March 2015 by McMahon Group

The Pharmacist’s News Source

pharmacypracticenews.com

UP FRONT

Link between vitamin D levels, colorectal cancer bolstered.

OPERATIONS & MGMT

Choosing to switch rather than fight specialty pharmacy.

TECHNOLOGY

9 12 14

Barcodes boost safety of insulin pens. Are CSTDs poised to break the 50% adoption barrier? Profiles in Pharmacy: Yuma Regional Medical Center.

CLINICAL

20 29

Fall prevention program cuts injury rate sixfold. ‘Practice-changing’ cancer treatments knocked down a peg by Phase III data.

POLICY

New payment models need better data: Are you doing your part?

Managing Venous Thromboembolism Risk in Hereditary Antithrombin Deficiency See insert after page 32.

Preventing Oral Chemo Rx Errors: A Team Approach

n recent years, oral antineoplastic agents have transformed the care of cancer patients. They have also brought new challenges, particularly in the case of medication errors. Oral cancer drugs are “some of the most toxic [compounds] on the market,” and when errors occur, they can be especially dangerous, noted Raymond Muller, MS, RPh, the associate director, Division of Pharmacy Services, Memorial Sloan-Kettering Cancer Center (MSKCC), New York City. Mr. Muller discussed strategies for reducing these errors during a recent webinar sponsored by the Institute for Safe Medication Practices (ISMP). Chemotherapy mishaps have multiple causes, Mr. Muller noted, including poor packaging/labeling, interruptions during order processing or a misunderstanding of a drug regimen’s total daily dose. A 2010 study identified 508 oral antineoplastic errors through MEDMARX and other databases (Cancer 2010;116:2455-2464).

Opioids for Pain Optimized By Stewardship Plan Anaheim, Calif.—An innovative inpatient pharmacy-directed pain management program combining “opioid stewardship” and physician-requested consultations has demonstrated significant cost avoidance, improvements in patient outcomes and increased patient satisfaction scores. The initiative saved roughly $1.6 million in costs related to opioid see STEWARDSHIP, P page 28

M e

tin

Volume 42 • Number 3 • March 2015

Is su h

Nearly a billion prescriptions could benefit annually

Pharmacogenomics Gains Traction—With Some Help

Anaheim, Calif.—Pharmacogenomics is poised to play a central role in the future care of cancer and other major diseases—even President Barrack Obama knows that. “I want the country that eliminated polio and mapped the human genome to lead a new era of medicine — one that delivers the right treatment at the right time,” he said in his State of the Union address on Jan. 20, 2015. And crucial to achieving that life- and cost-saving reality, said experts who addressed the 2014 Midyear Clinical Meeting of the American Society of Health-System Pharmacists (ASHP) a month earlier, is continued development and implementation of testing and decision support technologies, greater educational opportunities and the leadership of pharmacists. “This really is a drug-related issue. It’s natural for pharmacy to take a leadership role,” said

see CHEMO ERRORS, page 24

Major savings reported

see PHARMACOGENOMICS, page 16

Palliative Care a ‘Foreign’ But Vital Role for Pharmacists Anaheim, Calif.—When — treating a patient who is nearing the end of his or her life, Mary Lynn McPherson, PharmD, offers a key piece of advice: “Focus on what is important now.” “If you’re within a month of dying, if you can tolerate a blood sugar of 250 and are asymptomatic, then I’d say let’s get you a dozen donuts,” said Dr. McPherson, a professor and vice chair for education in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, Baltimore. Efforts to maximize comfort, in other words, should take the place of aggressive treatment during a patient’s final months,

New Product FDA approves first generic Nexium. See page 8

weeks or days, Dr. McPherson noted during a session on palliative care at the 2014 Midyear Clinical Meeting of the American Society of Health-System Pharmacists (ASHP). The benefits could extend from improved quality of life to reductions in both health care costs and hospital readmissions. It’s no easy task, of course. There may not be a more complex patient than one nearing the end of life— when the physical, psychological and social changes are vast, and can happen fast. “Sometimes the medications get lost because there’s so much to handle with see VITAL ROLE, page 22

Get the App

Take a bite out of G-CSF acquisition costs Based on whole esale acquissition cost (WAC C) of o all sho ort rt-a -act -a c in ct i g GG-CS CSF F pr prod oduc od ucts uc t ts as of November 11, 201 13. WAC AC rep pre rese sent se ntss pu nt publ blis bl ishe is he ed ca cata talo log gue gu g e or lisst pr pric ices e and es n may not represent acctual transa a tion ac o al pri r ce es. s. Ple leas ase e co con ntac actt yo your urr sup uppl plie er fo forr ac actu tual al pri r ce c s. s

GRANIX® is an option in short-acting G-CSF therapy » A 71 7 % red duct ctio io on in dur urat a io at ion n off sev ever ere e ne neutrro openia a vs placebo (1.1 days vs 3.8 8 da d ys, p<0 0.0 000 001) 11 – Effica c cyy was eva valu uat ae ed d in a m multtin mu nat ational, m multice enter, randomized, controlled, Phase III study of chem motherapy-naïve p tien pa ntss witth hi hig g -ris gh-r gh iskk br brea east stt cance er receivving do oxorubicin (60 mg/m2 IV bo olus)/docetaxel (75 mg/m2)1 » Th he sa safe fe etyy of GR GRA A IX was esta AN ablishe ed in 3 Phase III trials,, with 680 p patients receiving g chemotherapy py for either breast 1 ca ancer nccer er,, lu lung ng can ance ce er, or non-Ho odgkin lympho oma (N NHL) » No Now w of offe f ri fe ring n a new e presentation for self-ad dministration

Indication » GR G AN ANIX IX is a leukocyte ocyte growth factor indicat indicated ted forr reduction in the duration of severe ne neutropenia eutropenia in p patients atients with wi th non onm myeloid malig gnancies receiving myelosuppresssive anticancer drugs associated with a clinically significant inci in cide denc n e of febrile neu utropenia.

Important Safety Information » Sple Spleni n c ru upture: Splen nic rupture, including fatal cases, can occur following the administrattion of human granulocyte colo co lony-stimulating facttors (hG-CSFs). Discontinue GRAN NIX and evaluate for an enlarged spleen or sp s le enic rupture in patients who report up pa pper abdominal or shoulder pain after receiving GRANIX. » Ac Acut ute resspiratory disttress syndrome (ARDS): ARDS ca an occur in patients receiving hG-CSFs. Evaluate pa p tients t who wh o deve elop fever and d lung infiltrates or respiratory disstress after receiving GRANIX, forr ARDS. Discontinue GRANIX in patients with ARDS. » Al A lergic reactions: Serrious allergic reactions, including anaphylaxis, can occur in patientts receiving hG G-CSF S s. Reactions n ca an occurr on initial exp exposure. posure Permanentlyy discontinue GRANIX in patients with serious allergic reac actions. tions D Do o no not administe er GRANIX to patients with a histo ory of serious allergic reactions to o filgrastim or pe egfilgr g astim. » Use e in pa atients with sickle cell disease: Severe and sometimes fatal sickle e cell crises can occur in pa patients with sickkle cell diseasse receiving hG-CSFs. Consider the potential risks and benefits prrior to the administration of GRAN NIX X in patients with sickle cell disease. Discontinu ue GRANIX in patients undergoin ng a sickle cell crisis. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and iss charac a teriize z d by hyp pote ensiion o , hypoalbuminemia, edema and hemoconce entration. Episodes vary in freque ency, severity and may be life f -thre eatening if treatme ent is delayed. Patients who develop symptoms of CLS should be closelyy monitored and d re ece c ivve sttanda dard r symptoma atic treatment, which may include e a need for intensive care. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimullating fa actor o (G-CSF) re eceptor, through which GRANIX acts, has been fo f und on tumor ce ell lines. The pos o sibility tha hat GRAN NIX X acts as a grow wth factor for any tumor type, inclu uding myelo oid d malignancies and myelodysplasia, diseasses e for which GRA ANIX is not app proved, cannot be excluded. » Most com mmon treatment-emergent adve erse e reaction: The most common n treatment-eme ergent ad dvers r e re ea action that occurred in patients treated with GRANIX at the recommended do d se with an incidence of at leastt 1% or gre eat e a er and two ti t mess more frequent than in the placebo group wass bone pain. Please see brief summary of Full Prescribin ng Information on adjacent page.

For more information, visit GRANIXhcp.com. Refe Re fere renc nce: e 1. GRA ANIX® (tbo-filgrastim) Injection Prescribing g Info orm r ation. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva a Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved.. GRX-40582 January 2015.

Up Front 3

Pharmacy Practice News • March 2015

Your Letters

With Antibiotics, What Was Old Should Be New Again Re: “Duke Protocol Reduces Colorectal SSIs by 75%,” October 2014. I find the researchers’ preintervention surgical site infection incidence of about 20% and the postoperative sepsis rate of 8.5% alarming. If this is what goes on in centers of excellence and teaching institutions of high regard, there is something seriously wrong. Additionally, ertapenem [Invanz, Merck] seems a reasonable choice in that

it covers patients for a 24-hour period post-op, and in an age where a missed checkbox in the electronic medical record can result in disaster, the likely impetus. But there is no explanation or elaboration of oral presurgical antibiotics, which have shown benefit and are neither costly nor resistance-inducing. The same cannot be said for widespread, routine use of carbapenems. Someday what was old will be new again. —tmccl... wrote on: 10/21/2014

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: UÊ -« i VÊ,Õ«ÌÕÀiÊQsee Warnings and Precautions (5.1)] UÊ VÕÌiÊ,iÃ« À>Ì ÀÞÊ ÃÌÀiÃÃÊ-Þ `À iÊQsee Warnings and Precautions (5.2)] UÊ -iÀ ÕÃÊ iÀ} VÊ,i>VÌ ÃÊQsee Warnings and Precautions (5.3)] UÊ 1ÃiÊ Ê*>Ì i ÌÃÊÜ Ì Ê- V iÊ i Ê Ãi>ÃiÊQsee Warnings and Precautions (5.4)] UÊ >« >ÀÞÊ i> Ê-Þ `À iÊ[see Warnings and Precautions (5.5)] UÊ * Ìi Ì > Êv ÀÊ/Õ ÀÊ À ÜÌ Ê-Ì Õ >Ì ÀÞÊ vviVÌÃÊ Ê > } > ÌÊ i ÃÊQsee Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of *10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

Editor’s note: The primary investigator declined to comment, so we offer these observations from an infectious disease expert who authored an editorial accompanying the Duke study ((JAMA Surg 2014;14[10]:1053).

It sounds like the reader is concerned that a) a 20% wound infection rate is unacceptably high, b) ertapenem may not be appropriate for first-line antibiotic prophylaxis, and c) there was no mention of preoperative antibiotics. For the wound infection rate, 20% is toward the higher end but still well within the regularly quoted rates of surgical site infections among colorectal patients. All-procedure national studies of surgical site infections report rates of 10% to 16% ((N Engl J Med d 2010;362:1826), and colorectal-focused studies note that their rates are routinely higher, up to 30% ((J Am Coll Surgg 2010;211:812822; N Engl J Med 2006;355:2640-2651). Although 20% may sound high, this rate falls well within the literature norm for colorectal surgical site infections. Ertapenem may not be ubiquitous for antibiotic prophylaxis, but it is routinely used and is an accepted regimen for the national Surgical Care Improvement Project (SCIP). Discussion of antibiotic prophylaxis is ongoing ((J Am Coll Surg 2013;217:763-769), and there is limited consensus as to a single “best” option. The authors note in their methods that a preoperative oral antibiotic regimen of neomycin and erythromycin was employed. The use of such oral antibiotics with mechanical bowel prep has been reported widely and is practiced routinely by colorectal surgeons. It is important to note that there are variations in practice, with large proportions of surgeons differing in their preference for or against antibiotic bowel prep. Johns Hopkins Medicine has universally instituted oral antibiotic bowel preps as literature continues to support it as the superior object. Given its routine use, I would not have expected the Duke group to have to justify its use of such a regimen. —Ira L. Leeds, MD, MBA The Johns Hopkins University Baltimore, Md.

4 Up Front

Pharmacy Practice News • March 2015

Capsules

Study Bolsters Vitamin D, CRC Link

Web Exclusives

SAN FRANCISCO—Higher levels of vitamin D were associated with markedly improved progression-free survival (PFS) and overall survival (OS) in patients receiving treatment for metastatic colorectal cancer (mCRC), according to an analysis of more than 1,000 patients. The findings were presented at the recent Gastrointestinal Cancers Symposium (abstract 507). The study’s lead investigator, Kimmie Ng, MD, MPH, a physician at Dana-Farber Cancer Institute, in Boston, said the research adds to the existing evidence that vitamin D levels have an effect on cancer. Vitamin D is known to inhibit cell proliferation and angiogenesis, induce cell differentiation and apoptosis and have anti-inflammatory effects. “Many of these processes are dysregulated in cancer, which led to the hypothesis that perhaps vitamin D had anticancer activity,” Dr. Ng said. Laboratory data support this hypothesis, with experiments demonstrating that administering vitamin D to mice with intestinal cancer reduces tumor burden, she noted. Additionally, a previous prospective cohort study in 304 patients with CRC showed that higher blood levels of vitamin D (25-hydroxyvitamin D) were associated with a significant improvement in OS (J Clin Oncol 2008;26[18]:2984-2991). To shed more light on the issue, investigators analyzed pretreatment vitamin D levels and outcomes of patients with mCRC in the CALGB (Cancer and Leukemia Group B)/SWOG (Southwest Oncology Group) 80405 trial in a “preplanned, prospective, observational cohort study,” Dr. Ng said. Three different first-line regimens for newly diagnosed, advanced CRC were studied; all started with chemotherapy and added bevacizumab (Avastin, Genentech), cetuximab (Erbitux, Bristol-Myers Squibb) or both. The median vitamin D level in the 1,043 patients who had vitamin D information available was 17.2 ng/mL. The recommended healthy range is greater than 20 ng/mL. The investigators discovered that both PFS and OS were significantly improved in patients with higher vitamin D levels. The association persisted across all patient subgroups and after adjusting for multiple prognostic factors. “Patients who had levels in the highest quintile had a median survival of 32.6 months compared with 24.5 months for patients with levels in the lowest quintile,” Dr. Ng said. Older age, black race, lower dietary and supplemental vitamin D intake, higher body mass index, worse general physical condition and lower physical activity were associated with lower vitamin D levels. Patients whose blood specimens were drawn in the winter and spring months also had significantly lower vitamin D levels, as did patients who resided in the northern and northeastern sections of the United States and Canada. Few patients reported vitamin D supplement use. According to Dr. Ng, “randomized clinical trials are needed to establish causality,” and a randomized, double-blind, Phase II trial of vitamin D in mCRC is underway. Still, “I plan to discuss our findings with patients and screen for vitamin D deficiency, since we now know that metastatic patients are frequently deficient,” Dr. Ng noted. “Again, it’s too early to recommend vitamin D as a treatment, but since there are standard guidelines to replete to greater than 20 ng/mL for bone health, that is what I do with my patients.” —Kate O’Rourke

Visit us online for Web-exclusive content. Links to all of the articles below can be found at pharmacypracticenews.com/ webex0315 or via your smart phone by scanning the adjacent 2D barcode. Be sure to check the Pharmacy Practice News site every day for late-breaking news!

Yoga, Meditation Popular For Pain Control

lthough herbal supplements continue to be the most used complementary health approach in the United States, more Americans are rolling out their yoga mats to improve their health and manage various conditions, particularly pain, according to a new national survey.

Long-Term Opioid Use Doubled in Kids With IBD

hildren with inflammatory bowel disease (IBD) are more than twice as likely to use opioid painkillers chronically as are children without the gut condition, a new study indicates. The researchers warned that such use places children at risk for adverse gastrointestinal events and drug dependency.

FDA Approves Lenvima for Progressive Thyroid Cancer

he FDA approved lenvatinib (Lenvima, Eisai) to treat progressive, differentiated thyroid cancer (DTC) in patients whose disease has progressed despite radioactive iodine therapy. The oral targeted therapy selectively inhibits the activities of VEGFR and other molecules involved in tumor angiogenesis.

Dr. Ng reported no relevant ﬁnancial conﬂicts of interest.

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Volume 42 • Number 3 • March 2015 • pharmacypracticenews.com

ANESTHESIOLOGY/PAIN Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY

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6 Operations & Management

Pharmacy Practice News • March 2015

Finance

Millions of dollars in added revenue a carrot hard to ignore

Hospitals Continue Move Into Specialty Pharmacy Anaheim, Calif.— It can be challenging, but health systems have the capability to build a solid specialty pharmacy business, even if they are denied access to certain key medications and payor plans—and they can do so with only a minimal strain on their budgets. Just ask JoAnn Stubbings, MHCA, BSPharm, the assistant director of specialty pharmacy services at the University of Illinois (UI) Hospital & Health Sciences System, Chicago. Two years ago, UI specialty drug revenues stood at just $8 million, according to Ms. Stubbings, who spoke at the 2014 Midyear Clinical Meeting of the American Society of Health-System Pharmacists. By the end of 2014, she reported, that figure had jumped by more than fourfold, to $35 million—the result of both a 144% gain in dispensed prescriptions, to 4,555, and a sharp escalation in specialty drug prices. What’s more, Ms. Stubbings said, the gains were achieved using existing facilities and with only a minimal increase in dispensing and call center staffs, which grew from 2.125 fulltime equivalents in 2012 to 4.25 last year. How was this accomplished? By focusing on what Ms. Stubbings called “low-hanging fruit,” the open-access payors—mainly Medicaid and Medicare Part D—and the medications that manufacturers and distributors are

willing to make available to all qualified specialty pharmacies. It helped, she said, to have a specialty pharmacy model that played to UI’s strengths in coordinated care and access to patients’ electronic medical records. “It really works,” Ms. Stubbings told Pharmacy Practice News. “You don’t have to build a new building. You can start it in your own pharmacy. Start it small, pilot it and grow. The biggest investment is in people.” Don Carroll, MHA, BSPharm, the senior director of specialty pharmacy at Cleveland Clinic, in Ohio, agreed that the UI approach is “one potential strategy for getting started. There is definitely growth in those areas, and it definitely is substantial. You can build a viable business model based on anywilling-provider payors and also on the drugs that are currently accessible.” But Mr. Carroll also noted that Cleveland Clinic’s start-up approach to specialty pharmacy was very different from the University of Illinois’ “start small and grow” strategy. “We did the opposite,” he said. “We had to start big because there is so much volume here.” (See sidebar.) He added that it was important for all hospital and health-system pharmacy practices “to at least make a very serious assessment about what specialty pharmacy can bring to their marketplaces. What

‘You can build a viable business model based on any-willing-provider payors and also on the drugs that are currently accessible.’ —Don Carroll, MHA, BSPharm would be their investment to get in? What kind of value proposition can they consistently show in their marketplace? How can they make a difference? Because I do think the opportunities are out there.” At UI, Ms. Stubbings said specialty pharmacy volume has grown despite the continuing loss of patient prescriptions to outside specialty pharmacies.

