Consequences of Discontinuing Rivaroxaban in Patients with Atrial Fibrillation

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1 A summary of current literature of interest to pharmacists. March 2013 Alan Hopefl, Pharm.D., Amerinet Clinical Manager Consequences of Discontinuing Rivaroxaban in Patients with Atrial Fibrillation Patients with atrial fibrillation are at an increased risk of stroke or systemic embolism, which can be reduced by anticoagulation. The Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study showed that treatment with rivaroxaban (Xarelto ) was not inferior to warfarin for the prevention of thromboembolic events. Although the Food and Drug Administration approved Xarelto for the prevention of stroke, there was enough concern about an increased risk of thromboembolic events after discontinuation to merit a boxed warning. This reanalysis of the ROCKET AF study was done to evaluate patients who had a temporary interruption or an early permanent discontinuation of study drug, and the consequences of transitioning patients to open-label therapy at the end of the study. In the ROCKET AF study patients with atrial fibrillation at high-risk for stroke were randomized to receive rivaroxaban 20 mg (15 mg with a creatinine clearance of 39 to 49 ml/min) once daily or warfarin with the dose adjusted to an international normalized ratio of 2.0 to 3.0. This analysis looked at three clinical situations during the ROCKET AF study. The first was patients with temporary interruptions of anticoagulant therapy, defined as any interruption of more than three days. These temporary interruption patients were evaluated for clinical events that occurred from 3 days after study drug interruption to three days after resumption of study drug. The second was patients with early permanent study drug discontinuation who were analyzed for clinical events from 3 to 30 days after discontinuation. The third was patients who completed the study, and who underwent blinded transition to open-label therapy with warfarin. These patients were also followed up for events from 3 to 30 days after the end of the study. To evaluate the effect of interruption of discontinuation of therapy, this post hoc analysis was conducted in all ROCKET AF patients who received one dose of study drug and were followed up for events after temporary interruptions of three days or more, permanent discontinuations, and after the end-of-study transition. There were 14,143 patients who took at least one dose of study drug and were eligible for the analysis. During the 590 days of median treatment exposure, 8245 temporary interruptions occurred, 3734 in the rivaroxaban group and 4511 in the warfarin group. Early permanent discontinuations occurred in 4895 patients, 2470 in the rivaroxaban group and 2425 in the warfarin group. Completion of the study without a primary end point event, death, or early permanent discontinuation occurred in 9239 patients. The most common reasons for early permanent study drug discontinuation 1 included adverse events (39%), both nonbleeding and bleeding. Additionally, ROCKET AF investigators were instructed to stop study drug permanently when a primary end point was suspected, which occurred in 12.9% of discontinuations. A substantial number of discontinuations occurred when patients withdrew consent (27.4%, n=1343) or had study drug stopped based on investigator decision (7.4%). The most common reasons for temporary interruption were surgical or invasive procedures (38.2%) and adverse events (40.2%), both bleeding and nonbleeding. The median duration of all temporary interruptions was six days. A vitamin K antagonist was used in patients undergoing an early permanent discontinuation in 44.3% of rivaroxaban-treated patients and in 43.1% of warfarin-treated patients. Stroke and non-cns embolism occurred at similar rates after temporary interruptions (6.20 vs. 5.05/100 patient-years for rivaroxaban-treated and warfarin treated, respectively, hazard ratio (HR) = 1.28 and after early permanent discontinuation, vs /patient years, respectively, HR=1.10. When stroke or non- CNS embolism or any temporary interruption or permanent discontinuation of study drug was evaluated in aggregate up to study discontinuation, the rates were also similar between rivaroxabanand warfarin-treated patients. Significantly more strokes occurred in rivaroxaban-treated patients (n=22) compared with warfarin-treated patients (n=6) after the end-of-study transition from blinded study drug to open-label warfarin (6.42 vs. 1.73/100 patient