American Journal of Health-System Pharmacy

Traynor,, Kate

doi: 10.2146/news180048pmid: 30045845

A federal law that was enacted in May creates a new mechanism for U.S. patients to obtain investigational drugs, but the extent to which people will be able to use this option is unclear. The right-to-try legislation—officially known as the Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017—was signed into law on May 30. The act is named for 3 Americans with amyotrophic lateral sclerosis (ALS) and 1 with Duchenne muscular dystrophy who reportedly lacked access to investigational drugs through FDA’s expanded access programs. The new law amends the Federal Food, Drug, and Cosmetic Act to permit patients to obtain investigational drugs outside of clinical trials or expanded access programs. The law also shields physicians, dispensers, and drug companies from liability related to both the use of the drugs and the refusal to provide them. To be eligible, patients must have a diagnosis of a life-threatening disease or condition and must have exhausted FDA-approved treatment options. Patients must also be unable to participate in a clinical trial involving the investigational drug. The medication must have cleared Phase I development and be under FDA review for marketing approval or under investigation in a clinical trial that is intended to support FDA approval or licensure. “I think this legislation is something that sounded good but really isn’t going to do anything, unfortunately,” said Marjorie Phillips, clinical research pharmacist at Augusta University Health in Georgia. Georgia passed a right-to-try law in 2016, with a July 2017 effective date. Phillips said she is unaware of any attempt by her organization’s physicians or patients to obtain investigational drugs under the state law. An important obstacle to the success of the right-to-try law, she said, is that the drug companies that sponsor FDA-required investigational new drug (IND) applications have little incentive to make those drugs available to patients through the new pathway. “I can’t see them being willing to do something that would take resources away from trying to get a potentially beneficial product to market,” Phillips said. Chaim Lebovits, president and chief executive officer of Israel-headquartered BrainStorm Cell Therapeutics, acknowledged that concern during a June 7 conference call about right-to-try access for the company’s late-stage investigational cell therapy product for the treatment of ALS. “Any company has ample reasons not to want to do anything outside the trial,” Lebovits said. “My fiduciary obligation is to make sure that the Phase III trial is not derailed by anything.” View largeDownload slide View largeDownload slide Lebovits lent the company’s apparent support to the right-to-try law by appearing at the White House signing ceremony for the legislation. Nevertheless, BrainStorm on June 26 announced that it would not make its ALS therapy available under the right-to-try law. The announcement described the expense of preparing the investigational product, which is derived from autologous bone marrow stem cells, as the primary barrier to using the new access pathway. According to the company’s website, BrainStorm does not offer its investigational ALS therapy through FDA’s expanded access programs. FDA Commissioner Scott Gottlieb said during testimony before a congressional committee last October that the agency receives over 1,000 applications annually for expanded access to investigational drugs and approves 99% of them. He said emergency access is usually authorized immediately over the phone, and nonemergency access is approved within a few days. FDA’s individual patient expanded-access IND application process is the usual method for a treating physician to obtain an investigational drug for a patient outside of a clinical trial. The process requires the physician to submit a 2-page form to FDA that provides clinical information and describes the treatment plan, including the dose, route and schedule of administration, planned duration of treatment, monitoring procedures, and treatment modifications to be made in the event of toxicity. Applicants must also confirm that the manufacturer has authorized the use of the medication. Treating physicians must obtain informed consent from the patient and approval from an overseeing institutional review board (IRB), which is charged with protecting the welfare and rights of clinical research participants. Gottlieb noted during his testimony that FDA makes meaningful safety-related changes in the proposed treatment plan for about 10% of expanded access requests. Often, he said, the changes are based on confidential information from the NDA sponsor that is unavailable to the treating physician. The right-to-try process bypasses both FDA’s safety review and IRB involvement. Phillips, who chairs her hospital’s IRB, said the new law may be incompatible with established procedures at medical facilities. “For example, our pharmacy and therapeutics committee has policies related to procuring medications,” she said. “They have to be FDA approved unless they’re accessed through an IRB-approved protocol under an FDA IND. So, we would actually have to change our policies and procedures to be able to take drugs through this [right-to-try] pathway.” When considering such policy changes, she said, “I think we’d have a lot of concerns about whether it’s necessary or what value it adds.” Phillips said “a fair number” of her organization’s patients have obtained investigational drugs through individual-patient IND protocols. Often, she said, the treating physicians have experience using those medications in clinical trials and are able to determine whether an investigational therapy is the patient’s best option. She also praised the efforts of FDA staff members who handle inquiries about expanded access. “They’ve really bent over backwards . . . to get the applications approved quickly,” Phillips said. “And there’s been really, really good cooperation between the physician, the FDA, and the manufacturer to make this happen when it needs to happen for a patient.” Detailed information about expanded access programs, which are not supplanted by the right-to-try law, is available online from the nonprofit Reagan–Udall Foundation for the Food and Drug Administration. A key question about the right-to-try law—who will pay for medications obtained through the new access pathway—remains largely unanswered. The federal regulations that describe the process for IND sponsors to charge patients for investigational drugs require an IRB to authorize the proposed use of the drug and FDA to approve a plan to charge for the drug. Those regulations and a resultant 2016 guidance document from FDA refer specifically to the agency’s expanded access programs and don’t appear to fit the less regulated pathway created by the right-to-try law. A spokesman from FDA’s trade press office stated in an email that an internal group “will be addressing these and other questions from patients, manufacturers and providers” as the agency evaluates how to implement and support the right-to-try law. He stated that the agency will consider whether new guidance documents or other recommendations are necessary. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

doi: 10.1093/ajhp/75.15.1086pmid: N/A

Albumin-kjda solution for injection (Albuminex, Bio Products Laboratories USA): The plasma-derived product is indicated for the treatment of hypovolemia, hypoalbuminemia, acute nephrosis, and acute respiratory distress syndrome and prevention of central volume depletion after paracentesis due to cirrhotic ascites in adults and children. The product is also indicated for use as part of the priming fluids for cardiopulmonary bypass procedures. Binimetinib tablets (Mektovi, Array BioPharma): The kinase inhibitor is indicated for use in combination with encorafenib for the treatment of patients with unresectable or metastatic melanoma involving the BRAF V600E or V600K mutation. Desmopressin acetate sublingual tablets (Nocdurna, Ferring): The vasopressin analog is indicated for the treatment of nocturia due to nocturnal polyuria in adults who awaken at least twice per night to void. The drug is subject to FDA Medication Guide requirements. Doxycycline hyclate tablets (Lymepak, Chartwell RX): The tetracycline, packaged in a carton of blister cards containing the full 21-day regimen, is indicated for the treatment of early Lyme disease due to Borrelia burgdorferi in adults and children 8 years of age or older who weigh at least 45 kg. Encorafenib capsules (Braftovi, Array BioPharma): The kinase inhibitor is indicated for use in combination with binimetinib for the treatment of patients with unresectable or metastatic melanoma involving the BRAF V600E or V600K mutation. Moxidectin tablets (no brand name, Medicines Development for Global Health): The anthelmintic is indicated for the treatment of onchocerciasis due to Onchocerca volvulus in patients 12 years of age or older. Once the 500-tablet bottle is opened, the full contents should be used within 24 hours and the unused tablets discarded. Plazomicin injection (Zemdri, Achaogen): The aminoglycoside is indicated for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Enterobacter cloacae in patients 18 years of age or older. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Thompson, Cheryl, A.