A ‘Disruptive Force’ in the Marketplace

on Carroll, MHA, BSPharm, the senior director of specialty pharmacy at Cleveland Clinic, in Ohio, believes that health system—based specialty pharmacies can be a “disruptive force” in the marketplace. “There is enough uniqueness about us that we can all bring value to our prescribers and patients that no one on the outside can,” he told Pharmacy Practice News. Cleveland Clinic is putting that “value proposition” to the test, and so far it is paying off. Since opening its doors on Sept. 29 last year, the specialty pharmacy has seen its prescription volume nearly double every month. And that is just the beginning, according to Mr. Carroll. “We’re trying to get into the networks where we’re currently closed out of products,” he said, “and we’re also working through our supply chain executive team and myself to let the pharma world know that part of our intention is to be a soft landing for new products.” Cleveland Clinic, he said, can be a natural fit for any kind of limited distribution network. The reason, he added, is the presence on its clinical teams of “so many first adopters and original researchers.” A major thrust of pharmacy’s strategy is to prove that patients on high-risk specialty medications have better outcomes when their care is totally coordinated, from outpatient specialty clinics to pharmacy to home-based treatment. To realize this goal, Cleveland Clinic is investing in a data warehouse that will integrate pharmacy data with information from its Epic electronic medical record system. The aim is to show that patients in the specialty pharmacy program are more adherent to their therapy and have fewer emergency room visits and readmissions. “That’s the next big thing,” Mr. Carroll said, “that proof of

concept that we can take to the manufacturers and payors and to our internal customers and say, ‘We do make a difference and here’s the proof.’” Cleveland Clinic did not have to start from zero in developing its specialty pharmacy. Using an existing home-delivery pharmacy as a base, it built two new spaces to accommodate a call center and dispensing area. The pharmacy opened with patients from the medical center’s cancer and multiple sclerosis clinics. By the end of the year, it had added hepatitis patients. “Now we are evolving into other clinical areas,” Mr. Carroll said. “The list of drugs and diagnoses is huge. It’s a lot to cover, but we’re getting there.” Pharmacists are playing a key role as the new pharmacy evolves. “They are really the care coordinators and patient managers on our side,” he said. “They’re part of initial assessment phone calls. They review ongoing lab work. They’re helping to assess adherence. They’re meeting with our key clinical referral sources.” Mr. Carroll said he was looking to a “grander future,” when fee-for-service care gradually gives way to performance-based payments. “When we talk to payors at Cleveland Clinic, they want to talk about risk and risksharing models,” he said. “We need to be ‘all hands on deck’ in managing this change,” he continued, “and in making sure that therapies are always appropriate, and if something is not working, we identify it to the prescriber. I think the only place that can happen right now is with a health system–affiliated specialty pharmacy.” —B.B.

Such entities, she noted, are favored by many private insurers and pharmaceutical manufacturers because of their perceived advantage in capturing and reporting national patient usage and outcomes data. That perception has led to the migration of more than half of the UI specialty pharmacy’s privately insured prescriptions to external specialty pharmacies, according to Ms. Stubbings, even as the UI pharmacy has managed to fill virtually all Medicaid and Medicare Part D prescriptions. That loss is of increasing concern because of the large number of targeted medicines coming to market over the next decade. IMS Health reported in 2014 that the specialty drug pipeline was “bulging” with just under 700 products in development (http://goo.gl/Vw97kC). Restricted access can also have a serious impact on patient care. “These are high-risk drugs,” Ms. Stubbings said. “They can be managed to some extent by phone, but there is a lot of value in face-to-face communication and in having access to the medical record.”

Efficacy Data Needed The next step for the UI specialty pharmacy, Ms. Stubbings said, is to gather evidence showing that because of its ability to promptly handle prior authorizations and other hurdles that often slow patient treatment, it is able to get crucial medications to patients faster than an outside pharmacy. “We know these patients,” Ms. Stubbings said. “We have access to their see SPECIALTY MOVE, page 8

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8 Operations & Management

Pharmacy Practice News • March 2015

Finance

SPECIALTY MOVE continued from page 6

medical records. We can get them their medications the same day, delivered to their homes if needed. It would be very hard, in contrast, for them to be served by a company that is 2,000 miles away that doesn’t know their needs.” The pharmacy hopes the results from its new study will persuade insurers and manufacturers to ease policies that restrict specialty drug access and payments. “If this helps to convince them, that’s great,”

Ms. Stubbings said, “but frankly, I see a trend to continued restricted access.” If that is the case, she added, a health system should at least be paid for the clinical work that is done to support the drugs dispensed from other parts of the country. Currently, she said, financial support for the specialty pharmacy’s clinical services comes entirely from margins on medications dispensed internally. For this reason, Ms. Stubbings said, the health system has had to end serviceintensive call center support—including prior authorizations and medication

assistance—for patient prescriptions filled by outside specialty pharmacies. “We still obviously provide all medical and pharmacy services in the clinics,” she said, “but in the call center, we only provide services for the prescriptions we can fill.”

Gaining C-Suite Support James E. Smeeding, RPh, MBA, the executive director of the National Association of Special Pharmacy, disputed the notion that remotely located specialty pharmacies are at a disadvantage

to health systems in communicating with patients. Most specialty pharmacies, he said, use interactive technology tools, such as iPads along with applications, such as Apple’s Face Time “to communicate very effectively” with patients. The biggest challenges for hospitals, he said, is to gain C-suite support for the large investments required to establish a full-service specialty pharmacy as well as to create the data collection and reporting mechanisms “required to get limited distribution from manufacturers and innetwork opportunities from payors.” Still, he said, “I’m very bullish on health systems getting into this business. The fastest-growing individual membership in NASP is the hospital sector.”

A PBM’s Approach There certainly is no lack of players in the specialty pharmacy market. And each sector in that market tends to emphasize its “high touch” approach to patient care. Michael Zeglinski, BS Pharm, the senior vice president of specialty pharmacy at Catamaran Corp., Pittsburgh, noted in a statement that BriovaRx, his company’s specialty pharmacy, “employs a holistic approach to serving patients with complex specialty conditions. Our pharmacists and nurses are an educational resource for patients, a 24/7 support system and a trusted adviser to the patient’s care team.” As for the benefits of being a specialty pharmacy within a PBM, “we can see any comorbidities the patient may have, as we are able to see all of their prescription information, and help them better manage their overall health,” he said, with a support model “that helps engage patients and provides them with a wealth of knowledge and resources as it relates to their treatments.” —Bruce Buckley Ms. Stubbings, Mr. Smeeding, Mr. Carroll and Mr. Zeglinski reported no relevant ﬁnancial conﬂicts of interest.

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vax Pharmaceuticals, Inc., a subsidiary of Teva Pharmaceuticals USA, has gained FDA approval to market esomeprazole in 20- and 40-mg capsules. The product, indicated for several conditions including the treatment of gastroesophageal reflux disease (GERD) in adults and children ages 1 and older, is the first generic version of Nexium, according to the agency. Generic esomeprazole capsules will be dispensed with a patient Medication Guide that provides important information about the medication’s use and risks. The most serious risks are stomach problems, including severe diarrhea, and a warning that people who take multiple daily doses of PPIs for a long period of time may have an increased risk for bone fractures. —Based on a press release from the FDA

Technology 9

Pharmacy Practice News • March 2015

Medication Safety

Can a Customized Barcode Reduce Insulin Pen Errors? Anaheim, Calif.—A large urban medical center has developed a two-dimensional patient- and drug-specific barcode label for insulin pens in a preemptive effort to guard against a prime safety risk associated with the devices—using the same pen for more than one patient in the inpatient setting. Since completing the project, the institution, NewYork-Presbyterian Hospital in New York City, decided to discontinue inpatient use of the multipledose devices, reported Susan Kokura, PharmD, a clinical pharmacy manager specializing in computerized prescriber order entry and informatics. However, the barcoding strategy shows potential for hospitals where insulin pens continue to be used along with insulin vials for inpatient care, said Dr. Kokura, who presented the project at the American Society of Health-System Pharmacists’ (ASHP) 2014 Midyear Clinical Meeting.

Originally designed for ambulatory care and home use, insulin pens have made their way into hospitals, where the potential for incorrect use continues to challenge providers. Although research shows some nurses find the devices more convenient, less timeconsuming and easier to use than insulin vials ((Diabetes Educ 2009;35[5]:799809), human error or unawareness that the pens are designed for single-patient use only has put many patients at risk for exposure to bloodborne diseases. In a 2009 safety alert, the FDA warned patients and health care professionals that blood could be regurgitated into the insulin pen reservoir during an injection. Changing needles does not eliminate this risk, the alert stressed (http://goo.gl/xsvzTS). Unintentional caregiver misuse of the multiple-dose devices has potentially exposed thousands of hospital patients to hepatitis viruses, HIV and other pathogens. In one of the most recent instances, a hospital discovered that more than 3,100 hospitalized patients might have been exposed over a sixyear period (http://goo.gl/tL70eD). The hospital launched an internal investigation when a nurse asked whether an insulin pen could be used for more than

one patient, revealing a gap in knowledge of safety practices. To help close awareness and behavior gaps like these, the One and Only Campaign, a public health initiative focusing on safe injection practices led by the Centers for Disease Control and Prevention and the Safe Injection Practices Coalition, includes an education and awareness component devoted to insulin pen safety based on the mes-

sage, “Be Aware. Don’t Share. One Insulin Pen, Only One Person” (http:// goo.gl/MczN6e).

A Proactive Approach NewYork-Presbyterian Hospital chose to approach the safety issue proactively. “As we were learning about national trends, we decided to figure out what we could do instead of letting it happen at our institution,” Dr. Kokura said.

The health system formed a team of pharmacists, nurses, senior executives and information technology (IT) specialists to review existing processes. “You have to understand the root causes of errors at your own institution,” Dr. Kokura said, noting the importance of involving key stakeholders and decision makers in that process. After several meetings, the multidisciplinary group determined see PEN ERRORS, page 10

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10 Technology

Pharmacy Practice News • March 2015

Medication Safety

PEN ERRORS

Injection dial

continued from page 9

that a barcoded label containing both patient- and drug-specific information would offer the most viable solution. The team worked with the institution’s barcode vendor to combine two fields—the charge code and the visit account number—for a barcode that identifies the drug and the patient, but is not specific to the insulin order. Because a linear barcode containing all of this data would not have fit on

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the label, the vendor helped to create a customized, two-dimensional barcode to overcome space limitations. Developing the interface between the institution’s electronic medical record (EMR) and existing barcode systems also required extensive customization by the hospital’s IT Department— a challenging task that took several months, Dr. Kokura said. Tests of the new system showed that it functioned correctly, and feedback from end users was positive. When a nurse scans a pen that does not belong to the patient, a mismatch alert appears on the EMR. Pharmacists were trained to take special care when dispensing the medication to cover the manufacturer’s product barcode with the new label to prevent accidental scanning of the wrong barcode by nursing staff. The launch of major upgrades to the institution’s health information systems shortly after testing put implementation of the barcoding system on hold. However, the health system decided in December to discontinue use of insulin pens in the hospital environment. Like barcoding in general and any health IT, the barcoding system works only to the extent that caregivers adhere to the protocol and avoid using workarounds to override the system; however, the solution still offers key advantages over processes currently used by many facilities, Dr. Kokura said. These include scanning the manufacturer barcode, which does nothing to reduce the risk for improper use; and generating an order-specific barcode label, which also does not guard against pen sharing and which can stifle workflow and efficiency because one pen is commonly used for numerous insulin orders for a single patient during the course of a day. “Our solution is not foolproof, but it’s an example of how barcoding technology can be adapted to mitigate the conundrum surrounding insulin pens in inpatient settings,” Dr. Kokura said in an interview with Pharmacy Practice News. She added that the same patient- and drug-specific barcoding strategy might also have potential for monitoring the use of other high-risk medications.

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The ISMP’s Take Michael R. Cohen, RPh, MS, FASHP, president of the Institute for Safe Medication Practices (ISMP), said the solution is innovative, but he agreed it is unlikely to eliminate the problem of misuse. “I really like what this hospital has done by combining the two types of information, but you have to realize that you’re still going to have nurses who truly believe they’re doing the right thing, think there’s a quirk with the system, and end up using the wrong pen anyway. You have to keep your guard

Technology 11

Pharmacy Practice News • March 2015

Medication Safety up about these errors if you’re going to continue using pens in your hospital.” The ISMP recommended in 2013 that hospitals transition away from insulin pens for inpatient care (http://goo.gl/ s6u1Xf ). Although there is no clear evidence of pathogen transmission from insulin pen misuse, “it can’t be stated enough that pen sharing could lead to such an adverse outcome,” the ISMP stated in a 2014 Acute Care Medication Safety Alert. “The risk is there, and I wouldn’t be surprised if it has happened already,” Dr. Cohen stressed. Dr. Kokura said she agrees with ISMP’s position—as do other institutions. The potential exposure of more than 700 patients to HIV and hepatitis C virus at the Buffalo Veterans Administration Center, in New York, reported in 2013, led the Veterans Health Administration to discontinue inpatient use of insulin pens (with some exceptions) at its facilities (http://goo.gl/rIfA7U).

more than 400 times. Without barcode scanning, the wrong pen could have been used to administer insulin 400 times, a finding that underscores the safety risks of insulin pen use in the estimated 25% of hospitals that do not yet have access to barcoding technology, Dr. Cohen said. Mark F. Lutz, PharmD, CPPS, a drug information specialist at Beaumont Hospital in Royal Oak, Mich., and a faculty member of the ASHP’s insulin pen safety initiative ((www.onepenonepatient.orgg), suggested that hospitals with order- and/ or patient-specific barcoding systems for

insulin pens tap their systems’ reporting capabilities to identify when barcodes are not scanned or when barcodes of wrong patients are scanned. To identify “near misses” or “wrong pen” injections, Dr. Lutz advised looking for “wrong pen” scans triggering alerts, followed either by scans reflecting identification and administration from the correct pen, or no additional scan before documentation that the dose was given. These reports will “go a long way toward helping you understand and evaluate what’s happening at your site,” he said.

He agreed with Dr. Cohen’s assessment that training in proper technique, although essential, only goes so far. “You can educate all you want, but at least half the time or more when an error is made, the person knows the right thing to do but does it wrong unintentionally.” ASHP offers an online toolkit to help hospitals address these and other aspects of insulin pen safety. —Susan Birk Drs. Kokura, Cohen and Lutz reported no relevant ﬁnancial conﬂicts of interest.

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At the ASHP Midyear Clinical Meeting, Dr. Cohen presented data from a multihospital system (not NewYork-Presbyterian) revealing that inadvertent pen misuse persisted even with a number of high-level safety strategies in place, including patient- and order-specific barcodes, one-on-one staff education regarding insulin pen safety and a bedside electronic medication administration record. Following the study, the health system decided to replace insulin pens with 3-mL vials of rapid-acting insulin. During a three-month period, the health system uncovered numerous types of unintentional, systems-related errors and at-risk behaviors by clinicians, all of whom understood proper insulin pen use. These errors included instances in which nurses thought they had the correct patient’s pen and then mistakenly used it to administer a dose. The frequency of scanning was more than 99% for approximately 80,000 insulin pen doses administered. However, this meant that barcode scanning did not occur for 800 administrations of insulin via pen in three months. Errors for these patients could be neither confirmed nor ruled out. Additionally, nurses accidentally picked up the wrong patient’s pen

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1. Data on ﬁle. 2. Golf M, Daniels SE, Onel E. A Phase III, randomized, placebo controlled trial of DepoFoam® bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther. Sep 2011;28(9):776-788. 3. Gorﬁne SR, Onel E, Patou G, et al. Bupivacaine Extended-Release Liposome Injection for Prolonged Postsurgical Analgesia in Patients Undergoing Hemorrhoidectomy: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial. Dis Colon Rectum. Dec 2011;54(12):1552-1159. 4. Simone et al. Center for Drug Evaluation and Research, Application number 022496Orig1s000. 2010. 5. White et al. Use of a continuous local anesthetic infusion for pain management after median sternotomy. Anesthesiology. 2003;99:918-23. 6. Dowling et al. Improved pain control after cardiac surgery: Results of a randomized, double-blind, clinical trial. J Thorac Cardiovasc Surg. 2003; 126:1271-8. 7. Forastiere E, et al. Effectiveness of continuous wound infusion of .5% ropavacaine by ON-Q pain relief system for postoperative pain management after open nephrectomy. Brit J Anaesth. 2008; 101(6): 841-847. 8. Liu et al. Efficacy of continuous wound catheters delivering local anesthetic for postoperative analgesia: a quantitative and qualitative systematic review of randomized controlled trials. J Am Coll Surg. 2006; vol. 203, no. 6, 914-931. 9. Truitt, M. et al, Continuous Intercostal Nerve Blockade for Rib Fractures: Ready for Primetime?, The Journal of Trauma injury, Infection, and Critical Care, Vol. 71, No. 6, Dec. 2011. 10. Beaussier M, El’Ayoubi H, Schiffer E, et al. Continuous preperitoneal infusion of ropavacaine provides effective analgesia and accelerated recovery after colorectal surgery. Anesthesiology. 2007; 107(3):461-8. ON-Q* Pain Relief System. *Registered Trademark or Trademark of Halyard Health, Inc. or its affiliates. © 2015 HYH. All rights reserved. RX Only. MK-00751 3/2015.

