unfractionated Heparin for Prevention of Venous Thromboembolism in Overweight and Obese Patients.

STUDY OBJECTIVE: To determine the safety and efficacy of high-dose subcutaneous unfractionated heparin (UFH) for prevention of venous thromboembolism (VTE) in overweight and obese patients. DESIGN: Single-center retrospective observational cohort study. SETTING: Large academic tertiary care medical center. PATIENTS: A total of 1335 adults who weighed more than 100 kg on admission and received either subcutaneous UFH 7500 units every 8 hours (751 patients [high-dose group]) or 5000 units every 8 hours (584 patients [low-dose group]) for VTE prophylaxis during their hospitalization between January 1, 2013, and August 31, 2014. MEASUREMENTS AND MAIN RESULTS: The incidences of VTE and bleeding complications were assessed in each group. Each group was further divided into four groups based on their body mass index (BMI): overweight (BMI 25-29.9 kg/m(2) ), obese class I (BMI 30-34.9 kg/m(2) ), obese class II (BMI 35-39.9 kg/m(2) ), and obese class III (BMI ≥ 40 kg/m(2) ). The incidence of VTE was similar for patients in the high-dose group versus those in the low-dose group for all BMI categories. Bleeding complications were significantly higher for patients in the high-dose group. The proportion of patients with at least a 2-g/dl hemoglobin drop from admission was higher in patients in the high-dose groups in obese classes II and III: obese class II, 46 (30%) of 152 patients in the high-dose group versus 30 (18%) of 171 patients in the low-dose group (p<0.01); obese class III, 109 (25%) of 432 patients in the high-dose group versus 31 (12%) of 249 patients in the low-dose group (p<0.01). In addition, the proportion of patients who received at least 2 units of packed red blood cell transfusion was significantly higher in patients in the high-dose group who were in obese class III: 47 (11%) of 432 in the high-dose group versus 13 (5%) of 249 in the low-dose group (p<0.01). CONCLUSION: Administering a higher dose of heparin to patients weighing more than 100 kg may not impart additional efficacy in reducing the incidence of VTE. However, it may increase the risk for bleeding.

Statin therapy in cardiac allograft vasculopathy progression in heart transplant patients: Does potency matter?

Cardiac allograft vasculopathy (CAV) is a unique multi-factorial pathologic process encountered following heart transplantation. Several risk factors have been identified including a combination of immunologic and non-immunologic processes. Significant research has been conducted to elucidate the driving forces of CAV as well as improved identification, prevention and treatment strategies. Statin therapy following transplant remains the standard of care to help prevent the progression of CAV. The benefits of statin therapy following transplantation correspond to cholesterol control, anti-inflammatory and immunomodulatory mechanisms as well as potentially unknown mechanisms. Despite known drug interactions with calcineurin inhibitors, the use of statins is highly recommended in the current International Society for Heart and Lung Transplantation guidelines. Limited research has been conducted on the impact of higher intensity statin therapy following heart transplant and the relative risks and benefits are unknown. This review focuses on risk factors and pathophysiology of CAV, the role of statin therapy in heart transplantation, and the potential added benefit of more intense statin therapy to limit the progression of this graft-limiting complication.

The role of pharmacotherapy in the prevention of sudden cardiac death in patients with heart failure.

Sudden cardiac death remains a significant threat to the survival of patients with heart failure. Long-term cardiac remodeling predisposes these patients to develop malignant ventricular arrhythmias. Permanent implantable and temporary external defibrillators remain a mainstay for the prevention of sudden cardiac death in this population. For decades, researchers have attempted to identify reliable drug therapies to avoid such arrhythmias; however, to date, success has been inconsistent. This review aims to explore the evidence defining the role of drug therapies for direct and indirect suppression of arrhythmias that may cause sudden cardiac death in patients with heart failure.

Impact of Norepinephrine Shortage on Outcomes in Patients with Septic Shock.

PURPOSE: With the previous norepinephrine shortage, alternative agents were required to treat patients with septic shock. This retrospective study evaluated whether the shortage of norepinephrine had an adverse effect on patients admitted to the intensive care unit with a diagnosis of severe sepsis or septic shock. METHODS: This was a retrospective chart review, which compared patients who received norepinephrine versus those who did not. Eligible patients were those ≥ 18 years old who were admitted to an intensive care unit with a diagnosis of sepsis and were initiated on a vasopressor to maintain hemodynamic stability. The specific primary endpoint was whether using norepinephrine versus other vasopressors had an effect on ICU length of stay. Secondary outcomes included mortality, blood pressure, mean arterial pressure, development of renal insufficiency, and vasopressor requirements. RESULTS: There were 288 patients screened and 214 patients who met the inclusion criteria (norepinephrine group=106 and nonnorepinephrine group=108). After accounting for potential differences in disease severity (APACHE II score), age, weight and gender, there was no difference in ICU length of stay (p=0.4); however, the odds of survival were 5.9 (95% CI: 3.1 to 11.1) times higher for those in the non-norepinephrine group (p<0.0001). CONCLUSION: Based on this retrospective analysis, patients that did not receive norepinephrine had a similar ICU LOS but had a higher rate of survival. The norepinephrine shortage did not have an adverse effect on patient outcomes.