doi: 10.2146/news180049pmid: 30045846

When Timothy J. Atkinson, a clinical pharmacy specialist in pain management, has a first appointment with a veteran who has been on high-dosage opioid therapy for a long time, he shows his patient a laminated 3-by-5 card with 2 pie charts. At the top of the card is a single-color chart and a single label: “Pain Medications.” Underneath is a multicolored chart with several pie slices representing a variety of pain control alternatives—physical rehabilitation, pain-relieving procedures, psychology, transcutaneous electrical nerve stimulation, and acupuncture—in addition to pain medications. Atkinson called this “simple visual” the starting point in educating his patients—all of whom have been referred to him by an anesthesiologist or nurse practitioner at the Veterans Affairs (VA) Tennessee Valley Healthcare System’s pain management clinic in Murfreesboro. Emphasizing the message “It’s not your fault” during clinic visits, Atkinson said he explains to new patients that current pain management options do not consist entirely of pain medications. “When patients understand that they’re not being singled out [for their opioid use], that this is a national initiative, and that this is the direction that we’re going—that we want to extend these other services, we want to show them another way—then they tend not to take it personally and they’re willing to work with you in most cases,” he said. VA’s Opioid Safety Initiative started in 2013. It seeks to help ensure safe and effective prescribing and use of opioid pain medications. Two of the initiative’s goals are to review treatment plans for patients receiving high-dosage opioid therapy and offer complementary and alternative medicine modalities for chronic pain. According to VA data, opioids were received by 1 in every 4 veterans who obtained prescription medication in 2012 from the pharmacy at the Nashville VA Medical Center, part of the Tennessee Valley Healthcare System. The rate is less than 1 in every 7 veterans thus far this year. Adjusting patients’ beliefs can be difficult, Atkinson readily conceded. People who become dependent on opioids, he said, “do tend to be pretty focused on them.” Atkinson emphasized the need to educate patients about current pain management techniques and schedule sufficient time—an hour, for example—for the initial conversation. “They’re not used to providers taking the time to explain why we’re doing what we’re doing and what we want for them and [that] we’re doing this because we care,” he said of patients prescribed long-term, high-dosage opioid therapy to treat pain. Those patients need to be told that other pain management modalities are available and can be tried, Atkinson said. “But you still can’t throw it all at them at once and ask them to do 5 things when they’re used to doing just 1”—taking an opioid. Enactment of the Comprehensive Addiction and Recovery Act of 2016 (CARA) expanded the Opioid Safety Initiative. CARA requires every VA medical facility to have a pain management team of healthcare professionals to coordinate and oversee pain management therapy for patients with acute or chronic pain not related to cancer. Behavioral and rehabilitation medicine providers must be on the team, according to a VA memorandum. Nicole Elharar, a clinical pharmacy specialist in posttraumatic stress disorder (PTSD) and substance abuse at West Palm Beach VA Medical Center, said her south Florida facility in March started operating a clinic that treats veterans who have both pain and substance abuse disorder. Elharar called the new clinic a “CARA clinic” and described its work as an interprofessional effort to get veterans with pain who have been abusing opioids of any type to instead use nonopioid therapies. She said the clinic has 2 clinical pharmacy specialists in mental health (including herself), 2 clinical pharmacy specialists in pain, an addiction psychiatrist, and a physician pain specialist. According to a poster abstract at the ASHP 2017 Federal Forum during the Midyear Clinical Meeting in December, this clinic is a consultation service managed by some of the members of the medical center’s pain management team. “I definitely think this CARA clinic [approach] has been a huge success and should . . . be implemented nationwide,” Elahara said in mid-June. Managing these patients from just the perspective of substance use disorder or pain could let the other condition go untreated, perhaps resulting in the worsening of depression or PTSD symptoms, she said. The clinic’s healthcare providers meet for an hour before seeing patients so that everyone has the opportunity to say what they believe is needed most by each patient on the schedule, Elharar said. Some patients may benefit most from a substance abuse treatment approach involving the use of buprenorphine–naloxone, which Elharar is authorized to initiate, modify, and discontinue under the superversion of a psychiatrist. Some patients express a desire to try acupuncture. Some patients want physical therapy. Some prefer a pain-relieving procedure. During each appointment, the team invites the patient’s input, she said. Some patients with opioid use disorder, Elharar said, have turned out to be “drug seeking,” however. “We always take what the veteran says, and we weigh our options. We look at the risk versus benefit, and from there we’re able to make a decision.” She said she spends half a day at the CARA clinic, which operates out of 2 adjacent offices. CARA clinic patients come in every other week. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

doi: 10.1093/ajhp/75.15.1087pmid: N/A

Christene M. Jolowsky, M.S., FASHP, has been appointed Pharmacy Director, Hennepin County Medical Center, Minneapolis, Minnesota; previously she was executive director of applied and experiential education for the University of Minnesota College of Pharmacy. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Traynor,, Kate

doi: 10.2146/news180050pmid: 30045848

FDA on June 25 announced the agency’s first-ever approval of a drug product purified from the Cannabis sativa, or marijuana, plant. The drug, cannabidiol oral solution, is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age or older. Both syndromes are rare, severe forms of epilepsy that usually first manifest in young children. The oral solution is the first medication to earn an FDA-approved indication for the treatment of Dravet syndrome, according to the agency. The product will be marketed as Epidiolex by Greenwich Biosciences Inc., the U.S. subsidiary of United Kingdom–based GW Pharmaceuticals plc. The companies announced that they expect Epidiolex to be available in the United States by this fall, pending a scheduling decision by the Drug Enforcement Administration (DEA). Epidiolex contains a crystalline form of cannabidiol purified from C. sativa extract, according to briefing materials prepared for an FDA advisory committee meeting in April. GW Pharmaceuticals stated in its 2017 annual report that the product is manufactured entirely in the United Kingdom from plants grown for that purpose. Cannabidiol is among many compounds produced by C. sativa and is considered to lack the psychoactive properties of tetrahydrocannabinol (THC), which the plant also produces. C. sativa strains that have been selected for the production of cannabidiol and contain little THC are sometimes referred to as hemp. FDA Commissioner Scott Gottlieb said during a June 25 media briefing that unapproved drug products containing cannabidiol are illegally marketed in the United States. He said FDA has taken enforcement action against companies that make unproven medical claims about these products, and the agency will continue to do so. FDA’s approval of Epidiolex was based on data from 3 placebo-controlled studies involving a combined total of 396 patients with Lennox-Gastaut syndrome and 120 with Dravet syndrome. According to the agency, patients whose treatment regimen included the cannabidiol product instead of a placebo had less frequent seizures. According to the labeling for Epidiolex, elevations in serum transaminase levels were reported during clinical trials and were most common in patients concomitantly treated with valproate. The labeling recommends assessment of serum transaminase and bilirubin levels at baseline and 1, 3, and 6 months after initiation of therapy with the cannabidiol product. Interruption or discontinuation of therapy may be necessary on the basis of liver function test results. In clinical trials, the most frequently reported adverse events in patients treated with Epidiolex were somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder and poor-quality sleep; and infections. The product’s labeling includes an FDA-required Medication Guide to warn patients who use the drug about the risk of liver injury and somnolence. The Medication Guide also states that cannabidiol, like all antiepileptic drugs, is associated with a small increase in the risk of suicidal thoughts and behaviors. The recommended starting dosage of Epidiolex is 2.5 mg per kilogram of body weight twice daily, for a total of 5 mg/kg/day. After 1 week, the dosage can be increased to a maintenance dosage of 5 mg/kg twice daily. The maximum recommended maintenance dosage is 10 mg/kg twice daily. Epidiolex will be supplied in amber glass bottles containing 100 mL of a 100-mg/mL solution of purified cannabidiol. Each bottle will be packaged in a carton containing a pair of 5-mL calibrated oral dosing syringes and a bottle adapter. The labeling states that the dispensing pharmacy will provide 1-mL calibrated oral dosing syringes when doses less than 1 mL are required. The product should be stored in the original container at room temperature and not refrigerated or frozen. Once the bottle is opened, the contents should be used within 12 weeks and any remaining solution discarded. DEA currently classifies most C. sativa components, including cannabidiol, as Schedule I controlled substances, which include drugs and chemicals with no currently accepted medical use and a high potential for abuse. Douglas Throckmorton, deputy director of regulatory programs for FDA’s Center for Drug Evaluation and Research, said during the June media briefing that DEA’s rescheduling process for Epidiolex is underway. He also confirmed that because the cannabidiol product now has an accepted medical use, it will not be assigned to Schedule I. GW Pharmaceuticals, in its 2017 annual report, predicted that DEA would list the finished dosage form of Epidiolex in Schedule IV or V on the basis of clinical data describing the drug’s low potential for abuse. The company noted that if Epidiolex is listed as a Schedule II controlled substance, importation of the product from its U.K. manufacturing site would be prohibited “unless the DEA determines that domestic supplies are inadequate or there is inadequate domestic competition among domestic manufacturers for the substance.” Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

