Medication adherence is defined as the act of patients taking their medications as prescribed by their health care provider.

 The term adherence refers to a collaboration between a patient and a health care provider in which they mutually agree upon a course of treatment to produce a positive therapeutic result. Persistent medication nonadherence leads to emergency department visits, hospitalizations, and mortality; it is also associated with a high economic burden and poor clinical outcomes. In addition, medication nonadherence can increase the risk of hospital readmissions.

 According to the National Association of Chain Drug Stores, 50% to 70% of patients who receive a prescription take it to the pharmacy for processing, and 48% to 66% of those patients pick up their medications.

 Alarmingly, only 25% to 30% of patients take their medications properly, whereas 15% to 20% of patients refill their medications as prescribed.

The World Health Organization has proposed 5 interacting dimensions that affect adherence (

 Strategies to enhance medication adherence include a series of interventions known by the acronym SIMPLE (

 These strategies are typically incorporated into medication therapy management (MTM) services. MTM services have become widely recognized as an integral and vital part of patient care, with improvements being shown in clinical, economic, and humanistic outcomes.

MTM is a comprehensive, patient-centered counseling service provided by a health care practitioner in collaboration with a patient and health care team members. MTM services have 2 parts: therapeutics and patient counseling. The therapeutics component is for assessing the appropriateness of a patient’s medication regimen according to evidence-based guidelines. The counseling component is for educating and empowering patients to take an active role in their medical management.

Pharmacist’s Role in Medication Adherence

Pharmacist-provided services, such as medication reconciliation and MTM, both components of transitions of care, have been shown to have a positive effect on the management of multiple disease states and to reduce 30-day hospital readmission rates.

 MTM services are provided by pharmacists in various health care settings, especially in ambulatory care

; other settings include acute care, long-term care, home care, and managed care. Each setting requires the tailoring of services to fit a patient’s present and potential needs, while maintaining the 5 core elements of pharmacist-provided MTM services:

Not all settings are equal in terms of the availability of patient information required to provide comprehensive MTM services.

 Data-poor environments, such as community pharmacies, maintain important subjective information, such as patient allergy and medication profiles, refill histories, demographics, and insurance coverage. However, pharmacists working in data-poor environments are faced with multiple information-gathering challenges, such as inaccessible medical/discharge records (objective data), reliance on patients for providing a full medical history (recall bias, memory lapse), and medication lists built by prescription transactions instead of a confirmed, prescribed medication list. Other limitations include the retrospective identification of medication discrepancies, physician time constraints, and difficulty reaching physicians.

Pharmacists working in data-rich environments, such as hospitals, long-term care facilities, and medical clinics, have full access to objective patient information necessary to provide comprehensive MTM services.

 Hospital charts contain objective information, such as diagnoses, around-the-clock physical examinations, vitals, medications administered, laboratory and test results, and, possibly, a discharge plan. In a hospital setting, physicians and supporting health care team members are relatively more accessible for discussing patient therapy plans with the pharmacists. In addition, therapy modifications can be implemented immediately and prospectively, potentially avoiding an adverse event in the community.

Hospital Pharmacists and Adherence Counseling

Hospital pharmacists may begin the patient counseling and empowerment portion of MTM as a patient approaches treatment completion. During this time, counseling may relieve some of the information and instruction overload that patients typically experience during the discharge process. In addition, patient education can be reinforced during the discharge process to help patients remember their instructions. Developing a patient-pharmacist relationship early may help alleviate premature anxiety regarding self-management, and other patient-related factors that can lead to medication nonadherence.

A hospital setting can never replace MTM services provided in an outpatient setting, whether it is a data-rich or data-poor environment; however, the hospital setting is a good place to start. Inpatient counseling may extend the transition-of-care timeline, but follow-up care is always necessary to ensure that inpatient MTM efforts are worthwhile and beneficial. Although pharmacists have proved to be valuable MTM providers, a multidisciplinary effort involving collaboration among the patient and the health care team members will always be required to ensure safety, efficacy, and the best overall health outcomes.

. CB is a 42-year-old man admitted to the hospital for new-onset atrial fibrillation. He is initiated on intravenous (IV) diltiazem for rate control and IV unfractionated heparin for anticoagulation. The patient is currently stabilized, and is alert and oriented.

		How will you discuss with the patient his current medication regimen for new-onset atrial fibrillation?