years, HR=3.74, [P=0.0044]). When all discontinuation and interruptions before study end were added to events after the end-of-study transition, there were significantly more primary events with rivaroxaban (n=73) compared with warfarin (n=50), HR=1.50, [P=0.026]. After the end of the study, there were significantly more thrombotic events, which included strokes, non CNS embolism, MI, and vascular death, with rivaroxaban (n=31) compared with warfarin (n=14) HR=2.24, [P=0.012]. The rates of major bleeding were similar after temporary interruptions 16.66/100 patient-years for rivaroxaban versus 17.20/100 patient-years for warfarin, HR=1.02 and after early permanent discontinuation, HR=0.67. Significantly more major bleeding events were observed after the end of the study during the transition period in rivaroxaban-treated patients compared with warfarin-treated patients, 7.29/100 patientyears vs. 2.01/100 patient-years, respectively, HR=3.62, [P<0.0026]. The most important finding of this analysis is that there were no significant differences between rivaroxaban and warfarin in the rates of stroke or non-cns embolism after temporary interruption or early permanent discontinuation, when both blinded therapies were stopped. After the end of the study and after mandatory withdrawal of blinded study drug, when patients treated with rivaroxaban frequently were transitioned to open-label warfarin and patients treated with warfarin were continued on warfarin, there were

2 significantly more strokes and non-cns embolism events in patients who had received rivaroxaban compared with those who had received warfarin. Also, when all thrombotic events that included stroke, non-cns embolism, MI, and vascular death were evaluated for interruptions and discontinuation both during and after the study, there was no significant difference between rivaroxaban and warfarin. This study underscores the importance of therapeutic anticoagulation coverage during transitioning patients from rivaroxaban to a vitamin K antagonist. Patel M, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation. J Am Coll Cardiol 2013;61: Rivaroxaban for Thromboprophyaxis in Medical Patients Patients with active cancer, stroke, myocardial infarction, or acute exacerbations of other medical conditions are at increased risk for venous thromboembolism. Prolonged immobilization and risk factors such as age greater than 75 years, chronic heart failure, history of venous thromboembolism (VTE), and obesity can increase this risk. Clinical trials have shown the benefits of administering anticoagulation to these patients for up to 14 days. Therefore, clinical guidelines recommend the use of unfractionated heparin, low-molecular weight heparin, or fondaparinux for these patients. There is some evidence that the risk of VTE persists after hospital discharge, but there are no studies that support the use of extended thromboprophylaxis. The Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban with Enoxaprin (MAGELLAN) study was designed to assess the efficacy and safety of rivaroxaban administered for 35 days, compared with enoxaparin for 10 days followed by placebo in acutely ill medical patients. Patients were eligible for the study if they were 40 years of age or older, had been hospitalized for a specified medical illness for less than 72 hours before randomization, and had reduced mobility. Eligible patients were randomly assigned to receive subcutaneous enoxaparin 40 mg once daily for 10 days and oral placebo once daily for 35 days or to receive subcutaneous placebo for 10 days and oral rivaroxaban for 35 days. Ultrasonography was performed in all patients to detect asymptomatic deep-vein thrombosis at day 10 and day 35. During the follow-up period, clinically suspected cases of deep-vein thrombosis or suspected pulmonary embolus were evaluated with routine diagnostic tests. The primary study outcome was a composite of asymptomatic deep-vein thrombosis, symptomatic proximal or distal deep-vein thrombosis, symptomatic nonfatal pulmonary embolus, or death related to VTE from day 1 to day 10. The second outcome was the same composite outcome from day 1 to day 35. The principal safety outcome was clinically relevant bleeding, which was a composite of major bleeding or clinically relevant nonmajor bleeding events observed no later than two days after administration of the last dose of study medication. There were a total of 8101 patients with well balanced risk factors who underwent randomization and were included in the study. The 2 Amerinet