doi: 10.1093/ajhp/75.15.1089pmid: N/A

Rafael Saenz, Pharm.D., M.S., FASHP, in June was elected chairman of the Virginia Board of Pharmacy. Saenz, who started serving on the pharmacy board in 2015, is pharmacy administrator for the University of Virginia Health System, based in Charlottesville. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Jew, Rita, K.

doi: 10.2146/ajhp180373pmid: 30045849

guidelines, medication-use system, pediatric pharmacy, safeguard While we generally refer to pediatrics as 1 specialty, this specialty encompasses a diverse population, ranging from very-low-birth-weight premature neonates weighing as little as 0.4 kg, to infants and children, to adolescents weighing over 100 kg. Each subgroup of pediatric patients may exhibit variations in dose response due to pharmacokinetic and pharmacodynamic variations. Numerous federal regulations since the Food and Drug Administration Modernization Act in 1997 have fueled significant progress in the numbers and timeliness of drug studies in pediatric populations. Nonetheless, there remains a gap in published research on the pharmacokinetics, safety, and efficacy of medications use in the pediatric population. The lack of commercially available dosage forms, concentrations, and unit-dose packaging appropriate for pediatric patients often necessitates the use of extemporaneous preparations and patient-specific dose packaging. These manual activities are labor-intensive and time-consuming and often require complex calculations, thus making them error prone. These complexities present huge challenges when devising safe and effective medication-use systems and processes to serve this patient population. Thus, it is not surprising that medication errors are 3 times more likely to occur in pediatric patients than in adults, making pediatrics the most vulnerable patient population in a hospital or health system.1 The ASHP-PPAG Guidelines for Providing Pediatric Pharmacy Services in Hospitals and Health Systems published in this issue of AJHP are comprehensive guidelines addressing the needs of pediatric patients in a hospital or health system and are long overdue. The last set of pediatric pharmacy practice guidelines was published in 1991 and consisted of 3 pages of recommendations.2 Contrast that to the current 13-page guidelines, and one can appreciate the breadth and depth of these guidelines. The guidelines also reflect how far pediatric pharmacy practice has advanced over the past 27 years. While the guidelines encompass all aspects of pharmacy practice, a few items are worth highlighting. The guidelines specifically address qualifications of the director of pharmacy (DOP), underscoring the importance that “the director of pharmacy should understand the unique needs of pediatric patients and be knowledgeable about and have experience in pediatric hospital pharmacy practice.” While emphasis has always been placed on the qualifications and competencies of pediatric pharmacy staff, this is the first set of guidelines that put the same emphasis on the DOP. Since a DOP with pediatric experience may be difficult to find, a DOP who does not have experience in pediatric hospital pharmacy practice should complete the same initial competencies as pediatric pharmacists to ensure his or her comprehensive understanding of the unique needs of pediatric patients. Pediatric leadership staff in an adult hospital or a large health system should have the same qualifications and competencies as the DOP. This is especially important since the DOP is often the only advocate in a leadership position for pediatric patients in the entire hospital or health system. The guidelines also include important details of health information technology. Commercially available software (e.g., computerized prescriber order-entry system, infusion pumps) often are not developed with pediatric patients’ needs in mind. The expertise of a pediatric pharmacist is especially crucial during the software build and implementation process of these technologies. Due to the labor-intensive, error-prone manual manipulations necessary to provide appropriate medication dosages to pediatric patients, the importance of leveraging automation and technology whenever possible cannot be overemphasized. Finally, a focus in continuity of care is especially critical for pediatric patients due to the frequent need for extemporaneous formulations that require insurance authorization and accessibility to pharmacies that will provide these medications. The pediatric pharmacist should be the coordinator of transitions of care for this population. As eloquently stated in the guidelines, “The goal should be to provide all children with the same level of clinical expertise on a consistent basis.” Achieving this goal, however, can be especially challenging in a children’s hospital within a large health system or a pediatric ward in an adult hospital. These guidelines are even more valuable in these practice settings, where the needs of pediatric patients may sometimes be an afterthought. It is a privilege and huge responsibility to provide care to the pediatric population. Guidelines such as these, as well as PPAG’s guidelines for preventing medication errors in pediatrics3 and initiatives such as ASHP’s Standardize 4 Safety,4 should be the beacon when devising safe and effective medication-use systems and processes for pediatric patients. It is our professional duty to abide by these guidelines in order to safeguard the medication-use system to protect this most vulnerable patient population. Disclosures: The author has declared no potential conflicts of interest. 1 Kaushal R Bates DW Landrigan C et al. Medication errors and adverse drug events in pediatric inpatients . JAMA . 2001 ; 285 : 2114 – 20 . Google Scholar Crossref Search ADS PubMed 2 Pediatric Pharmacy Administrative Group Committee on Pediatric Pharmacy Practice . Pediatric pharmacy practice guidelines . Am J Hosp Pharm . 1991 ; 48 : 2475 – 7 . PubMed 3 Levine SR Cohen MR Blanchard NR et al. Guidelines for preventing medication errors in pediatrics . J Pediatr Pharmacol Ther . 2001 ; 6 : 427 – 43 . 4 American Society of Health-System Pharmacists . Standardize 4 Safety Initiative overview . www.ashp.org/Pharmacy-Practice/Standardize-4-Safety-Initiative/Initiative-Overview (assessed 2018 Jun 18). Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Hickman, Skip, R.