. CB is maintained in sinus rhythm overnight and is converted to oral diltiazem ER 180 mg once a day and apixaban 5 mg twice a day. The date of discharge remains undetermined, and no discharge treatment plan is set up at this time.

		What will you discuss with the patient to prepare him for self-management after discharge? What questions will you ask to assess the patient’s medication adherence barriers?

. CB will be discharged this afternoon with diltiazem ER 240 mg once a day and apixaban 5 mg twice a day. The patient feels he can trust you, and decides to admit that he is illiterate.

		How will you assist the patient in overcoming this adherence barrier? What recommendations do you have to help the patient overcome this adherence barrier after discharge?

Dr. Chu is an internal medicine pharmacist specializing in transitions of care and anticoagulation therapy management at Swedish Covenant Hospital, Chicago, Illinois.

		Ho PM, Bryson CL, Rumsfeld JS. Medication adherence: its importance in cardiovascular outcomes. 

. 2009;119(23):3028-3035. doi: 10.1161/CIRCULATIONAHA.108.768986. 

		Medication adherence time tool: improving health outcomes. American College of Preventive Medicine website. acpm.org/?MedAdherTT_ClinRef. Published 2011. Accessed February 21, 2016.

		Koeler BE, Richter KM, Youngblood L, et al. Reduction of 30-day post discharge hospital readmission or emergency department (ED) visit rates in high-risk elderly medical patients through delivery of a targeted care bundle

. 2009;4(4):211-218. doi: 10.1002/jhm.427.

		Adherence to long-term therapies: evidence to action. World Health Organization website. apps.who.int/medicinedocs/pdf/s4883e/s4883e.pdf. Published January 2003. Accessed February 15, 2016.

		Medication adherence. CDC website. cdc.gov/primarycare/materials/medication/docs/medication-adherence-01ccd.pdf. Published March 27, 2013. Accessed February 15, 2016.

Medication Therapy Management in Pharmacy Practice: Core Elements of an MTM Service Model

. Version 2.0. American Pharmacists Association and the National Association of Chain Drug Stores Foundation; March 2008.

		Gilberson S, Yoder S, Lee MP. Improving patient and health system outcomes through advanced pharmacy practice: a report of the US surgeon general. Office of the Chief Pharmacist. US Public Health Service; Dec 2011.

		Yoder VG, Dixon DL, Barnette DJ, Beardsley JR. Short-term outcomes of an employer sponsored diabetes management program at an ambulatory care pharmacy clinic. 

. 2012;69(1):69-73. doi: 10.2146/ajhp110041.

		Morello CM, Zadvorny EB, Cording MA, Suemoto RT, Skog J, Harari A. Development and clinical outcomes of pharmacist-managed diabetes care clinics. 

		Stebbins MR, Cutler TW, Parker PL. Assessment of therapy and medication therapy management. In: Alldredge BK, Corelli RL, Ernst ME, et al. 

Koda-Kimble and Young’s Applied Therapeutics: The Clinical Use of Drugs

. 10th ed. Baltimore, MD: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013.

Articles

Health System Information

Discussing Medication Adherence with a Hospitalized Patient

Hazardous drug contamination is an issue of vital importance for specialty pharmacists. Abundant evidence has shown links between the handling of hazardous drugs (HDs) and increased risks for cancer, teratogenicity, and reproductive problems.

The risks surrounding the handling and manipulation of HDs have been recognized since the late 1970s, with more than 17 guidelines for HDs published over more than 30 years by 6 organizations and government agencies. However, despite the meticulous attention focused on drug safety, HD handling regulations continue to change.

Although the US Pharmacopeial Convention (USP) addressed HDs in a 2008 update to USP <797> for the issue of compounding sterile parenteral HDs, the update fell short due to a lack of guidance for nonparenteral products. As a result, in March 2014, USP published a proposed set of guidance known as USP <800> that dealt with HD handling in health care settings.

In the nearly 2 years since its initial publication in draft form, USP <800> has undergone periods of public comment and revision. As of February 1, 2016, USP <800> is approved and final.

Due to provisions of USP numbered below 1000 being legally enforceable, following the adoption of these rules by individual state boards, USP <800> may subject pharmacies to both state board and FDA inspections.

Like USP <797> and USP <795>, the provisions of proposed USP <800> deal with product transport, product storage, compounding, preparation, and administration of parenteral products. However, USP <800> builds on earlier regulations by focusing on HDs and occupational safety.