12 Technology

Pharmacy Practice News • March 2015

Oncology

Are CSTDs Poised To Break the 50% Adoption Barrier? A

lthough some closed system drugtransfer devices (CSTDs) have been shown to reduce environmental contamination that can occur during the handling of hazardous medications, less than half of the nation’s hospitals use the devices, according to the latest industry figures. But interviews with several users of these drug compounding systems suggest that more widespread acceptance may be in the offing. Part of that increased traction is due to strengthened regulatory language supporting the use of CSTDs. In the proposed update to the United States Pharmacopeia (USP) Chapter <800> on safe handling, for example, new language states that “CSTDs must be used for administration when the dosage form allows” and recommends the use of CSTDs in drug compounding. “The USP chapters numbered under <1000> are federally enforceable standards. As more organizations become knowledgeable about the devices, I expect more will use CSTDs,” said Patricia C. Kienle, BS Pharm, FASHP, chair of the USP Hazardous Drug Subcommittee and Expert Panel. The first step in that learning process is to understand what a CSTD is—at least in the eyes of regulators. The National Institute for Occupational Safety and Health (NIOSH) defines CSTDs as devices “that mechanically prohibit the transfer of environmental contaminants into the system and the escape of hazardous drugs or vapor concentrations outside the system.” As for how CSTDs fit in to the larger picture of safe drug compounding, Ms. Kienle noted that emphasis traditionally has been placed on primary engineering controls, such as biological safety cabinets (BSC) or compounding aseptic containment isolators (CACI), as well as the secondary engineering control—the room in which the BSC or CACI is placed. The proposed USP Chapter <800> now recognizes CSTDs as a third tier of protection, said Ms. Kienle, who is also the director of accreditation and medication safety for Cardinal Health’s Innovative Delivery Solutions business.

The Evidence for Potential Harm Numerous studies have shown that some individuals (e.g., nurses and pharmacists) who work with chemotherapy—one of the most common classes of hazardous drugs—have traces of chemotherapy medications in their urine. In one study, those traces were significantly higher in workers who prepared the medications without using environmental controls, such as a BSC, or personal protective equipment ((J Oncol

Pharm Pract 2011;17[1]:14-19). Additionally, NIOSH has warned that hazardous drug workplace exposures may cause skin rashes, infertility, miscarriage, birth defects and possibly leukemia or other cancers (http://goo.gl/b9vtVk). Several studies conducted over the past 10 years have shown that CSTDs can help protect health care workers from such dangers by reducing workplace contamination from chemotherapy agents. In one of the more recent studies, by Sessink et al, investigators compared surface contamination in 30 U.S. hospitals after cyclophosphamide was prepared using standard drug preparation techniques or BD PhaSeal, a CSTD marketed by BD Medical; the

Clark et al study was not supported by the CSTD manufacturer—“a definite plus,” she said. Still, as do many studies of CSTDs, it has some limitations, she noted. For example, “there are many factors that could affect surface contamination in a year-long period that could not be determined by a single snapshot of 12 wipe samples,” she said. “Also, there are few details on the type of cleaning done just before the last samples were obtained.” Although analyzing the data on CSTDs thus may be problematic, Ms. Power said, that is by no means the main reason why only about 40% of hospitals are using the devices. Until recently, cost has been the main barrier to entry, she noted.

Equashield, BD PhaSeal and the Chemo Safety System (clockwise, left to right) are among the closed system drug-transfer devices that hospitals use to reduce workplace surface contamination during chemotherapy preparation.

device reduced contamination by 86% ( <0.001; Hosp Pharm 2013;48:204-212). (P In another study of a CSTD’s effect on surface contamination, Clark et al focused on use of the Equashield CSTD (Equashield Medical) in an ambulatory cancer chemotherapy infusion center ((J Oncol Pharm Pract 2013;19:99-104). Twelve wipe samples were taken, with each set of sampling done at three different time periods: baseline, 60 days after implementing the CSTD and cleaning procedures, and one year later. Results from sampling at the first two time periods showed low levels of contamination in approximately 50% of the department areas where chemotherapy mixing was taking place, the investigators reported. At the final collection period, no detectable chemotherapy contamination was found, the researchers noted. (In a separate study conducted at the Karmanos Cancer Center in Detroit, investigators found that Equashield also prevented plunger contamination, which the investigators noted can be a major route of exposure to hazardous drugs [[J Oncol Pharm Practt 2014;20:381-385]). Luci Power, MS, RPh, a senior pharmacy consultant, Power Enterprises, San Francisco, pointed out that the

Michael Edwards, PharmD, MBA, BCOP, the director of oncology pharmacy residency at Walter Reed National Military Medical Center, in Bethesda, Md., agreed that while cost has been a main roadblock to more widespread CSTD adoption, that objection is starting to lose some of its power. “I had to justify the CSTD pretty heavily when I put [PhaSeal] in at Johns Hopkins; I didn’t have much trouble putting it in at Walter Reed,” Dr. Edwards told Pharmacy Practice News.

The Evidence for Cost Savings At some hospitals, cost concerns over CSTD implementation have been replaced by a far more encouraging development: actual cost savings. The facilities have found that the devices can help save scarce health care dollars by allowing single-use vials of chemotherapy drugs to be kept for seven days, thus significantly reducing drug waste. (These single-use vials normally must be discarded after six hours if accessed in International Organization for Standardization Class 5 air quality or within one hour otherwise.) In a study led by Dr. Edwards, PhaSeal provided an annual savings of roughly

$700,000 by extending the beyonduse date (BUD) of single-use vials of 25 antineoplastic medications (J ( Oncol Pharm Pract 2013;19:338-347). The savings more than offset the roughly $106,556 the pharmacy spent for the system during the year. Sara Kim PharmD, BCOP, an oncology clinical pharmacy specialist at Mount Sinai Hospital, in New York City, co-authored a study showing that the Equashield CSTD provided a cost savings of $44,192 during a one-month study period. This translated to savings of about $530,000 annually that Dr. Kim and her colleagues attributed to BUD implementation. Given the roughly $235,000 annual cost of the device, the hospital still saved money, noted the researchers, who presented the poster study (1-839) at the American Society of Health-System Pharmacists 2014 Midyear Clinical Meeting in Anaheim, Calif. However, in Ms. Power’s view, the literature on BUD and CSTDs is limited by a lack of hard evidence that the practice is free of risk for microbial contamination. “The U.S. studies published to date for extending the beyond-use dating of single-dose/single-use vials have used media fills, which is not a test for resisting microbial ingress, but a test of aseptic processing,” she explained. “A robust European study did a true microbiologic challenge on protective systems used for the reconstitution and administration of cytotoxic drugs, and found that the devices did not guarantee total sterility of the vial content.” The 2008 study ((Lett Appl Micro 2008; 47:543-548) looked at several device types, including the PhaSeal CSTD. Although Phaseal was associated with the lowest rate of transfer of microorganisms, “the disinfection process used by the investigators was the most significant factor in maintaining sterility,” Ms. Power noted. That point was echoed by the investigators, who concluded that “adequate disinfection of the vial prior to connection remains required.” As for Dr. Edwards’ research, Ms. Power pointed out that although it identified a significant cost savings by not discarding used single-dose/ single-use vials, the study did not test the vials for sterility. “USP Chapter <797> makes it clear that maintaining sterility of a compounded sterile preparation is dependent on the environment, equipment, staff and work practices, which change from one facility to another,” she said. “Any extending of beyond-use dating of single-dose/ single-use vials without appropriate testing in a given facility is a risk to see CSTD ADOPTION, page 27

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14 Technology

Pharmacy Practice News • March 2015

Profiles in Pharmacy

Technology Helps Pharmacists Help Patients in Yuma Y

uma Regional Medical Center (YRMC), a 406-bed facility, is unique, and pharmacists here face many challenges that their colleagues in other U.S. facilities do not see. Located in the southwest corner of Arizona in the city of Yuma, YRMC is at least 180 miles from the nearest U.S. acute care hospital. The city of Yuma has a population of at least 100,000 people, but six months out of the year, the population of Yuma County almost doubles when the “snowbirds” return to Yuma like the swallows to Capistrano, bringing with them ailments, such as heart disease, diabetes and other conditions common to older patients. All of which will be treated at YRMC. Additionally, Yuma sits about 20 miles north of the U.S.-Mexico border, and it is not unusual to treat Mexican nationals who cross the border for care. Yet, despite its size, Yuma feels like Smalltown USA, which is one of its charms, according to Bob Goodwillie, PharmD, MBA, assistant pharmacy director/clinical coordinator of YRMC. More often than not, he said, a pharmacist will run into his or her child’s

are going to see them again.” Dr. Goodwillie tells new hires and residents to treat patients with the “mom principle.” “How would you want your mom treated? I would want medications sent up as quickly and as accurately as possible for my family member.” To accomplish this goal, YRMC relies on technology, but not for the sake of having a new toy, Dr. Goodwillie said. Rather, the hospital uses automation to help pharmacists better serve their community, decrease medication errors, increase patient safety and support the doctors and nurses.

In Two Places YRMC recently installed Phocus Rx (Grifols International), a camera verification system that allows a pharmacist to remotely document and validate the preparation of IV drugs. Two compact, high-definition cameras located outside the hood in the cleanroom ceiling communicate to software that enables pharmacists to review high-resolution images and validate or send a warning message about the product the IV technician is compounding. Because it Flagstaff gs

Using a ceiling camera, the Phocus Rx verification system (shown left) enables a pharmacist to remotely verify and validate the preperation of IV medications.

are never questioned, and it lasts 21 days or longer rather than only a few days.” A pass-through box that only opens one way at a time enables easy distribution from the IV storage area to the cleanroom, which features HEPA filters that help achieve 20 air exchanges per hour. From the automatic hand-cleaning station to the shoe cover dispenser, suiting up for the cleanroom is practically hands-free. The less one has to touch, the fewer surfaces that can be contaminated, Dr. Goodwillie explained. Inside the cleanroom, there is even a hands-free telephone that is voice activated so the pharmacy technician does not need to stop what he or she is doing to touch another surface. All of these devices are also time savers, he said.

Integrated Tactic to Automation

Phoenix Ph ho oenix n Y Yuma

Tucson Tu so

teacher, a neighbor or the local mechanic while walking through the halls of the main hospital building. As if verifying the truth of this statement, a neighbor who was visiting his wife stopped Dr. Goodwillie as he was showing a visitor one of the wards. As they continued walking through another ward, someone else called out a greeting. “Because we are a community hospital, Yuma is not so big that you can hide,” joked Mark Jordan, PharmD, director of pharmacy. “The people who work here and the people we take care of are the same people that we will see in church or the grocery store. You want to be able to walk down the aisle in the grocery store and hold your head high because you delivered good service, because you

is virtual, the validation can be done anywhere in the hospital. The Phocus Rx system was one of the final pieces of a new cleanroom, which is separate from the rest of the pharmacy, enabling the department to more than double its space. When a hospital such as YRMC is located in such a remote area, maintaining adequate inventory levels is particularly important. Where other facilities might reconstitute their IV bags, YRMC found that it resulted in too much waste, so the pharmacists use frozen antibiotics distributed by Baxter. “It costs us more money than if we were going to reconstitute it, but there are other advantages,” Dr. Goodwillie said. “The sterility and accuracy of the preparation

The centerpiece of the main pharmacy is an integrated automation solution by Aesynt, which integrates robotics, barcoding, software and a medication carousel to deliver more than 90% of patient medications. The physician inputs the order through the electronic medical record, which is an Epic system; the pharmacist verifies the order for allergies, drug–drug interactions, dosing and so on; and then the robot fills the order. The various tablets and capsules are repacked into single-dose units that are barcoded and marked with TALLman letters recommended by the Institute for Safe Medication Practices to increase patient safety. TALLman or mixed-case lettering enables pharmacists to highlight the differences in similar-sounding medications, such as predniSONE and prednisoLONE. The single packages go into the robot for dispensing. Once a pharmacist verifies the order, the robotic arm gathers the individual packets and puts them into a barcoded envelope that is marked with the patient information and put into a cart for delivery. Medications are distributed hourly to a locked single-dispensary cabinet outside the patient rooms. (If medications are needed more quickly, they are sent through a pneumatic tube.)

“The robot has done more than 40 million doses without dispensing the wrong medication or an expired medication,” Dr. Goodwillie said. Although it is not new technology, the Aesynt MedCarousel will dispense medications, such as creams and gels that are not suitable for the robot to dispense. “The carousel is also nice for inventory control,” he explained. “Some hospitals will pull meds three or four months before they expire so that they won’t inadvertently give an expired medication. We can actually monitor the expiration date better and wait until the last week before we pull soon-to-be expired medications.” Additionally, the carousel automatically orders supplies as they start to dwindle. “We order it absolutely at the perfect time and if there is a generic product available, it will order

The integrated YRMC pharmacy uses Aesynt robotics and a medication carousel to deliver more than 90% of patient medications. Photos by Marie Rosenthal

Technology 15

Pharmacy Practice News • March 2015

Profiles in Pharmacy the cheapest generic available, which helps keep pricing down. Barring national shortages, we are always going to get the medication the next day,” he explained. “These devices never call in sick and never ask for a raise,” Dr. Goodwillie said, adding that the technology allows the pharmacists to be on the floors with the nursing and medical staff. “We are always a resource,” Dr. Jordan said. “Someone can always call down here and talk with a pharmacist, but when you are a real presence among them, they are more likely to access you.” Inventory control is critical in a rural hospital, explained Dr. Jordan, because YRMC can’t just call up the hospital down the street and “borrow” a needed medication. YRMC can call on the local rehabilitation facility and retail pharmacies for more common items, but for those medications that only an acute care hospital would have, they have to get creative. “We keep a little more stock around than a typical hospital might,” he said. In a few circumstances, they have had to rely on the “nearby” hospitals a couple hundred miles away. Once, a highway patrolman was dispatched to Phoenix to pick up a critical

A pharmacy technician takes the lots of medication and puts them into single-dose packaging labeled with TALLman lettering that increases patient safety.

medication for a patient. Although YRMC is the largest private employer in the county, it can be difficult to find qualified pharmacists and pharmacy technicians. “Yuma can be a tough place to recruit to,” Dr. Jordan said. “No one has Yuma on his or her agenda when they graduate, but once they get here, they want to stay.” YRMC has a postgraduate year 1 general residency program, which showcases the facility and the area to new pharmacists. The residents keep everyone on their toes, according to Dr. Jordan. “These folks just came out of pharmacy school so they have a lot of questions, and we have to be able to answer them.” Additionally, YRMC can capitalize on

their enthusiasm to develop new programs. “Our [anticoagulation] clinic was started after a resident took it on as a project. It is great for our community and it is a revenue generator for the hospital,” Dr. Jordan said. The anticoagulation clinic, which is pharmacy-run under a physician protocol, sees about 600 patients, Dr. Goodwillie explained. “Patients rarely wait more than five or 10 minutes beyond their appointment times,” he said proudly. “And for the most part, they see the same pharmacist every time, so the patients get to know their caregiver and we get to know the patients.” Embracing technology that takes care of the nuts and bolts of dispensing medica-

tions frees up pharmacists to devote time to patient care and working with the nurses and doctors. “They take for granted that things magically appear when they need them, but that is not so easy. You need a good team working with the machinery and the technology,” Dr. Jordan said. “It is no small thing to have a system that will get the right medication in a safe way to the people who need to use it.” Dr. Goodwillie added: “We have great staff. This is the kind of work environment that a pharmacist or pharmacy technician likes to work in. “I love coming to work every day.” —Marie Rosenthal Drs. Jordan and Goodwillie reported no relevant ﬁnancial conﬂicts of interest.

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16 Clinical

Pharmacy Practiiccee New New ews • March 2015

Personalized Medicine Paclitax xel

PHARMACOGENOMICS continued from page 1

Julie Johnson, PharmD, the dean of the University of Florida College of Pharmacy, and who led the launch of University of Florida’s pharmacogenomics program in 2012. “It’s pretty awesome that it’s risen on Obama’s radar,” she added. “It points to the vision that people are unique and that there are things we have to learn both from studies done on large populations and from teasing out differences in individuals.” Evidence continues to underscore how variations in human genetic makeup may help explain differences in individual responses to treatments for cancer, HIV/AIDS and depression, among other health conditions. To date, 138 drugs including codeine, proton pump inhibitors, abacavir (Ziagen, ViiV) and irinotecan now have genetic data in their FDA-approved product labeling. In the case of irinotecan, labeling states that dosage adjustments should be considered in patients who test positive for the UGT1A1*28 allele and who are thus poor metabolizers of the colorectal cancer medication. This genetic variant can lead to severe and potentially life-threatening side effects, especially when irinotecan is given at higher dose levels. If a patient tests positive for UGT1A1*28, prescribers can order lower doses, often with no loss of efficacy ((J Clin Oncol 2006;24[28]:4534-4538). Similarly, data suggest that genetic polymorphisms can influence how patients respond to paclitaxel (Figure 1). In one study, investigators reported a near doubling of the risk for paclitaxel-induced neuropathy in patients with CYP2C8*3 status ((Breast Cancer Res Treat 2012;134[1]:401-410). Fully utilizing this type of genetic information could have profound implications for health care, experts said. In 2013, U.S. pharmacies dispensed 738 million prescriptions whose uses may have been improved with pharmacogenomics (Annu ( Rev Pharmacol Toxicol 2015;55:89-106). Total prescription drug expenditures that same year, according to the Centers for Medicare & Medicaid Services, reached $271 billion. “There’s been a dramatic increase in not only the cost of health care but also the availability of data that helps us select the best therapies for patients,” said Philip Empey, PharmD, an assistant professor of pharmacy at the University of Pittsburgh’s School of Pharmacy. “The completion of the Human Genome Project, and the plummeting costs of getting genetic information on patients, creates an opportunity.” “A few years ago, it was a promise that was coming,” added Dr. Empey. “Now, it’s real.”