doi: 10.2146/ajhp180273pmid: N/A

acetaminophen, postoperative pain We wholeheartedly agree that there needs to be a continued emphasis on strategies to improve postoperative pain control while deemphasizing opioid use. There was not a standardized intraoperative analgesic nerve-block regimen used across the study. According to our standard of care, nerve blocks were allowed and used according to the preference of individual surgeons. However, we did track the administration of bupivacaine liposomal injection and found that it was given in 325 (67%) of 486 procedures. This agent was given with about equal frequency to patients receiving oral acetaminophen (68%) and i.v. acetaminophen (66%) (p = 0.72). Our institution does use a standardized regimen to treat documented postoperative nausea or vomiting, but that regimen does not include prophylactic dexamethasone. The regimen allows for ondansetron or promethazine to be administered as needed. Postoperative pain scores were collected by clinical nurses in accordance with our standard protocol. We acknowledge that assessor bias may be present in pain assessment by individual nurses. Our study relied on their assessments and did not allow for validation by trained research personnel. However, the clinical nurses were blinded to the study groups, and we believe that randomization and the involvement of multiple nurses in assessing pain minimized the likelihood that our median pain scores reflected a statistical anomaly created by the nurses who collected the data. The author has declared no potential conflicts of interest. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Kendall, Mark, C.

doi: 10.2146/ajhp180158pmid: 30045850

acetaminophen, acute pain, analgesic regimen, orthopedic surgery I read with great interest the recent report by Hickman et al.1 about oral versus i.v. acetaminophen. The authors performed a prospective randomized study of 486 patients undergoing orthopedic surgery and concluded that oral acetaminophen given preoperatively was equivalent to i.v. acetaminophen administered in the operating suite in controlling pain in the immediate postoperative period. The authors should be congratulated for studying an important topic (acute pain) in patients undergoing orthopedic surgery.2 The current emphasis on the need for nonopioid strategies to improve postoperative pain makes the topic very relevant in perioperative medicine.3,4 Nonetheless, clarifications are needed to confirm the authors’ findings. First, it is unclear if the authors had a standardized intraoperative analgesic regimen, as the presence of such a regimen can substantially alter the main outcomes. The use of intraoperative nerve blocks may also be a major confounding factor. Second, it is unclear if the authors have standardized the prophylaxis regimen for postoperative nausea and vomiting; dexamethasone used for this indication can decrease postoperative pain. Last, the authors did not clearly describe who collected the immediate postoperative data. The collection of pain scores by clinical nurses has been shown to be problematic in analgesic studies.5 Additional information on these points could further substantiate the findings of this important clinical study. The author has declared no potential conflicts of interest. The Letters column is a forum for rapid exchange of ideas among readers of AJHP. Liberal criteria are applied in the review of submissions to encourage contributions to this column. The Letters column includes the following types of contributions: (1) comments, addenda, and minor updates on previously published work, (2) alerts on potential problems in practice, (3) observations or comments on trends in drug use, (4) opinions on apparent trends or controversies in drug therapy or clinical research, (5) opinions on public health issues of interest to pharmacists in health systems, (6) comments on ASHP activities, and (7) human interest items about life as a pharmacist. Reports of adverse drug reactions must present a reasonably clear description of causality. Short papers on practice innovations and other original work are included in the Notes section rather than in Letters. Letters commenting on an AJHP article must be received within 3 months of the article’s publication. Letters should be submitted electronically through http://ajhp.msubmit.net. The following conditions must be adhered to: (1) the body of the letter must be no longer than 2 typewritten pages, (2) the use of references and tables should be minimized, and (3) the entire letter (including references, tables, and authors’ names) must be typed double- spaced. After acceptance of a letter, the authors are required to sign an exclusive publication statement and a copyright transferal form. All letters are subject to revision by the editors. 1 Hickman SR Mathieson KM Bradford LM et al. Randomized trial of oral versus intravenous acetaminophen for postoperative pain control . Am J Health-Syst Pharm . 2018 ; 75 : 367 – 75 . Google Scholar Crossref Search ADS PubMed 2 Lu J Chen G Zhou H et al. Effect of parecoxib sodium pretreatment combined with dexmedetomidine on early postoperative cognitive dysfunction in elderly patients after shoulder arthroscopy: a randomized double blinded controlled trial . J Clin Anesth . 2017 ; 41 : 30 – 4 . Google Scholar Crossref Search ADS PubMed 3 Zhang Z Xu H Zhang Y et al. Nonsteroidal anti-inflammatory drugs for postoperative pain control after lumbar spine surgery: a meta-analysis of randomized controlled trials . J Clin Anesth . 2017 ; 43 : 84 – 9 . Google Scholar Crossref Search ADS PubMed 4 Li XD Han C Yu WL . Is gabapentin effective and safe in open hysterectomy? A PRISMA compliant meta-analysis of randomized controlled trials . J Clin Anesth . 2017 ; 41 : 76 – 83 . Google Scholar Crossref Search ADS PubMed 5 McCarthy RJ De Oliveira GS . The trouble with using provider assessments for rating clinical performance: it’s a matter of bias . Anesth Analg . 2015 ; 120 : 714 – 6 . Google Scholar Crossref Search ADS PubMed Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Lekura,, Jona;Kalus, James, S.

