Warfarin and aspirin versus warfarin alone for prevention of bleeding and thrombotic events in patients with a HeartMate 3™ left ventricular assist device.

BACKGROUND: We conducted a single-center, retrospective comparison of adult patients who received warfarin and ASA or warfarin alone after HeartMate 3 (HM3) LVAD placement. METHODS: The primary outcome was a composite of bleeding and thrombotic events. RESULTS: Of 81 patients, 53 patients received warfarin and ASA, and 28 patients received warfarin alone. A primary outcome event occurred in 22 of 53 patients (41.4%) in the warfarin and ASA group and in 2 of 28 patients (7.1%) in the warfarin alone group (p = 0.0533). The odds of a bleeding event occurring were higher in the warfarin and ASA group (32.1% vs. 7.1%, p = 0.01309). The odds of a thrombotic event occurring were not significantly different between the warfarin and ASA group and the warfarin alone group (9.4% vs. 0%, respectively, p = 0.1582). CONCLUSION: The complete omission of ASA from the antithrombotic regimen of patients with a HM3 LVAD was associated with less bleeding events without an increase in thrombotic events.

Review of anticoagulation considerations in extracorporeal membrane oxygenation support.

Since its first success in 1975, extracorporeal membrane oxygenation (ECMO) has been used with increasing frequency for pulmonary and cardiopulmonary bypass. Use in adults has increased exponentially since the early 2000s, but despite thousands of international cannulations using both veno-arterial (VA) and veno-venous (VV) ECMO, there are still significant hemocompatibility-related adverse events. Current management of anticoagulation has been based on the Extracorporeal Life Support Organization guidance published in 2014 with recent updates published in 2022. Despite this guidance, there is still limited international consensus on how to manage anticoagulation in ECMO. For this review, we completed a comprehensive search of multiple electronic databases to identify studies pertaining to anticoagulation of adult patients on VV or VA-ECMO. The highest priority was given to sources that were prospective, randomized, controlled studies, but in the absence of such resources, observational studies, retrospective uncontrolled studies, and case series/reports were considered for inclusion. This document serves to provide a comprehensive review of the current understanding of management pertaining to anticoagulation relating to ECMO.

Impact of Inpatient Initiation of SGLT2 Inhibitors on Diuretic Requirements in Patients With Heart Failure.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve outcomes in patients with heart failure (HF) and are now included in guideline-directed medical therapy. Trials reporting the change in loop diuretic dose following SGLT2i initiation have indicated conflicting results. There is no clear guidance on whether reducing loop diuretic doses following SGLT2i initiation is appropriate. Objective: The purpose of this study is to assess the impact of SGLT2i initiation on diuretic adjustment in hospitalized patients with known or new HF. Methods: This was a retrospective, single health-system study assessing the change in loop diuretic dose in the 60 days following discharge for patients with HF initiated on SGLT2i therapy during a hospital admission or upon discharge. Secondary outcomes assessed effect on renal function and discontinuation of SGLT2i within the 60 day follow up period. Results: Forty percent of patients required loop diuretic dose adjustment, with 29% requiring a dose reduction within the 60 days following discharge. There was minimal change in serum creatinine or blood urea nitrogen. The SGLT2i was discontinued in 6 patients. Conclusions: After inpatient initiation of SGLT2is, approximately one-third of patients required a reduction in loop diuretic dose within 60 days following hospital discharge. Further study is recommended to confirm if empiric diuretic dose adjustments are appropriate in this HF population.

Safety and Efficacy of Prophylactic Amiodarone After Left Ventricular Assist Device.

