currents in military...

Currents in Military Pharmacy - Dec 2015

Inside This Issue

Letter from the Old & New SAFP President pg 2

Letter from the Associate Corps Chief pg 3

Air Force Sig Group Updates pg 3-4

Article: Med Management Inspection Prep pg 4

Article: Inspection Readiness pg 5

Article: Evolution of the Inspection Process pg 6

Article: Legal Capsules pg 7-8

CE: Dabigatran and Atrial Fibrillation pg 9-14

Currents in

Military Pharmacy Volume: 22 I s sue: 3

President: Lt Col Stephanie Forsythe

President Elect: Maj David Jarnot

Past President: Lt Col Ann McManis

Vice President: Maj Daniel Oh

Pharmacist Secretary/Treasurer: Maj Julie Meek

Technician Secretary/Treasurer: SSgt Raechael Evans

Pharmacist Director-At-Large: Col (Ret.) Phil Samples

Pharmacist Director-At-Large: Maj Rebekah Mooney

Technician Director-At-Large: MSgt Jason Christianson

Director-At-Large: Col Scott Sprenger

Director-At-Large: CMSgt Paula Eischen

SAFP Board Members

Caption: Stanislas Limousin was a French retail pharmacist and the inventor of the glass ampule in 1886

2 Currents in Military Pharmacy - Dec 2015

Greetings Society of Air Force Phar-macy members! In this issue of the news-letter we are focusing on improving AF Pharmacy. Along that same theme, your officers have been working hard to im-prove the Society.

While the Society may not have in-spections or checklists to contend with, we are always looking for ways to be more

valuable and beneficial to our members. Our biggest effort has been to publish a quarterly newsletter for the member-ship. The purpose of the newsletter is to provide updates on the Society, helpful information about AF Pharmacy, and provide a continuing education article that is free of charge for all members.

Another effort that we have been working on is adapting to the current AF environment. Not only do we face fiscal limitations, we also have to respect that the Society of Air Force Pharmacy is a private organization and not a DoD enti-ty. As a result, we held the annual membership meeting in a

webinar format on November 6th. This format seemed to work well and we appreciate those who were able to partici-pate!

Finally, we rolled out a new certificate program reim-bursement membership benefit. The Society is offering to reimburse members for certificate programs or advance inten-sive study programs. The maximum reimbursement is $200 per member per year for certificate programs that include but are not limited to MTM, Diabetes Care, and Immunization Delivery. A description of the benefit and details on how to request the reimbursement are available on the SAFP website in the education section.

It has been my honor to serve as your President for 2015 and I look forward to continuing to help the Society succeed as we enter 2016. I think the Society has been able to accom-plish some big things this past year and that was in large part due to our outstanding members. Thank you to each and eve-ry one of you for your commitment, feedback, and support!!

Proud to be Your President, Stephanie Forsythe

Lt Col Forsythe

Le er from the SAFP President

Le er from the 2016 SAFP President

Society of Air Force Pharmacy Members,

I sincerely hope everyone had a won-derful holiday season and is energized to make 2016 a fruitful and productive year. The votes have been tallied and it is my pleasure to announce the newly elected board members for 2016:

President-elect – Maj Daniel Oh

Vice President – Maj Jennifer Baker

Pharmacist Director at Large – Maj Rebekah Mooney

Technician Director at Large – Ms. Samantha Garcia

Technician Secretary/Treasurer – TSgt Jackie Wolfe

I would also like to give a huge “Thank You!” to the outgoing SAFP board members; President Stephanie For-sythe, Enlisted Secretary/Treasurer TSgt Raechael Evans, and Enlisted Director at Large MSgt Jason Christianson. The so-ciety moves forward with the leadership and guidance of the board members serving on behalf of the membership. Great

strides were made in 2015 to improve the value of SAFP membership and enhance the community of those associated with military pharmacy. This could not have been done with-out the dedicated service of these board members.

Finally, I would like to welcome the new leadership team. The 2016 board has large shoes to fill, but I know the team will work their hardest to continue the forward momen-tum and maximize the support SAFP provides to its member-ship. If you have ideas for ways the society can better sup-port you, please let a board member know or contact me di-rectly at [email protected].

Thanks for all you do and cheers to an amazing 2016 for all!

David Jarnot 2016 SAFP President

Maj Jarnot


AF Pharmacy Team,

I know that I am “preaching to the choir” when I say that the Air Force is well known for establishing a lot of rules and ex-pecting them to be followed. A rules-driven environment isn’t unique to the Air Force and isn’t necessarily a bad thing either. Fol-lowing the rules is only half the battle, being aware of all applicable rules can be equally

challenging. The past several years have brought many changes to not only the rule sets, but also in how we go about validating compliance with meeting those expectations. Historically that validation process has involved both self and external inspec-tions.

One of the biggest changes to the inspection process for the AF as an organization in recent years has been introduction of the Unit Effectiveness Inspection (UEI). The UEI is intended to shift the responsibility of oversight closer to the unit and the emphasis is placed on “effectiveness” to the mission rather than how well you “complied” with the rules. That emphasis is criti-cal whether you are safely flying an F-16 sortie or accurately filling a prescription for a patient at the pharmacy window. Monitoring our effectiveness in pharmacy operations and healthcare in general translates into better patient care and better outcomes for our beneficiaries.

Although the UEI process involves less frequent outside of the unit monitoring, an external set of eyes remains an important part of the validation process. The ultimate goal is for sustained

effectiveness and taking steps to always improve the areas we identify as weaknesses in meeting that goal. Process weakness will likely always occur in any large organization undergoing constant change (PCS, new staff, new patients, more patients, changing guidelines, new drugs, etc).