Seizing the ‘Opportunity’ The antiplatelet drug clopidogrel was the first drug of focus for Dr. Johnson’s pharmacogenomics team. “At the population level, this drug is really effective in preventing heart attacks and strokes,” she said. “But within that population, there are some people [who are] not benefitting.” Dr. Johnson cited, as an example, the case of 60-year-old man who presented to the University of Florida with a heart attack in October. As Dr. Johnson told ASHP meeting attendees, the patient’s providers did not initially order a pharmacogenomics test and discharged him a few days later with a bare metal stent and a prescription for 75 mg of daily clopidogrel. Dr. Johnson’s pharmacogenomics program team then followed up and ordered the test for *2, *17 and several other rare loss-of-function alleles. The patient turned out to have a CYP2C19 *2*17 genotype. Because clopidogrel is not metabolized in patients with this genetic variant, prasugrel (Effient, Daiichi Sankyo) was therefore a better choice than clopidogrel for this patient. “In the meantime, some bad things happened,” she recalled, noting the patient was readmitted a few days later with in-stent thrombosis. “We can’t prove that those [negative outcomes] wouldn’t have happened if we’d put him on a different drug from the outset. But it’s a definite possibility.” The case came early in the implementation of their clopidogrel program, perhaps before the physicians were comfortable with it, Dr. Johnson noted. (See Figure 2 for a sample pharmacogenomics-driven clopidogrel dosing protocol.) At the University of Florida, a clinical decision support program fires an alert if a drug is not optimal for a patient given his or her genotype—much like a drug interaction warning. And the institution’s list of supported drugs continues to expand. Next up are a variety of pain medications, including codeine and oxycodone. The presence of CYP2D6 genetic polymorphisms can predict how well a patient will metabolize these drugs, Dr. Johnson explained. Pharmacists, she added, remain “front and center” in the program—surrounded by a multidisciplinary team of pathologists, physicians, nurses, phlebotomists and information technology experts. With an in-house pharmacogenomics lab, they’ve achieved 24-hour turnaround times. Outside labs can take days, even weeks. “We’re trying to do our program in a way that might be able to be adopted at different institutions,” she said. James Hoffman, PharmD, MS, BCPS, the medication outcomes and safety officer at St. Jude Children’s Research

Drug selection

Somatic mutations Re esidual dissease de etection

Dosing toxicity risk

Host germline mutations RefSeq genes SNPs Human mRNAs

Figure 1. Pharmacogenomic variations in both the tumor (somatic changes) and normal tissues (germline variants) can influence cancer therapy. mRNAs, messenger RNAs; SNPs, single nucleotide polymorphisms Adapted from McLeod H. Sciencemag.org. 2013;339:1563-1566.

Hospital, Memphis, Tenn., and another presenter at ASHP, helps run the Clinical Pharmacogenetics Implementation Consortium (CPIC). The CPIC aims to address some of the barriers to the use of pharmacogenomics in clinical practice, by offering providers anywhere with evidence-based guidelines for translating test results into prescribing decisions. Behind the guidelines are peer-reviewed studies, like recent research from Dr. Hoffman and his colleagues that found a patient’s genotype can predict response to mercaptopurine, an essential leukemia drug ((Am J Med Genet C Semin Med Genet 2014;166C:45-55). The CPIC also has created informatics tools to further aid clinicians. These tools include passive and active clinical decision support (CDS) programs that are vendor-agnostic and can be applied to any electronic health record, Dr. Hoffman noted.

Gaining Traction Programs like those at the University of Florida and St. Jude are cropping up at more institutions. The Center for Health-System Pharmacy Leadership, in their “Pharmacy Forecast 2015-2019,” reported that 79% of experts surveyed predicted “at least one academic medical center in their region will have a formal pharmacy-based pharmacogenetic information/consultation service for health professionals and patients within the next five years.” “Health care is becoming increasingly integrated. Pharmacogenomics is going to be part of programs led by health systems,” Dr. Hoffman said.

“That’s where the future of health care overall lies, and that’s how pharmacogenomics is going to be more broadly implemented—with pharmacists taking broad leadership roles.”

Roadblocks Remain Still, a number of barriers continue to stymie progress in making pharmacogenomics a standard of care. Cost and limited availability of the tests continue to limit uptake. The University of Florida, for example, has the capability to run multigene tests in its pharmacogenomics laboratory, yet struggles to implement the tool due to a lack of billing codes. “Unfortunately, as is often true, the way that things can be billed or paid influences how things actually get done,” Dr. Johnson said. “We’re still in the very early stages.” Largely driving that payment gap is the state of the science. With the exception of oncology, most currently available pharmacogenomics evidence has not been clinically relevant enough to be translated into practice. “As more evidence emerges, we will be able to move the practice forward,” said Grace Kuo, PharmD, MPH, a professor of clinical pharmacy at Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego. Dr. Kuo created PharmGenEd, an evidence-based curriculum first funded in 2008 by the Centers for Disease Control and Prevention. Its continued goal is to overcome another obstacle impeding progress in pharmacogenomics: lack of education. Courses on the topic are rare in medical schools. The PharmGenEd program’s materials,

Clinical 17

Pharmacy Practice News • March 2015

Personalized Medicine which cover the validity and utility of pharmacogenomic tests and the potential implications of their therapeutic use, now reach pharmacy, nursing and medicine health care professionals in more than 100 countries. Meanwhile, starting in 2016, noted Dr. Kuo, accreditation standards will require all schools of pharmacy in the United States to teach pharmacogenomics/genetics, including “the genetic basis for disease and individual differences in drug disposition that underpins the practice of personalized medicine.” As the terrain of pharmacogenomics continues to expand, education and navigation can become even more difficult. Several types of tests are now offered, including targeted genotypes and broad panels. An evolving regulatory landscape further complicates the scene. “The FDA is becoming more involved in making sure genetic tests are clinically useful before they are marketed,” Dr. Empey said. “It’s a good thing. But it’s a hurdle for innovators.” Drs. Kuo, Hoffman and Empey are among the experts who agree that preemptive testing is the future of pharmacogenomics. By testing and filing away a patient’s genetic profile, the information is ready and waiting whenever it’s needed. Turnaround time is no longer a concern. An approach that uses combinatorial genomics is also showing promise. Assurex Health (sidebar) has conducted five clinical studies with

Figure 2. Pharmacogenomics-driven dosing protocol for clopidogrel. ACS, acute coronary syndrome; CYP, cytochrome P450; EM, extensive metabolizer; IM, intermediate metabolizer; PCI, percutaneous coronary intervention; PM, poor metabolizer

external collaborators that support the cost-effectiveness of its broad-panel weighted test. The latest study, published in February, found that the company’s testing predicts poorer antidepressant outcomes better than results derived from single genes (Pharma( cogenomics J 2015;1-9).

Improving Depression Therapy Honing in early on the best drug is particularly critical in the treatment of depression, noted Bryan Dechairo, the senior vice president of medical affairs and clinical development at Assurex Health, in Mason, Ohio. About one in every two patients fail

to improve on their first antidepressant. What’s more, he explained, it takes about eight weeks to determine whether the drug is working. If, after eight weeks, a patient is among the unlucky 50%, then their expected success on the next attempted treatment drops to about 27%. Response rates fall further to around 15% in the third round (Curr Psychiatr Rep 2007;9:449-459). “You’re in this downward spiral of lower and lower benefits, plus adverse events,” Dr. Dechairo said. By applying knowledge of a patient’s unique genetic information, he added, his company has helped providers nearly double response rates in that

second round—up to 50% (Pharmaco( genet Genomics 2013;23[10]:535-548). Between the moment a swab is taken from the patient and the result is back to the doctor 36 hours later, Dr. Dechairo and his team have used their combinatorial genomics approach to look at eight genes—six related to liver enzymes—as well as two serotonin-pathway receptors in the brain. A weighted algorithm compares a patient’s genetics against these targets and then provides recommendations for a suite of 38 antidepressants and antipsychotics. “Lots of different places are taking a lot of different approaches to figuring out how to implement pharmacogenomics,” Dr. Johnson said. “We’re all learning from each other. There’s not one right way to do it.” —Lynne Peeples Drs. Johnson, Empey, Hoffman and Kuo reported no relevant ﬁnancial conﬂicts of interest. Dr. Dechairo is an employee and stockholder at Assurex Health.

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Outsourcing Helps To Fill In-House Pharmacogenomics Void

mong the obstacles slowing widespread implementation of pharmacogenomics, according to experts, is a lack of staff expertise and equipment in U.S. hospitals. Many institutions—especially smaller community hospitals—simply do not have the ability to conduct and analyze a genetic test. “We’re all still in the pioneering stage, because health systems haven’t fully embraced it,” said Todd S. Eury, a pharmacy entrepreneur with Pennsylvania-based Well Med Rx. “They aren’t sure how to manage it.” Partially filling that void are dozens of laboratories that now offer pharmacogenomic testing. Assurex Health, as one example, specializes in tests that match patients with the best psychiatric drugs for their genetic makeup. (See sample report.) Well Med Rx aims to take this outsourcing a step further. The company provides genetic tests that cover up to 150 FDAflagged cardiovascular, pain management and psychiatric drugs, as well as help on the front and back end. Additionally, their system integrates with most electronic health records to identify patients who may qualify for testing, and they offer template letters and forms and personalized patient prescription reports to help providers use the

test results, among other tools. “When starting a pharmacogenomics program, it does take a pharmacist with expertise in the area,” said James Hoffman, PharmD, MS, BCPS, the medication outcomes and safety officer at St. Jude Children’s Research Hospital, Memphis, Tenn. “You do have to figure out how to develop that expertise, and external partnerships may be needed, especially for pharmacogenomic testing.” Well Med Rx has conducted nearly 1,000 tests since its launch in November 2014, Mr. Eury said, adding that he expects rapid growth in 2015. He also noted that his company is the first at a national level to leverage the pharmacist, rather than the physician, as the go-to clinical coordinator of pharmacogenomic testing. (The pharmacist manages medication therapies and acts as the primary source of health care guidance in collaboration with the physician.) “Expecting a physician, based on how incredibly busy they are, to add this to their plate isn’t realistic,” Mr. Eury said. “It’s never going to happen.” Placing pharmacogenomics as a proactive tool in the hands of the clinical pharmacist, in contrast, “makes absolute sense.”

—L.P.

Dr. Hoffman reported no relevant ﬁnancial conﬂicts of interest. Mr. Eury works for Well Med Rx.

18 Clinical

Pharmacy Practice News • March 2015

Infectious Disease

Start With Internal Data To Streamline IG Therapy Anaheim, Calif.—A multidisciplinary working group of health care providers developed a customized immune globulin (IG) therapy order set to reduce drug waste and enhance clinical decision making and safety for this expensive, complex and frequently prescribed treatment. Launched in 2009, the multiphase initiative joined pharmacists from neurology, critical care, infectious diseases,

transplantation, hematology/oncology, pediatrics and information technology (IT) across the campuses of NewYorkPresbyterian Hospital in New York City, according to Demetra Tsapepas, PharmD, BCPS, the clinical pharmacy manager of the hospital’s solid organ transplantation department. The working group developed a medication use guideline for physicians, pharmacists and nurses to support safer and

more judicious prescribing, dispensing and administration practices. The team also implemented safety measures for specific patient populations related to product choice, noted Dr. Tsapepas, who presented the initiative at the American Society of Health-System Pharmacists’ 2014 Midyear Clinical Meeting. To minimize waste, the working group modified the pharmacy’s traditional IG drug dispensing practice of dispensing all

of the medication for an order in a single vial. This traditional practice resulted in considerable waste, since IG therapy is so frequently adjusted or discontinued based on patient responses. Now, pharmacists label each manufacturer vial for nurses to administer and account for each component of an order. Clinicians can view the total and individual doses administered in the electronic medical record. The change allows nurses to scan a barcode and account for individual vials in the medication administration record as well.

A Checklist For Change

nterested in developing and implementing an IG protocol at your institution? Dr. Tsapepas recommended the following steps:

✔ Establish the need for change. At NewYork-Presbyterian, IVIG therapy represented the institution’s largest drug spend. ✔ Identify the key stakeholders for collaboration. ✔ Vet the process for development and approval through the appropriate committees and departments. ✔ Include an appropriate strategy and infrastructure in your plan. ✔ Plan for training. ✔ Integrate feedback from end users. ✔ Ensure continual quality assurance, safety, data analysis and further optimization.

The working group’s major accomplishment is an IG therapy order set for the computerized prescriber order entry (CPOE) system. The customized entry is embedded with clinical decision support and medical logic modules that guide prescribers through indication and dosing algorithms. These algorithms were created based on a review of internal data. “Continuous updates to commercially available CPOE systems are essential to ensure meaningful use and patient safety, as well as to streamline therapy for special patient populations,” Dr. Tsapepas said. “We were able to drive these collaborations and enhancements and, in the process, optimize IVIG therapy.” All such therapy at NewYork-Presbyterian Hospital is now ordered through the order set. Data for the order set were collected by incorporating a mandatory indication field into the existing IG entry form. Prescribing was monitored for six months. Of 123 unique indications for IG therapy, 74 were included in the order set. Clinical pharmacists developed dosing recommendations that are now an

Clinical 19

Pharmacy Practice News • March 2015

Infectious Disease integral component of ordering. The group also developed and incorporated restriction criteria for indications that are not approved for use at the organization. To provide clinical flexibility, the system includes an “other” field to allow a prescriber to administer an item that is not included on the list if it is appropriate for the patient. The new IG order set asks the clinician to first select the high-level therapeutic condition (immunologic, solid organ transplant, neurologic, oncologic, hematologic), then asks a series of safety questions. If the patient is undergoing plasmapheresis, for example, the system automatically places an order for the nurse to contact pharmacy to make sure IG is appropriately scheduled around this treatment. The order set also selects the appropriate branded product based on the prescriber’s response to a safety question about immunoglobulin A deficiency. The system also prompts the prescriber to select the specific indication (e.g., under neurologic conditions: chronic inflammatory demyelinating polyneuropathy, dermatomyositis, polymyositis and Guillain-Barré syndrome), and automatically defaults the organization-specific approved dosing for the selected indication.

Kudos From the Field Eric M. Tichy, PharmD, BCPS, the senior clinical pharmacy specialist at Yale-New Haven Hospital in New Haven, Conn, congratulated NewYork-Presbyterian Hospital for the extent to which they automated clinical decision support for IG therapy. At his institution, prescribers order a pharmacy consult electronically, indicating the disease they are treating and the dose, and pharmacists verify the orders for accuracy and to ensure formulary compliance. “We verify everything, but we’re not quite as automated as what

they’ve been able to achieve,” Dr. Tichy said. “Whether you have the providers order a consult and answer questions or you have them work through an order set, you’re achieving the same end goal, which is to put some criteria around the use and the dosing guidelines.” Pharmacists at Dr. Tichy’s organization conduct a medical use evaluation for IG agents every two years. “We need to see that the data supports the indications,” he said. For example, some early data showed potential benefit of IG therapy for Alzheimer’s disease, but the

Drs. Tsapepas and Kurian reported no relevant ﬁnancial conﬂicts of interest. Dr. Tichy has been a consultant for Baxter and Grifols.

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A Successful IT Collaboration Dr. Tsapepas stressed the value of internal data as a method of generating organization-specific indications and dosing within the order set. “We relied heavily on the mandatory indication field to drive the rest of the process,” she said. The group worked closely with the health system’s IT Department to implement a mechanism that calculates dosing according to adjusted body weight for obese patients and automates dose rounding to ensure that commercially available products could be used in the dispensing process. “The dispensing process has become efficient, and we are able to optimize drug utilization; each commercial IG vial is labeled and numbered in sequence, making it easy for nurses to follow and ensure the dose is administered in its entirety,” said staff pharmacist Bromley Kurian, BS Pharm. The dose calculation based on the patient’s body weight is also displayed in a box on the order entry screen so the prescriber can double-check the dose. The standardized dosing regimens programmed into the CPOE system have led to reductions in drug use for 17 of the 25 most common indications, slight increases for six and no change for one—“overall, a very positive effect on utilization in total grams,” Dr. Tsapepas reported. Recent improvements have included the addition of premedications to enhance safety. Work has begun to integrate billing codes for each indication to optimize reimbursements.

evidence has not panned out. Although the treament is still expensive, the failure of larger studies to support several other potential new indications for IG therapy has led to a surplus of agents and more competitive pricing, he said. Manufacturers ramped up production in anticipation of increased demand—demand that has not materialized. —Susan Birk

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20 Clinical

Pharmacy Practice News • March 2015

Medication Safety

Preventing Falls—A Success Story Phoenix—Seventeen hospitals in Nebraska have significantly reduced the rate of falls in at-risk patients— with one facility reporting a fivefold decline—thanks in large part to a culture change that embraced a multidisciplinary approach to fall prevention, according to team members who presented the results at the American Hospital Association’s (AHA) Rural Health Care Leadership Conference. The team, which included pharmacists, nurses and other caregivers, used a wide range of tools to achieve its success, including standardized risk assessments for falls, creating and distributing lists of drugs that are most prone to causing falls and bolstering staff education. But none of the efforts would have worked if not for the culture shift that the hospitals embraced at the start of the program, according to Megan Schlaebitz, PharmD, a clinical pharmacist who was part of the interprofessional team at St. Francis Memorial Hospital, in West Point, Neb. Dr. Schlaebitz compiled and distributed the drug lists and also participates in post-fall “huddles” to determine contributing causes.

the incident was not considered a fall, thus thwarting efforts to determine contributing factors that could be targeted in future prevention efforts. The hospital also had no system in place to train staff about fall prevention during orientation. Nurses would put a star on the door frame of a patient’s room and note in the patient’s chart if they thought the person was at risk for falls, but other hospital personnel did not necessarily know what the stars meant. So when the hospital was offered the chance to participate in a University of Nebraska Medical Center research project called Collaboration And Proactive Teamwork Used to Reduce (CAPTURE) Falls, leaders quickly agreed. After pulling together an interprofessional fall risk reduction team and instituting the risk reduction strategies, the hospital’s fall rates dropped dramatically. The fall rate per 1,000 patient-days decreased from 7.1 in 2012 (when St. Francis Memorial started the intervention) to 1.4 in 2014, and the injurious fall rate per 1,000 patient-days declined from 2.28 in 2012 to 1.13 in 2014. Among all 17 hospitals participating in the program, fall rates per 1,000 patient-days decreased from 5.31 to 4.30, and injurious falls decreased from 1.82 to 1.31.