The prophylactic use of amiodarone to reduce the incidence of postoperative arrhythmias is effective for patients undergoing general cardiac surgeries; however, no data exists for the use of prophylactic amiodarone to prevent postoperative arrhythmias after CF-LVAD. This single-center, retrospective analysis compared patients with CF-LVADs placed between April 2014 and June 2020 who received prophylactic postoperative amiodarone to those who did not. Based on institution practice at the respective times, patients with a CF-LVAD placed between April 2014 and June 2018 were included in the group receiving postoperative amiodarone arrhythmia prophylaxis and patients with a CF-LVAD placed July 2018 to June 2020 were included in the group not receiving arrhythmia prophylaxis. The primary outcome was the incidence of first occurring atrial or ventricular arrhythmia from CF-LVAD placement to 21 days or hospital discharge. Sixty patients received amiodarone for arrhythmia prophylaxis and 27 patients did not receive prophylaxis. The primary outcome occurred in 40% of the prophylaxis group and 66.7% in the no prophylaxis group (RR, 0.60; 95% CI, 0.40-0.90; p = 0.038). In patients receiving CF-LVADs, the use of prophylactic amiodarone was associated with a reduction in the incidence of postoperative arrhythmias, which was driven primarily by a reduction in postoperative atrial arrhythmias, without significantly increasing the rate of amiodarone-related adverse events.

Safety and Efficacy of Early Post-Operative Intravenous Iron Replacement In Patients With HeartMate III Left Ventricular Assist Device.

BACKGROUND: While guidelines suggest intravenous (IV) iron to improve functional status and quality of life (QoL) in patients with NYHA class II-III heart failure (HF), continuous flow left ventricular assist device (CF-LVAD) recipients were not included in early IV iron studies. Our study compared outcomes between patients who did and did not receive IV iron during the index admission following Abbott HeartMate III™ (HM 3) CF-LVAD placement. METHODS: Thirty-three adult patients with a HM3 placed at our institution who received early post-operative IV iron (n = 20) or no IV iron replacement (n = 13) were compared. The co-primary outcomes were mean change in quality of life (by the Minnesota Living with Heart Failure Questionnaire [MLHFQ]) and 6-minute walk distance (6MWD) from baseline to first >90 day clinic follow-up. RESULTS: At first clinic follow-up there was no significant difference between the IV iron and no-IV iron groups in MLHFQ (-27 ± 38 vs -21 ± 41, P = .8822) or 6MWD (360 ± 740 vs 786 ± 722, P = .208). CONCLUSION: Patients receiving IV iron during index admission following HM3 implantation did not experience an improvement in quality of life or functional capacity when compared to those who did not receive IV iron.

Impact of Thrombocytopenia on Postoperative Bleeding Incidence in Patients Receiving Aspirin Following Coronary Artery Bypass Grafting.

BACKGROUND: Early postoperative aspirin following coronary artery bypass graft (CABG) surgery has been shown to maintain bypass graft patency, reduce mortality, and prevent adverse cardiovascular events. Despite this known benefit, aspirin may be delayed due to thrombocytopenia and perceived higher bleeding risk. The purpose of this study was to assess the impact of postoperative platelet count on bleeding in patients receiving aspirin after CABG. METHODS: A retrospective analysis included all patients who underwent CABG surgery at our institution from April 2014 to June 2018 and received aspirin within 24 hours. The primary outcome was International Society on Thrombosis and Hemostasis (ISTH) major bleeding within 7 days (or up to discharge) following CABG surgery compared between patients with and without postoperative thrombocytopenia. RESULTS: This study included 280 patients. Major bleeding occurred in 24.6% of the population, with no difference when stratified by the presence or absence of postoperative thrombocytopenia (27.3% versus 23.8%, p = 0.571). There was no significant difference in hemoglobin fall (13.6% versus 14%, p = 0.948), transfusion requirement (6.1% versus 4.2%, p = 0.531), or critical site bleeding (12.1% versus 7.9%, p = 0.298). CONCLUSION: In this single-center analysis of patients who received aspirin within 24 hours of CABG, postoperative thrombocytopenia was not associated with an increase in bleeding.

Pharmacotherapy for durable left ventricular assist devices.