The regulations require HD storage and preparation in areas separate from non-HDs and will eliminate the practice of compounding small volumes of HDs in areas where non-HDs are routinely prepared, which is allowed under USP <797>.

In another important change, USP <800> requires the administration of HDs with the use of closed-system transfer devices (CSTDs) to minimize HD exposure to nurses who administer these drugs to patients.

The new requirements in USP <800> may pose major implementation challenges for pharmacists and pharmacy managers, as certain provisions may require pharmacies to change workflow patterns and make major purchasing decisions. In addition, limited financial resources may pose an important challenge to implementation of USP <800> regulations.

It is important to be familiar with the provisions of these proposed regulations and to take early steps to reduce implementation difficulties later on.

USP <797>: Adoption of and Compliance With Existing Regulations 

Although compliance with USP <797> has improved over time, current legislation governing sterile product compounding is a patchwork of state-specific regulations with wide variations between jurisdictions.

Despite the fact that USP <797> is a legally enforceable standard irrespective of state-specific legislation, only about half of state regulations specifically reference USP <797> in sterile compounding rules.

In a nationwide survey conducted in 2014, two-thirds of respondents from 719 pharmacies throughout the United States and Canada reported handling HDs. Several reasons were cited by respondents for a lack of full USP <797> compliance (

State pharmacy boards, including the state boards of California, Florida, Minnesota, and Texas, have conducted inspections ensuring compliance with USP <797> standards in hospitals. Partially as a result of this increased regulatory oversight, between 2011 and 2014, self-reported compliance rates with USP <797> increased from 73.9% to 81.3% for sterile products and from 71.3% to 75.4% for hazardous drugs (

Of the primary engineering controls used to protect health care workers from HDs, the 2014 survey found that Class II biological safety cabinets (BSCs) were the most common equipment used for HD compounding, followed by compounding aseptic containment isolators (CACIs).

Under USP <800>, Class II BSCs or CACIs remain the standard primary engineering controls for preparation of sterile HDs.

For nonsterile HD compounding, primary engineering controls include externally vented Class I BSCs and containment-ventilated enclosures (CVEs).

Because Class I BSCs and CVEs prevent the escape of HDs but do not guarantee product sterility, these cannot be used for preparation of sterile HDs. USP <800> continues to allow Class II BSCs and CACIs to be used for nonsterile compounding.

However, a BSC or CACI that is used for nonsterile HD compounding must be dedicated for that purpose only. Switching back and forth from nonsterile to sterile HD compounding in a CACI or BSC without thorough cleaning and disinfection is not permissible.

Negative-Pressure Environments: A New Requirement 

Regardless of the type of primary engineering control used, under USP <800>, HD preparation must always occur in a negative-pressure environment. Currently, many BSCs and CACIs reside in positive-pressure or neutral-pressure environments.

Building a clean room is one way to meet the negative-pressure environment requirement. However, this is prohibitively expensive for many organizations. Some organizations may opt for a less expensive alternative: building a negative-pressure containment segregated compounding area (C-SCA) that is vented to the outside, with at least 12 air changes per hour.

Unlike clean rooms, these negative-pressure environments do not need to meet the standards of the International Organization for Standardization. However, sterile products prepared in C-SCAs may have a shorter beyond-use date (12 hours) than sterile products prepared in clean rooms.

In addition to the costs for building a negative-pressure environment, pharmacies may need to purchase additional primary engineering controls (eg, BSCs, CACIs, and CVEs) to use in negative-pressure rooms dedicated to HD preparation.

Under USP <797>, pharmacies could prepare HDs using the same BSCs or CACIs used for non-HDs (provided the volume of HD prescriptions was not very high). This provision is often referred to as the, “low-volume exception.”

With the implementation of USP <800>, however, this exception will be eliminated.

Because negative-pressure rooms intended for HD compounding cannot be used for non-HD compounding, USP <800> regulations will require pharmacies to furnish a separate negative-pressure room with an additional primary engineering control system used exclusively for HD compounding.

It is unlikely that pharmacies will simply discontinue compounding HDs, as the scope and range of products considered HDs has expanded considerably beyond antineoplastic drugs through HD definitions set by the National Institute for Occupational Safety and Health (NIOSH).