Dr. Schlaebitz then created the drug list, which was a straightforward chart of medications that could increase fall risk, such as tranquilizers, opioids, diuretics, antidepressants and anticonvulsants. The pharmacy began reviewing medication lists before starting patients on new medications, and in one case worked with a physician to discontinue lorazepam for a

risk reduction, are available online at http://goo.gl/ho6W6h.

Pharmacists Need To Be Involved Making sure pharmacists are part of a fall prevention team is key to ongoing success, said Burl Beasley, DPH, MPH, MSPharm, a clinical pharmacist with the Oklahoma Health Care Authority

Need for Action

M Megan Schlaebitz, S hl bit PharmD Ph D (third (thi d from f left), and Carol Kampschneider, RN, MSN (fifth from left) and other members of the interprofessional CAPTURE Falls team at St. Francis Memorial Hospital, in West Point, Neb.

“I feel like almost after every postfall huddle, we identify something that maybe we didn’t realize was a risk, or something else to do to improve,” Dr. Schlaebitz told Pharmacy Practice News. “It really has become a cultural change with people being aware of preventing falls.”

Baseline for Improvement St. Francis, a 25-bed facility, was particularly ripe for a culture change given the historical inconsistencies in its approach to patient falls. For example, the hospital did not have a tool in place to assess patients’ risk for falls, although if a fall occurred, nurses would document it in the patient’s chart during their shift. If hospital staff caught a patient mid-fall and assisted him or her to the ground,

Katherine J. Jones, PT, PhD, the principal investigator of the fall prevention program and an associate professor of physical therapy education at the University of Nebraska, Omaha, and Carol Kampschneider, RN, MSN, St. Francis’ vice president of clinical and regulatory services, discussed their steps to success at the AHA conference. They first noted that the need for such programs is acute: As many as 1 million hospitalized patients fall each year, and 30% to 50% of falls result in injury. As for why it was important to take a team approach to fall prevention, they cited studies showing that fall risk is reduced significantly when interprofessional teams are actively engaged in the effort. Hence, the approach taken at St. Francis, Dr. Jones noted. The team included Ms. Kampschneider, other nurses, a pharmacist, a quality improvement/ patient safety coordinator, a physical therapist, an occupational therapist and a dietitian. With coaching from the university experts, one of the team’s first steps was to evaluate standardized falls risk assessment tools. Nurses did the initial testing and discovered that the Falls Risk Assessment Scoring System (FRASS) worked best for their environment.

Vid Videos that th t teach t h pharmacists h i t and d other th clinicians li i i how h to t handle h dl bedridden b d idd patients ti t in a way that helps prevent falls are available at http://goo.gl/ho6W6h.

patient with multiple falls. The hospital changed its definition of a fall to include assisted falls, and used physical therapists to train other staff in how to assist patients (photo). The team also instituted post-fall huddles held immediately after a patient fall to assess what happened and to make additional changes if necessary. Additionally, patient rooms are stocked with gait belts to help transfer patients, and as noted, magnetized stars that are posted on door frames of patients at risk for falling. “One of my major goals is that small hospitals have access to the same knowledge base as large hospitals,” Dr. Jones said. “What they have now is a tool to learn and improve patient care, and they can apply that to other topics.” Other hospitals participating in the project have started applying similar principles to 30-day hospital readmission rates, she said. St. Francis will extend its program to its assisted living facility, Ms. Kampschneider added. Program materials, including educational webinars on medication review, patient mobility assessment and fall

in Oklahoma City. In his previous position at Oklahoma City’s Mercy Health Center, he developed a medication risk tool to complement a standardized fall risk assessment tool that halved the number of harmful patient falls on medical and surgical units. During that time he would round on patients every morning and make recommendations, such as changing medications if necessary. Even if patients ranked low on standardized fall risk scores, he said, their medications could put their risk higher: “The medication piece is underrecognized in the risk for falls. Not pulling in the pharmacy piece is a missed opportunity.” Hospital staff can take additional steps to reduce patients’ fall risk such as lowering beds, making sure bedside tables are locked and telling patients not to go to the restroom unassisted. Some hospitals use brightly colored booties with nonskid bottoms to identify patients at risk for falls. —Karen Blum None of the sources had any relevant ﬁnancial conﬂicts of interest to disclose.

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22 Clinical

Pharmacy Practice News â&#x20AC;˘ March 2015

Palliative Care

VITAL ROLE continued from page 1

these patients,â&#x20AC;? added co-presenter Kathryn Anne Walker, PharmD, the regional director of Palliative Clinical Outcomes, Research and Education at MedStar Health, a multi-hospital system based in Columbia, Md. Involvement of pharmacists during this challenging time is therefore not just nice, â&#x20AC;&#x153;itâ&#x20AC;&#x2122;s necessary,â&#x20AC;? Dr. Walker noted during the ASHP session. Palliative care is among the new-

est specialties in medicine. Driven in part by an aging society and emerging medical technologies that can prolong life, experts agree that the need may be greater than ever. The culture of the baby boomers has further pushed palliative care into prime time, said Robert Wahler Jr., PharmD, a clinical assistant professor of pharmacy practice in the School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo. â&#x20AC;&#x153;Compared with previous generations,â&#x20AC;? he said, â&#x20AC;&#x153;they [baby boomers] take a more pro-

active approach to their own parentsâ&#x20AC;&#x2122; health care, as well as their own.â&#x20AC;? â&#x20AC;&#x153;Itâ&#x20AC;&#x2122;s forcing us to address end-of-life care much more,â&#x20AC;? added Dr. Wahler. Pharmacists, however, have moved much slower than other disciplines in establishing themselves within the emerging specialty. â&#x20AC;&#x153;This is still seen as a foreign role for pharmacists,â&#x20AC;? said James Ray, PharmD, a clinical pharmacy coordinator for pain and palliative care at University of Virginia Health System, in Charlottesville. â&#x20AC;&#x153;But pharmacists are particularly well

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positioned to work in palliative care.â&#x20AC;? Dr. Wahlerâ&#x20AC;&#x2122;s research demonstrated that acceptance of pharmacistsâ&#x20AC;&#x2122; recommendations strongly predicted the achievement of desired clinical outcomes for patients in palliative care ((Am J Hosp Palliat Care 2011;28[5]:316-320). Other studies underscored the high rate of medication errors in this setting. A survey of two hospice programs found an average of 8.7 medication discrepancies per patient ((Am J Hosp Palliat Care 2009;26[3]:193-199). At least some universities and health systems are starting to take notice of the relatively untapped opportunity. â&#x20AC;&#x153;Youâ&#x20AC;&#x2122;re going to see more and more schools of pharmacy getting on board,â&#x20AC;? said Dr. Ray, who will be leaving Virginia in June for a newly created professorship in hospice and palliative care at the University of Iowa College of Pharmacy, Iowa City. Meanwhile, MedStar Health has made it mandatory that each of its palliative care teams includes a pharmacist. Also, in its statement on palliative therapy, the ASHP noted that pharmacists have a â&#x20AC;&#x153;pivotal roleâ&#x20AC;? to play in hospice and palliative care ((Am J Health Syst Pharm 2002;59:1770-1773). That role goes beyond those traditional to pharmacy. â&#x20AC;&#x153;You canâ&#x20AC;&#x2122;t just be a pharmacist,â&#x20AC;? said Dr. Walker, noting the nontraditional hats a pharmacist may need to wear, from spiritual supporter to facilitator of family meetings. Another important role for the pharmacist: team member. Working with chaplains and music therapists, among others, for example, is novel for most pharmacists, added Dr. Ray. â&#x20AC;&#x153;Doing this kind of work does take a village,â&#x20AC;? he said. â&#x20AC;&#x153;Everyone brings different strengths to the table.â&#x20AC;?

Tough Transitions Teamwork is especially crucial during the frequent health care transitions that occur at the end of life. The average patient goes through three. Dr. Walker recalled a recent case in which multiple specialists were involved as a patient was discharged from the hospital to hospice care. The endocrinologist changed the patientâ&#x20AC;&#x2122;s insulin dose after the primary care physician had already written the discharge plan. Fortunately, Dr. Walker was able to catch the discrepancy before the patient actually left the hospital. Chances for mix-ups may be particularly great given how many drugs a person may take during this life stage. Another patient of Dr. Walker was on 35 medications. Such lists can also evolve quickly as a result of rapid changes in health. Common end-of-life symptoms include pain, constipation, shortness of breath, nausea and delirium. So a patientâ&#x20AC;&#x2122;s treatment regimen may be supplemented to

Clinical 23

Pharmacy Practice News • March 2015

Palliative Care

include drugs such as opioids, anticholinergics and antipsychotics. What’s more, the use of those drugs, in turn, may trigger other changes. A stimulant laxative may be needed alongside an opioid, for example, due to the latter’s side effects. Organ dysfunction at the end of life can further complicate treatment. Impacts on metabolism or the ability to swallow, for example, can affect the benefits and risks associated with certain medications. Modifications may then be needed in dosage and route of administration. “We need more transparent communication during the last few weeks and months,” Dr. McPherson said. “Sometimes it is switching drugs; sometimes it is not drugs at all.”

‘More Harm Than Good’ “Mrs. J” represents a typical patient seen by Dr. McPherson. The 78-year-old woman is in a long-term care facility and meets hospice guidelines for admission with a FAST (Functional Assessment Staging) score of 7C, indicating advanced dementia. She has suffered repeated falls over the past three months, and is receiving lisinopril, pravastatin, memantine hydrochloride (Namenda, Forest Labs) and donepezil (Aricept, Esai). She dry heaves after taking the latter. A pharmacist, Dr. McPherson noted, must look at all the benefits and burdens of the drugs. “When do you say enough already of the statins or enough of the drugs for dementia? At some point, those drugs can do more harm than good,” she stressed. In the above case study, she suggested that pravastatin would be unlikely to alter the patient’s risk for cardiovascular disease and could be safely discontinued. Depending on the patient’s blood pressure, lisinopril might be discontinued as well. Meanwhile, care also would need to be taken should other drugs be added to the patient’s regimen, such as pain medications, which can actually worsen dementia. It can be a delicate balance. Some of the side effects of a patient’s drug regimen can lead to a “cascade of prescribing,” added Dr. Walker. “Sometimes, when you peel some medications back, it really cleans things up.” Furthermore, the benefits of discontinuing unnecessary drugs may go beyond patient comfort to cost savings. Upward of $600 million could be saved annually if patients who have a late-stage fatal illness stop taking statins, according to a study (abstract LBA9514) presented at the 2014 annual meeting of the American Society of Clinical Oncology, in Chicago.

“Sometimes, if we don’t give everybody and their mother Nexium at $6 a day, then maybe when we really need a $3,000 drug for bowel obstruction we can use that appropriately,” added Dr. McPherson. “We can provide more care to more people if we can make it more cost-effective.” Palliative chemotherapy is among the pricier regimens. A growing body of evidence suggests that the treatment can actually worsen symptoms and decrease the quality of life. A study by Wright et al ((BMJ J 2014;348:g1219) found an

association between the use of chemotherapy during the last months of life and increased risks for cardiopulmonary resuscitation, mechanical ventilation and dying in the ICU. Palliative care itself, on the other hand, has been found to be beneficial in oncology. A study by Temel et al ((N Engl J Med d 2010;363:733-742) found that early integration significantly improved both quality of life and mood, and even lengthened survival, for patients with metastatic non-small cell lung cancer. In the face of the evidence, and their

own experiences, experts noted that part of their motivation to propel pharmacy into palliative care might just be a bit of selfishness. “Quite honestly, we’re all going to die,” Dr. Ray said. “When my time comes, I hope people around me know what they’re doing and know how to take care of my symptoms.” —Lynne Peeples Drs. McPherson, Walker, Ray and Wahler reported no relevant ﬁnancial conﬂicts of interest.

24 Clinical

Pharmacy Practice News • March 2015

Biosimilars Expert Q&A:

Entering the New Era of Biosimilars W

ith an FDA advisory committee’s recent support for the approval of Sandoz’s filgrastim biosimilar, pegfilgrastim, health care has entered uncharted drug territory. How will payors, health systems, providers and Pharmacy and Therapeutics (P&T) committees take to the availability of these agents? What factors will affect the decision to use or not to use them? Ali McBride, James Stevenson, To gain insights into this emerging new drug PharmD PharmD, MS class, Pharmacy Practice News spoke with James Stevenson, PharmD, the president of Hospital & Health Systems Services at Visante Inc., a consulting firm with offices in St. Paul, Minn., Toronto and London; and Ali McBride, PharmD, MS, the clinical coordinator of Hematology/ Oncology at the University of Arizona Cancer Center, in Tucson. PPN: What is a biosimilar and how is it different from a generic? Dr. Stevenson: A biosimilar is a copy of a “reference” biologic product. Because biologics are much larger and more complex molecules than smallmolecule generics, and are produced through more complicated processes, it is virtually impossible to create an exact duplicate of a biologic drug. Therefore, the FDA’s approval process is designed to ensure that biosimilars are clinically similar, meaning they can be expected to produce a similar level of clinical efficacy and safety as the reference drug. PPN: Is the FDA’s biosimilar approval pathway adequate for ensuring timely, safe marketing of these products? Dr. Stevenson: The complexity of these agents means the FDA cannot use a single parameter to assure that biosimilars will behave in a similar manner to the reference product. Rather, they have taken a “totality of the evidence” approach, meaning they require the biosimilar manufacturer to conduct a series of evaluations, including pharmacoki-

netic, pharmacodynamic, preclinical and clinical testing, to demonstrate biosimilarity. That approach is very similar to that of the European Medicines Agency (EMA), which has successfully brought biosimilars to market since 2008. PPN: To what extent will biosimilars replace their reference products? Dr. Stevenson: That will depend largely on pricing and contracting arrangements. If the savings are significant, payors will likely take steps to encourage the use of biosimilars, such as offering reimbursement incentives to providers and copayment/coinsurance support to patients. Stakeholders making formulary decisions will also consider the extent and quality of resources offered by biosimilar manufacturers, such as patient assistance programs, copay foundations and other important services to help ensure access to, and compliance with, medications. But we are indeed in uncharted territory: Because the first biosimilar was only just [recommended for approval] in the United States and it has not yet been marketed, it’s not clear what resources

biosimilar manufacturers will be offering. Dr. McBride: The most critical factor in determining interchangeability between biosimilars and their reference products will be clinical equivalence, and so it’s important to think about surrogate vs. therapeutic end points. In the case of Sandoz’s filgrastim biosimilar, I suspect it will be an easy fit into oncology practice, since it has met the surrogate end points of neutrophil engraftment acceleration and febrile neutropenia prevention. However, biosimilars of monoclonal antibodies such as rituximab [Rituxan, Genentech] and trastuzumab [Herceptin, Genentech] will need to demonstrate similar curative and therapeutic end points—not simply surrogate end points—as their reference products to be widely adopted. Oncology clinicians will expect to see the same percentages of progression-free survival or overall survival with these biosimilars as the reference product. But here’s the challenge: those therapeutic end points will be more difficult to demonstrate because of the complexity of clinical trials required. Furthermore, the data will be very closely scrutinized by clinicians, P&T committees and payors, as they decide whether these biosimilars are acceptable. So there may be more reservations than anticipated in adopting these biosimilars. Many other factors will affect biosimilars adoption, including payor and reimbursement models, pharmacovigilance requirements, institution-specific considerations and the availability of clinical support services for patients. Other issues include whether there are any challenges integrating the drug’s use into our electronic medical record systems,

and whether payors themselves have a preference because of pricing contracts or other financial incentives. PPN: Are P&T committees capable of making informed formulary decisions regarding biosimilars? Dr. McBride: It will be very important to provide all stakeholders with adequate education on biosimilars. Understanding the differences in the approval processes for biosimilars and chemical drug therapies, for example, will be critical for administrators, pharmacists, physicians and other health care professionals in deciding which agents to use. How the Sandoz product hits the U.S. market will be important in terms of laying down the foundation of knowledge upon which P&T committees and other stakeholders will evaluate future biosimilars. PPN: How much of a cost savings is possible with biosimilars? Dr. Stevenson: Discounts in the range of 20% to 30% are being projected. In Europe, those discounts have led manufacturers of reference products to offer discounts to national governments to retain their market share. I expect reference product manufacturers in the United States will also create contract proposals to try and retain their own market share. —Reported by David Wild Dr. McBride reported serving on the advisory board for Hospira. Dr. Stevenson reported serving on the advisory boards for Amgen and Baxter.

Oncology

CHEMO ERRORS continued from page 1

The most common reason for error was wrong dose (38.8%), followed by wrong drug (13.6%), wrong number of days supplied (11.0%) and missed doses (10%). Roughly one-third of the mishaps were due to pharmacy dispensing errors. “That is significantly higher than most medication safety studies,” Mr. Muller said. “Usually, if you look at [the literature], dispensing errors are typically responsible for about 15% of events.” Most errors identified in the study resulted in a near miss, but 39.3% of reports involving the wrong number of days supplied resulted in an adverse drug event, he pointed out. (For more details on common causes of oral che-

motherapy errors, see Tables 1 and 2). Confusion caused by similar-sounding drug names or the use of abbreviations is a special challenge with cancer agents. “Many oral cancer agents have a common suffix of ‘nib’ and have the same size and color for all dosage strengths,” Mr. Muller said. To guard against medication errors, MSKCC uses electronic alerts and posters to educate clinicians about lookalike/sound-alike medications, refers to all drugs by their generic names, and uses the TALLman lettering system, which uses upper- and lowr-case letters (SORAFenib or SUNITinib) to help distinguish between similar drug names. As an additional safeguard against medication errors, MSKCC has a computerized prescriber order entry (CPOE) system that contains more than

3,000 customized order sets for chemotherapy, including oral agents. A CPOE system is “one of the single best things” that a cancer center can implement to reduce errors, Mr. Muller said. Indeed, one study showed that e-prescribing cut medication errors in half ((J Am Med Inform Assoc 2013;20:470-476). Having a full electronic medical record (EMR) system also can help boost medication safety, Mr. Muller noted, adding that at MSKCC, 100% of the medical records are electronic. The EMR system tracks inpatient and outpatient doses and provides cumulative dose tracking to warn clinicians when they are nearing the maximum dose allowed. “There is an automatic interface for 125 drugs that interfere with common laboratory tests; height and weight limits

are embedded,” he said. “We have an incredibly robust electronic system to report and review actual and near-miss events, which tend to improve our care.” Additionally, clinicians are encouraged to refer to clinical guidelines that are accessible online via thousands of computers throughout the hospital, and there are two- to three-page drug information summaries for all oral cancer agents, Mr. Muller noted.