Left ventricular assist devices (LVADs) have revolutionized the care of patients with advanced heart failure, yet still require concomitant medications in order to achieve the best possible clinical outcomes. Since the outset of routine placement of durable, continuous-flow LVADs, much of the medication management of these patients to date has been based on International Society of Heart and Lung Transplantation (ISHLT) guidance, most recently published in 2013. Since 2013, numerous multidisciplinary pharmacotherapy publications have increased the LVAD community's understanding of best practices with respect to medications. We identified the major domains of LVAD medication management and conducted a comprehensive search of US National Library of Medicine MEDLINE® database using keywords chosen to identify medication-related publications of significance dated 2013 or later. Trials pertaining to the HeartMate II™ and the HeartMate™ 3 LVADs (Abbott, Chicago, IL) and the HeartWare™ HVAD™ System (Medtronic, Minneapolis, MN) were chosen for inclusion. Highest priority for inclusion was given to prospective, randomized, controlled studies. Absent these, controlled trials (retrospective or prospective observational) were given next-highest consideration, followed by retrospective uncontrolled studies, and finally case series. Reference lists of qualified publications were reviewed to find any other publications of interest that were not discovered on initial search. Case reports were generally excluded, except where the insight gained was deemed to be uniquely pertinent. This document serves to provide a comprehensive review of the current understanding of optimal medication management in patients with durable, continuous-flow LVADs.

Predictors of Warfarin Time in Therapeutic Range after Continuous-Flow Left Ventricular Assist Device.

INTRODUCTION: Patients with a continuous-flow left ventricular assist device (CF-LVAD) require anticoagulation with a vitamin K antagonist to prevent thromboembolic events. Fluctuations in the international normalized ratio are associated with both increased thrombotic and bleeding episodes. To date, risk factors for low time in therapeutic range (TTR) among ambulatory patients with a CF-LVAD have not been explored. METHODS: A retrospective single-center analysis of 121 patients implanted with a CF-LVAD was performed. International normalized ratios were systematically recorded from the initial postdischarge outpatient visit to 12 months of time on the device. Risk factors for low TTR were evaluated using a multivariable linear regression analysis. Each of the 21 independent variables was entered into a stepwise regression designed to minimize the Akaike information criteria. RESULTS: In the multivariable analysis, the model output revealed that every 1-year increase in age was associated with a 0.4% increase in TTR (p=0.008), and every 1 mile further from clinic was associated with a 0.08% increase in TTR (p=0.03). Female sex was associated with a 10.1% decrease in TTR (p=0.04), type 2 diabetes was associated with an 11.5% decrease in TTR (p=0.006), and prior warfarin use was associated with an 8.3% decrease in TTR (p=0.03). CONCLUSION: In CF-LVAD recipients receiving warfarin, increasing age and distance from clinic are independent predictors of higher TTR. Female sex, type 2 diabetes, and prior warfarin use are independent predictors of lower TTR.

Perioperative Bridging With Glycoprotein IIb/IIIa Inhibitors Versus Cangrelor: Balancing Efficacy and Safety.

OBJECTIVE: To review the efficacy and safety of perioperative administration of intravenous (IV) antiplatelet agents as a substitute for oral P2Y12 inhibitors and to provide clinicians guidance on optimal and cost-effective use of these medications. DATA SOURCES: A MEDLINE literature search (1950 to November 2018) was performed using the key search terms abciximab, bridging, cangrelor, cardiac surgery, coronary artery bypass surgery, eptifibatide, intravenous antiplatelet agent, and tirofiban. Additional references were identified from a review of literature citations. STUDY SELECTION AND DATA EXTRACTION: In all, 18 original research reports and case reports/series were included in the review. DATA SYNTHESIS: Prevention of postoperative bleeding is critical to decrease morbidity and mortality after cardiac surgery. IV antiplatelet medications have short half-lives and are frequently used to substitute for oral P2Y12 inhibitors to allow platelet function recovery before procedures. Functional recovery of platelets is delayed after abciximab discontinuation and increases postoperative bleeding risk. Eptifibatide and tirofiban have similar pharmacokinetic/pharmacodynamic properties and comparable efficacy and safety in the setting of perioperative bridging. Cangrelor may be considered in patients with renal insufficiency as decreased clearance of eptifibatide or tirofiban may increase the risk of postoperative bleeding. Relevance to Patient Care and Clinical Practice: Comparative studies of IV antiplatelet medications have not been published. Appropriate use of IV antiplatelet medications can prevent perioperative ischemic events and bleeding. CONCLUSIONS: Eptifibatide, tirofiban, and cangrelor are preferred over abciximab as a perioperative bridge. The choice of agent should be tailored to clinical characteristics of the patient and institutional acquisition costs.