Another big change for AF MTFs is the outside reviewing organization standardizing to The Joint Commission for all sites instead of the AAAHC for ambulatory patient only locations. Folks, this isn’t new. We are going back to a way of doing busi-ness as we had done before, standardization can be a good thing. Understanding and applying the same applicable rule sets across the spectrum of care is better for MTFs and ultimately our pa-tients.

I’ve always been an advocate of doing tasks smarter and most efficiently. Tools are a means to help do just that. Kudos to Lt Col Wes Rainey, Maj Dave Jarnot, Capt Brian Welch, and Capt Ben Beidel in leading an effort in developing a comprehen-sive Pharmacy Inspection Tracker. This is an amazing tool that will help you not only wrap your arms around understanding all the rules, but also in tracking your success in meeting their in-tent and being effective in meeting our mission.

Thanks to all of you for your strong efforts in working to-wards effectively meeting the mission and providing outstanding patient care.

Col Sprenger

Your Readiness SIG leaders are Maj Anthony Dargush and SSgt Stephen Iles. We are responsible for ensuring the 43Ps and 4Ps have the proper tools for readiness operations in the AOR and in garrison. One often over looked deployment tool is prop-er vault operations. Although the AOR is an austere environ-ment, the standards for narcotic control do not disappear. In fact, since you will have less electronic tools to aid in your in-ventory process, standards become even more important. Inven-tories should be conducted just as they are at home station. A critical aspect of narcotic control is documentation.

An ideal situation is one where a CHCS like system is available, like TC2, which can serve as an electronic continuous inventory of your narcotics, similar to our home station system. However, in the case that documentation is completely paper

based, the AF Form 582 or Pharmacy Stock Record will have to be used for every individual narcotic on hand. Any narcotic movement on the wards or clinics should be documented on an AF Form 579 or Control Substance Register.

Ensure you spend ample time in your vault, especially prior to a deployment to ensure you can operate independently. With-out these skills you will not be prepared for you time down range. Ensure narcotic standards are upheld. You will feel pres-sure to bend your rules in order to support the mission, but re-member, there is always a way to support the mission AND practice proper narcotic control.

Please contact us with any questions or if you are interested in participating with the Readiness SIG.

Le er from the Associate Corps Chief for Pharmacy

AF Sig Group Updates: Readiness

Col Sprenger


2015 was a very productive year for the Practice SIG with the following products all completed!

- Air Force Pharmacy Practice Manual - Air Force Pharmacy Inspection Prep Tool - Automated Non-Comp and Prescription Transfer Tools - Deployment MOD-12 Screen Standardized Tool - AF Pharmacy Compounding Manual - AF Corrections Facility Training Guide All these projects could not have been completed without the dedicated support and assistance of PPSIG team members. Through their hard work the SIG has taking great strides to help improve pharmacy operations across the AFMS. All of the com-pleted products are posted of the AFMS KX website. Addition-ally, the PPSIG has created a site on MilSuite to help improve communication among members and provide enhanced support to ongoing projects.

PPSIG Kx Site: https://kx2.afms.mil/kj/kx2/Pharmacy/Pages/pharmacy_practice_sig.aspx PPSIG MilSuite Site: https://www.milsuite.mil/book/groups/air-force-pharmacy-practice-subject-interest-group-sig PPSIG projects are often generated from the field. If you have a process that is innovative please let the SIG know and we can begin looking at the potential of standardizing it. You can send ideas directly to SIG leadership Maj David Jarnot and MSgt Rosland Upshaw, or make a post on the PPSIG MilSuite page. Thank you all for what you do every day! Maj David Jarnot PPSIG Leader

AF Sig Group Updates: Pharmacy Prac ce

MEDICATION MANAGEMENT INSPECTION PREP Recently the 88th Medical Group at Wright-Patterson Air

Force Base underwent a Joint Commission inspection. Over a span of four days the hospital was inspected from top to bottom. There were a total of five surveyors; a nurse, engineer, physi-cian, administrator, and a social worker. Each day was sched-uled out for each surveyor to have meetings with element lead-ers and/or running tracers through different facets of the hospi-tal. For the purposes of this article I will focus primarily on the medication management portion of the inspection.

The medication management portion was scheduled for the third day and was performed as a sit down meeting to answer and show validators to the surveyors followed by a short tour of the pharmacy. In attendance was the surveyor, a representative from the organizational improvement office, multiple pharmacy leadership, the pharmacy and therapeutics chair, patient safety representative, and two nurses from the ICU. The overarching concern from the surveyor was a majority of sentinel events be-ing reported from the various hospitals that were directly related to medication errors. Many items were discussed including eve-rything from medication reconciliation, therapeutic substitution, medication shortages, communication in the hospital, and our antibiotic stewardship program. A few more items pertaining directly to policy items included beyond-use dates, medication titration, and look-alike/sound-alike list. The surveyor ended the face to face portion of the meeting by a short discussion about

PSRs/ADRs and challenging us to always be looking at the val-ue-added response to tracking and reporting these.

The next part of the survey included the surveyor taking a brief tour of the pharmacy. Their tour started with our quality process improvement board. The surveyor was very interested in any and all process improvements we were currently working on. The next step was focusing on our inpatient pharmacy, where the surveyor discussed with the inpatient staff all the way down to the technician level about intravenous medication prep-aration and unit-dose prepacking. The surveyor the did a quick walk through and discussed with our outpatient pharmacists and technicians about their day to day processes.

Once the medication management inspection was complet-ed, the pharmacy leadership team had a quick hot wash to talk about lessons learned. A few items we discussed in our hot wash included to continually improve our communication with our providers and hospital staff through various avenues and not just one single source. The final take away was that preparing for the Joint Commission inspection should be a year round ac-tivity, with continuous quality improvement and inspection trackers throughout the year. Overall, the 88th Medical Group pharmacy did a fantastic job, with the medication management inspection having zero write-ups!