Clinical News median duration of hospitalization in both groups was 11 days. In the day 10 analysis,2.7% of patients in the rivaroxaban group and 2.7% of patients in the enoxaparin group had a primary outcome event, with rivaroxaban meeting the prespecified criterion for noninferiority, [P=0.003 for non-inferiority]. In the 35 day analysis, 4.4% of the patients receiving extended rivaroxaban, compared with 5.7% of those in the enoxaparin/placebo group had a primary outcome event and the extended administration of rivaroxaban met the conventional criterion for superiority, [P=0.02]. The primary efficacy outcome events between day 11 and day 35 occurred in 2.5% of the rivaroxaban group and in 3.8% of the enoxaparin/placebo group, [P=0.004]. Between day 1 and day 10, an episode of clinically relevant bleeding occurred in 2.8% of patients receiving rivaroxaban compared with 1.2% of patients receiving enoxaparin, [P<0.001]. Between day 1 and day 35, an episode of clinically relevant bleeding occurred in 4.1% of the group that received extended-duration rivaroxaban compared with 1.7% of patients who received enoxaparin/placebo, [P< 0.001]. Fatal bleeding occurred in seven patients that received extended-duration rivaroxaban and in one patient who received enoxaparin. The seven fatal bleeding events involved intracranial bleeding in two patients, and pulmonary bleeding in three patients. This study showed that the standard 10 day duration of therapy in acutely ill medical patients treated with rivaroxaban was non-inferior to enoxaparin. It also showed that rivaroxaban administered for an extended duration was superior to enoxaparin administered for 10 days for the prevention of thromboembolic events. However, the rate of clinically relevant bleeding was significantly higher in the rivaroxaban group than the enoxaparin group. The incidence of major bleeding events was also significantly higher in the rivaroxaban group than in the enoxaparin group. The majority of bleeding events in both groups led to a fall in hemoglobin level of at least 2 g/dl or to the transfusion of at least 2 units of blood. The study also did an analysis of net clinical benefit or harm for each drug regimen, which did not show a benefit for rivaroxaban at either day 10 or day 35. While there may be some benefit for extended thromboprophylaxis in medical patients, this appears to be associated with an increased risk of bleeding. Cohen AT, Spiro TE, Bueller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013;368: Usefulness of Daptomycin for Patients with Staphylococcus aureus Bacteremia Optimal management of methicillin-resistant Staphylococcus aureus (MRSA) infections is a common problem in most hospitals, with bacteremia and infective endocarditis having special concerns. Vancomycin has been the preferred agent for the treatment of MRSA infections, but outcomes have become suboptimal, particularly when the minimum inhibitory concentration (MIC) is greater than 1 µg/ml. One alternative therapy, daptomycin, has been shown to be noninferior to standard vancomycin in the treatment of S. aureus bacteremia and endocarditis. However, its optimal place in therapy has not been definitively established. In 2007, the Detroit Medical Center convened a multidisciplinary task force to work with

3 Amerinet Clinical News the antimicrobial stewardship team to improve the management of patients with MRSA bacteremia. This resulted in the development of a therapeutic pathway for the management of MRSA bacteremia. The objective of this quasi-experimental study was to analyze the impact of the pathway on clinical response and resource utilization. Phase 1 of the study was a retrospective baseline period of 24 months beginning in November Phase 2 of the study was a 24 month period beginning in January 2008 after implementation of the MRSA treatment guidelines. Both study phases included patients with MRSA bacteremia susceptible to vancomycin. Phase 1 was limited to patients who had an initial blood MRSA isolate with a vancomycin MIC greater than 1µg/ml by the Etest method and had received vancomycin for at least 48 hours. In phase 2 patients with confirmed or suspected MRSA bacteremia were started on vancomycin targeting trough levels of 15 to 20 µg/ml. Once susceptibility results were available, those with a vancomycin MIC of greater than 1 µg/ml had their therapy changed to daptomycin 6 mg/kg/day, based on total body weight. In phase 2, the vancomycin MICs were done using the Microscan method. During implementation of the MRSA bacteremia pathway