Effects of Dicloxacillin on Warfarin Dose in Patients With a Left Ventricular Assist Device.

Patients with a durable, continuous flow left ventricular assist device (CF-LVAD) require anticoagulation with warfarin to prevent thromboembolic events. Driveline infections (DLIs) are a common CF-LVAD complication. A common pathogen implicated in DLI is oxacillin-sensitive Staphylococcus aureus (OSSA), which is effectively treated by oral dicloxacillin. Previous published experiences have observed a significant drug interaction between dicloxacillin and warfarin resulting in decreased international normalized ratio (INR) and increased warfarin dosing requirements. We sought to analyze the effect of dicloxacillin on INR and warfarin dose when used for DLI in our CF-LVAD program. Five of 106 patients having received an CF-LVAD at our institution met the inclusion criteria for this case series. These patients required a mean 51.8% (standard deviation of 29.8%) weekly warfarin dose increase to restore INR to the therapeutic range after the addition of dicloxacillin. Three of the five patients subsequently had their dicloxacillin discontinued, with a mean decrease in weekly warfarin dose of 30.6% (standard deviation of 19.1%). In our experience, when coalesced with prior published reports, an empiric warfarin dose increase of 25% to 33% is reasonable upon initiation of dicloxacillin and an empiric warfarin dose reduction of 10% to 15% is recommended upon discontinuation of dicloxacillin. Close INR follow-up is warranted during and after dicloxacillin treatment.

Safety and tolerability of high-intensity statin therapy in heart transplant patients receiving immunosuppression with tacrolimus.

BACKGROUND: Following heart transplantation (HT), HMG CoA reductase inhibitors (statins) have been shown to reduce total and low-density lipoprotein (LDL) cholesterol, development of cardiac allograft vasculopathy (CAV), and mortality. Studies in HT patients have demonstrated the safety of low/moderate intensity statins; however, little data exist using high-intensity (HI) statins. The study aim was to evaluate the safety and efficacy of HI statins in HT recipients receiving tacrolimus. METHODS: This single-center, retrospective analysis included adult HT recipients from January 1, 2005, to December 31, 2015, who received HI statin therapy during posttransplant follow-up. The primary outcome, tolerability, was defined as the absence of myalgias, hepatotoxicity, rhabdomyolysis, or HI statin dose reduction/discontinuation. The secondary end point was the mean reduction in total and LDL cholesterol. RESULTS: Among the 24 patients included, one experienced myalgias and therapy discontinuation (4%; P > 0.99). No other HI statin dose reduction/discontinuation occurred, and no instances of rhabdomyolysis or hepatotoxicity were observed. The average reduction in total and LDL cholesterol after conversion to HI statin was 35 mg/dL (P = 0.02) and 19 mg/dL (P = 0.10), respectively. CONCLUSIONS: High-intensity statin therapy appears safe and efficacious in HT recipients receiving tacrolimus and is a reasonable option for the treatment of refractory hyperlipidemia.

PARADIGM-HF Trial: Secondary Analyses Address Unanswered Questions.