USP <800> uses a broad definition of HDs set by NIOSH that include drugs in any of 6 categories: carcinogenic drugs, teratogenic drugs, reproductive toxins, drugs with organ toxicity at low doses, genotoxic drugs, or new drugs that mimic existing HDs.

This list may be useful as a starting place in distinguishing between HDs and non-HDs. However, each institution will need to develop its own individual list.

The NIOSH list, which was last updated in 2014, is available at cdc.gov/niosh/docs/2014-138/pdfs/2014-138.pdf.

As the list is updated every 2 years, a revised list is expected later this year. Sample products from the list are listed in the Table.

Reviewing the current list and demarcating HDs from non-HDs is a useful first step in preparing for USP <800>. Importantly, USP <800> regulations mandate reviewing the HD list (and documenting the review process) at least once each year.

USP <800> requires the receipt and unpacking of antineoplastic HDs in a negative-pressure or neutral-pressure area. It also requires storage of most HDs in a negative-pressure room with at least 12 air changes per hour (some HDs, such as capsules or film-coated tablets, may be kept with non-HDs if certain precautions are in place).

Additionally, USP <800> requires storage of all HDs in a separate refrigerator from non-HDs, with the HD refrigerator kept in a negative-pressure room with at least 12 air changes per hour. These regulations may require pharmacies to build additional storage areas and purchase additional refrigerators.

Handling HDs and Supplemental Engineering Controls 

For many HDs, exposure can occur not only during the receipt, transport, storage, compounding, and dispensing of medications (typically handled by pharmacy staff), but also via activities managed by nurses.

These nursing activities include exposure during the administration of hazardous parenteral medications and contact with the bodily fluids of patients taking HDs in the course of patient care activities.

Supplemental engineering controls, such as CSTDs, have an important role in protecting health care workers from occupational exposure to HDs. Once connected to the reservoir, such as a drug vial, CSTD devices equalize the pressure gradient between the vessel containing the drug and the syringe.

Without a pressure equalization system, differences in pressure can generate fine aerosols. These aerosols may escape into the air and expose the environment, patients, and health care professionals to HDs.

Whereas some CSTDs equalize pressure using a pressure equalization chamber, other CSTDs use an integrated filter to cleanse escaping air contaminated with hazardous drug vapors or aerosols.

Although the use of CSTDs in the pharmacy is recommended during preparation of HDs but not required under USP <800>, the regulations require nurses to use a CSTD when administering HDs to patients. Although CSTDs can be used by nurses in most cases, some highly reactive alkylating agents (eg, bendamustine) may not be compatible with CSTD materials.

In these rare cases, the USP <800> regulations recognize that a CSTD cannot be used.

USP <800> introduces many new provisions that will eventually require hospital pharmacies to build additional storage rooms and compounding areas, and to purchase additional primary engineering controls (eg, BSCs, CACIs, and CVEs) to ensure that HDs are prepared separately from non-HDs.

Additionally, because hospitals will eventually gain access to CSTDs in nursing units, they may also extend CSTD use to hospital pharmacies.

The CSTD selection process should include several considerations

Adherence with the closed system definition set by NIOSH, the Oncology Nursing Society (ONS), and International Society of Oncology Pharmacy Practitioners (ISOPP) as a device that is mechanically closed, prevents anything from entering the system, and does not allow drug or drug vapor to exit the system

Consideration of published literature on maintenance of dry connections (membrane litmus testing, fluorescence dye testing, or smell tests)

Consideration of ease-of-use and ergonomic concerns

Hazardous drug contamination is an issue of vital importance for specialty pharmacists.

USP : Key Changes and Additions to USP 

The Institute for Safe Medication Practices (ISMP) recently added new best practices for improving patient safety in hospitals. According to ISMP, the purpose of the 2016-2017 Targeted Medication Safety Best Practices for Hospitals is to “identify, inspire, and mobilize widespread national adoption of consensus-based best practices on specific medication safety issues that continue to cause fatal and harmful errors in patients, despite repeated warnings in ISMP publications.”

Health-system pharmacists should get familiarized with the following 5 best practices in order to promote patient safety in their hospitals:

Segregate, sequester, and differentiate all neuromuscular blocking (NMB) agents from other medications, wherever they’re stored in the organization.