Comorbidities a Concern Mr. Muller noted that managing comorbidities in patients taking oral cancer medications can be tricky. Adjustments often have to be made to concomitant drugs, which could include oral anticoagulants, proton pump inhibitors, antifungals, vitamins and many others

Clinical 25

Pharmacy Practice News • March 2015

Oncology (Table 3, page 26). But those adjustments may never occur if, during the course of cancer treatment, the patient isn’t asked about other medications they may be taking, Mr. Muller noted. “There are a lot of drug interactions that we don’t see when we have a patient in a chair having IV chemo infused,” he said. Thus, “we strongly encourage a comprehensive [medication] profile and have the patient record everything that they take, including alternative meds, vitamins, etc.” Poor adherence to oral cancer drug regimens is another potential problem spot that can introduce a medication error. “One patient came back and said, ‘I figured if I’m supposed to take one tablet twice a day, then two tablets twice a day might work better,’” Mr. Muller said. It is thus important to stress to patients that no dose adjustments can be made without a physician’s approval. Patients also must be cautioned to not crush, break or chew tablets because doing so can affect the pharmacokinetics of some drugs, he added.

Table 1. Common Causes of Cancer Chemotherapy Errors Miscommunicated verbal orders

Table 2. Sample of Oral Chemotherapy Drug Errors Drug

Error

Methotrexate

Multiple deaths caused by accidental daily administration when weekly was intended

Lomustine (CCNU, Bristol-Myers Squibb)

Given daily instead of every 6 wk. A patient took 450 mg instead of intended 150 mg: patient died

Idarubicin (Idamycin, Pfizer)

An oral dose of 60 mg was given daily for 4 d instead of a single dose over 4 d

Temozolomide (Temodar, Merck)

Physician ordered 10-fold overdose resulting in patient death

Capecitabine (Xeloda, Genentech)

Many dispensing errors cited due to multiple dosage forms and regimens

Source: Guide to Prevention of Chemotherapy Errors 2012; Cancerr 2010;116:2455-2464; ISMP Med Safety Alert, July 17, 2014; ISMP Med Safety Alert, February 12, 2013.

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Excessive interruptions during order processing Lack of patient information, such as past medications, lab data and demographics Poor packaging/labeling Confusion because of similarsounding drug names or the use of abbreviations Legibility issues due to handwriting or a poor copy/fax Misunderstanding total course dose given every day Failure to round a dose

Advancing Ambulatory Care Practice Through Education

Innovate, Implement, Interactive, Ideas, Improve

A Meeting for the Entire Patient Safety Team

Professional, Provider Status, Practical, Prevention

Miscalculation in the ordering or dispensing process Drug shortages, which lead to drug concentration changes or the use of alternative agents

Mr. Muller also stressed the importance of taking a standardized approach to chemotherapy administration. In fact, he recommended that cancer centers standardize everything (e.g., order sets, calculation methods, supportive therapy approaches and emergency management of reactions) and regularly assess staff competency. When consistent protocols are combined with team care, medication safety can improve significantly, he noted. In one study, a pediatric cancer center that see CHEMO ERRORS, page 26

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26 Clinical

Pharmacy Practice News • March 2015

Oncology Table 3. Selected Drug Interactions With Oral Antineoplastic Agents

CHEMO ERRORS

Capecitabine (Xeloda, Roche)

Increases serum levels of oral anticoagulants, phenytoin

continued from page 25

Dasatinib (Sprycel, Bristol-Myers Squibb)

Avoid proton pump inhibitors or H2 antagonists, St. John’s wort

Everolimus (Afinitor, Novartis)

Avoid phenytoin, carbamazepine, voriconazole (Vfend, Pfizer), posaconazole (Noxafil, Schering-Plough)

Imatinib (Gleevec, Novartis)

Do not give warfarin. Use low-molecular-weight heparin instead

Nilotinib (Tasigna, Novartis)

Do not use in patients with hypokalemia, hypomagnesemia or long QT syndrome; avoid most cardiac medications

used a multidisciplinary team approach involving clinical pharmacy specialists, oncologists and nurses, achieved a 0.18% actual chemotherapy error rate ((Pediatr Blood Cancerr 2013;60:1320-1324).

The Power of Actual Events MSKCC regularly distributes the ISMP Medication Safety Alert and periodically offers educational programs about medication errors using actual

Sou ce J Oncol Source: O co Pract actt 2014;10(4):e255-e268. 0 ; 0( ) e 55 e 68

events. “Staff respond much better to [actual events]; they think, ‘if it can happen to one of my colleagues who

I respect, it could certainly happen to me,’” Mr. Muller said. To further strengthen staff education, MSKCC

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provides annual competency pharmacy tests and an annual chemotherapy error prevention course for medical oncology fellows. Several medication safety experts interviewed by Pharmacy Practice News echoed Mr. Muller’s cautions and concerns about medical errors with oral antineoplastic drugs. Joseph Bubalo, PharmD, an oncology pharmacy specialist, Oregon Health & Science University, in Portland, noted that the pharmacokinetics of these medications make them particularly prone to mishaps if not managed appropriately. “Most of the oral agents are metabolized by liver enzymes that metabolize lots of other drugs, and some new agents change the metabolism of other drugs,” he explained. Ginah Nightingale, PharmD, BCOP, an oncology pharmacy specialist at Thomas Jefferson University Hospital, in Philadelphia, agreed that the complex nature of the new oral targeted cancer treatments can pose problems. “The newer small-molecule tyrosine kinase inhibitors are definitely complex, in terms of how to take them,” she said, adding that the look-alike, soundalike issue adds another layer of risk. “Sunitinib [Sutent, Pfizer], pazopanib [Votrient, GlaxoSmithKline], sorafenib [Nexavar, Bayer] regorafenib [Stivarga, Bayer] … I think all of these drugs sound alike, and they also have their own independent drug–drug interactions and their own independent nutritional considerations.” Added Dr. Nightingale, “Between the indications, spellings, drug–drug interactions and dietary considerations, I look everything up, because it is hard to keep everything straight.” Although oral cancer agents are challenging to manage, Mr. Muller believes pharmacists and other clinicians are making strides in terms of safety. “Many academic centers in the U.S. have safeguards, including electronic prescribing and guidelines,” he said. “I think we, as a medication management community, have gotten considerably safer in the past five years or so.” —Kate O’Rourke Mr. Muller and Drs. Bubalo and Nightingale reported no relevant ﬁnancial conﬂicts of interest.

Technology 27

Pharmacy Practice News • March 2015

Oncology

CSTD ADOPTION continued from page 12

patient safety.” Ms. Kienle also stated that BUD and other waste avoidance practices, sometimes referred to as drug vial optimization, have not been studied adequately.

Currently Available Devices Five CSTDs are FDA-approved for use in the United States: BD PhaSeal, Equashield, CareFusion’s Chemo Safety System, ICU Medical’s ChemoClave Needle-free Closed System Transfer Device, and Onguard Contained Medication System (B. Braun Medical). USP Chapter <800> proposes that “since there is no published universal performance standard for evaluation of CSTD containment, users should carefully evaluate the performance claims associated with available CSTDs based on independent studies and demonstrated containment reduction.” Dr. Edwards emphasized the importance of thorough research when choosing a CSTD. “Hospitals should rely on literature produced by independent sources, not companies,” he said. According to Ms. Kienle, “there is confusion concerning evaluation of CSTDs that are on the market.” Ms. Power agreed. The FDA’s process for clearing CSTDs for marketing may be of limited help in choosing a given device, Ms. Power noted. In 2012, the agency established a new category of CSTDs, where a new “ONB” code designates that a product can be used for hazardous drug reconstitution and transfer. However, the FDA, regardless of the product’s ONB code status, grants clearance to market based on a new CSTD device being substantially equivalent to a “predicate” device, Ms. Power pointed out. “Many pharmacists think that the FDA uses the same, extensive testing process for medical devices that it does for drugs,” she said. “This is not the case, and pharmacists or any user selecting a CSTD must be aware of this.”

—Sara Kim, PharmD, BCOP for successful CSTD implementation: the process works best when a team approach is taken. “This is a task for an interdisciplinary group, including nursing, pharmacy, risk management and others who can evaluate products

and oversee workflow in the pharmacy and oncology areas,” Ms. Kienle said. “Staff also needs to be included, since they will be the ones who use the CSTDs. Organizations should also ask vendors for peer-reviewed literature

Ms. Power has worked with BD, CareFusion, Equashield and TEVA. Drs. Edwards and Kim, and Ms. Kienle, reported no relevant ﬁnancial conﬂicts of interest.

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Vendor Selection In choosing a CSTD vendor, Dr. Kim said hospitals should consider whether a CSTD product has obtained an FDA marketing clearance that recognizes the device’s BUD capabilities. “PhaSeal and Equashield have been cleared by the FDA to prevent microbial ingress for up to seven days in an ISO Class 5 environment,” she said. She stressed, however, that “institutions that employ [BUD] using these CSTD products are required to prove that they have good internal procedures in place to manage this process safely.” All clinicians interviewed for this article agreed on another important tip

that demonstrates the containment properties of their products.” User friendliness is another key consideration. “Some products may be less user-friendly and/or more time-consuming to use than others,” Dr. Kim said. “Performing a pilot trial before implementing a CSTD hospital-wide is a wise choice.” —Kate O’Rourke

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28 Clinical

Pharmacy Practice News • March 2015

Pain Management

STEWARDSHIP continued from page 1

Identification of untreated pain

$48,708

adverse events, nearly $400,000 of which was directly attributed to the stewardship components of the program, according to Richard Poirier, PharmD, a pain management clinical pharmacy specialist at Kaweah Delta Medical Center in Visalia, Calif., who helped develop the Pharmacy Pain Management Service (PPMS) program. The PPMS team also reduced opioid-associated rapid response and Code Blue calls by nearly 60% over a nine-month period after the program was rolled out, according to Dr. Poirier, whose team presented the initiative at the 2014 Midyear Clinical Meeting of the American Society of Health-System Pharmacists (ASHP). “These are very impressive outcomes,” said Benjamin Stevens, PharmD, who is a medical information officer at APCER Pharma, a consulting firm located in Princeton, N.J., that specializes in drug safety reporting, medical information and regulatory affairs. The improvements “can certainly be used to justify rolling out this protocol in other health systems,” said Dr. Stevens, who was not involved in the project and has previously published research on opioid oversedation. Dr. Poirier said he and his colleagues developed the PPMS after the Joint Commission issued a warning on safe opioid use in hospitals ((Sentinal Event Alert 2012;49:1-5). “We wanted to optimize use of pain management pharmacotherapy, minimize opioid-associated adverse events and costs, and improve HCAHPS [Hospital Consumer Assessment of Healthcare Providers and Systems] scores specific to pain management,” he explained. To achieve these goals, three fulltime clinical pharmacists with specialized pain management training were assigned to conduct a combination of proactive opioid stewardship activities and as-requested consultations for adult patients admitted to general medical or surgical floors or intermediate ICUs. The stewardship component comprises a daily review of lists that include patients who are deemed to be at risk for opioid-related complications or inadequate analgesia, such as those using more than four doses of as-needed pain medication in the p previous 24 hours, patients w with risk factors for opioidrelated oversedation (box) and individuals prescribed high-risk opioid medications, such as opioid dripss, patient-controlled analgessia pumps, fentanyl patches and a methadone.

Alternative drug recommendations

$75,208

$51,057

Drug interactions and incompatibilities Prevention or management of adverse drug effects

$27,324

Adjustment of dosage, frequency or route of administration

$171,600

$373,897 Total Cost Savings With Stewardship Interventions a

Data collected over nine months.

Figure. Indirect cost savings with stewardship interventions.a

‘These are very impressive outcomes ... [and] can certainly be used to justify rolling out this protocol in other health systems.’ —Benjamin Stevens, PharmD “We want to make sure these agents are dosed appropriately, taking into consideration whether a patient is opioid-tolerant or opioid-naive,” Dr. Poirier said. Provider-requested opioid consultations include a complete review of a patient’s medical records, a meeting with the patient to assess his or her pain, and treatment recommendations based on the obtained information. PPMS recommendations can include adding adjunctive pain medications for untreated pain, dose adjustments or conversions to alternative lower-risk pain medication. “Our PPMS pharmacists also perform daily rounds to evaluate the efficacy of newly implemented analgesic regimens

and to assess the presence of drugrelated toxicity,” Dr. Poirier added. Finally, within two to three days of hospital discharge, a PPMS pharmacist attempts to contact patients they have provided consults for, with the goal of ensuring patients’ pain is managed effectively and safely, as well as to check that any insurance-related barriers to pain treatment are addressed while the patients wait for a follow-up outpatient appointment. This followup component reduces the risk for readmission, he explained. Word of the program spread quickly, with 1,335 interventions—81% of which were consult-related—carried out over the nine-month period after the program’s launch in October 2013, he not-

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ed. Over the same period, he said, there was a 59% drop in opioid-associated rapid response and Code Blue calls. “We also saw an overall decrease in use of opioids, particularly high-dose parenteral hydromorphone and transdermal fentanyl,” added Dr. Poirier, noting that despite a decrease in opioid usage, pain-specific HCAHPS scores simultaneously increased “to an alltime high for our institution.” The researchers used published cost avoidance data ((Pharmacotherapy 2003; 23:113-132) to estimate the average value of each intervention at $1,000 to $2,000. Based on direct interventions they performed and documented, they estimated a cost avoidance savings of $1,622,449 during the nine-month period. Although only $373,897 of the savings were stewardship-related (Figure), Yleana Garcia, PharmD, who is a pain management clinical pharmacy specialist for the PPMS, said more staff time could have led to greater savings. “Because of the potential for greater cost avoidance and, most importantly, decreased preventable rapid response and Code Blue calls attributed with opioid stewardship interventions, we are requesting a half FTE [full-time equivalent] to be dedicated to stewardship alone,” said Dr. Garcia, whose team received an ASHP Best Practices Award for its project.

A Strain on Resources PPMS pharmacists were initially meant to spend roughly equal time performing consults and stewardship activities, but Dr. Garcia said, “Provider satisfaction with the consult service resulted in an increase in the number of consults, which has decreased time allocated doing stewardship.” Other PPMS initiatives have also chipped away at their resources, she added, including institutional pain management order set revisions, ongoing pain medicine education to providers and nurses, and reviews of newstart fentanyl patches to ensure dosing takes prior opioid use and age into consideration. Although he is enthusiastic that the Kaweah program is replicable at other institutions, Dr. Stevens said comparing the hospital’s overall opioid use on a per-patient basis with that of other sites of care would help determine whether other facilities should expect similar results. “If other health systems have similar patient populations and opioid use rates, I would assume these [outcomes] could be carried over to other institutions with equally strong results.” —David Wild Drs. Garcia, Poirier and Stevens reported no relevant ﬁnancial conﬂicts of interest.

Clinical 29

Pharmacy Practice News • March 2015

Oncology Reports From ESMO:

Phase III Trial Results Refute Earlier Findings Negative studies in breast, lung, pancreatic cancers confirm value of this test of benefit Madrid—Five Phase III trials testing potentially practice-changing approaches to cancer control delivered negative results at the 2014 Congress of the European Society for Medical Oncology (ESMO). The results, some of which were presented as late breakers at the Congress, were highly anticipated and each yielded a surprising refutation of a promising hypothesis. The number of failed Phase III trials provides particular reinforcement for the need for multicenter trials, regardless of the promise of clinical data from smaller studies.

HER2-Negative Breast Cancer: RESILIENCE In women with HER2-negative metastatic breast cancer, sorafenib (Nexavar, Bayer) provided a highly significant progression-free survival (PFS) advantage over placebo ((P<0.001) when added to capecitabine in a Phase II trial. In a confirmatory Phase III trial presented at ESMO, called RESILIENCE (abstract LBA8), no such benefit was observed. In fact, there was a trend for worse overall survival (OS) for those who received sorafenib. In this multinational double-blind trial, presented by Jose Baselga, MD, PhD, the physician-in-chief and the chief medical officer at Memorial Sloan-Kettering Cancer Center, in New York City, 537 women with locally advanced or metastatic HER2negative breast cancer were randomized to receive sorafenib or placebo in combination with capecitabine. Most of the treated cancers were hormone receptor–positive, but about one-third were triple-negative. Almost 60% of the patients had received prior chemotherapy.

The median PFS was 5.5 months in the sorafenib arm and 5.4 months in the placebo arm ((P=0.4). The median OS was 18.9 and 20.3 months, respectively. There were no differences in objective response and most other measures

of activity. Grade 3 or higher adverse events (AEs) were more frequent in the sorafenib arm (64.3% vs. 43.5%). Despite the Phase II results and the theoretical benefits from a tyrosine kinase inhibitor (TKI) with both antiangiogenic and antiproliferative effects, RESILIENCE was soundly negative.

Adjuvant Immunotherapy In NSCLC: MAGRIT Trial In patients with completely resected non-small cell lung cancer (NSCLC), a Phase II trial suggested that adjuvant therapy with a vaccine targeting the MAGE-A3 (melanoma-associated antigen-3) protein could delay progression

when administered with an immunostimulant. In the Phase II study, a variety of outcomes favored the vaccine, including OS, although none were statistically significant in the relatively small study. In a larger multinational Phase III trial called MAGRIT, the therapy was well tolerated, but there did not appear to be even any trends for clinical benefit after a mean 38 months of follow-up. Characterized as the largest trial ever conducted in NSCLC (N=2,272) and the first to evaluate adjuvant immunotherapy in early NSCLC, the study showed no relative advantage for the recombinant MAGE-A3 immunotherapeutic, even in a careful analysis of subgroups, according to investigator Johan K. Vansteenkiste, MD, of the Respiratory-Oncology Unit at University Hospitals of Leuven, in Belgium. MAGE-A3–positive NSCLC, which is identified in about 35% of patients with resectable NSCLC, was required for trial enrollment. MAGE-A3 is expressed by several cancers besides NSCLC, including melanoma and some hematologic malignancies, and is an attractive target for immunotherapy. Although the therapy was well tolerated, with no difference in grade 3 or higher AEs observed in the two arms of the MAGRIT study, the disappointing results do not encourage further study.