daptomycin use was restricted to approval by infectious diseases physicians or pharmacists, with pharmacists from the Antimicrobial Stewardship Service closely monitoring use of the drug. Data was captured from all patients from the time of first positive S. aureus blood culture through the end of inpatient antimicrobial therapy. The information included patient demographics, severity of illness utilizing the APACHE II scoring system, site of infection, S. aureus cultures and susceptibilities, treatment outcomes, and adverse events. Treatment success was defined as the resolution or improvement in baseline signs and symptoms of infection, absence of new signs and symptoms of infection while receiving therapy, and eradication of the organism from the bloodstream at the end of at least 7 days of primary therapy. During the study period, 170 patients met the inclusion criteria, 70 patients in phase 1 and 100 patients in phase 2. The median initial vancomycin trough concentration in phase 1 was 11.2 µg/ml versus 15.2 µg/ml in phase 2. The median dose of daptomycin administered in phase 2 was 7.5 mg/kg/day with a range of 6 to 10 mg/kg/day. In phase 2 of the study approximately 78.2% of S. aureus isolates had a daptomycin MIC of 0.5 µg/ml or less and five patients had MIC exhibiting elevated daptomycin MICs of 4µg/ml. These five patients all failed daptomycin therapy and were switched to an alternative agent. The percentage of patients achieving clinical success in phase 2 was 75% versus 41.4% in phase 1, [P<0.001]. Patients in phase 2 compared with those in phase 1 had 2-day shorter total hospital length of stay (14 versus 16 days, [P=0.04]) and a 4-day reduction in duration of inpatient therapy (9 versus 13 days, [P=0.001]). Nine of the patients in phase 1 experienced nephrotoxicity, and no patients in phase 2 exhibited nephrotoxicity. Two patients in phase 2 experienced an asymptomatic increase in creatine kinase levels. The median total cost associated with hospitalization was similar in patients in phase 1 versus phase 2, $18,385 versus $19,755, respectively, with only the pharmacy costs being significantly higher in phase 2. Because many new anti-infective agents are brought to market at an increased drug acquisition cost versus their comparators, these 3 agents are often restricted by requirements for prior approval or for specific indications. However, some of these novel agents can introduce the possibility of improvements in patient care, such as reductions in clinical failure or length of stay as was seen in this study. Overall, this study showed that an early switch to daptomycin in patients with S. aureus bacteremia and vancomycin MICs > 1 µg/ml led to significantly higher clinical success rates with similar total hospital costs. Kullar R, Davis SL, Kaye KS, et al. Implementation of an antimicrobial stewardship pathway with daptomycin for optimal treatment of methicillin-resistant Staphylococcus aureus bacteremia. Pharmacotherapy 2013;33:3-10. Dosing and Clinical Outcomes from Converting from Insulin Glargine to Insulin Detemir To achieve tight glycemic control most patients with type 1 or type 2 diabetes require a long-acting insulin. There are two long-acting insulins currently available, insulin glargine (Lantis ) and insulin detemir (Levemir ). However, while both of these insulins have long durations of action, there are some pharmacokinetic differences between. Insulin detemir has a dose-dependent onset and duration of action. Unlike insulin glargine, insulin detemir has neutral ph and does not precipitate on injection. It depends on a strong self-association between insulin molecules and reversible albumin binding to prolong its half-life. The manufacturer of insulin detemir suggests using a unit-for-unit dose conversion when switching from insulin glargine to insulin detemir. However, studies do not always show that this is appropriate. The objective of this retrospective observational study was to evaluate the dose and frequency when converting patients with diabetes from insulin glargine to insulin detemir. On May 1, 2006, Iowa Medicaid switched its preferred long-acting insulin from insulin glargine to insulin detemir. This required the majority of Medicare patients receiving insulin glargine as their basal insulin to convert to insulin detemir. Between January 2006 and March 2007, 31 patients at a large academic medical center underwent conversion from insulin glargine to insulin detemir and are the subjects of this report. Electronic medical records were used to identify patients