Laura V. Tsu

Bivalirudin Dosing Adjustments for Reduced Renal Function with or Without Hemodialysis in the Management of Heparin-Induced Thrombocytopenia

Background: While not approved by the Food and Drug Administration for treatment of heparin-induced thrombocytopenia (HIT), except in patients undergoing percutaneous interventions, the direct thrombin inhibitor bivalirudin is a treatment option that is gaining use. An initial dose of bivalirudin 0.15–0.2 mg/kg/h, adjusted to an activated partial thromboplastin time (aPTT) of 1.5–2.5 times the baseline value, has been suggested. Initial dosing in patients with renal dysfunction, including those on hemodialysis, is unclear. Objective: To evaluate initial bivalirudin dosing requirements in patients with and without renal dysfunction, including patients on different forms of dialysis. Methods: A retrospective analysis of 135 patients treated with bivalirudin for HIT between June 2004 and October 2009 was conducted at a tertiary care medical center. The patients were divided into groups, based on renal function. Patients receiving dialysis were divided into 3 subgroups based on the mode of hemodialysis: intermittent hemodialysis (IHD, n = 24), sustained low-efficiency daily diafiltration (SLEDD, n = 12), or continuous renal replacement therapy (CRRT, n = 5). Patients not receiving dialysis were separated into 3 subgroups based on calculated creatinine clearance (CrCl): CrCl >60 mL/min (n = 52), CrCl 30–60 mL/min (n = 26), and CrCl <30 mL/min (n = 16). Results: Compared with patients with normal renal function (CrCl >60 mL/min), patients with differing degrees of renal dysfunction (CrCl 30–60 and <30 mL/min) required lower doses of bivalirudin to achieve aPTT goal (0.13 vs 0.08 vs 0.05 mg/kg/h, respectively; p < 0.001). Patients on dialysis (IHD, SLEDD, CRRT) also required dose reductions (0.07, 0.09, and 0.07 mg/kg/h) compared with patients with normal renal function, but higher dosing requirements than patients not receiving dialysis with CrCl <30 mL/min. Conclusions: Patients with renal dysfunction require a reduced dose of bivalirudin to reach a therapeutic aPTT goal. Slightly higher doses may be observed in patients receiving hemodialysis.

Vitamin K Dosing to Reverse Warfarin Based on INR, Route of Administration, and Home Warfarin Dose in the Acute/Critical Care Setting

Background: Vitamin K is commonly used for reversal of anticoagulation of warfarin. However, the optimal dose and route of vitamin K that does not increase the duration of bridging therapy is unknown. Objective: To determine factors influencing the extent and rate of INR reversal with vitamin K in the acute/critical care setting. Methods: This was a chart review of 400 patients who received vitamin K for reversal of warfarin effects between February 2008 and November 2010. Data collected included international normalized ratios (INRs) 12 hours, 24 hours, and 48 hours prior to vitamin K administration; intravenous or oral vitamin K dose; and whether or not fresh frozen plasma (FFP) was administered. Results: Intravenous vitamin K reduced INR more rapidly than oral vitamin K (5.09, 1.91, 1.54, and 1.41 vs 5.67, 2.90, 2.14, and 1.58) at baseline, 12, 24, and 48 hours, respectively. The dose of vitamin K (p < 0.001), route of administration (p < 0.001), and baseline INR (p < 0.001) influenced subsequent INR values. The INR reduction was similar for intravenous vitamin K doses 2 mg or greater. Home warfarin dose did not affect INR responses to intravenous (p = 0.27) or oral vitamin K (p = 0.98). FFP did not influence INR values at 48 hours. Although longer anticoagulation bridge therapy seemed to be associated with higher vitamin K doses, the incidence (p = 0.63) and duration (p = 0.61) were not significant. Conclusions: Vitamin K dose, route, and initial INR influence subsequent INR values. INR reduction is similar for intravenous vitamin K doses of 2 mg or greater. Preadministration of FFP does not alter INR values at 48 hours or more after vitamin K administration.

Bivalirudin for Anticoagulation During Hypothermic Cardiopulmonary Bypass and Recombinant Factor VIIa for Iatrogenic Coagulopathy