Capt Brian Welch


Inspections involving pharmacy come in many forms within the AFMS. The Joint Commission (TJC) has taken over as the civilian accreditation body to cover all Air Force MTFs. While inpatient facilities will be familiar with a TJC inspection, this experience will be new for most ambulatory care clin-

ics. The Air Force also conducts inspections via Unit Effectiveness Inspections and audits coordinated through the Air Force Audit Agency. Finally, govern-ment agencies like the Drug Enforcement Agency and Environmental Protection Agency are able to conduct no-notice inspections to determine compliance with federal regulations.

Inspections often generate a good amount of stress and anxiety for pharmacy staff. This usually occurs when the focus for inspections preparation involves a ramp-up in activity to “validate” compliance items be-fore the inspectors arrive. This is the wrong approach to inspection preparedness! Inspection agencies can only inspect based on published regulations. Therefore, in-spections are really an open book test and success (passing) can be achieved with an effectively managed Pharmacy Continuous Inspection Program (Pharm-CIP). USAFE Pharmacy Consultant Lt Col Tam Dinh could not have described it any better in a recent email where she stated:

“My philosophy has been if you know the policies/ standards and ensure to im-plement them 100% of the time, then there is no need to “prep” for an inspec-tion or any auditing/accreditation agen-cies… Keep in mind that the AFIS-CCIP's culture highly encourages honest self-inspection, Commander's Inspection Program (CCIP) rewards the "Red”. Do not hesitate to identify "deficiencies" and develop solid corrective action plans (CAP) for them. The Unit Effectiveness

Inspection (UEI) conducted by the MAJCOM/Wing IG is focused on the “non-detected deficiencies,” not the one that you are already detected.”

The Pharmacy Practice SIG has created several tools to assist MTF pharmacies with creating a robust Pharm-CIP. Posted to the Knowledge Exchange is a comprehensive Pharmacy Inspection Preparation Track-er. This tool was created by a group of subject matter experts and provides the regulations and a self-assessment tool for any inspection agency that may visit the pharmacy. This tool is extremely valuable in provid-ing visibility to the regulations that a pharmacy will be inspected against. In addition to the inspection tracker, the Knowledge Exchange also provides “lessons learned” documents from pharmacies that have recently completed an inspection. This information will help ed-ucate pharmacy leadership on focus areas and also iden-tify best practices.

If deficiencies are discovered during self-inspection you will need to develop a corrective action plan. The best format to drive a corrective action is utilizing the 8-Step AFSO-21 problem solving model. If you are not familiar with documenting process improvements using an 8-Step, most MTFs provide training and there are several examples of 8-Steps on the PPSIG Kx page. Finally, regulations sometimes can be interpreted differ-ently. If there is ever a question on what compliance looks like don’t hesitate to contact your MAJCOM Con-sultant, Lt Col Jason Lennen at AFMOA, or the Pharma-cy Practice SIG to get additional guidance. A robust Continuous inspection Program will take the anxiety out of inspections, and replace it with excitement (ok..maybe a stretch) to showcase to inspection agencies the great things your pharmacy does every single day.

INSPECTION READINESS By: Major David Jarnot

Maj Jarnot


When one hears the word “inspection,” what came to mind? Thoughts of Joint Commission on Accredita-tion of Healthcare Organizations, Accreditation Associa-tion for Ambulatory Health Care, Health Services In-spections, Operational Readiness Inspections, Combined Unit Inspections, and Unit Effectiveness Inspections most likely are prominent. Although not all-inclusive, these are just some of the voluntary and mandatory in-spections which military treatment facilities have under-gone in the Air Force. In the past 22 years, I have per-sonally observed the evolving changes in the inspection process for hospitals and clinics. While these improve-ments may have been painful at times, admittedly, over-all inspection changes appear to be moving in the right direction.

Initially, when the inspection date was announced, up to six months in advance if fortunate, the designated military treatment facility would start preparing and as-sign an inspection POC. This person’s job was to col-lect all the documents and act as a liaison between the organization and inspection entity. On-site inspections were comprised of meetings with committee members, reviewing of meeting minutes to ensure standard agenda items were discussed and issues resolved, walking-through specific sections to observe and dialogue with front-line workers and scheduling question and answer interviews with section leads. Who doesn’t remember the stressful months spent in preparation and anticipa-tion of doing well, even though the inspection lasted three to four days at most?

In August 2013, the Air Force launched the new Air Force Inspection System (AFIS) with the publication of AFI 90-201, updated as of April 2015. “It provides poli-cy for all inspections involving Air Force units, process-es, programs, or procedures irrespective of the inspect-ing organization.” The most painful transition for mili-tary treatment facilities came with MEDFACTS replace-ment by the Management Internal Control Toolkit (MICT). MICT serves as a checklist repository, devised from AFIs governing functional areas and deploys tools

to self-evaluate and address deficiencies in self-assessment programs. It is absolutely essential under AFIS to acknowledge all “observations” or deficiencies up front, develop a tracking plan and ECD, document monthly progress, and close out when compliance is met.

Leaders at all levels can continuously track and manage programs and discrepancies. The necessity of preparing for an inspection no longer exists. In fact, in-spectors do NOT want organizations to allocate re-sources and spend countless hours preparing for any fac-et of the inspection. Inspectors can and will pull the web-based checklists before they arrive and review what the units are doing and what needs corrected before they arrive. By streamlining the inspection and results, fewer inspections are needed. Who wouldn’t be pleased to hear that fewer inspections are needed and staff can con-centrate on providing patient care and medical support? When one hears the word “inspection,” what comes to mind?