Our aim was to summarize published secondary analyses of the PARADIGM-HF trial. In the original trial, published in September 2014, sacubitril/valsartan significantly reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared to enalapril. This summary provides a resource for clinicians to review subsequent analyses of the landmark trial evaluating the benefit of sacubitril/valsartan in various subgroups and providing information regarding optimal use of this new therapy in the broader heart failure population. A full list of publications of the existing PARDADIGM-HF post hoc analyses was obtained and summarized, grouped by focus (e.g., severity of illness, tolerability). Twenty-six publications and one abstract analyzing the PARADIGM-HF trial were reviewed, summarizing the most important results that compared the benefits of sacubitril/valsartan to enalapril, including pertinent subgroup information from each analysis. Key publications evaluated the treatment effect of sacubitril/valsartan based on heart failure severity (i.e., ejection fraction or heart failure risk scores), impact on alternate outcomes, influence of additional therapies, tolerability in patients with comorbidities (i.e., diabetes), long-term benefits, and cost-effectiveness. In addition, nine ongoing phase III and phase IV clinical trials with sacubitril/valsartan were briefly summarized to address potential future uses in more extensive heart failure settings. The benefit of sacubitril/valsartan over enalapril for the primary endpoint in the PARADIGM-HF trial is maintained throughout numerous secondary analyses. Though the subgroups analyzed are based on participants from a single clinical trial, clinicians can more confidently incorporate this novel therapy into practice with expanded knowledge of these existing analyses as well as ongoing prospective trials.

Medication Management of Patients Undergoing Transcatheter Aortic Valve Replacement.

Aortic stenosis (AS) is the most common form of valvular heart disease. A detailed diagnostic workup is necessary to promptly stage and classify disease severity to determine optimal management. Medical therapy and valvuloplasty are options that fail to delay or reverse disease progression. Surgical aortic valve replacement (SAVR) is curative but has significant limitations for some patient populations. A newer option, transcatheter aortic valve replacement (TAVR), has become more widely available to patients with intermediate- or high-operative risk. Periprocedural medication management is imperative for successful valve implantation and to minimize adverse events. Stroke remains one of the most common complications of TAVR and is associated with increased mortality. Thus, intra- and postprocedural antithrombotic therapy is required, although the regimen that best minimizes thromboembolic events and bleeding complications has yet to be defined. Patients undergoing TAVR with comorbid conditions requiring oral anticoagulation or individuals who develop subvalvular thromboses pose unique challenges. Antiplatelet and anticoagulant therapy should be carefully balanced. This article summarizes key literature supporting the pharmacologic management of patients receiving TAVR.

Warfarin and Aspirin Versus Warfarin Alone for Prevention of Embolic Events in Patients with a HeartMate II Left Ventricular Assist Device.

Acquired von Willebrand disease increases bleeding risk in patients implanted with a continuous-flow left ventricular assist device. Lower aspirin (ASA) doses decrease the risk of bleeding without an increased risk of embolic events. No published studies in the United States have compared the incidence of bleeding and thrombotic events between antithrombotic regimens with and without ASA. A single-center, retrospective analysis was conducted of adult patients implanted with a HeartMate II (HM II). Patients received warfarin and ASA 81 mg daily or warfarin alone. The primary end-point was a composite of death, bleeding events, and thrombotic events from the date of HM II implantation to first event or 18 months. Secondary end-points included the individual components of the primary end-point and the proportion of patients alive with HM II or transplanted. The Wilcoxon rank sum test and Fisher's exact test were used for statistical analysis. Of the 76 patients meeting inclusion criteria, 44 received warfarin and ASA and 32 received warfarin alone. Baseline characteristics were similar between groups. Warfarin alone was not associated with an increased risk of the primary composite outcome (53 vs. 59%, respectively, p = 0.64). No significant difference was observed in any bleeding event (34 vs. 43%, respectively, p = 0.48) nor any thrombotic event (9 vs. 11%, respectively, p = 1.00) with warfarin alone compared with warfarin and ASA. Elimination of antiplatelet therapy from the HM II antithrombotic regimen was associated with no significant difference in the composite outcome of bleeding events, thrombotic events, or death, nor the individual components of each end-point.

Inhaled Desmopressin for Refractory Gastrointestinal Bleeding in a Patient With a HeartMate II Left Ventricular Assist Device.