Objective: To describe management of anticoagulation with a decreased dose requirement of bivalirudin during cardiopulmonary bypass using deep hypothermic circulatory arrest (DHCA) and the reversal of the ensuing coagulopathy with recombinant factor VIIa (rFVIIa). Case Summary: A 46-year-old male developed chest pain, hypertension, and an aortic aneurysm requiring urgent surgical repair. At the time of surgery, the patient reported an allergy to heparin, so bivalirudin was used for anticoagulation (1 mg/kg loading dose, followed by intermittent infusions of 1.25-2.5 mg/kgm over the 5 hours of cardiopulmonary bypass). When the cooling process was initiated, bivalirudin was stopped in anticipation of loss of the clotting cascade function and potential slowing of drug elimination. Bivalirudin was restarted for 45 minutes during the rewarming period because of concern for potential clot formation in the bypass circuit with recovery of hemostasis; it was again stopped due to the patients activated clotting time (ACT) of 504 seconds. Despite this measure, diffuse and severe coagulopathy was observed upon rewarming, with ACTs longer than 999 seconds. Although multiple blood products were administered, visualization of a clot in the surgical field was not notable. A total dose of rFVIIa 20 μg/kg was administered, resulting in visual clot formation within 4 minutes. On postsurgical day 6, bilateral asymptomatic distal deep vein thromboses were noted on imaging; on postsurgical day 8, fondaparinux 2.5 mg subcutaneously was administered daily to prevent clot extension. The patient was discharged on postoperative day 23 with no acute issues and no further anticoagulants. Discussion: Alternative anticoagulation agents such as bivalirudin are used in patients who have an allergy or contraindication to heparin. We propose that prolonged coagulopathy after the induction of hypothermia is due to decreased clotting cascade function as well as stowing of protease activity resulting in decreased bivalirudin elimination. We observed a positive response to low-dose rFVIIa, which could be due to activation of the extrinsic pathway and/or a thrombin burst, resulting in hemostasis. Currently, there is limited evidence supporting reversal of direct thrombin inhibitors with rFVIIa. Conclusions: In the setting of DHCA, bivalirudin should be used cautiously, with frequent monitoring of the ACTs and potential cessation of the infusion in anticipation of prolonged drug effect with subsequent potential coagulopathy. If coagulopathy ensues, use of low-dose rFVIIa may be an option to initiate hemostasis. When using rFVIIa, it is important to consider the risk of thrombosis and monitor patients accordingly.

Use of Ranolazine in the Prevention and Treatment of Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery

Objective: To determine the evidence for use of ranolazine for treatment and prevention of postoperative atrial fibrillation (POAF) in patients undergoing cardiac surgery. Data Sources: A literature search of MEDLINE (1946 to January 2014) was conducted, using the search terms ranolazine, atrial fibrillation, and cardiac surgery. A search of reference citations was conducted to identify additional references. Study Selection and Data Extraction: Clinical trials investigating the use of ranolazine for POAF were included in the review. Data Synthesis: Three clinical trials were reviewed; 2 trials, 1 retrospective and 1 prospective, compared ranolazine with amiodarone or usual care for prevention of POAF and demonstrated a significant decrease in the incidence of POAF without increasing the incidence of postoperative complications. A third prospective trial used ranolazine in combination with amiodarone for the treatment of POAF and demonstrated a significant reduction in the time required to convert patients from atrial fibrillation to normal sinus rhythm compared with amiodarone alone. Conclusions: In these current small trials, ranolazine appears to be a safe and efficacious therapeutic alternative for the treatment and prevention of POAF in patients undergoing cardiac surgery. However, larger randomized controlled trials are needed before ranolazine should be considered for the treatment or prevention of POAF. It is an attractive option compared with current treatments for this indication—primarily β-blockers and amiodarone—because ranolazine has minimal effects on heart rate and blood pressure.

Comparison of Bivalirudin Dosing Strategies Using Total, Adjusted, and Ideal Body Weights in Obese Patients with Heparin-Induced Thrombocytopenia

To compare dosing strategies using total body weight (actual measured body weight), adjusted body weight, and ideal body weight when starting bivalirudin for the treatment for heparin‐induced thrombocytopenia (HIT) in obese patients, and to compare differences in dosing requirements and clinical outcomes between obese and nonobese patients.

Care transitions in elderly heart failure patients: current practices and the pharmacist's role.

OBJECTIVE To provide an up-to-date review of current care transitions in elderly heart failure (HF) patients and assess the role of the pharmacist in improving patient care. DATA SOURCE A PubMed search of articles in the English language published between 1995 and May 2013 was done using a combination of the following words: discharge counseling, elderly, heart failure, multidisciplinary team, pharmacist, pharmacy, readmission, transition of care. STUDY SELECTION/DATA EXTRACTION Relevant original studies, review articles, and guidelines were assessed for current practices in HF transitions of care. References from the above literature were also evaluated for relevance. Articles were selected for inclusion based on relevance to the topic, detailed methods, and clear, comprehensive results. DATA SYNTHESIS The incidence of HF is rapidly increasing, and emphasis has been placed on reducing readmissions. Although present practices are primarily nurse-led, pharmacists are in a key position to educate patients through multidisciplinary teams, discharge counseling, and medication reconciliation. Because of concerns about pharmacist provider status and reimbursement, pharmacists should identify areas in their practices where they can intervene and improve patient care to reduce readmissions. CONCLUSION Pharmacists are an integral part of the multidisciplinary team in optimizing care for elderly HF patients to prevent readmissions.