Repeated Course of Gefinitib In NSCLC: IMPRESS Anecdotal experience has suggested that continuation of a TKI beyond disease progression (as defined by RECIST criteria) might provide benefit to patients with NSCLC that is positive for an activating epidermal growth factor receptor ((EGFR) mutation who responded previously to a first-line TKI before developing resistance. New Phase III data from the IMPRESS trial proves otherwise. In the randomized, multinational trial, the PFS was the same (5.4 months) in those randomized to receive the TKI gefinitinb and those given placebo on top of the cisplatin-pemetrexed doublet. The IMPRESS trial randomized 265 patients who had metastatic NSCLC with an activating EGFR mutation at disease progression after first-line gefitinib. There were no differences in objective response. Although the OS analysis is not yet mature, the hazard ratio (HR) in follow-up at the time of analysis suggested a relative disadvantage for the addition of gefitinib (HR, 1.62; P=0.0029). Although there was no additional or unexpected toxicity with the combination, investigator Tony S.K. Mok, MD, a professor of clinical oncology at the Chinese University of Hong Kong, concluded that patients with EGFR mutation–positive NSCLC should receive chemotherapy alone after development of clinical resistance to first-line EGFR TKI treatment.

showed that chemoradiation is feasible and did not complicate surgery, but no conclusion could be drawn about its routine use in clinical care.

Adjuvant Therapy in Pancreatic Cancer: CONKO-006 Although a Phase IIb, rather than Phase III trial, CONKO-006 was characterized as the largest clinical trial ever conducted in R1-resected pancreatic cancer. It tested the ability of adjuvant sorafenib plus gemcitabine to improve disease-free survival (DFS) after surgery over adjuvant gemcitabine alone. The DFS difference was one month (9.6 vs. 10.7 months); it was not statistically significant ((P=0.89), and favored gemcitabine alone. Moreover, AEs, including those that were grade 3 or higher, were more common among patients who received sorafenib.

Neoadjuvant Radiation in Locally Advanced NSCLC: SAKK 16/00 Radiation is a common adjuvant therapy in patients with locally advanced NSCLC, but providing radiation with chemotherapy before surgery produced ambiguous results in a multinational Phase III trial called SAKK 16/00. In this trial, which randomized 232 patients at 23 centers, all the patients received three cycles of neoadjuvant cisplatin and docetaxel but were randomized to receive a concomitant boost of radiotherapy delivered in 22 fractions over three weeks. Relative to chemotherapy alone, the addition of radiation increased response rates and the proportion of patients who achieved a complete resection, but it failed to provide a statistically significant improvement in local control, event-free survival or OS, according to Miklos Pless, MD, from the Tumor Center, Kantonsspital Winterthur, in Switzerland. The study

Despite the theoretical advantage of sorafenib for halting pathways for tumor growth, the lead author of this multinational trial, Marianne Sinn, MD, from the University of Berlin’s Charite Hospital, in Germany, reported no signal of increased benefit and no plans to evaluate this approach further. —Ted Bosworth Drs. Baselga and Sinn reported no relevant financial relationships. Dr. Vansteenkiste reported a financial relationship with GlaxoSmithKline, the sponsor of the MAGRIT study. Dr. Mok reported financial relationships with Amgen, AstraZeneca, AVEO, BioMarin, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Eisai, Eli Lilly, Janssen, Merck Serono, Novartis, Pfizer, Roche and Taiho. Dr. Pless reported a financial relationship with Sanofi.

30 Policy

Pharmacy Practice News • March 2015

Reimbursement Matters

“Reimbursement Matters” is a tool for maintaining your health system’s fiscal health. Please email the author at bkirschen@aol.com with suggestions on reimbursement issues that you would like to see covered.

Are You Guilty of Complicit Behavior? S

everal new payment mechanisms are being fast-tracked by both government and private insurers, and they are based in part on the large pool of claims data submitted by the nation’s health systems. From a pharmacy perspective, this means that all recently billed medications and drug administration fees form the basis of the drug components of these new payment offerings. Are you confident that yourr claims data are accurate and will contribute to the success of these programs? Or are you complicit in billing errors and misrepresenting costs? That is an important consideration, because these new reimbursement models, including accountable care organizations and bundled payments, are quickly gaining traction. They have been designed to reward value, improve patient outcomes and cut down on the volume of unnecessary procedures, and they are being pushed with an aggressive implementation time frame. In late January, for example, the Department of Health and Human Services announced a fundamental change to the way it wants to pay for covered services in the coming years, with a new

emphasis on rewarding cost-effective, high-quality care. The agency’s goal is to move from the 20% of Medicare payments that currently comes from alter-

native payment programs to 30% by the end of 2016 and 50% by the end of 2018. Anthem Blue Cross and UnitedHealthcare are good examples of pri-

Figure. Follow the money (CMS model). CMS, Centers for Medicare & Medicaid Services; MAC, Medicare Administrative Contractor

Bonnie Kirschenbaum, MS, FASHP

vate insurers that are surging ahead with newly defined plans. Anthem wants to transition away from the traditional feefor-service model toward value-based, risk-sharing payments, according to a report in Forbes (http://goo.gl/8h9klf ). Similarly, in 2014, UnitedHealthcare announced a new bundled payment program that will pay the University of Texas MD Anderson Cancer Center in Houston a flat fee to provide head and neck cancer care, according to a joint press release by the two companies (http://goo. gl/EGKMXa). UnitedHealthcare, which started requiring prior authorization for all injectable chemotherapy in Florida last May, said it will expand that requirement nationally this summer. The new online prior authorization process requires an oncology practice to submit clinical information about a patient that allows acceptable treatment regimens to be identified. “We’re using the same NCCN [National Comprehen-

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Policy 31

Pharmacy Practice News • March 2015

Reimbursement Matters

CMS Updates sive Cancer Network] rules that we’ve always used, but this process automates the selection of the regimen and makes it easier for physicians to know that they’re going to get coverage,” Lee N. Newcomer, MD, MHA, the senior vice president at UnitedHealthcare, said in an interview with trade press. “The physician won’t have to guess whether or not the regimen is NCCN-compliant.”

CMS Seeks To Bolster Cancer Care In mid-February, the Centers for Medicare & Medicaid Services (CMS) announced new details regarding its longawaited Center for Medicare & Medicaid Innovation Oncology Care Model (OCM). OCM is a five-year initiative with two primary goals: to create incentives for the provision of efficient, high-quality cancer care to Medicare fee-for-service beneficiaries, while at the same time lowering the overall cost of that care. The initiative targets high-volume cancers (e.g., lymphoma, leukemia, breast, prostate, lung, colorectal, ovarian and pancreatic), with episodes of care defined as lasting six months, beginning with the initiation of chemotherapy. The OCM model covers all costs (under Medicare Part A, Part B and some Part D) for all care for all conditions that arise during treatment. Payments are made on a per-beneficiary per-month basis and include both management fees and performance-based payments. The disbursements are made in addition to standard FFS payments. Practice requirements for participants include the following: • Patient access to clinicians 24/7 with real-time access to the practice’s medical record; • Attestation and use of electronic medical records certified by the Office of the National Coordinator (ONC) for Health Information Technology; • Use of data for continuous quality improvement;

s always, it is important to stay informed about key coding changes and resources. Details on these topics can be accessed at the CMS website (cms.gov). One area you should be paying attention to is immunizations. Through its Medicare Learning Network, CMS has published several resources that update language and answer questions related to immunizations for influenza, pneumococcal and hepatitis B vaccines. Definitely something to add to your e-library! Load the following URLs that link to the relevant pages on cms.gov into your browser for more details: http://goo.gl/TiuAWs; http://goo.gl/0Nnyp8. The pediatric immunization schedule can be accessed at http://goo.gl/uhHpqj. As for recent coding changes, I suggest you brush up on paclitaxel. For more than 10 years, Paclitaxel Injection has been associated with Healthcare Common Procedure Coding System (HCPCS) code J9265, with a billing unit of 30 mg. But on Jan. 1, 2015, the HCPCS code changed to HCPCS J9267, with a billing unit of 1 mg.

• Provision of core functions of patient navigation; • Documentation of care plans in accordance with the Institute of Medicine (IOM); • Chemotherapy treatments consistent with nationally recognized guidelines. This exciting new program is accepting applications through mid-June, and practices that your facility works with may choose to participate. As with all of the new payment models discussed, this one also relies on claims data to establish baselines.

It Takes Two to Tangle With Payors Complicity refers to the act of helping someone else behave inappropriately or illegally either deliberately or accidentally because of lack of attention or failure to look for and correct problems. Most facilities are shocked when payment schemes change, especially when the reality sets in concerning which products and services are being reimbursed and their corresponding rates of reimbursement. The response from health care providers usually is: “How could this have happened?” Many times the answer is siloed, complicit behavior. Several of my 2014 columns were centered on recognizing and correcting

this following the theme of “getting it right.” They addressed behaviors that come back to haunt you: • Failure to pay strict attention to pharmacy billing systems; • Failure to use appropriate codes and descriptions and billing unit conversions; • Neglecting to bill for drugs at all because it’s “too complicated for too little return.” These patients and products get averaged into calculations, but at zero $; • Failure to ensure appropriate and complete documentation; • Assuming computer systems work without careful checks and confirmation. Certainly, the hospital or health care facility has a revenue cycle team, groups of financial executives and an information technology infrastructure. All of these departments are tasked with ensuring appropriate and correct reimbursement. But they don’t set the budget for the products that are streaming through their system; you do! Given that level of accountability, do you really want to entrust the accuracy of being paid for that tremendous amount of drug spend to someone else, without even looking into the intricacies of reimbursement?

You own that drug spend just as you own the clinical components of medication use in your facility.

Perform Your Own Mini-Audit To take more control over the intricacies of payment, start with a small claims sample and track it through the myriad of systems from entering the drug order through what actually is paid by the payor. CMS patients are a good place to begin because most other payors base their models on CMS (Figure). Another effective strategy is to perform a case study of reimbursement at your facility, focusing on a commonly used class of drugs such as infused medications. Here are some key steps to consider: 1. Choose five drugs used in the infusion clinic. 2. Choose five CMS patients who received these medications. Go back approximately two months to allow for the payment cycle to have been completed. 3. Convert the dose of drug administered into CMS-defined billing units. 4. Determine local or national coverage determinations or prior authorization status of the drug. 5. Determine which drug administration fees were charged for the infusion of these drugs. 6. From the actual payment summaries, determine if the drug was paid for and if so, for how many billing units. If not, why not? 7. Find problems? Work through each step of the cycle to see where the problem(s) arose. Past “Reimbursement Matters” columns will help with details and can be accessed at Pharmacypracticenews. com. Click on “Columns” in the navigation bar at the top of the page, then on “Reimbursement Matters” and you will be set to go. ■

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REPORT Managing Venous Thromboembolism Risk in Hereditary Antithrombin DeďŹ ciency ďŹ Introduction

fatal complication, many may Faculty be at increased risk for longHereditary antithrombin defiMichael Cordisco, MS, CCP term sequelae, such as pulmociency (HAD) magnifies the risk nary hypertension or venous for venous thromboembolism Chief of Perfusion insufficiency. From 10% to 30% (VTE) in affected patients.1 Its Stamford Hospital may die within a month of diagdisproportionate contribution to Stamford, Connecticut nosis.4,6 Inherited thrombophilVTE, a potentially life-threaten1,2 Medical Writer ing event, supports the value ias are detected in a small but clinically significant proportion of screening in individuals with Theodore Bosworth of patients with VTE, particurisk factors. The estimated lifeMcMahon Publishing larly those with a prior histotime risk for VTE in patients with ry of thrombosis.7,8 A diagnosis HAD ranges from 50% to 85%,3 before or early within the period of risk offers an oppor opporbut many of these individuals, particularly those with mild tunity to modify risk with anticoagulant therapies. forms, may never receive a diagnosis.1 The risk for VTE In the general population, the incidence of HAD is variin patients with HAD can be readily modified with antiably estimated at up to 0.2%.9 Of inherited thrombothrombin replacement during high-risk situations along 1 with other strategies to reduce hypercoagulability. Thus, philias involving defects in endogenous suppression of coagulation factors, which includes deficiencies in proa systematic approach toward evaluating patients for teins S and C, HAD is among the least common and HAD and initiating VTE prophylaxis in patients with HAD most severe.9 Although deficiencies in proteins S and C is potentially beneficial for this population. each increase the thrombotic risk by about 10-fold, HAD Background increases the risk 20-fold (Figure 1).8,9 HAD is less common than many of the inherited thrombophilias assoVTE is defined as deep vein thrombosis (DVT), pulciated with increased levels or function of coagulation monary embolism (PE), or both.4 In the United States, factors, such as factor V Leiden, factors Leiden hyperhomocysteinemia hyperhomocysteinemia, approximately 550,000 550 000 cases of VTE are diagnosed 5 and elevated factor VIII, but its effect on VTE risk is 4- to each year. Of the patients who develop this possibly

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REPORT 6-fold higher.9 Overall, inherited thrombophilias may play a role in the pathogenesis of approximately 40% of provoked and unprovoked VTE episodes.7 As an endogenous anticoagulant, antithrombin binds to thrombin to prevent its activation, a critical step in the coagulation cascade, while also exerting inhibitory effects on coagulating factors Xa, IXa, XIa, XIIa, and plasmin.9-11 More than 250 genetic mutations have been associated with HAD that fall under 2 major subtypes.10 Type 1 is characterized by a quantitative deficit in functionally active antithrombin. Deficiency is variably defined as 70% to 80% of normal circulating levels.10,12 Type 2, which is more common in the general population,11 is characterized by normal levels of antithrombin but impaired binding activity. Further subdivision of type 2 can be made according to specific protein-binding defects,13 but screening for HAD is based on functional assays that detect deficiency in antithrombin activity regardless of type or subtype.1 Essentially, all patients with HAD have a heterozygous form because homozygous inheritance typically leads to death in utero.11 The risk for VTE in patients with HAD is low in individuals younger than age 20, increasing progressively with older age.14 The degree of impaired antithrombin activity in patients with either type 1 or 2 HAD varies.13 Importantly, even mild deficiency in antithrombin has been shown to increase the risk for VTE.12 In the hospital setting, the risk for VTE can be substantially increased in patients with HAD; the rates of VTE among patients undergoing cardiac, gynecologic, oncologic, or other surgical procedures associated with high VTE risk climb from

Number of Times Relative to General Population

less than 5% in patients without HAD15 to approximately 20% in those with the disorder.16 In pregnant women with HAD, the incidence of VTE also has been shown to be greater than 50%.3 Although VTE can occur outside of the hospital and in the absence of other risk factors,17 the first clinical manifestations of HAD often are triggered by surgery or prolonged immobility during hospitalization.11 For this reason, idiopathic VTE in otherwise low-risk hospitalized patients may prompt evaluation for HAD or another inherited thrombophilia. Prior history of VTE provides another consideration for thrombophilia evaluation.7

Diagnosis The diagnosis of HAD involves gathering information including patient and family history and repeated screening assays.1 Kenichi Tanaka, MD, MSc, anesthesiologist and professor at the University of Maryland School of Medicine, noted that without preadmission diagnosis, it can be difficult to differentiate HAD from acquired deficiency in the acute setting. “Medical history is of prime importance here. You can talk to the patient and figure out if there’s any personal or family history of thrombophilia,” Dr. Tanaka said. “Look at recent medical history to determine if the patient had any thrombotic events particularly within 3 months of any type of surgery or if the patient had experienced any complication during or after pregnancy. You really have to know if these patients are at risk for antithrombin deficiency.” Dr. Tanaka added that clinicians should pay attention to all patient factors that may reduce antithrombin levels, particularly when an initial HAD diagnosis cannot be made in the

5 3

Prothrombin gene mutation

Hyperhomocysteinemia

0 HAD

Protein C deﬁciency

Protein S deﬁciency

Factor V Leiden

Elevated factor VIII levels

Coagulation Disorder Figure 1. HAD presents the highest risk for thrombosis among inherited thrombophilias. Patients heterozygous for factor V Leiden have approximately a 5-fold greater risk for venous thrombosis, whereas homozygotes have approximately an 80-fold greater risk. Thrombate III (antithrombin III [human]) is not indicated for the treatment of thrombophilias other than HAD. HAD, hereditary antithrombin deficiency Adapted from reference 9.

In clinical studies of Thrombate III, the most common adverse events were dizziness, chest discomfort, nausea, and dysgeusia.

REPORT acute setting. Dr. Tanaka noted that antithrombin levels might be reduced in patients with ongoing major organ infection, disseminated intravascular coagulation (DIC), or sepsis. “Then, I also pay attention to the production of antithrombin. Antithrombin is made in the liver so if the patient has cirrhosis or any end-stage liver dysfunction, that’s an important sign that antithrombin might be low.” Right-side heart failure causing liver congestion as well as heparin exposure for more than 3 to 4 days can reduce antithrombin levels. Overall, testing antithrombin levels can help explain the response to anticoagulation used during surgery, such as heparin, which depends on antithrombin as a cofactor. Thrombophilia screening often is not recommended in an unselected population due to the low prevalence of these disorders. However, thrombophilia evaluation in patients with risk factors, such as personal or family history of VTE,7 and who are facing situations associated with high thrombotic risk, including surgery, pregnancy, trauma, or extended immobilization, may offer an opportunity for significant risk reduction.18 Of the functional tests available for antithrombin activity, the factor Xa inhibition assay is generally preferred over a thrombin inhibition assay because it avoids the confounding effects of heparin cofactor II activity, which may mask HAD.11 When screening is performed, clinicians also should be mindful of other clinical variables and interpret results accordingly. For example, at the time that the blood sample is taken, if patients are receiving anticoagulants, such as heparin or the direct Xa inhibitors, results could be affected by these medications.3 When ordering an antithrombin functional assay, a hematologist consult may be appropriate for considering the result in the context of other clinical factors. Antigenic assays should be reserved for defining HAD type after the initial diagnosis as these would be expected to miss type 2 HAD, which is the more common form.11 Although a functional antithrombin level in the normal range rules out HAD, a single abnormal test does not confirm HAD.11 Once antithrombin deficiency has been confirmed by repeated tests, the opportunity arises to educate patients about its relationship to VTE and the risk it imposes for thrombosis over the lifetime. Testing of family members also may be appropriate.11 Genetic testing also may be useful as the mechanisms for specific antithrombin deficiency can be further investigated by geneticists; however, such testing usually is not performed.1,11

Management Clotting disorders require a comprehensive approach to balance prevention of VTE against risk for bleeding events.12 Anticoagulants already are broadly applied in hospitalized patients at risk for VTE.7 HAD management should be considered within this context. In HAD, replacement of antithrombin in high-risk situations offers the most direct approach to managing the underlying disorder,1 but other steps to modify risk also should be considered. Steps to correct disorders with the potential to contribute to VTE risk, such as malnutrition or anemia,4 should not be overlooked. Discontinuing or reducing exposure to procoagulant therapies, such as oral contraceptives,4 also may be appropriate. Confirming HAD patients are on optimal doses of anticoagulants as indicated is also an important step to consider independent of antithrombin replacement.