I highly encourage leaders to review AFI 90-201, ensure MICT checklists are current with identifying and tracking observations, and practice articulating how eve-ryone in your unit fits in and are accomplishing the mis-sion under the four Major Graded Areas (Managing Re-sources, Improving the Unit, Leading People and Exe-cuting the Mission). AFIS is here to stay and by em-bracing the changes, leaders at all levels will already be “prepared” for a successful inspection.

EVOLUTION OF THE INSPECTION PROCESS By: Lt Col Melissa Howard


Hopefully, since we all strive to practice in a safe man-ner, prescription errors only occur rarely at your pharmacy. However, if a prescription is filled with the wrong medica-tion, the patient has taken some of the incorrect medication, and the patient returns the remainder of the improper medica-tion to the pharmacy, what do you do with that prescription vial and the medication? Do you throw away the prescription container and incorrect medication, place it in the medication to be returned/destroyed bin, set it aside, or something else? Does your pharmacy have a policy that covers such an in-stance? Let’s take a look at the case Randolph Scott Burton v. Walgreen Co.(case no. 2:14-CV-84 JCM (VCF), July 2015), a case in front of the United States District Court for the district of Nevada to see if we can get some guidance.

In this case, the plaintiff, Mr. Burton, was being treated for his hypertension with Diovan, to be taken once daily. On March 3, 2012, a Walgreen’s pharmacist incorrectly filled his prescription with a mixture of Diovan tablets and Lithium capsules. The plaintiff did not notice the difference between the tablets and capsules and took one tablet or capsule each day as directed. After about five days, Mr. Burton’s wife no-ticed the mixture of tablets and capsules in the bottle and re-turned the medication to Walgreen’s. A Walgreen’s employ-ee looked in the prescription vial, noted the capsules looked like Lithium, checked a computerized product identification database, and confirmed that the capsules were indeed Lithi-um.

Sometime between March 3, 2012 and March 14, 2012 when the patient checked into the hospital emergency room, he started to experience numbness and weakness in his left hand. Plaintiff’s wife shared with the hospital staff that her husband had improperly taken Lithium capsules, and the emergency room records stated that he potentially took one 300 mg Lithium capsule each day for five days. The emer-gency room physician diagnosed the plaintiff with an adverse reaction to the improperly dispensed Lithium. Both the plain-tiff and the defendant believed the hospital learned detailed information surrounding the incorrect Lithium dosage from communications with Walgreen’s pharmacists.

Soon thereafter, Mr. Burton followed up with his family physician, who referred him to a hand specialist. When Mr. Burton’s symptoms worsened over the next few months, the hand specialist conducted nerve tests which revealed carpal

tunnel syndrome and polyneuropathy due to the improper ingestion of Lithium. On June 22, 2012, the hand specialist performed surgery on the plaintiff’s hand and arm, but the plaintiff asserted he still had residual effects from the Lithium incident. The defendant disputed the cause of numbness maintaining that the plaintiff was never exposed to a toxic dose of Lithium.

The plaintiff commenced his suit against Walgreen’s on March 14, 2013 and during the discovery process asked the defendant to produce its policies and procedures for handling misfilled and returned prescriptions. In addition, the plaintiff asked Walgreen’s to produce the medication vial that con-tained the improper Lithium so the capsules could be tested to ensure they were Lithium. Walgreen’s produced its policies and procedures, but informed the plaintiff it had destroyed the prescription vial and its contents in accordance with store policy. Upon learning that the defendant had destroyed the vial and its contents, the plaintiff moved for spoliation sanc-tions against the defendant. These sanctions included the court striking any of Walgreen’s affirmative defenses, allow-ing the bench trial to only determine the plaintiff’s damages, requesting an adverse inference to the jury, and the awarding of attorney’s fees and costs. In short, the plaintiff wanted spoliation sanctions severe enough to prevent Walgreen’s from providing just about any kind of defense to the plain-tiff’s claim.

The legal standard of spoliation is the significant altera-tion or destruction of evidence, or the failure to preserve property for another’s use as evidence in pending or reasona-bly foreseeable litigation. In other words, a party must pre-serve evidence it knows or should know is relevant to a claim or defense of any party, or that may lead to the discovery of relevant evidence. The decision by a court to impose spolia-tion sanctions is discretionary. The key question the court must decide is whether relevant evidence existed. If so, then the question is whether the non-moving party had a duty to preserve the evidence.

When a defendant destroys evidence according to its internal policies or in the normal course of business, the de-fendant has not engaged in spoliation if the defendant had no notice of the evidence’s potential relevance in future litiga-tion.

Continue on Next Page

Legal Capsules By: Col (Ret.) David W. Bobb, RPh, Esq


Cont…

In addressing the first part of this legal standard, Walgreen’s argues that its policy states that it quarantines returned medication and then destroys it after a certain amount of time. In this case, when the plaintiff’s medication was returned, the pharmacist placed it in a depository safe. Then, the medication was sent to Walgreen’s prescription return center where it was destroyed according to company policy. Since the plaintiff produced no contrary evidence, Walgreen’s meets the first part of the legal standard.

The plaintiff then contends that the defendant had a duty to preserve the evidence because it knew of the “significant potential of litigation” as soon as it completed an incident report for its insurance carrier. Walgreen’s responded that customers return medications frequently and that it would be impractical, if not impossible, to preserve medications just in case someone brings a future lawsuit. The court did not buy into this argument by Walgreen’s. The court was uncon-vinced that customers return a significant portion of their medications because of misfilled prescriptions. Further, since Walgreen’s filed an incident report with its insurance compa-ny when the medication was returned, it was on notice that a potential lawsuit may follow due to the dispensing error. The court ruled that Walgreen’s had a duty to preserve the evidence.