Developing an Anti-Xa-Based Anticoagulation Protocol for Patients with Percutaneous Ventricular Assist Devices.

Because of the complexities associated with anticoagulation in temporary percutaneous ventricular assist device (pVAD) recipients, a lack of standardization exists in their management. This retrospective analysis evaluates current anticoagulation practices at a single center with the aim of identifying an optimal anticoagulation strategy and protocol. Patients were divided into two cohorts based on pVAD implanted (CentriMag (Thoratec; Pleasanton, CA) / TandemHeart (CardiacAssist; Pittsburgh, PA) or Impella (Abiomed, Danvers, MA)), with each group individually analyzed for bleeding and thrombotic complications. Patients in the CentriMag/TandemHeart cohort were subdivided based on the anticoagulation monitoring strategy (activated partial thromboplastin time (aPTT) or antifactor Xa unfractionated heparin (anti-Xa) values). In the CentriMag/TandemHeart cohort, there were five patients with anticoagulation titrated based on anti-Xa values; one patient developed a device thrombosis and a major bleed, whereas another patient experienced major bleeding. Eight patients received an Impella pVAD. Seven total major bleeds in three patients and no thrombotic events were detected. Based on distinct differences between the devices, anti-Xa values, and outcomes, two protocols were created to guide anticoagulation adjustments. However, anticoagulation in patients who require pVAD support is complex with constantly evolving anticoagulation goals. The ideal level of anticoagulation should be individually determined using several coagulation laboratory parameters in concert with hemodynamic changes in the patient's clinical status, the device, and the device cannulation.

Antiplatelet Therapy Considerations in Ischemic Cardiogenic Shock: Implications of Metabolic Bioactivation.

Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist remains a mainstay in the prevention of ischemic events following coronary stent placement. Significant controversy exists regarding the optimal management of high platelet reactivity despite antiplatelet therapy; however this finding has been consistently associated with poor clinical outcomes including greater risk of stent thrombosis and myocardial infarction. Variability in antiplatelet effects of clopidogrel and prasugrel has been linked to genetic polymorphisms and potential drug-drug interactions. Both of these factors have significant influence on the cytochrome P-450 enzyme system activity of the liver responsible for their biotransformation to the active form of both drugs. Very little has been publicized regarding differences in antiplatelet effects which may be associated with conditions in which the functional capacity of the liver may be temporarily compromised. Patients who present with cardiogenic shock due to acute coronary syndromes have evidence of multiorgan dysfunction including liver dysfunction that may affect the activity of these drugs. This review aims to explore existing evidence and propose additional considerations to the selection of antiplatelet therapy in patients with cardiogenic shock who receive catheter-based revascularization and stent placement.

Evaluation of Dosing Practices of Rivaroxaban and Dabigatran.

Background: Anticoagulation is standard practice for the prevention and treatment of thromboembolic events. Two of the newer agents, rivaroxaban (Xarelto) and dabigatran (Pradaxa) are being utilized frequently in the inpatient and outpatient settings. Prescribers may not appreciate the need for dose reduction in the setting of renal insufficiency. Objective: The objective of this study was to evaluate whether rivaroxaban and dabigatran were dosed according to recommendations in the package insert for patients with renal insufficiency. Methods: Eligible patients were those >18 years of age who received rivaroxaban or dabigatran as an inpatient or had a prescription filled from the outpatient pharmacy. The use of the Cockcroft-Gault equation was utilized to calculate creatinine clearance to evaluate whether patients had appropriate manufacturer recommended dose reductions based on their renal function. Results: There were very few patients (8 of 355, or 2.3%) who should have received a reduced dose when creatinine clearance was calculated utilizing actual body weight. In those patients with renal insufficiency, 3 of 6 (50.0%) patients receiving rivaroxaban and 1 of 2 (50%) patients receiving dabigatran were appropriately dosed. When ideal body weight was substituted for creatinine clearance calculation, there were 15 patients receiving rivaroxaban and 10 patients receiving dabigatran who fell below the creatinine clearance threshold for dose reduction. Conclusions: Based on this evaluation, very few patients required a dose reduction due to renal insufficiency. It is important for clinicians to always monitor renal function when utilizing these medications to optimize the benefits of the new oral anticoagulants while limiting potential deleterious effects. Furthermore, it is necessary to ensure that actual body weight is being utilized for creatinine clearance calculations with the new oral anticoagulants and not to base dosing on estimated glomerular filtration rate or other calculated creatinine clearance as this could lead to inappropriate dose reductions.