doi: 10.2146/ajhp170785pmid: 29941506

Purpose The role of betrixaban in the prevention of venous thromboembolism (VTE) in acutely medically ill patients and its efficacy and safety profiles are reviewed. Summary Acutely medically ill patients have a high risk of developing VTE during hospitalization, and this risk continues into the postdischarge phase. Extended-duration betrixaban therapy has been evaluated in a large clinical trial (the APEX trial) and in a meta-analysis of pooled data on acutely medically ill patients. These studies have shown positive outcomes when betrixaban was compared with conventional-duration subcutaneous enoxaparin therapy for prevention of VTE in acutely medically ill patients. In parallel with these results, oral betrixaban therapy was found to be associated with a rate of major bleeding comparable to that associated with subcutaneous enoxaparin therapy; however, betrixaban use was associated with a higher cumulative rate of major and clinically relevant nonmajor bleeding. In the APEX trial, the primary endpoint was not met in 1 of the prespecified cohorts, but betrixaban appeared to confer benefit in another cohort and in the overall study population. Certain populations of patients, including the elderly, are at high risk for bleeding (mainly attributable to altered pharmacokinetics and polypharmacy); such patients are not appropriate candidates for extended-duration betrixaban therapy. Betrixaban can be a potential option for VTE prevention in medical patients; however, drug interaction potential and third-party coverage should be evaluated prior to prescribing. Conclusion Betrixaban is an oral option for VTE prevention in medical patients. acutely medically ill, anticoagulation, betrixaban, bleeding, direct-acting oral anticoagulant, venous thromboembolism KEY POINTS Betrixaban is the only oral factor Xa inhibitor approved by the Food and Drug Administration for thromboprophylaxis in acutely medically ill patients. When compared with conventional-duration subcutaneous enoxaparin therapy for prevention of venous thromboembolism in acutely medically ill patients, betrixaban provided positive outcomes and was associated with a rate of major bleeding comparable to that reported with enoxaparin use. Evidence on use of betrixaban in patients receiving potentially interacting drugs (especially P-glycoprotein inducers) or dual antiplatelet therapy and in transitions-of-care situations is lacking. Venous thromboembolism (VTE) is a serious and potentially life-threatening disease that, according to the Centers for Disease Control and Prevention, affects about 900,000 U.S. patients.1 Hospitalization for acute medical illness is an independent risk factor for development of VTE.2 Evidence suggests that VTE risk is highest during the first 19 days after hospital admission and therefore extends into the postdischarge phase of patient care.3 The conventional pharmacotherapy approach recommended for medically ill patients by the American College of Chest Physicians (CHEST) in guidelines that were published before Food and Drug Administration (FDA) approval of direct-acting oral anticoagulants (DOACs) includes the use of low-molecular-weight heparin (LMWH), low-dose unfractionated heparin, or fondaparinux.4 Furthermore, the CHEST guidelines recommend against extending the duration of thromboprophylaxis beyond the period of patient immobilization or an acute hospital stay, primarily due to the increased bleeding risk observed with extended-duration prophylaxis with enoxaparin.4 Since all of the currently recommended agents for VTE prophylaxis are administered parenterally, use of pharmacologic prophylaxis is often considered inconvenient for the patient, who must receive subcutaneous injections. Additionally, renal elimination of LMWH or fondaparinux could limit the use of these agents in some patients. Hence, providers are often faced with dilemmas of both agent selection and duration of therapy when choosing a VTE prophylaxis strategy. Betrixaban (Bevyxxa, Portola Pharmaceuticals, San Francisco, CA), the first oral factor Xa inhibitor approved by FDA for prevention of VTE in acutely ill medical patients, offers a more convenient anticoagulation option for providers and patients.5 It has some superficial resemblance to the rest of the factor Xa inhibitors; however, it also has some distinct properties. Betrixaban has a half-life of 19–27 hours, which is longer than values for the rest of the agents in its class. Betrixaban has a quick onset of action, and the time it takes for the drug to reach maximum plasma concentration is 3–4 hours; thus a patient is fully anticoagulated relatively quickly after therapy initiation. Betrixaban is about 35% bioavailable. There is no published information on how crushing or chewing can affect bioavailability, and the package insert suggests that betrixaban should be administered with food. Furthermore, betrixaban is about 60% protein bound. Unlike other factor Xa inhibitors, betrixaban does not undergo extensive hepatic metabolism. Because the cytochrome P-450 isozyme system does not play a major role in the metabolism of betrixaban, drug interactions through this pathway are not a major concern. On the other hand, betrixaban is a substrate of P-glycoprotein (P-gp); therefore, decreased or increased levels should be expected when betrixaban is administered with strong P-gp inducers or inhibitors, respectively. Since the publication of the CHEST guidelines in 2012, results of 2 trials that investigated the use of DOACs in medically ill hospitalized patients have been published. In the MAGELLAN trial, researchers enrolled 6,024 patients and compared the use of rivaroxaban 10 mg orally daily for a mean ± S.D. duration of 35 ± 4 days (n = 3,057) with the use of enoxaparin 40 mg subcutaneously daily (mean ± S.D. duration, 10 ± 4 days) plus a placebo for a mean ± S.D. of 35 ± 4 days (n = 2,967).6 In the rivaroxaban group, the rate of VTE events was 4.4%, whereas in the enoxaparin group it was 5.7% (p = 0.02). However, the reduced rate of VTE events came at the expense of higher bleeding rates. In the rivaroxaban group, the bleeding rate was 1.1%, and in the enoxaparin group it was 0.4% (p < 0.001). In the ADOPT study (n = 4,495), the effects of apixaban 2.5 mg orally twice daily for 30 days (n = 2,211) were compared with the effects of enoxaparin 40 mg subcutaneously daily (administered for 6–14 days) plus placebo use for a total treatment period of 30 days (n = 2,284).7 In the apixaban group, the rate of VTE events was 2.7%, whereas in the enoxaparin group it was 3.1% (p = 0.44). These results were accompanied by an increased rate of major bleeding with apixaban versus enoxaparin use (0.5% versus 0.2%, p = 0.04). Neither apixaban nor rivaroxaban has been approved in the United States for VTE prevention in acutely medically ill patients, mainly due to the fact that efficacy benefits were negated by safety issues. The standard of care has remained essentially unchanged over the past few years; however, with the recent approval of betrixaban by FDA, providers may have more prescribing options for thromboprophylaxis.8 The purpose of this article is to summarize clinically relevant data regarding betrixaban use for thromboprophylaxis and its role in clinical practice. Betrixaban clinical trial data Betrixaban efficacy and tolerability were first investigated in the Phase II EXPERT trial.9 This parallel-group, multicenter study evaluated 2 different betrixaban oral doses (15 and 40 mg) and subcutaneous enoxaparin for prevention of VTE (deep vein thrombosis [DVT] on venography, symptomatic proximal DVT, or pulmonary embolism [PE]). The objective of this exploratory proof-of-concept study was to confirm the antithrombotic potential and safety of betrixaban at dosages that were predicted to inhibit thrombin generation and maintain levels of anti–factor Xa activity typically associated with thromboprophylaxis. Two hundred fifteen patients who underwent elective total knee replacement (TKR) surgery were randomly assigned in a 2:2:1 ratio to receive postoperative betrixaban 15 or 40 mg orally twice a day or enoxaparin 30 mg subcutaneously every 12 hours for 10–14 days. Of the 215 patients, 214 received at least 1 dose of a study drug. Although betrixaban has a relatively long half-life, a twice-daily dosing regimen was chosen with the intent of simulating effects of a possible future controlled-release formulation. Baseline demographics were similar in the 3 study groups. Among the 214 treated patients, the rates of VTE were 20% (14 of 70 patients), 