However, instead of issuing spoliation sanctions, the court stated that the error was harmless and no prejudice to the plaintiff’s case exists. The reason for this is because Walgreen’s had already admitted an error had been made when the plaintiff’s wife returned the medication to the phar-macy and the pharmacy employee told her the incorrect medi-cation was Lithium. Also, when the plaintiff first went to the emergency room, the plaintiff and defendant both stipulated that much of the information regarding the Lithium error came from the Walgreen’s pharmacist. The court reasoned

that now, since the error had been admitted, the crux of the case turns on whether the amount of Lithium ingested amounted to a toxic dose and/or caused the symptoms and conditions the plaintiff was experiencing. The fact that the actual prescription bottle was not available would not impact or prejudice the plaintiff’s ability to prove causation. There-fore the court declined to impose spoliation sanctions.

While I believe this court thoughtfully reasoned its way through the case and came to a correct conclusion, there are several questions left open. First, what if Walgreen’s had not admitted that it was Lithium in the bottle and just stated that an error had been made? Would spoliation sanctions be prop-er then since the plaintiff would not have the opportunity to know exactly what medication he received? What if the plaintiff had received a 90-day supply, but only one or two Lithium capsules were in the vial when it was returned? Would that influence how the plaintiff presented his case or how the defendant defended the case? Perhaps most im-portantly though, is how this case effects your pharmacy and your practice. Do you have a written policy addressing the return of a medication that was improperly dispensed? Do you fill out incident reports each time this occurs? How long do you keep a bottle with a medication that was not filled cor-rectly? If you do not have a policy covering this type of sce-nario, I highly suggest you write one. In respect to a timeline to keep a bottle of medication that was filled improperly, my suggestion is two years if you believe it is reasonably foresee-able that a lawsuit will commence due to the improper filling. This is based on the fact that just about any negligence law-suit filed will fall under the Federal Tort Claims Act. This Act has a two year statute of limitations for a person wishing to file a claim. And lastly, as always, if you have a policy make sure that everyone in your pharmacy knows the policy and is following the policy. It can save you many headaches down the road if something goes wrong. Until next time, practice safely!

Call for Future Ar cles

The Society of Air Force Pharmacy Executive Team is excited to have published its third issue of the 2015 SAFP Newsletter. We have received numerous submis-sions that has made this issue a success. We are now accepting articles for our first newsletter issue of 2016. Please feel free to contact the editor if you are unsure of a topic or would like to submit an article. Ad-ditionally, we are always looking for new CME topics.

As with any organization, we need your help to make the next issue a success! Please submit any article(s) focusing on this topic. If you have any questions, then please reach out to the SAFP Editor, Maj Rohin Kasudia. The Editorial Team looks forward to your submissions!


Accreditation Statement

Postgraduate Institute for Medicine is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Credit Designation Postgraduate Institute for Medicine designates this continuing education activity for 1.1 contact hour(s) (0.11 CEUs) of the Accreditation Council for Pharmacy Education.

(Universal Activity Number - 0809-9999-16-082-H01-P ) - Pharmacists

(Universal Activity Number - 0809-9999-16-082-H01-T ) - Pharmacy Technicians

Type of Activity

Knowledge

Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identi-fied COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activi-ties and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

The following PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CCMEP, and Jan Schultz, MSN, RN, CCMEP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

Method of Participation and Request for Credit

There are no fees for participating and receiving CME credit for this activity. During the period January 15, 2015 through January 17, 2017, participants must read the learning objectives and faculty disclosures and study the educational activity.

PIM supports Green CME by offering your Request for Credit online. If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation on www.cmeuniversity.com. On the navigation menu, click on “Find Post-test/Evaluation by Course” and search by Course ID 11359 . Upon successfully completing the post-test with a score of 75% or better and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service.

Media

Newsletter

Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medica-tions, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and com-parison with recommendations of other authorities.

Name of Faculty or Presenter Reported Financial Rela onship

Daniel J. Oh, Maj, USAF, Pharm D, MHA, BCPS Ownership Interest; Pfizer, Bristol‐Myers Squibb,

Gilead, Isis

Name of SAFP Manager Reported Financial Rela onship

Rohin N. Kasudia, Maj, USAF, Pharm D, BCACP None


Learning Objectives 1) Describe the mechanism of action and pharmacokinetics of

dabigatran 2) Identify the most common side effects of dabigatran 3) Identify which pivotal trial demonstrated the efficacy of

dabigatran against warfarin for use in patients with atrial fi-brillation

4) Identify five other trials published with dabigatran for the prevention of venous thromboembolism

5) Explain the American College of Chest Physician’s recommen-dations on dabigatran’s use in the management of patients with atrial fibrillation

6) Provide accurate and appropriate counsel as part of the treat-ment team.

Released: 15 January 2016 Expiration Date: 15 January 2017 Time to Completion: 1.1 Hour

Jointly provided by Postgraduate Institute for Medicine and the Society of Air Force Pharmacy

This activity has been designed to meet the educational needs of phar-macists involved in the care of patients with Atrial Fibrillation.

Introduction

Atrial fibrillation (AF) is the most common heart arrhythmia. It affects approximately 3 million people in the United States and this number is expected to grow as high as 7 million by 2050.1 The economic impact of AF is substantial because of the high consump-tion of health care resources, most notably hospitalization, associat-ed with the disorder which amounts to an annual cost exceeding $12 billion.2,3 Patients with AF have a 4.5 fold risk of stroke, which account for more than half of all patients hospitalized for acute neu-rological disease.4,5 As a result, prevention of stroke, especially with anticoagulation, is of the utmost importance.

Patients with AF have mainly been managed with warfarin, which reduces the stroke risk by 64%, but increases the risk of all major bleeds by 69% compared with placebo.6 Warfarin has been the mainstay in preventing thrombosis in patients with atrial fibril-lation. However, there are limitations to warfarin use, such as a narrow therapeutic index, frequent monitoring, many drug and food interactions, a slow therapeutic onset, and risk of hemorrhage.