In an ASHP 2016 Summer Meetings lecture devoted to the new best practices, Darryl S. Rich, PharmD, MBA, FASHP, a medication safety specialist at ISMP, noted that the organization has received more than 100 reports of accidental administration of NMBs in recent years. Specifically, he said, inadequate labeling and unsafe storage have been the “root cause of most of these errors.” As of February 2016, 54% of health systems report partially implementing this practice.

Administer high-alert intravenous (IV) medication infusions through a programmable infusion pump using dose error-reduction software.

 This practice applies to inpatient and outpatient hospital settings and in all situations in which high-alert medications are infused by the IV route (eg, anesthesia, patient-controlled analgesia).

Additionally, health systems should do as follows:

· Ensure that dose error-reduction software is employed on all smart pumps.

· Verify that drug libraries are built and installed on all smart pumps, and make sure staff is using the error-reduction software.

· Require periodic maintenance, updating, and testing of the software.

Identify which antidotes, reversal agents, and rescue agents should be administered immediately in emergency situations to prevent patient harm.

 To comply with this best practice, health-system pharmacists should make sure all appropriate antidotes, reversal agents, and rescue agents are readily available. Additionally, directions for use and administration should be easily accessible in all clinical areas where these agents are used.

According to a report from the Agency for Healthcare Research and Quality, prescription opioid misuse and abuse resulted in approximately 660,000 emergency department visits in 2010 alone.

Eliminate all 1000-mL bags of sterile water labeled for injection, irrigation, and inhalation from all areas outside of the pharmacy.

 Instead, health-system pharmacists should use alternatives in patient care areas, such as 2-L bags or vials. Dr. Rich suggested that the pharmacy should work with respiratory therapy teams and other relevant hospital departments to establish guidelines.

When compounding sterile preparations, perform an independent verification to ensure that the proper ingredients (medications and diluents) are added, including confirmation of the proper amount (volume) of each ingredient prior to its addition to the final container.

At a minimum, health-system pharmacists should ensure verification is completed for the following:

· All high-alert medications, such as chemotherapy drugs

· All pediatric and neonatal preparations

· Pharmacy-prepared source and bulk containers

· Drugs administered through high-risk routes

News & Highlights

Health-system pharmacists should get familiarized with these 5 best practices in order to promote patient safety in their hospitals.

5 New Best Practices for Medication Safety All Hospital Pharmacists Should Know

A 51-year-old obese woman with a history of hypertension, hyperlipidemia, and bipolar disorder presented to the emergency department with shortness of breath and sudden onset of dyspnea. She was given a diagnosis of bilateral submassive pulmonary embolisms (PEs) as seen on a computed tomography scan. She denied having a history of thromboembolism in the past, but her sister has a history of deep vein thrombosis (DVT). She denies smoking, use of oral contraceptives, and recent travel or surgery.

The patient’s pertinent examination results follow:

Pulmonary Vascular Service was consulted, and the patient was admitted to medicine service and started on unfractionated heparin infusion (goal partial thromboplastin time: 60-80 seconds). The consult team was concerned that direct oral anticoagulation (DOAC) medications would be ineffective due to the patient’s obesity. She was started on warfarin instead, in addition to parenteral therapy for acute PE.

Venous thromboembolism (VTE) is defined by the diagnosis of DVT, PE, or both. In the United States, as many as 900,000 individuals (1 or 2 per 1000) are affected by VTE each year. VTE is the third leading cardiovascular cause of death, affecting up to 100,000 people per year. The risk of death is especially higher within 1 month after diagnosis, and one-third of people given the diagnosis have a VTE recurrence within 10 years.

Patients at risk for thromboembolism are those who have undergone recent surgery or trauma, have had prolonged immobility, are of increased age, or have active cancer.

 Patients should be evaluated for thrombosis risk and provided with prophylaxis therapy to prevent blood clots from forming. However, these are not the only patients at risk. Many lifestyle factors can also increase the risk of blood clots; examples include smoking, hypertension, metabolic syndrome, hyperlipidemia, and obesity.

 As seen in the patient case here, obesity was a contributing factor in developing VTE.

Obesity in the United States has become a public health problem. Between 2011 and 2012, an estimated 35% of adults 20 years or older were obese.