Several exogenous therapies are available to increase antithrombin activity. These are the human plasma-derived antithrombin, marketed as Thrombate III® (antithrombin III [human]) (Grifols; Research Triangle Park, NC); the non-human recombinant antithrombin derived from goat’s milk, marketed as ATryn® (antithrombin [recombinant]) (rEVO Biologics; Framingham, MA); and fresh frozen plasma (FFP; Table).19-22 FFP was once the only available source for antithrombin replacement.23 As mentioned above, concentrated antithrombin replacement options are now available. The much lower concentration of antithrombin in FFP compared with antithrombin concentrate necessitates administration of high volumes of FFP to normalize antithrombin in a patient with HAD. Thrombate III is antithrombin concentrate derived from human plasma. It has a half-life (3.8 days) consistent with endogenous antithrombin. Because it is derived from plasma, there is a theoretical risk for transmission of infectious disease including the Creutzfeldt-Jakob disease (CJD) agent, despite steps in the manufacturing process designed to reduce this risk. However, no cases of viral disease or CJD transmission have ever been reported.19 It is indicated for the treatment of HAD in connection with surgical or obstetric procedures or when HAD patients develop a thromboembolism. In clinical studies with Thrombate III, the most common side effects were dizziness, chest discomfort, nausea, and dysgeusia.19 Thrombate III is administered in a bolus intravenous infusion (not continuous infusion) and is dosed according to patient weight to achieve antithrombin function levels between 80% and 120% of normal activity. Maintenance doses equal to 60% of the loading dose are administered as infrequently as once daily, but the interval should be assessed based on the antithrombin level achieved. Thrombate III is stored at room temperature and is readily reconstituted with sterile water.19 The non-human antithrombin concentrate ATryn (antithrombin [recombinant]), which is indicated for the prevention of perioperative and peripartum VTE but not the treatment of VTE in patients with HAD, is produced from the milk of genetically modified goats.20 The most common adverse reactions reported in clinical trials were hemorrhage and infusion site reaction. ATryn has a half-life of approximately 12 to 18 hours and is administered as a loading dose based on patient weight followed by a continuous infusion.20 ATryn requires refrigerated storage and must be brought to room temperature no more than 3 hours prior to reconstitution. ATryn is contraindicated in patients with known hypersensitivity to goat proteins.20 The difference in half-life between the plasma-derived and recombinant antithrombin formulations and the resulting difference in dosing volume and administration requirements are important clinical considerations. The products should not be considered as interchangeable. Protocols for dosing and administration must be tailored to the specific antithrombin concentrate being used. Additionally, Thrombate III is stored at room temperature19 ; therefore, there is no waiting time to bring it up to room temperature if a higher dose is needed beyond what was initially anticipated for a case.

Surgery In HAD patients scheduled for surgery, different paths are defined by the use of systemic anticoagulation with heparin. Antithrombin is essential for anticoagulation with heparin

Please see Important Safety Information on page 6 and refer to accompanying full Prescribing Information for complete prescribing details.

REPORT as heparin’s mechanism of action is to bind to and catalyze the effects of antithrombin by 1,000-fold.24,25 Therefore, doses of both heparin and antithrombin must be adjusted to accommodate this effect. Intraoperative monitoring of coagulation factors, such as prothrombin time and partial thromboplastin time, international normalized ratio, and activated clotting time are appropriate. Measurement of antithrombin also is advisable, recognizing that a baseline level in anticipation of surgery may differ from the level at the time of the procedure. The degree of functional antithrombin deficiency before surgery should influence the decision of how much antithrombin concentrate to have available over the period of prophylaxis, but dosing is variable and antithrombin levels may fluctuate over the duration of a case requiring antithrombin replacement. Tengborn and colleagues reported a thrombotic complication rate of 17% in patients with HAD who underwent surgery without any supplemental antithrombin and 22% in those treated with other methods (Figure 2).16 In patients not receiving systemic anticoagulation or those receiving lowdose heparin typical during percutaneous catheterizations,26 greater attention may be applied to repletion of antithrombin to restore normal functional activity. However, management of these patients must be individualized due to variables such as the use of antifibrinolytics, which preserve clots by slowing their breakdown.27

In all patients undergoing surgery, the type and duration of anesthesia is another variable associated with risk for VTE.6 This risk is increased in patients with HAD due to the higher incidence of VTE in this population.1 Steps such as positioning of the body to improve blood flow should be employed to mitigate this risk. A diagnosis of HAD also should intensify attention to blood monitoring during surgical procedures. The goal of close monitoring is not only to reduce clotting risk but also to avoid bleeding events. If a bleeding event occurs, the focus should be to reverse the activity of heparin. “We can neutralize heparin with protamine sulfate28 but adjusting the dose of protamine can be a complex process if the clinician has given a large amount of heparin during surgery,” Dr. Tanaka added.

Immobilized Patients In HAD patients with VTE risk defined by prolonged immobilization, variables that should influence the dose and duration of antithrombin therapy, or whether to initiate antithrombin therapy, include the degree of functional deficiency, the types of other therapies being employed to prevent clot formation, and the frequency and types of blood monitoring. More conservative approaches may be most appropriate for individuals at high risk for bleeding, but sustained antithrombin therapy should be considered in patients with severe forms of HAD with multiple risk factors for VTE and a prolonged period of risk.29

Table. Properties of Thrombate III® (Antithrombin III [Human]), ATryn® (Antithrombin [Recombinant]), and Fresh Frozen Plasma Thrombate III

ATryn

Fresh Frozen Plasma

Source

Human plasma

Milk from transgenic goats

Whole blood or pooled human plasma

How supplied

500 IU vials

525 IU or 1,750 IU vials

250 mL bags

Antithrombin concentration

50 IU/mL a

164 IU/mL or 175 IU/mLb

~1 IU/mLc

Antithrombin dose for example patient: 80 kg, 60% baseline antithrombin activity level, treated for 24 hd

3,429 IUd

8,921 IUd

3,429 IUd

Volume needed for example patient

69 mL administered 54 mL administered via bolus infusion over via continuous infu10-20 min sion over 24 h

3,429 mL administered via continuous infusion over 24 h to achieve equivalent dose

After reconstitution with 10 mL sterile water for injection.

After reconstitution with 3.2 mL (525 IU vial) or 10 mL (1,750 IU vial) sterile water for injection.

Fresh frozen plasma will contain approximately 1 IU/mL of antithrombin.

Total dose in 24 h based on an 80 kg surgical patient with 60% baseline antithrombin activity. See complete Prescribing Information for Thrombate III and ATryn for full dosing guidance.

Thrombate III (antithrombin III [human]) is indicated for the treatment of patients with hereditary antithrombin deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism. Adapted from references 19-22.

The anticoagulant effect of heparin is enhanced by Thrombate III. Reduced dosage of heparin is recommended during treatment with Thrombate III to avoid bleeding.

REPORT Conclusion

For VTE management in pregnant women with HAD, postpartum prophylaxis is recommended by the American College of Chest Physicians even among those without a previous VTE, but with a positive family history, because of the high rate of events.30 For all women, including those with HAD who have had a previous VTE, heparin is further recommended by the College during the postpartum period, when the risk for VTE also remains elevated. Additional strategies for VTE prophylaxis during the postpartum period, such as the use of compression stockings, may be appropriate in severe cases of HAD.30 The inclusion of antithrombin replacement therapy provides an important opportunity to act directly on the source of elevated VTE risk in patients with HAD. More than 40% of VTE in patients with HAD occurs during defined periods of high risk.17 Although it is important to individualize therapy in the context of the complex and interrelated factors that contribute to VTE risk, antithrombin concentrate can be used in community as well as tertiary health care centers when coagulation activity is appropriately monitored.

VTE is a serious but largely preventable complication of surgery or hospitalization. Individuals with HAD, which poses the greatest risk for VTE among inherited defects in control of the coagulation cascade, are overrepresented in cases of VTE.1,2 Screening for HAD in patients with a prior history of VTE offers an opportunity to identify this disorder in advance of the period of risk. Appropriate application of strategies to lower VTE risk in these patients, including antithrombin replacement, would be expected to favorably affect overall VTE rates and isolate patient groups who could benefit from lifetime risk management.

Long-Term VTE Risk Prevention In patients with HAD, the use of antithrombin replacement therapy typically is confined to periods of acute risk, such as during perioperative or peripartum periods. Longer periods of treatment may be appropriate in nonambulatory hospitalized HAD patients when VTE risk remains elevated. Other situations associated with high risk for VTE, such as the presence of an in-dwelling catheter, also may warrant extended periods of antithrombin therapy, particularly in patients with significant impairment of antithrombin function due to HAD. After the period of acute risk, it is unclear whether patients with HAD require any change in the type or duration of anticoagulants other than antithrombin, such as vitamin K antagonists or low-molecular-weight heparin, relative to those without HAD. Referral to a hematologist for extended follow-up may be appropriate not only for guidance in the post-discharge period but for counseling in regard to modifying and avoiding the lifetime risk for thrombotic events. Despite the potential for screening and risk modification to reduce the risk for VTE in patients with HAD, published guidelines regarding the acute or long-term management of this or other inherited thrombophilias remain limited. In a review of guidelines that addressed clinical strategies for reducing VTE recurrence, some guidelines advocated specifically for tests to determine the cause of VTE, whereas others did not address this question at all.31 One remaining guideline called for testing to be limited to patients who also have a strong family history of recurrent unprovoked VTE.32 One explanation is that the limited number of prospective studies conducted in patients with HAD are an obstacle to evidence-based guidelines. However, the established risk for recurrent VTE in patients with HAD, as well as other inherited thrombophilias, supports proactive efforts to identify populations suitable for prophylaxis.

Prophylaxis Before Surgery

Pregnancy

Antithrombin concentratea,b 0 n=10

No treatment n=29

17.2%

Other treatmentsc n=18

22.2%

Incidence of Thrombotic Complications, %

Figure 2. Antithrombin replacementa helps prevent thromboembolism during surgery in patients with HAD. No patient administered antithrombin concentrate alone or in combination with other methods had signs of thromboembolism. Retrospective study of 57 surgical cases.d a

Not Thrombate III (antithrombin III [human]); plasmaderived antithrombin concentrate used was studied but not marketed.

Also combined with other types of prophylaxis.

Dextran, low-dose heparin, peroral anticoagulants, and combinations.

Twenty-three patients underwent 57 operations of various types. Fourteen of the 23 patients had previous deep vein thromboses. In 29 procedures, patients were not given thromboprophylaxis. In 28 procedures, thromboprophylaxis was used.

HAD, hereditary antithrombin deficiency Adapted from reference 16.

Because Thrombate III is made from human plasma, it may carry a risk of transmitting infectious agents, eg, viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have ever been identified for Thrombate III. Please see Important Safety Information on page 6 and refer to accompanying full Prescribing Information for complete prescribing details.

REPORT

Case Study Managing Hereditary Antithrombin Deficiency in a Patient Undergoing Cardiac Surgery With Cardiopulmonary Bypass Introduction Outside of a known familial trait for antithrombin deficiency, thrombotic events often are the first indication that a patient may have hereditary antithrombin deficiency (HAD) and can provide clinicians an opportunity to evaluate the underlying cause of thrombosis. The following case report will discuss how the cardiac surgical team evaluated periprocedural risks, anticoagulation technique, and the conduct of cardio-pulmonary bypass (CPB) of a patient after a diagnosis of HAD.

Case Presentation A 44-year-old man was diagnosed with pulmonary embolism (PE) after several days of shortness of breath that he described as more severe than usual. The patient related a family history consistent with a genetic thromboembolic disorder and was found to have HAD based on a functional antithrombin assay result of less than 45%. The acquired form of antithrombin deficiency was ruled out after a thorough history of present illness and lack of recent heparin administration, enteric protein loss, or bleeding history. Additionally, the patient was found to have atrial fibrillation and moderate to severe mitral valve insufficiency discovered during a transesophageal echocardiogram. The patient underwent thrombolytic therapy for the PE and was subsequently referred to and followed by both a hematologist and a cardiologist who recommended elective mitral valve repair (MVR). In preparation for the MVR, the cardiac surgical team identified 3 specific risks that are unique to the patient with HAD who would need to be heparinized in order to be placed on CPB: 1) the inability to adequately and safely heparinize for CPB, 2) postprocedural bleeding due to consumptive coagulopathy from inadequate anticoagulation with heparin, and 3) the risk for thrombotic complication relative to patient positioning while under general anesthesia. To address these risks, presurgical supplemental antithrombin was administered via a commercially available preparation of Thrombate III (antithrombin III [human]) (Grifols; Research Triangle Park, NC). Thrombate III is an FDA-approved, human

plasma–derived therapy for the treatment of HAD.19 In clinical studies with Thrombate III, the most common side effects were dizziness, chest discomfort, nausea, and dysgeusia. Because Thrombate III is made from human plasma, it may carry a risk for transmitting infectious agents, such as viruses or, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of virus or CJD transmission have ever been identified.1 The loading dose of Thrombate III for this patient was calculated based on the patient’s weight and baseline antithrombin level, using the equation presented in Figure 3.19 After invasive monitoring line placement, the patient received approximately 500 additional units of reconstituted Thrombate III over several minutes in the operating room. After the median sternotomy, the patient was administered 3 mg/kg of bovine heparin before cannulation for CPB, which facilitated a safe activated clotting time (ACT) for CPB of more than 450 seconds using the Medtronic Heparin Management System (Medtronic, Minneapolis, MN). The CPB circuit consisted of a Terumo (Terumo, Ann Arbor, MI) custom tubing pack and Capiox SX-18 oxygenator with “X-Coating,” a poly2-methoxyethyl acrylate (PMEA) surface modification. Normothermic CPB, surface-modified circuitry, and Thrombate III were all part of the CPB strategy and were intended to reduce the likelihood of activation of the coagulation cascade and minimize the patient’s risk for bleeding. The surgical repair of the patient’s mitral valve was uneventful and he was weaned from normothermic CPB, transferred to the ICU, and extubated. He did not require a subsequent dose of Thrombate III and was not transfused with allogeneic blood during his surgical course.

Discussion CPB necessitates the total suspension of the coagulation cascade and normal hemostatic mechanisms with systemic unfractionated heparin as the CPB circuit and cardiac surgery will activate the common pathway of the coagulation cascade. Antithrombin deficiency, whether hereditary or acquired, makes anticoagulation with heparin difficult.

Important Safety Information Thrombate III® (antithrombin III [human]) is indicated for the treatment of patients with hereditary antithrombin deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism. In clinical studies, the most common adverse events were dizziness, chest discomfort, nausea, and dysgeusia. The anticoagulant effect of heparin is enhanced by concurrent treatment with Thrombate III in patients with hereditary

AT-III deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with Thrombate III. Thrombate III is made from human plasma. Plasma products carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite steps designed to reduce this risk. No cases of transmission of viral disease or CJD have ever been identified for Thrombate III.

REPORT

Units required (IU) = [desired – baseline AT activity level] × weight (kg) 1.4 Figure 3. Dosing formula for Thrombate III (antithrombin III [human]). AT, antithrombin Based on reference 19.

It remains unclear whether or not the inability to achieve an “adequate” ACT for CPB in antithrombin-deficient patients represents a true inability to anticoagulate versus current point-of-care testing limitations. For this reason, it has been reported that anticoagulation in antithrombin-deficient patients often necessitates extreme and potentially unsafe doses of unfractionated heparin.33 This is potentially due to the inability to form heparin–ATIII complexes that are necessary to inhibit factors Xa and IIa.34 Thrombate III (antithrombin III [human]) allows for replacement of antithrombin and may avoid the potential overdosing of heparin. General anesthesia by its very nature and intent will increase the risk for thrombotic complication relative to patient positioning through stasis of blood and immobility for long periods of time. This increases the risk for thrombosis in a patient with HAD greater than that of the general population. Our concern for thromboembolism was during the post-anesthetic induction period of the operation: before anticoagulation with heparin and after reversal with protamine. The weight-based

replacement dose of Thrombate III was calculated for supplemental repletion of antithrombin and was given to reduce the risk for thrombosis. Activation of the coagulation cascade and the subsequent stimulation of labile coagulation factors will cause the consumption of those factors regardless of whether or not a fibrin clot is formed. The resultant effect is coagulopathic bleeding via depletion of coagulation factors through their consumption. This degree of coagulation factor depletion is particularly dangerous in the post-cardiac surgical setting.35

Conclusion A deficiency of antithrombin naturally occurring in the plasma whether hereditary or acquired can complicate a surgical procedure increasing risk to the patient and costs to the facility. A complete assessment of risks and development of a multimodal surgical and pharmacologic strategy for the treatment of patients with HAD can help to attenuate the increased risks associated with surgery in these patients.

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Please see Important Safety Information on page 6 and refer to accompanying full Prescribing Information for complete prescribing details.

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Editorial support for this piece was provided by McMahon Publishing. Disclosures: Mr. Cordisco reported no relevant financial conflicts of interest.

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Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Grifols, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.