15.4% (10 of 65 patients), and 10% (4 of 40 patients) in the betrixaban 15-mg, betrixaban 40-mg, and enoxaparin groups, respectively. The majority of events were asymptomatic distal DVT. Although no bleeding was reported with use of betrixaban 15 mg, 2 patients (2.4%) experienced clinically relevant nonmajor (CRNM) bleeding with use of betrixaban 40 mg. In the enoxaparin group, 2.3% of patients experienced major bleeding and 4.6% experienced CRNM bleeding. The results of this study suggested that there is a dose-related antithrombotic effect of betrixaban, with a minimal increase in bleeding risk relative to enoxaparin use. The EXPLORE-Xa study involved assessment of the safety and tolerability of betrixaban at 3 different daily oral doses versus dose-adjusted warfarin in patients with atrial fibrillation (AF) at risk for stroke.10 The primary outcome was the time to occurrence of major bleeding or CRNM bleeding. Of the 561 screened patients, 508 were randomly assigned in a 1:1:1:1 ratio to receive betrixaban 40 mg (n = 127), 60 mg (n = 127), or 80 mg (n = 127) orally once daily or warfarin therapy adjusted to attain target International Normalized Ratio values of 2–3 (n = 127). Antiplatelet therapy to provide supportive care was permitted; however, use of verapamil was not permitted due to a lack of data regarding potential interaction with betrixaban. The study groups were balanced in terms of baseline demographics. The majority of the patients were Caucasian, and the mean patient age was 73 years. Less than 10% of patients had a glomerular filtration rate of <40 mL/min. The mean percentage of time in the therapeutic range for patients in the warfarin group was 63.4%. The mean CHADS2 score was 2.2. (CHADS2 is a clinical tool for predicting stroke risk based on the presence or absence of congestive heart failure, hypertension, age of ≥75 years, diabetes, and prior stroke or transient ischemic stroke; CHADS2 scoring ranges from 0 to 6, with higher scores indicating increasing stroke risk.) The maximum follow-up duration was 329 days, and the median follow-up was 150 days. Overall, the rate of major or CRNM bleeding was low. Specifically, in the betrixaban 40-mg group, there was 1 event; in the betrixaban 60- and 80-mg groups, there were 5 events in total. The betrixaban 40- and 80-mg groups had lower rates of any bleeding. There were 32 events in the betrixaban 40-mg group and 24 events in the betrixaban 80-mg group. The EXPERT and EXPLORE-Xa studies established the safety of betrixaban in doses of 40 and 80 mg, for a relatively short duration of treatment, in patients undergoing TKR or with AF. After the results of these 2 studies were published, investigators sought to determine the impact of extended-duration betrixaban therapy for thromboprophylaxis in acutely medically ill patients in the APEX study, a randomized, double-blind, double-dummy, active-controlled, multinational clinical trial.11 Patients were eligible for inclusion if they were 40 years of age or older, had been hospitalized for less than 96 hours for a specified acute medical illness, and had reduced mobility and other specific risk factors for VTE. Clinically important exclusion criteria included factors posing an increased risk of bleeding (e.g., body weight of <45 kg, a history of significant bleeding, known intracranial lesions, metastatic disease, aneurysm); surgery or invasive procedures within 3 months of or during study enrollment; end-stage renal disease (ESRD), with creatinine clearance (CLcr) of <15 mL/min or current use of dialysis; a history of intracranial bleeding, trauma, or lesions; concurrent or historical (within the previous year) alcohol or drug abuse; shock; and current receipt of most forms of dual antiplatelet therapy. The APEX study investigators established 2 subcohorts within the overall study population (designated as cohort 3): cohort 1 (the surrogate marker group) consisted of patients with a local d-dimer value of ≥2 times the upper limit of normal (ULN), and cohort 2 (the surrogate marker and elderly group) consisted of patients with a local d-dimer value of ≥2 times the ULN and an age of ≥75 years. This recruitment strategy was based on findings from the MAGELLAN trial and also published guidance for industry from FDA.12 Briefly, the FDA document recommended identification of patients with the greatest likelihood of having a disease-related endpoint and who were deemed more likely to respond to drug treatment in order to enrich the study population and increase the likelihood of identifying a treatment benefit. Patients enrolled in the APEX study were randomly assigned to receive either betrixaban (a loading dose of 160 mg orally followed by 80 mg once daily orally for 35–42 days) or enoxaparin 40 mg subcutaneously once daily for a mean ± S.D. of 10 ± 4 days. The betrixaban group also received a placebo injection once daily for a mean ± S.D. of 10 ± 4 days, whereas the enoxaparin group received placebo tablets once daily for 35–42 days. Doses of betrixaban were reduced to 50% of the prespecified doses (i.e., an 80-mg loading dose followed by 40-mg doses once daily were administered) if patients had renal insufficiency (CLcr of 15–30 mL/min) or were concomitantly using a strong P-gp inhibitor. No modification to the treatment regimen was made in the case of concomitant use of a P-gp inducer and betrixaban. The dose of enoxaparin was reduced to 20 mg subcutaneously daily if patients had severe renal insufficiency (CLcr of 15–30 mL/min); this is an unconventional enoxaparin dose in the United States but is used worldwide and was chosen for the APEX study in order to align with worldwide use of enoxaparin. Given that the majority of the clinical trial centers were not in the United States, this was a reasonable decision. The primary efficacy outcome in the APEX study was a composite of (1) asymptomatic proximal DVT between days 32 and 47, (2) symptomatic proximal or distal DVT, (3) symptomatic nonfatal PE, and (4) death from VTE between days 1 and 42. The 2 major secondary efficacy outcomes were symptomatic VTE (death from VTE, nonfatal PE, and/or symptomatic DVT) through day 42 and a composite of (1) asymptomatic proximal DVT between days 32 and 47, (2) symptomatic DVT (proximal or distal), (3) nonfatal PE, and (4) death from any cause through day 42. DVT events were confirmed by means of ultrasonography or other vascular imaging techniques, and clinically suspected PE was confirmed with computed tomography, ventilation–perfusion lung scanning, pulmonary angiography, or autopsy. The primary safety outcome was the occurrence of major bleeding at any point until 7 days after the discontinuation of all study medications. Major bleeding and CRNM bleeding were evaluated as the primary safety endpoints. Major bleeding and CRNM bleeding were defined according to International Society on Thrombosis and Haemostasis (ISTH) definitions.13 Treatment randomization in the APEX study included 7,513 patients. Characteristics of the patients at baseline were well balanced in the study groups. The majority of the patients were Caucasian males over 75 years of age. Roughly 40% of the patients had CLcr of 30–60 mL/min, and 18% were using a P-gp inhibitor. It was not reported whether any patients included in the study used strong P-gp inducers along with betrixaban. Less than 5% of the patients had severe renal insufficiency, defined as CLcr of <30 mL/min. The most common acute medical conditions were New York Heart Association classes II–IV heart failure (45%) and acute infection (30%). The remainder of the patients had acute respiratory failure (12%), ischemic stroke (11%), or an acute rheumatic disorder (3%). In the overall APEX study population, a lower percentage of patients in the betrixaban group versus the enoxaparin group experienced an event included in the composite primary efficacy endpoint (5.3% [165 of 3,112 patients] versus 7% [223 of 3,174 patients]; relative risk [RR], 0.76; 95% confidence interval [CI], 0.63–0.92]; p = 0.006). In cohort 1 (the surrogate marker group), there was no significant difference in the primary efficacy endpoint with use of betrixaban versus enoxaparin. In this subgroup, 6.9% (132 of 1,914) of the patients in the betrixaban group and 8.5% (166 of 1,956) of the patients in the enoxaparin group had a primary endpoint event (RR, 0.81; 95% CI, 0.65–1.00; p = 0.054). In cohort 2 (the surrogate marker and elderly group), the primary efficacy endpoint occurred in 5.6% (160 of 2,842) of the patients in the betrixaban group and 7.1% (204 of 2,893) of the patients in the enoxaparin