and data was collected during the 3 months before and 12 months after insulin conversion. The primary outcome measures were mean basal insulin doses in both units/day and units/kg/day on the index date (the date of conversion) and at 12 months. In addition, frequency of basal insulin administration was recorded. There were 31 patients, 10 with type 1 and 21 with type 2 diabetes included in the analysis. The patients generally had poorly controlled diabetes, with a mean baseline HbA1c level of 9.6%. Seven patients discontinued insulin detemir before completing the 12 months of therapy. Four of these patients discontinued insulin detemir as a result of lack of improvement in or worsening of blood glucose levels. Of the other three patients, one had an allergic reaction to insulin detemir, one was stared on an insulin pump, and one discontinued insulin after developing hyperkalemia. The majority of patients were converted from insulin glargine to insulin detemir on a

4 unit-for-unit basis. Of the eight patients who were not converted on a unit-for-unit basis, five were placed on a higher dose of insulin detemir, and three had a decrease in insulin dose on conversion. Twelve months after switching, no significant change in mean insulin detemir dose was noted compared with baseline insulin glargine dose in patients with type 1 diabetes (31.1 vs units/day, 0.41 vs units/kg/day). Conversely, patients with type 2 diabetes required a higher mean insulin detemir dose compared with baseline insulin glargine (74.2 vs units/day, [P=0.002]; 0.68 vs unit/kg/day, [P=0.001]). Patients switched to insulin detemir required steadily increasing doses over the course of the study. Fifteen patients were administering insulin detemir twice daily at the end of the 12 month study, compared with four patients administering insulin glargine at baseline, 48% vs. 13%, [P=0.043]. Seven of the 15 patients who were taking twice daily basal insulin at the end of the study period were automatically converted from once-daily to twice daily administration on conversion to insulin detemir on the index date. With the conversion to insulin detemir, a lower proportion of patients achieved a goal HbA1c of less than 7% at the end of 12 months as recommended by the American Diabetes Association. In this study, treatment with insulin detemir required higher basal insulin doses compared with insulin glargine, with 33% higher doses observed in patients with type 2 diabetes 12 months after conversion. Most of the patients enrolled in this study had poorly controlled diabetes, but the higher doses of insulin detemir did not result in improved glycemic control. These results suggest that a unit-for-unit conversion from insulin glargine to insulin detemir, as suggested by the manufacturer of insulin detemir, may not be adequate. In addition, the need for twice daily administration of insulin detemir was found to be more frequent than with insulin glargine. This is likely to be due to the pharmacokinetic differences between insulin detemir and insulin glargine. Insulin glargine typically has a duration of action of 24 hours, whereas the duration of action of insulin detemir is dose dependent. Other studies also show inconsistency in support of the unit-for-unit conversion from insulin glargine to insulin detemir. This would make it difficult to provide blanket recommendations for the interconversion of these two long-acting insulins in a given patient. Bryant GA, McDanel DL, Horner KE, et al. Evaluation of dosing an clinical outcomes in patients undergoing conversion of insulin glargine to insulin detemir. Pharmacotherapy 2013;33: A Potential Alternative Drug to Linezolid Linezolid (Zyvox ) an oxazolidinone, is the only oral drug approved to complicated skin and skin structure infections (csssis) caused by methicillin-resistant Staphylococcus aureus (MRSA) infections. There have been sporadic outbreaks of linezolid-resistant strains of MRSA and enterococci. In addition, there are significant safety concerns with linezolid that have emerged since its approval. Tedizolid phosphate is a novel, oxazolidinone prodrug that is under development and is rapidly converted to microbiologically active tedizolid. Tedizolid interacts with the 23S portion of the bacterial ribosome to inhibit translation and is active against all clinically relevant gram-positive pathogens, including linezolid-resistant S. 4 Amerinet Clinical News aureus. Both tedizolid phosphate and linezolid can be administered orally or intravenously. The Efficacy and Safety of 6-day Oral