Warfarin

Warfarin is a vitamin K antagonist approved for the prophy-laxis and management of thromboembolic disorders. The half-life can be up to 60 hours with maximal anticoagulant effect reached after 5-7 days of therapy or when all the vitamin K dependent coag-ulation factors have been inhibited.7 Warfarin is monitored by the International Normalized Ratio (INR) and patients with atrial fibril-lation have a therapeutic INR of 2.0-3.0 for adequate anticoagula-tion. An INR below 2.0 or above 3.0 may indicate improper antico-agulation. Until the recent introduction of dabigatran, warfarin was

the only oral anticoagulant available to manage patients with atrial fibrillation.

Dabigatran

In Oct 2010, the Food and Drug Administration (FDA) ap-proved the first new oral anticoagulant in 62 years, Pradaxa® (dabigatran etexilate), to prevent stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Mechanism of Action

Dabigatran is a reversible direct thrombin inhibitor of both free and fibrin-bound thrombin and reduces thrombin-induced platelet aggregation in the coagulation cascade as seen in Figure 2.

Pharmacodynamics and Pharmacokinetics

Dabigatran etexilate is converted into its active form, dabigatran, by serum esterase that is independent of cytochrome P-450.8 There-fore, dabigatran should be less susceptible to dietary and drug inter-

actions and genetic polymorphisms... Continue on Next Page

Sixty Years Later a New Oral An coagulant Emerges for Atrial Fibrilla on: Dabigatran But how RE‐LY‐able is it?

By: Daniel J. Oh, Maj, USAF, Pharm D, MHA, BCPS

Figure 1: Dabigatran at a Glance Brand name: Pradaxa Type: Prodrug Mechanism: Reversible direct thrombin inhibitor U.S. Indication: Primary prevention of stroke and systemic embolization in nonvalvular atrial fibrillation Precaution/Warning/Contraindication: Do not use in pa-tients with active bleeding, creatinine clearance (CrCl) <15mL/min. Not recommended for patients with moderate to severe hepatic impairment. Dose adjustment for CrCl of 15-30mL/min Most common side effects: Dyspepsia and bleeding Dosage: 150mg PO bid with or without food. 75mg PO bid for CrCl 15-30mL/min Cost: ~$9/day

Figure 2. Dabigatran’s Effect on Coagulation Cascade

Image Credit: Eriksson, et al, adapted.16


Cont… that can be seen with warfarin. Dabigatran has poor bioa-vailability ranging from 3-7% and a volume of distribution (Vd) of 50-70L. The manufacturer recommends that the capsules not be opened, crushed or chewed due to an increase in bioavailability of up to 75%.9 It reaches peak levels approximately 30 minutes to 2 hours after ad-ministration with a half-life of 15 hours to 17 hours; thus, there is no need to use bridge therapy with dabigatran for nonvavular atrial fibrilla-tion.12, 14 It is almost exclu-sively excreted through the kidneys with 80% excretion in the urine. As a result, dabigatran is renally dosed in patients with a creatinine clearance (CrCl) of > 30mL/min at 150mg twice daily and CrCl of 15-30mL/min at 75mg twice daily. The manu-facturer in November 2011 revised the expiration date of dabigatran from 30 days to 120 days after opening. The medication should be kept in its original container and not in a pill organizer since it con-tains a desiccant due to the potential for product breakdown and loss of potency.

In addition, on October 16, 2015, the FDA has given an accel-erated approval to Praxbind® (idarucizumab) a reversal agent to the anticoagulant effects of Pradaxa® during emergency situations.11 Praxbind®, administered intravenously, is the first reversal agent approved specially for Pradaxa® and works by binding to the drug compound neutralizing dabigatran’s effect within minutes.12

Clinical Trial Efficacy

A comparative study that evaluated the efficacy of dabigatran with warfarin was seen in the Randomized Evaluation with Long –Term Anticoagulation Therapy (RE-LY) and was the FDA’s prima-ry decision to approve dabigatran etexilate.

The RE-LY trial was an open label, randomized, noninferiori-ty study that randomized 18,113 patients to receive either warfarin with unblinded INR-adjustment or dabigatran etexilate in doses of either 110mg or 150mg twice daily given in a blinded fashion. The primary study and safety outcomes were stroke or systemic embo-lism and major hemorrhage, defined as a hemoglobin decrease of 20g/L, transfusion of > 2 units of blood, or symptomatic bleeds in critical area or organs. Secondary outcomes included all-cause

mortality, stroke, myocardial infarction, pulmonary embolism, and vascular deaths.

The study population consisted of patients with increased risk for stroke defined as hav-ing a stroke history or transient ischemic attack, a left ventricular ejection fraction of < 40%, New York Heart Association (NYHA) class II or high-er, heart failure symptoms within 6 months, an age over 75, an age of 65 to 74 with diabetes, hyperten-sion, or coronary artery disease. The study exclud-ed patients with severe heart-valve disorder, stroke within 14 days, severe stroke within 6 months of screening, con-dition with increased risk

of hemorrhage, creatinine clearance < 30 mL/min, active liver dis-ease, and pregnancy.13

The study population composed of majority male, 63.6%, with a mean age of 71, with almost even distribution of patients having persistent, paroxysmal, or permanent atrial fibrillation. Patients risk stratification for stroke was performed using the CHADS2 score assigning point values for the following: Congestive heart failure, Hypertension of systolic > 160mmHg, Age > 75, Diabetes, and pri-or Stroke or transient ischemic attack. The higher the CHADS2 score, the greater the risk for stroke, with a max score of 6.