Patients with a durable, continuous-flow left ventricular assist device (LVAD) are commonly prescribed the combination of an oral anticoagulant and an oral antiplatelet agent as prophylaxis against device thrombosis and systemic embolic events. Current International Society of Heart and Lung (ISHLT) guidelines recommend warfarin with an INR goal of 2-3 and concomitant aspirin 81-325 mg daily for patients with a HeartMate II LVAD. Unfortunately, gastrointestinal (GI) bleeding is very common in these patients because of multiple factors including the development of arteriovenous malformations and acquired von Willebrand syndrome. If this bleeding cannot be corrected through interventional measures, it then requires at least temporary, and potentially permanent, cessation of antiplatelet or anticoagulant therapy. Patients who continue to bleed while off all antithrombotic therapies present a clinical challenge. We describe the successful management of a patient with refractory GI bleeding through the use of inhaled desmopressin.

Medication management of cardiac allograft vasculopathy after heart transplantation.

Cardiac allograft vasculopathy (CAV) is a common complication following heart transplantation (HT), resulting in diminished graft survival. The preferred strategy for preventing CAV is optimal medical management; however, for patients who develop CAV, delaying disease progression through effective medication management is equally important. A review of the literature regarding medication management of CAV was conducted via a search of the MEDLINE database. Studies were included if they were published in English, conducted in humans ≥ 18 years of age or older, and used noninvestigational medications. Immunosuppressive medications such as the antiproliferative mycophenolate, the calcineurin inhibitor tacrolimus, and the proliferation signal inhibitors sirolimus and everolimus have been shown to prevent the development of CAV. Certain cardiovascular medications, such as HMG-CoA reductase inhibitors (statins), gemfibrozil, calcium channel blockers, and angiotensin-converting enzyme inhibitors, have also demonstrated efficacy in preventing this disease process. Prevention of CAV has also been observed with prophylaxis against cytomegalovirus infection and antioxidant medications. Despite being commonly used in HT patients, neither antiplatelet agents nor glycemic control have proved effective at preventing CAV. Only sirolimus has been shown to arrest the progress of existing CAV.

Key articles and guidelines in the management of patients undergoing cardiac surgery.

Significant numbers of patients undergo cardiac surgery worldwide each year. A large evidence base exists regarding the optimal pre-, intra-, and postoperative mediation management for patients undergoing coronary artery bypass grafting (CABG) surgery, valve replacements or repairs, and mechanical circulatory support (MCS). Prevention and treatment of perioperative arrhythmias, perioperative antimicrobial prophylaxis, prevention of thrombosis, and bleeding through proper management of perioperative antiplatelet and anticoagulant therapies, and the use of pharmacotherapy to optimize both short- and long-term patient outcomes after cardiac surgery are the focus of this first compilation of guidelines and key articles in this patient population to be published in the Journal of Pharmacy Practice.

Advanced therapies for end-stage heart failure.

Management of the advanced heart failure patient can be complex. Therapies include cardiac transplantation and mechanical circulatory support, as well inotropic agents for the short-term. Despite a growing armamentarium of resources, the clinician must carefully weigh the risks and benefits of each therapy to develop an optimal treatment strategy. While cardiac transplantation remains the only true "cure" for end-stage disease, this resource is limited and the demand continues to far outpace the supply. For patients who are transplant-ineligible or likely to succumb to their illness prior to transplant, ventricular assist device therapy has now become a viable option for improving morbidity and mortality. Particularly for the non-operative patient, intravenous inotropes can be utilized for symptom control. Regardless of the treatments considered, care of the heart failure patient requires thoughtful dialogue, multidisciplinary collaboration, and individualized care. While survival is important, most patients covet quality of life above all outcomes. An often overlooked component is the patient's control over the dying process. It is vital that clinicians make goals-of-care discussions a priority when seeing patients with advanced heart failure. The use of palliative care consultation is well-validated and facilitates these difficult conversations to ensure that all patient needs are ultimately met.