 There was no change in prevalence of obesity in this population from the previous decade. Estimates indicate that by 2030, more than 50% of the adult US population will be considered obese, and 10% will be considered morbidly obese (BMI >40 kg/m

 Obesity not only increases the risk of VTE but also is associated with other cardiovascular conditions, such as myocardial infarction, congestive heart failure, atrial fibrillation, and stroke. Obesity can also affect the treatments used to manage these conditions because pharmacokinetic parameters, such as volume of distribution, half-life, and drug elimination, can be altered in obese patients. Changes in pharmacokinetic parameters in obese patients may be seen in any of the various classes of anticoagulants.

According to guidelines published in February 2016,

 the DOACs dabigatran, rivaroxaban, apixaban, and edoxaban are recommended as first-line therapy over vitamin K antagonists (VKA), such as warfarin, for DVT of the leg or PE without cancer for the first 3 months of treatment. In patients who are not started on a DOAC, VKA therapy is recommended as an alternative to treatment with low molecular weight heparin. Parenteral therapy must be given for at least 5 days prior to initiation of dabigatran and edoxaban treatment, and it must be overlapped with VKA therapy. No parenteral therapy is recommended prior to treatment with the DOACs rivaroxaban or apixaban. After the first 3 months of therapy, the patient should be evaluated to determine if extended treatment is warranted.

Despite the recommendations in the treatment guidelines, there is still concern regarding the use of anticoagulant medications in patients who are obese, as shown by the medical team’s decision in the case presented here. This concern stems from the low number of patients enrolled in DOAC studies. Reviews of DOAC studies evaluating efficacy and safety in treatment and prevention of VTE and stroke prophylaxis in atrial fibrillation found that the frequencies of patients with a body weight >100 kg ranged from 14% to 19%, and the percentages were even lower for participants who were obese or morbidly obese.

 A meta-analysis published in 2015 evaluated 6 randomized controlled trials (27,000 participants) comparing DOACs to warfarin in VTE treatment, and concluded that there was similar efficacy and safety at various levels of body weight (ie, low, medium, and high).

 However, the authors concluded that more studies with larger study populations should be performed to confirm these findings. At present, there are no recommendations to adjust doses of DOACs for patients who are obese, but in underweight patients with body weight <60 kg, an adjusted dose may be needed if other factors are present.

 As stated in the treatment guidelines, DOAC therapy should be considered first-line therapy for acute VTE, but if treatment with DOACs is not started due to patient characteristics, as in the patient case here, then VKA treatment, overlapped with parenteral therapy, should be started to reduce mortality and prevent recurrence. 

 advanced practice clinical pharmacist who works in the Collaborative Drug Therapy Management clinics, specifically in Infectious Disease and Anticoagulation, at the Brigham and Women’s Hospital in Boston, Massachusetts.

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In the United States, as many as 900,000 individuals are affected by venous thromboembolism each year. 

Treatment of Acute Venous Thromboembolism in Obese Patients

Heart failure (HF) contributes to significant morbidity and mortality in the United States. Despite a variety of mainstay medications, such as angiotensin I converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), aldosterone antagonists, and beta-blockers, HF is associated with 1 in 9 deaths in the United States. Approximately 50% of patients given a diagnosis of HF will die within 5 years. Sacubitril/valsartan (Entresto; by Novartis) was approved by the FDA in July 2015 under the priority review program, and was granted fast-track designation. Sacubitril is the first FDA-approved neprilysin inhibitor (NI).

Neprilysin catalyzes the degradation of natriuretic peptides. Natriuretic peptides are produced in response to volume overload and cardiac dysfunction, and exert a beneficial response in HF. Sacubitril is a prodrug, and its active metabolite inhibits neprilysin, thus allowing natriuretic peptides to persist longer and promote vasodilation, diuresis, and natriuresis, as well as prevent cardiac hypertrophy. Sacubitril is combined with valsartan, an ARB that acts on the renin-angiotensin-aldosterone system and prevents vasoconstriction and decreases both aldosterone secretion and renal reabsorption of sodium.

Therapeutic Use, Dosing, and Administration

Sacubitril/valsartan is FDA-approved to reduce the risk of cardiovascular death and hospitalization in patients with chronic HF (NYHA class II-IV) with reduced ejection fraction. Sacubitril/valsartan is used in place of an ACE inhibitor or ARB. The initial dose is 24/26 mg twice daily if a patient is not currently taking an ACE inhibitor or ARB, and 49/51 mg twice daily if a patient is converting from either of these classes. Allow at least 36 hours after the last ACE inhibitor dose before initiating therapy. The dose should be increased every 2 to 4 weeks to achieve a target dose of 97/103 mg twice daily.