The average CHADS2 score in the RE-LY population was 2.1. Approximately 20% of the patients had a smoking history, 16% myocardial infarction history, 23% diabetes, and 79% hypertension. Baseline medications included 40% aspirin, 66% angiotensin con-verting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), 63% beta blocker, 44% statin, 14% proton pump inhibitor, 11% amiodarone, and 4% H2 receptor antagonist.

After a median follow-up of 2 years, dabigatran 150mg was found to be statistically superior to warfarin in preventing stroke or systemic embolism and was associated with a 1.11% per year stroke risk compared to warfarin’s 1.69% (hazard ratio: 0.66, 95% CI: 0.52-0.81, P<0.001 for superiority).12 Whereas dabigatran 110mg was found to be statistically noninferior to warfarin with a rate of 1.53% per year (HR: 0.90, 95% CI: 0.74-1.10, P < 0.001).12




Figure 3. Dabigatran Pharmacodynamics and Pharmacokinetics

Image Credit: Bereznicki, et al, adapted.10


Cont… Major bleeding occurred at a rate of 2.71% per year in the dabigatran 110mg group (RR 0.80; 95% CI 0.69-0.93; P = 0.003), 3.11% in the dabigatran 150mg group (RR 0.93; 95% CI, 0.81-1.07; P = 0.31), and 3.36% per year in the warfarin group. Rate of hem-orrhagic stroke was 0.38% per year in the warfarin group com-pared to 0.12% and 0.10% per year in the 110mg (P<0.001) and 150mg (P<0.001) groups, respectively. Although not signifi-cant, the mortality rate was lower in the dabigatran 110mg group (P=0.13) at 3.75% per year and 150mg (P=0.51) at 3.64% per year com-pared to warfarin’s mortality rate of 4.13%.18

The RE-LY trial had a large study pop-ulation of over 18,000 that compared two blinded dabigatran doses with a blinded adjudicator for its outcomes. Of note, 99.9% of patients completed follow-up with only 20 patients lost to follow-up. The quality of warfarin management in RE-LY was assessed by measur-ing the percentage of time in the time-in-therapeutic range (TTR), which averaged 64%.12 This is comparable to the TTR seen in the outpatient anticoagulation clinics of 63%, however, only approxi-mately 33% of patients had a CHAD2 score of >2 which may not extrapolate to higher risk patients.14

Dabigatran reported a number-needed-to-treat (NNT) com-pared to warfarin for the primary efficacy outcome of stroke and systemic embolism of 172 patients. This NNT translates to 172

patients, with the same study characteristics, to be treated for 1 year in order to prevent 1 incident of a stroke or systemic embolism. An

analogous measure, the number needed to harm (NNH), refers to the number of indi-viduals who must receive the same treatment to cause one death or other serious injury.

Dabigatran was favorable over warfa-rin at the primary safety efficacy of ma-jor bleeds with the number needed-to-harm (NNH) of 77. Of note, the number-needed-to-treat (NNT) ranges from 172 to 385 while the NNH ranges from 77 to 285. By evaluating Tables 1 and 2, a health care provider can put the results of the RE-LY trial into perspective before deciding on a clinical decision.

There was a higher discontinuation rate in patients receiv-ing dabigatran com-pared with those re-ceiving warfarin due

to patients choice, outcome event, serious adverse events. Dyspep-sia was the most common gastrointestinal symptoms, most com-monly with a NNH of 17 and 18 in the 110mg and 150mg, respec-tively. As a result, dabigatran 150mg had a 15.5% discontinuation rate compared to warfarin’s 10.2% during the first year and 21.2% vs. 16.6% at two years. Roughly 20% of patients in each study group were on concomitant aspirin therapy throughout the trial, thereby affecting study results and bleeding risk. However, the war-farin patients reflected a real practice setting TTR throughout the study period.





Cont… Overall, the RE-LY study showed that dabigatran 110mg twice daily had similar rates of stroke and systemic embolism to that of warfarin but had lower rate of major hemorrhage. Dabigatran 150mg twice daily was associated with lower rates of stroke and systemic embolism but had comparable rates of major hemorrhages compared to warfarin.

Potential Future FDA Indications

Dabigatran’s place in therapy for atrial fibrillation has been studied for other uses such as prevention of venous thromboembo-lism (VTE) in patients undergoing total hip and knee replacement. These include the RE-NOVATE15, RE-MODEL16, RE-MOBILIZE17, Boehringer Ingelheim Study in Thrombosis I (BISTRO I)18, and Boehringer Ingelheim Study in Thrombosis II (BISTRO II)19 trials. The results of all these trails, except for RE-MOBILIZE, showed dabigatran noninferior to enoxaparin in the prevention of VTE in patients undergoing total hip and knee re-placement. Currently, prevention of VTE after total hip and knee replacement is only approved in Canada and Europe and not in the United States.

However, in April 2014 the FDA approved dabigatran in the treatment of VTE indicating that diabigatran was effective as warfa-rin as reflected in the RE-COVER II study. The RE-COVER II study was a double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given par-enteral anticoagulation therapy, generally unfractionated heparin administered intravenously or low-molecular weight heparin admin-istered sub-cutaneously, for a median of 9 days then treated for 6 months with dabigatran 150mg twice daily compared to dose-adjusted warfarin to achieve an INR of 2.0 to 3.0.20

The average retail cost of dabigatran 75mg and 150mg is $9 daily, respectively, versus the cost of warfarin at $4 for a 30 day

supply at most retail pharmacies. However, the annual cost per patient for routine anticoagulation management care is $6,795 per year which does not include cost for hospitalizations or emergency department visits due to warfarin’s side effects.21 Although dabigatran has the convenience of less monitoring along with less drug and diet interactions compared to warfarin, it is countered with a higher medication cost.