Safety of New Oral Anticoagulants with Dual Antiplatelet Therapy in Patients with Acute Coronary Syndromes

OBJECTIVE To determine the safety of dabigatran, rivaroxaban, or apixaban with dual antiplatelet therapy in patients with acute coronary syndromes. DATA SOURCES A literature search of MEDLINE (1946–January 2013) was conducted, using the search terms dabigatran, rivaroxaban, or apixaban in combination with dual antiplatelet therapy. A search of literature citations was conducted to identify additional references. STUDY SELECTION AND DATA EXTRACTION Randomized controlled trials involving the use of one of the new anticoagulants with concomitant dual antiplatelet therapy were included in the review. DATA SYNTHESIS Five randomized controlled trials were reviewed, including 1 trial of dabigatran, 2 trials of rivaroxaban, and 2 trials of apixaban. These studies were conducted in patients with a recent acute coronary syndrome, so most patients were receiving aspirin and clopidogrel as dual antiplatelet therapy in addition to a therapeutic dose of one of the anticoagulants. The 3 Phase 2 dose-ranging trials (1 each of dabigatran, rivaroxaban, and apixaban) found an increasing risk of major and clinically relevant nonmajor bleeding with increasing doses of the anticoagulants. The Phase 3 trial of apixaban was terminated early due to an excess of bleeding events, and the trial of rivaroxaban also found an increased risk of bleeding. CONCLUSIONS The emerging use of dabigatran, rivaroxaban, and apixaban into clinical practice has introduced additional management options, but also safety concerns when combined with antiplatelet agents. Due to the increased risk of bleeding when combining an anticoagulant with 2 antiplatelet agents, clinicians should monitor and educate patients on avoiding potential complications. The need for continued triple regimens should be periodically reviewed.

Managing acute coronary syndromes in the elderly.

OBJECTIVE To provide an up-to-date review of the available evidence regarding treatment of acute coronary syndromes (ACS) in elderly patients. DATA SOURCE A PubMed search of articles published through January 2015 was done using a combination of the following words: acute coronary syndrome, pharmacy, elderly, geriatric, myocardial infarction, beta-blocker, statin, antiplatelet, antithrombin, angiotensin-converting enzyme inhibitor, and aspirin. STUDY SELECTION/DATA EXTRACTION Relevant original research, review articles, and guidelines were assessed for the management of elderly patients with ACS. References from the above literature were also evaluated. Articles were selected for inclusion based on relevance to the topic, detailed methods, and complete results. DATA SYNTHESIS Because of the high prevalence of ACS in elderly patients, appropriate treatment is necessary to reduce morbidity and mortality; however, these patients are often under-represented in trials. This article provides a review of the current literature on treatment of ACS in the elderly and provides guidance to pharmacists regarding optimal pharmacotherapy for these patients. CONCLUSION Appropriate treatment of ACS can help improve outcomes in elderly patients, and the pharmacist can provide guidance regarding evidence-based therapy.

Modified HAS-BLED Score and Risk of Major Bleeding in Patients Receiving Dabigatran and Rivaroxaban: A Retrospective, Case-Control Study.

OBJECTIVE To determine if a modified HAS-BLED score (hypertension, abnormal renal/liver dysfunction, stroke, bleeding history, elderly, drugs) predicts risk for major bleeding in patients prescribed dabigatran or rivaroxaban. DESIGN A retrospective, case-control study. SETTING Two inpatient medical centers. PATIENTS Patients prescribed dabigatran or rivaroxaban who experienced a major bleed from June 1, 2011, to August 31, 2013. INTERVENTIONS Medication and demographic information were collected for patients who experienced a major bleeding episode. Each bleeding case was matched to four control patients based on drug, indication, month and year, and hospital. MAIN OUTCOME MEASURES The primary outcome was the association between a modified HAS-BLED score and major bleeding in patients receiving dabigatran or rivaroxaban. The secondary objective was to determine which risk factors, whether individual components of HAS-BLED or alternative variables, were associated with major bleeding in patients receiving dabigatran or rivaroxaban. RESULTS Thirty-eight major bleeds were identified, with 23 bleeds having occurred in patients receiving rivaroxaban, and 15 patients taking dabigatran. The most frequent type of bleed was gastrointestinal. Logistic regression yielded only protime (P < 0.001) and albumin (P < 0.042) as statistically significant risk factors for bleeding. CONCLUSIONS A modified HAS-BLED score was not predictive of risk of major bleeding in this cohort of primarily elderly patients taking dabigatran or rivaroxaban.

A Clinical Review of Surgical vs Transcatheter Aortic Valve Replacement in Geriatric Patients

OBJECTIVE To provide an up-to-date review of the available evidence regarding management of elderly patients after transcatheter aortic valve replacement (TAVR). DATA SOURCES A PubMed search of articles published (September 1969-December 2016) was done using a combination of the following words: aortic valve stenosis, geriatric, elderly, transcatheter aortic valve replacement, surgical aortic valve replacement, transcatheter aortic valve implantation (TAVI), and dual antiplatelet therapy. STUDY SELECTION/DATA EXTRACTION Relevant original research, review articles, and guidelines were assessed for the management of elderly patients after TAVR. References from the above literature were also evaluated. Articles were selected for inclusion based on relevance to the topic, detailed methods, and complete results. DATA SYNTHESIS Aortic valve stenosis is common in the geriatric population. While patients were historically treated with surgical aortic valve replacement (AVR), more patients are now undergoing TAVR. This article reviews the current literature regarding outcomes and pharmacotherapy between surgical and TAVR in the elderly population. CONCLUSION Appropriate management of pharmacotherapy after surgical or TAVR can help improve outcomes in elderly patients, and pharmacists can provide guidance regarding evidence-based therapy.