group (RR, 0.80; 95% CI, 0.66–0.98; p = 0.03). Overall (in the entire study population), the betrixaban-treated patients had lower rates of symptomatic DVT and PE than those receiving enoxaparin. In the overall APEX study population, there was no significant difference in rates of major bleeding between the betrixaban group (0.7%, 25 of 3,716 patients) and the enoxaparin group (0.67%, 21 of 3,716) (RR, 1.19; 95% CI, 0.67–2.12; p = 0.55). However, there was a significant between-group difference in the combined rate of major and CRNM bleeding in the betrixaban group (3.1%, 116 of 3,716 patients), as compared with the enoxaparin group (1.6%, 59 of 3,716) (RR, 1.97; 95% CI, 1.44–2.68; p < 0.001). Overall, there was no significant between-group difference in mortality. The net clinical benefit was significantly greater, in favor of betrixaban, in the overall population but not in the 2 specified cohorts. In the overall patient population, the cumulative rate of occurrence of the primary efficacy and safety endpoints was 5.8% (179 of 3,112 patients) in the betrixaban group versus 7.3% (233 of 3,174 patients) in the enoxaparin group (RR, 0.78; 95% CI, 0.65–0.95; p = 0.01). Based on these results, betrixaban was approved by FDA for extended thromboprophylaxis in acutely ill medical patients.7 Some of the investigators from the APEX trial published a follow-up article several months later in which they described conflict among the groups charged with independent review of the APEX study data.14 They reported that there was some variability in interpretation of the statistical analysis plan for the APEX trial and that, as a result, the 3 research groups conducting analyses of the data did not arrive at the same conclusion about the primary efficacy endpoint. Specifically, it was suggested that different coding of a DVT event in 1 patient by the data review teams led to a conclusion that the overall study population, cohort 1 (the surrogate marker group), and cohort 2 (the surrogate marker and elderly group) all had a significant reduction in the primary endpoint with betrixaban use. Given the potential “alternative conclusion” proposed in the article, the true impact of betrixaban, at least in cohort 1, is somewhat uncertain. Despite the controversy noted in the later publication,14 the findings of the APEX study were noteworthy albeit limited by the fact that the between-group difference in the primary endpoint was mainly driven by asymptomatic proximal DVT, which occurred in 4% of patients (133 of 3,112) in the betrixaban group and 5% of patients (176 of 3,174) in the enoxaparin group. The remainder of outcomes (symptomatic DVT, symptomatic PE, and death) occurred in less than 1% of patients in both groups. In clinical practice, asymptomatic DVT is rarely assessed unless incidentally discovered while clinicians are performing other examinations. Symptomatic DVT or PE would be more likely to be diagnosed and treated. Ultimately, in the overall population there was a numerical difference in death from VTE between the betrixaban group (n = 13) and the enoxaparin group (n = 17); however, this was not statistically significant. Extended-duration anticoagulation seems logical given the persistent risk of postdischarge VTE3; however, it is unclear to what extent the efficacy benefits in the APEX trial were related to the longer duration of betrixaban therapy. In a time-to-event analysis available in the APEX study appendix material,11 there appeared to be a beneficial effect of longer versus shorter treatment with betrixaban on the occurrence of symptomatic VTE (hazard ratio, 0.65; 95% CI, 0.42–0.99; p = 0.046). It is less clear whether prolonged prophylaxis led to the increased combined risk of major and CRNM bleeding with betrixaban observed in the APEX study. Given that the increased major bleeding risk in the previously mentioned MAGELLAN and ADOPT trials was likely related to prolonged prophylaxis duration, it may be reasonable to hypothesize that the bleeding findings in the APEX study could also have been related to therapy duration.6,7 The dosage of enoxaparin was reduced to 20 mg subcutaneously daily for patients with CLcr of <30 mL/min in the APEX trial, whereas the FDA-approved enoxaparin dosage for patients with CLcr of <30 mL/min is 30 mg subcutaneously once daily. While this alternative dosing regimen was used intentionally by the APEX study investigators to align with common practice in the majority of study centers, it is unclear how outcomes might have been affected if the common U.S. renal dose adjustment had been performed. The main APEX study was followed by 3 different subgroup analyses in an effort to better understand the impact of betrixaban use at different doses, for different durations, and in specific patient populations. Gibson and colleagues15 assessed the pharmacokinetic, efficacy, and safety profiles of betrixaban 80 and 40 mg relative to enoxaparin. In this analysis, the investigators found that the primary efficacy outcome (asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic nonfatal PE, or VTE-related death) occurred at a lower rate among patients who received full-dose betrixaban relative to enoxaparin-treated patients (6.3% versus 8.4%; relative risk reduction [RRR], 0.26; 95% CI, 0.04–0.42; p = 0.023); however, there was no significant difference in the primary outcome. There was no difference in major bleeding with use of either dose of betrixaban, as compared with enoxaparin use. This study generated uncertainty about the efficacy of the reduced dose of betrixaban. Another subgroup analysis of APEX study data evaluated the impact of extended-duration prophylaxis with betrixaban on the risk of multiple VTE events.16 Analyses were performed using data on the overall study population and the 2 aforementioned APEX cohorts. A time-to-multiple-event analysis was performed using the Wei, Lin, and Weissfeld method, which accounts for the correlation of multiple events within each patient. This analysis suggested that extended-duration betrixaban was associated with a significant 31–48% RRR in multiple VTE events (ascertained through last subject contact), as compared with standard-duration enoxaparin. The number of patients with multiple events tended to be lower in the betrixaban group than in the enoxaparin group (1 patient versus 6 patients, p = 0.07). The subgroup analysis findings suggested that the extended duration of therapy likely provided additional VTE risk reduction beyond that measured in the APEX trial. The effect of extended-duration betrixaban on prevention of stroke was evaluated in an exploratory analysis of APEX study data.17 The retrospective substudy revealed that relative to the enoxaparin group, the betrixaban group had lower rates of all-cause stroke (0.54% versus 0.97%; RR, 0.56; 95% CI, 0.32–0.96; p = 0.032; adjusted RR, 0.43; number needed to treat [NNT] = 233) and ischemic stroke (0.48% versus 0.91%; RR, 0.53; 95% CI, 0.30–0.94; p = 0.026; adjusted RR, 0.43; NNT = 233) through 77-day follow-up. This analysis was post hoc and should be considered hypothesis generating only. Meta-analyses of DOAC use for VTE prophylaxis As mentioned previously, betrixaban is the only FDA-approved oral option for prevention of VTE in acutely medically ill patients. Two recently published meta-analyses have focused on the role of DOACs in VTE prophylaxis in medically ill patients. Tao and colleagues18 conducted a meta-analysis of data from the ADOPT, MAGELLAN, and APEX studies on 11,064 patients who received extended-duration DOAC therapy (with apixaban, rivaroxaban, or betrixaban) and 11,078 patients who received conventional-duration LMWH prophylaxis. Asymptomatic or symptomatic VTE occurred in 4.3% of patients who received a DOAC and 5.61% of patients who received LMWH (RR, 0.76; 95% CI, 0.67–0.87; p < 0.0001). Furthermore, DOAC recipients had significantly lower rates of symptomatic VTE (RR, 0.66; 95% CI, 0.51–0.86; p = 0.002). However, when the researchers assessed total and major bleeding, as defined by the ISTH criteria in all 3 studies, there was a higher rate of any bleeding with use of extended-duration DOAC (4.82%) versus LMWH (3.16%) (RR, 1.74; 95% CI, 1.05–2.90; p < 0.001). Major bleeding was also more frequent among DOAC recipients than among LMWH recipients. This meta-analysis suggested that DOAC use was associated with a significant decrease in VTE, including symptomatic VTE, when compared with standard-duration LMWH. DOAC use also appeared to be associated with increases in any bleeding and major bleeding. In another meta-analysis, the