New Practice Guidelines

The 2014 recommendation by the American College of Cardi-ology Foundation (ACCF), American Heart Association (AHA), and the Heart Rhythm Society (HRS) gave the use of dabigatran a 1B recommendation (strong recommendation with benefits and risk from randomized, controlled trials with important limitations such as imprecise results) and stated that it will be useful/effective as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with prior stroke, TIA, or CHADS2 > 2.22 In addition, dabigatran is not recommended inpatients with AF and end-stage chronic kidney disease (CKD) or on dialysis because of a lack of evidence from clinical trials regarding the balance of risks and benefits and should not be used in those with a mechanical heart valve.20

Conclusion

Dabigatran (Pradaxa®) is the first new oral anticoagulant in 62 years since warfarin became the main medication utilized in managing patients with a thromboembolic condition. As compared with adjusted-dose warfarin, dabigatran 150mg twice daily prevent-ed more strokes and dabigatran 110mg twice daily caused fewer hemorrhages as seen in the RE-LY trial.23 Advantages of dabigatran over warfarin include the lack of frequent monitoring, a fixed dose regimen, potentially fewer drug interactions, and no need for bridge therapy. Drawbacks of dabigatran include limited trial data, accu-mulation in renal impairment, lack of reversal agent, and limited long-term safety data. However, dabigatran may offer healthcare providers an alternative treatment option in patients intolerant to

warfarin. Continue on Next Page



Table 4. Advantages and Disadvantages of Dabigatran

Table Credit: Naccarelli, et al, adapted.1


REFERENCES

1. Naccarelli,G., Varker, H., Lin, J., & Schulman, K. (2009). Increasing prevalence of atrial fibrillation and flutter in the United States. American Journal of Cardiology, 104, 1534-1539

2. Snoski, R., Bauman, J., Dekker, S., (2008). The arrhythmias. In: DiPiro J., Talbert, R., Yee, G., et al. Pharmacotherapy: A pathophysiologic approach. (7th ed.), Yew York, NY: McGraw-Hill, 279-314

3. Cheng, J. (2008) Vernakalant in the management of atrial fi-brillation. Annals of Pharmacotherapy, 42, 533-542

4. Al-Saady, N., Obel, O., & Camm, A. (1999). Left atrial appendage: Structure function, na drole in thromboembolism. Heart, 5, 547-554

5. Laupacis, A., Albers, G., Dalen, J., Dunn, M., Jacobson, A., & Singer, D. (1998). Antithrombotic therapy in atrial fibrillation, Chest, 114, 579S-589S

6. Shah, S & Gage, B. (2011). Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation, 123, 2562-2570

7. Ufer, M. (2005). Comparative pharmacokinetics of vitamin K antagonists: Warfarin, phenprocoumon and acenocoumarol. Clinical Pharmacokinetics, 44, 1227-1246

8. Ma, T., Yan, B., & Lam, Y. (2011). Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clini-cal data. Pharmacology & Therapeutics, 129, 185-194

9. Pradaxa (Package insert). (2010). Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.

10. Bereznicki, L. (2010). New antithrombotics for atrial fibrilla-tion. Cardiovascular Therapeutics, 28, 278–286

11. Food and Drug Administrations (FDA). (2015). FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa. Retrieved from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm

12. Casseis, C. (2015). FDA Approves Praxbind to Reverse Anticoagulant Pradaxa. Retrieved from http://www.medscape.com/viewarticle/852804

13. Connolly, S., Ezekowitz,, M., M.B., Yusuf, S., Eikelboom, J., … Wallentin, L. (2009). Dabigatran versus warfarin in patients with atrial fibrillation. The New England Journal of Medicine, 36, 1139-1151

14. Baker, W., Cios, D., Sander, S., & Coleman, C. (2009). Meta-analysis to assess the quality of warfarin in atrial fibrillation patients in the United States. Journal of Managed Care Phar-macy, 15(3), 244-252

15. Eriksson, B., Dahl, O., Rosencher, N., Kurth, A., … Buller, H. (2007). Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a

randomized, double-blind, non-inferiority trial. Lancet; 370, 949-56

16. Eriksson, B., Dahl, O., Rosencher, N., Kurth, A., … Buller, H.(2007) Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. Journal of Thrombosis and Haemostasis, 5, 2178-2185

17. Ginsberg, J., Davidson, B., Comp, P., Francis, C., … Caprini, J. Oral thrombin inhibitor dabigatran etexilate vs. North Ameri-can enoxaparin regimen for prevention of venous thromboem-bolism after knee arthroplasty surgery. The Journal of Arthro-plasty, 24, 1-9

18. Eriksson, B., Dahl, O., Ahnfelt, L., Kalebo, P., … Kohlbrenner, V. (2004). Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. Journal of Thrombosis and Haemostasis, 2, 1573–1580

19. Eriksson, B., Dahl, O., Buller, H., Hettiarachchi, R., … Reilly, P. (2005) A new oral direct thrombin inhibitor, dabigatran etex-ilate, compared with enoxaparin for prevention of thromboem-bolic events following total hip or knee replacement: the BIS-TRO II randomized trial. Journal of Thrombosis and Haemo-stasis, 3, 103–111

20. Schulman, S., Kearon, C., Kakkar, A., Mismetti, P., … Goldha-ber, S. (2010). Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. The New England Journal of Medicine, 361, 2342-2352

21. Caro, J. (2004). An economic model of stroke in atrial fibrilla-tion: The cost of suboptimal oral anticoagulation. The Ameri-can Journal of Managed Care, 10, S451-S461

22. January, C., Wann, L., Alpert, J., Calkins, H., … Yancy, C. (2014). 2014 ACCF/AHA/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary. Journal of the American College of Cardiology. Retrieved from http://content.onlinejacc.org/article.aspx?articleid=1854230

23. Gage, B. (2009). Can we rely on re-ly? The New England Jour-nal of Medicine, 361, 1200-1203



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