Improved ticagrelor antiplatelet effect on discontinuation of phenytoin.

OBJECTIVE: To report the influence of phenytoin on the antiplatelet effects of ticagrelor using a validated platelet aggregation study. CASE SUMMARY: A 71-year-old man with coronary artery disease underwent percutaneous coronary intervention to revascularize several major coronary arteries. The patient was previously on phenytoin and was initiated on ticagrelor for antiplatelet therapy following stent placement. While the patient was receiving both drugs, platelet aggregation studies revealed less platelet inhibition than would be expected in a patient not taking a concomitant inducer of ticagrelor metabolism. On discontinuation of phenytoin, platelet inhibition improved. DISCUSSION: Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist following placement of coronary stents is critical to prevent stent thrombosis and subsequent myocardial infarction. Ticagrelor is a recently approved P2Y12 receptor antagonist that is subject to drug-drug interactions involving the hepatic cytochrome P450-3A4 enzyme system because of its metabolic elimination pathway. This case demonstrates ticagrelor's drug-drug interaction with phenytoin through a platelet aggregation study and supports the manufacturer recommendation to avoid the combination of ticagrelor with any known inducers of cytochrome P450-3A4 metabolism. CONCLUSION: The combination of ticagrelor and phenytoin may represent a potentially clinically significant drug-drug interaction because of phenytoin induction of ticagrelor metabolism and reduced P2Y12 receptor inhibition in patients who have recently undergone percutaneous coronary intervention and cardiac stent placement.

Comparison of Hospitalwide and Custom Antibiograms for Clinical Isolates of Pseudomonas aeruginosa.

BACKGROUND: Hospital antibiograms, which are commonly used to determine empiric antibiotic therapy and as a tool in stewardship in a given institution, are open to bias when combining susceptibility results from various sources, hospital locations, and patient groups. METHODS: We assessed such differences, using Pseudomonas aeruginosa as a test case, with susceptibility data from 2008 through 2010 in our institution. Each year's data were analyzed separately. A variety of specific or subcategorical antibiograms were compared with each other as well as with versions including all tested isolates and those with results from inpatients and outpatients only. Statistical significance was determined at the .01 level using either chi-square or Fisher exact test, and clinical significance was defined as ≥10 percentage points. RESULTS: A variety of clinically significant differences were found that illustrated important differences within the intensive care unit environment and based on population, specifically adult versus pediatric. Concordance between statistically significant and clinically significant differences was poor. CONCLUSION: These results corroborate and extend previous similar observations and point to the potential importance of subanalyses in preparing the annual hospital antibiogram.

Aldosterone and aldosterone receptor antagonists in patients with chronic heart failure.

Aldosterone is a mineralocorticoid hormone synthesized by the adrenal glands that has several regulatory functions to help the body maintain normal volume status and electrolyte balance. Studies have shown significantly higher levels of aldosterone secretion in patients with congestive heart failure compared with normal patients. Elevated levels of aldosterone have been shown to elevate blood pressure, cause left ventricular hypertrophy, and promote cardiac fibrosis. An appreciation of the true role of aldosterone in patients with chronic heart failure did not become apparent until the publication of the Randomized Aldactone Evaluation Study. Until recently, the use of aldosterone receptor antagonists has been limited to patients with severe heart failure and patients with heart failure following myocardial infarction. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) study added additional evidence to support the expanded use of aldosterone receptor antagonists in heart failure patients. The results of the EMPHASIS-HF trial showed that patients with mild-to-moderate (New York Heart Association Class II) heart failure had reductions in mortality and hospitalizations from the addition of eplerenone to optimal medical therapy. Evidence remains elusive about the exact mechanism by which aldosterone receptor antagonists improve heart failure morbidity and mortality. The benefits of aldosterone receptor antagonist use in heart failure must be weighed against the potential risk of complications, ie, hyperkalemia and, in the case of spironolactone, possible endocrine abnormalities, in particular gynecomastia. With appropriate monitoring, these risks can be minimized. We now have evidence that patients with mild-to-severe symptoms associated with systolic heart failure will benefit from the addition of an aldosterone receptor antagonist to the standard therapies of angiotensin-converting enzyme inhibitors and beta-blockers. This review will address the pharmacologic basis of aldosterone receptor antagonists in patients with heart failure and the clinical impact of this therapy.