effects of extended- and short-duration prophylaxis with betrixaban and other agents in the anticoagulant class were studied by Liew and colleagues.19 Four randomized controlled trials (the MAGELLAN, ADOPT, and APEX trials and also the EXCLAIM trial) representing the thromboprophylaxis experience of 34,068 patients were included. Unlike the other included studies, the EXCLAIM study compared subcutaneous anticoagulation using enoxaparin with placebo use.20 When compared with short-duration prophylaxis, extended-duration prophylaxis was associated with decreases in symptomatic proximal DVT (RR, 0.52; 95% CI, 0.35–0.77; p = 0.001; absolute risk reduction [ARR], 0.32%; NNT = 313) and symptomatic nonfatal PE (RR, 0.61; 95% CI, 0.38–0.99; p = 0.04; ARR, 0.16%; NNT = 625). Relative to short-duration thromboprophylaxis, extended-duration thromboprophylaxis was associated with an increase in major bleeding (RR, 2.08; 95% CI, 1.50–2.90; p < 0.0001; ARR, 0.41%; number needed to harm = 244), with no significant impact on VTE-related mortality (RR, 0.69; 95% CI, 0.45–1.06; p = 0.09) or all-cause mortality (RR, 1.00; 95% CI, 0.89–1.12; p = 0.95). In reporting their findings, the investigators highlighted the fact that the analysis was affected by heterogeneity with regard to major bleeding due to inclusion of data from the APEX study, in which there was no difference in rates of major bleeding between the betrixaban and enoxaparin groups. The conclusion of this analysis was that extended treatment with apixaban, enoxaparin, or rivaroxaban—but not betrixaban—increased the risk of major bleeding. This meta-analysis had a high degree of clinical heterogeneity, especially due to the inclusion of the EXCLAIM trial data. The findings of these 2 meta-analyses suggested that as a class, extended-duration prophylaxis with DOACs may be associated with a decrease in symptomatic VTE when compared with standard-duration prophylaxis LMWH in medically ill patients. These meta-analyses also suggested an association of DOACs with increased major bleeding. These meta-analyses should be interpreted cautiously, as there was a great deal of clinical and statistical heterogeneity in the included studies, which differed in terms of the medications evaluated, the patient populations enrolled, and overall findings related to bleeding. Special considerations for use of betrixaban Patient selection. The data summarized above indicate the efficacy of betrixaban as a new alternative for the prophylaxis of VTE in acutely medically ill patients. However, it is important to highlight a few important concepts regarding its use. One aspect is the lengthy list of exclusion criteria applied in the APEX trial. For example, patients with CLcr of <15 mL/min or ESRD were excluded from the study; this added a layer of complexity, because the methodology of the APEX study dictated that patients with estimated CLcr of <30 mL/min would receive 50% of the original betrixaban dose. In the APEX trial, less than 5% of the patients had renal insufficiency (i.e., CLcr of <30 mL/min). Thus, only a small number of patients with CLcr of 15–30 mL/min received the reduced dose of betrixaban. Furthermore, in the subgroup analysis that evaluated the 2 doses of betrixaban against enoxaparin, use of the 40-mg dose was not associated with significantly different outcomes when compared with enoxaparin use.16 This finding suggested that dose reduction of betrixaban may not produce optimal patient outcomes, but more study is needed. Patients who had invasive procedures during the 3 months prior to the APEX study enrollment process or were anticipated to need such procedures during the study time frame were excluded from the trial. Thus, when deciding whether betrixaban would be appropriate for a patient, consideration of that patient’s likelihood of needing an invasive procedure or surgery would be critical. Another APEX study exclusion criterion that should be considered prior to betrixaban use pertained to patients with a history of clinically significant bleeding within 6 months prior to the enrollment window. There are limited data on use of betrixaban in this patient population, and thus betrixaban would not be an optimal choice for this group. At this point, certain questions related to betrixaban and transitions of care remain. Most importantly, the risks versus benefits of extended-duration VTE prophylaxis should be considered prior to initiation of betrixaban therapy. The APEX study demonstrated an efficacy benefit with extended-duration prophylaxis; however, this came at the cost of increased bleeding risk. The bleeding risk with betrixaban use may be less significant than that with use of other DOACs; however, assessment of this risk versus the expected benefits should be based on individual patient characteristics. It is also unclear what the best approach should be for a patient who is started on betrixaban during hospitalization but who is unable to obtain the medication as an outpatient due to insufficient insurance coverage and/or cost issues. Failure to consider this potential issue early in the hospitalization may result in a patient being initiated on betrixaban in the inpatient setting but then being unable to afford the medication’s extended-duration regimen as an outpatient. It is unknown whether safety and efficacy would be adequate if a patient were to discontinue betrixaban use at hospital discharge. Exploratory analyses suggest that premature discontinuation could have a negative impact on VTE occurrence, but more study is needed in this area.15 Additional factors to take into consideration before initiation of betrixaban include potential drug–drug interactions and issues related to anticoagulation reversal. Drug–drug interactions. Although there are published data on bextrixaban use along with other DOACs for triple antithrombotic therapy,21,22 betrixaban has not been studied in patients receiving dual antiplatelet therapy and thus should be used cautiously, if at all, in patients with recent acute cardiovascular events or who are otherwise candidates for dual antiplatelet therapy. Additionally, caution should be exercised when betrixaban is administered concomitantly with P-gp inhibitors (e.g., amiodarone, azithromycin, verapamil, ketoconazole, clarithromycin) due to an increased risk of bleeding events; in this case, the dose of betrixaban should be reduced in an effort to avoid bleeding. A notable knowledge gap regarding drug interactions with betrixaban relates to the concomitant use of betrixaban with P-gp inducers; in such cases, there are limited data to guide treatment decisions. Anticoagulation reversal. An important concern associated with the use of betrixaban, as well as the other factor Xa inhibitors, is the absence of a method to fully reverse the anticoagulation effect. Bleeding associated with enoxaparin use can be partially reversed with the use of protamine. There is no definitive antidote for betrixaban; however, there are ongoing studies investigating the effect of andexanet alfa as a potential reversal agent for the factor Xa inhibitor class.23 Place in therapy Betrixaban is the only oral factor Xa inhibitor approved by FDA for thromboprophylaxis in acutely medically ill patients. Oral betrixaban administered over approximately 40 days was found to be more efficacious than subcutaneous enoxaparin administered over approximately 10 days.11 Rates of major bleeding were similar with betrixaban use and with enoxaparin use; however, the combined rate of major bleeding and CRNM bleeding was higher with betrixaban use. Overall, the net clinical benefit of betrixaban was favorable over enoxaparin, and the NNT to prevent 1 VTE event (approximately 59) was slightly lower than the number needed to harm (approximately 67) when harm was defined as the combination of major bleeding and CRNM bleeding. Patient characteristics and individualized risk–benefit evaluation will be important when determining whether betrixaban is the best choice for VTE prophylaxis in a patient. Specific considerations to be evaluated prior to initiation of betrixaban use include VTE risk, bleeding risk, whether concurrent use of potentially interacting medications is required, and whether the patient might not have access to betrixaban after discharge due to insurance coverage and cost issues. Conclusion Betrixaban is an oral option for VTE prevention in medical patients. Disclosures The authors have declared no potential conflicts of interest. References 1 Centers for Disease Control and Prevention . 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