Tedizolid in Acute Bacterial Skin and Skin Structure Infections vs 10-day Oral Linezolid Therapy (ESTABLISH-1) study was a randomized, double-blind, double dummy, multicenter noninferiority trial. The study was designed to examine the efficacy and safety of 200 mg of oral tedizolid phosphate administered once daily for 6 days compared to 600 mg of oral linezolid administered twice daily for 10 days in patients with acute bacterial skin and skin structure infections. Patients were eligible for the study is they were 18 years of age or older and had cellulitis/erysipelas, major cutaneous abscess, or wound infections surrounded by erythema with a minimum total lesion surface area of 75 cm 2, accompanied by at least one local and one regional or one systemic sign of infection, and a gram-positive pathogen suspected or documented. Patients were randomized to receive tedizolid phosphate 200 mg once daily for 6 days or linezolid 600 mg twice daily for 10 days, packaged in blister packs that contained active drug and placebo tablets. The primary efficacy outcome was early clinical response at 48 to 72 hours in the intention-to-treat (ITT) analysis set. Each patient was categorized as a treatment responder, nonresponder, or indeterminate. The response to treatment was assessed at the 48 to 72 hour visit after the first dose of study drug, at the end-of-treatment (day 11 relative to the first dose), and at the posttherapy evaluation, 7 to 14 days after the end-of-treatment. A total of 667 patients were randomized to receive study drug an comprised the ITT analysis set. Approximately 90% of patients who were randomized completed the trial. Patients in the two treatment groups had similar demographics, baseline characteristics and infection characteristics. Infection types occurred with similar frequency in both tedizolid and linezolid groups with cellulitis/erysipelas (40.7% vs. 41.5%), major cutaneous abscess (30.1% vs. 29.3%), and infected wound (29.2% vs. 29.3%). At least one pathogen was isolated from the primary infection site in approximately 63% of patients and most isolated pathogens were gram-positive aerobes (98.6%). The most common pathogen isolated from the primary ABSSI site was S. aureus (82.8%), with MRSA identified in 42.1% of infections in the tedizolid phosphate group and 43.1% of infections in the linezolid group. Tedizolid minimum inhibitory concentrations (MICs) ranged from to 0.5 µg/ml and from 1 to 4 µg/ml for linezolid. The primary efficacy outcome response at 48 to 72 hrs was 79.5% in the tedizolid versus 74.8% in the linezolid group, thereby meeting the non-inferiority criterion. Sustained clinical treatment response at the end-oftreatment (day 11) were similar in the tedizolid phosphate and linezolid groups, 69.3% vs. 71.9%, respectively. Outcomes for subgroups stratified by type of infection were similar, although treatment response rates at the early and EOT time points were lower for cellulitis/erysipelas than for all infections combined. Treatment-emergent adverse events occurred in 40.8% of patients in the tedizolid phosphate group and 43.3% of the linezolid group. The most common adverse events were gastrointestinal wit 43.3% of patients in the linezolid group affected versus 40.8% in the tedizolid phosphate group. Commonly reported treatment-emergent adverse event were nausea (8.5% of the tedizolid group and 13.4%

5 Amerinet Clinical News of the linezolid group), headache (6.3% and 5.1%, respectively), and diarrhea (4.5% and 5.4%, respectively). Treatment with 200 mg of oral tedizolid phosphate once daily for 6 days was statistically non-inferior in efficacy to 600 mg of oral linezolid twice daily for 10 days at both early and late time points and was generally well tolerated. Prokocimer P, De Anda C, Fang E, et al. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections, The ESTABLISH-1 randomized trial. JAMA 2013;309: About Amerinet As a leading national healthcare solutions organization, Amerinet collaborates with acute and non-acute care providers to create and deliver unique solutions through performance improvement resources, guidance and ongoing support. With better product standardization and utilization, new financial tools beyond contracting and alliances that help lower costs, raise revenue and champion quality, Amerinet enriches healthcare delivery for its members and the communities they serve. To learn more about how Amerinet can help you successfully navigate the future of healthcare reform, visit Amerinet, Inc. Two CityPlace Drive, Suite 400 St. Louis, MO