Sacubitril/valsartan carries a boxed warning for fetal toxicity; therefore, discontinue when pregnancy is detected. Discontinue immediately if angioedema occurs, and do not readminister. The most common adverse reactions of sacubitril/valsartan compared with those of enalapril are hypotension (18% vs 12%, respectively), hyperkalemia (12% vs 14%, respectively), and cough (9% vs 13%, respectively).

NIs should not be used with ACE inhibitors. A clinical trial studying a combination ACE inhibitor/NI demonstrated an increase in angioedema frequency associated with this combination compared with use of an ACE inhibitor alone (2.17% vs 0.68%; 

 <.005). Both ACE inhibitors and NIs interrupt the degradation of bradykinin, and high levels of bradykinin are associated with angioedema. Do not use sacubitril/valsartan in combination with an ARB, because one is already contained in the formulation. In addition, serum potassium may be increased when used with potassium-sparing diuretics or potassium supplements. Elderly patients should not use sacubitril/valsartan with nonsteroidal anti-inflammatory drugs, as this may worsen renal function. Monitor the serum lithium level, as increased concentrations have been reported.

FDA approval was based on a double-blind, randomized, multinational trial (PARADIGM-HF) comparing sacubitril/valsartan with enalapril in patients with NYHA class II-IV HF with left ventricular ejection fraction ≤40%. Patients were previously taking an ACE inhibitor or ARB and a beta-blocker at a maximally tolerated dose and had a systolic blood pressure of at least 100 mm Hg. During a run-in period, patients were exposed to enalapril twice daily for 2 weeks, and then sacubitril/valsartan for 4 to 6 weeks. There was a 1-day washout period between the enalapril and sacubitril/valsartan run-in, as well as before randomization. Patients who tolerated both medications during this run-in period were randomized to sacubitril/valsartan 97/103 mg twice daily (n = 4187) or enalapril 10 mg twice daily (n = 4212). All patients randomized were included in the analysis.

Death from cardiovascular causes or hospitalization for HF (the composite primary end point) occurred in 21.8% and 26.5% of patients in the sacubitril/valsartan and enalapril groups, respectively (hazard ratio [HR], 0.80; 95% CI, 0.73-0.87; 

 <.001; number needed to treat,22). Death from cardiovascular causes occurred in 13.3% of the sacubitril/valsartan group and 16.5% of the enalapril group (HR, 0.80; 95% CI, 0.71-0.89; 

 <.001). Hospitalizations for HF occurred in 12.8% and 15.6% of patients in the sacubitril/valsartan and enalapril groups, respectively (HR, 0.79; 95% CI, 0.71-0.89; 

 <.001). Median follow-up was 27 months; the trial was discontinued after a preplanned interim analysis showed overwhelming benefit with sacubitril/valsartan. The authors concluded that sacubitril/valsartan was superior to enalapril in reducing death and hospitalization due to HF.

The American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) Guidelines for the Management of Heart Failure were updated in May 2016 to include a recommendation for ARB/NI combination therapy. This class is recommended to replace an ACE inhibitor or ARB in patients with chronic symptomatic HF with reduced ejection fraction (NYHA class II or III) in order to further reduce morbidity and mortality. This is a class I, level B-R strong recommendation, defined by ACC/AHA/HFSA as the benefit greatly outweighs the risk and is based on moderate-quality evidence from at least 1 RCT. To further investigate the utilization of sacubitril/valsartan, Novartis recently announced FortiHFy, an umbrella clinical program encompassing more than 40 trials. These trials will study use in different populations and settings, and will promote a better understanding of HF.

NIs combined with ARBs are novel agents recommended in the ACC/AHA/HFSA HF guidelines to reduce hospitalizations and death. However, the only currently available medication in this class, sacubitril/valsartan, is notably more expensive than other mainstay medications. The average wholesale price for a 30-day supply is $450, and the wholesale acquisition cost is $375. Studies in the FortiHFy program are designed to provide further insight regarding exactly when and how this therapy should be used.

Jennifer L. Cruz, PharmD, BCPS, is an assistant professor of clinical education at UNC Eshelman School of Pharmacy. Katherine Summers is a PharmD candidate at UNC Eshelman School of Pharmacy.

		Entresto [package insert]. Cambridge, MA: Novartis Pharmaceuticals; 2015.

		Mozaffarian D, Benjamin E, Go A, et al. AHA statistical update. Heart disease and stroke statistics — 2016 update. A report from the American Heart Association. 

		FDA approves new drug to treat heart failure [news release]. Silver Spring, MD: FDA; July 7, 2015. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm453845.htm. Accessed June 2, 2016.

		Gordin JS, Fonarow GC. New medications for heart failure [epub ahead of print]. 

		Bavishi C, Messerli FH, Kadosh B, Ruilope LM, Kario K. Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials. 

. 2015;36(30):1967-1973. doi: 10.1093/eurheartj/ehv142.

		Valsartan [package insert]. Cambridge, MA: Novartis Pharmaceuticals; 2015.

		Sacubitril/valsartan (Entresto). Micromedex online database. www.micromedexsolutions.com. . Updated February 9, 

		Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. 

		McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. 

. 2014;371(11):993-1004. doi: 10.1056/NEJMoa1409077.

		Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure [epub ahead of print]. 

		Novartis announces investment in FortiHFy clinical program of Entresto and heart failure [press release]. Basel, Switzerland: Novartis; May 19, 2016. novartis.com/news/media-releases/novartis-announces-investment-fortihfy-clinical-program-entrestor-and-heart. Accessed June 2, 2016.

		Red Book Online. Truven Health Analytics. www.micromedexsolutions.com. Accessed June 2, 2016.

Formulary Drug Review

Heart failure contributes to significant morbidity and mortality in the United States. 

Use of Neprilysin Inhibitors in Chronic Heart Failure

Acute pain is the body’s normal response to noxious stimuli. Acute pain typically lasts for days to weeks, but it may last for months during the healing process.

 Because pain is a highly subjective experience, it is important for a thorough assessment to be conducted to determine the cause of pain and the most appropriate course of treatment. A pain management plan should consider the assessment of pain and all pertinent patient factors, as well as drug and nondrug measures that can be employed to relieve a patient’s pain. When a medication is selected to treat pain in a geriatric patient, factors that should be considered include drug metabolism mechanism, renal or kidney function, concomitant medical conditions, and social history, including the potential for drug abuse or history of addiction. If an assessment takes place in a community pharmacy setting, it is important to consider when a patient may require referral to a health care provider for a more in-depth acute pain evaluation.

The assessment of pain requires a multidimensional approach by clinicians because pain can present in many different ways and can affect patients physically and psychologically. A patient’s report of pain, in his or her own words, is the most reliable indicator of pain. A thorough pain assessment should inquire about the characteristics of the pain, past and current management strategies, medical history, family history, psychosocial concerns, and the patient’s goals and expectations for pain management. Characteristics of pain may include location and distribution, duration and periodicity, quality, and associated signs or symptoms.

Pain may be assessed using a unidimensional or multidimensional tool. Unidimensional scales are useful for a quick measurement of the intensity of an individual’s pain. The most common unidimensional pain assessment tools are the numeric rating scale, the visual rating scale, or a categorical rating scale. The 

 provides illustrations of unidimensional pain assessment tools. Because of potential “oversimplification of the pain problem” when using only unidimensional pain assessment tools, experts often prefer to use a multidimensional pain assessment tool. Multidimensional tools offer the advantage of providing information on characteristics of pain, in addition to pain intensity. They may be provided in a visual, verbal, or written format. Examples of multidimensional assessment tools include the initial pain assessment tool, a brief pain inventory, the McGill pain questionnaire, a memorial pain assessment card, and a pain drawing.

Elderly patients, in particular, may have difficulty articulating an accurate description of their pain for several reasons. It is common for this population of patients to underreport their pain due to fear, cultural factors, or stoicism. Changes in the patterns of an individual’s activities of daily living, such as walking or participating in social activities, may be an indicator of unrelieved pain. Elderly patients should be assessed for hearing, vision, or verbal impairments that may affect the assessment technique. When assessing pain in elderly patients, ensure that enough time has been allocated to perform a thorough assessment and that the tool selected is amendable to the needs of the patient.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are best used to treat pain that is inflammatory in nature, such as muscle sprains or strains.

 Particular patients who should be cautious of NSAID use include those who are at risk for cardiovascular events (eg, heart attack, stroke), those with high blood pressure, and those with renal impairment.

July 2016

Discussing Medication Adherence with a Hospitalized Patient

USP : Key Changes and Additions to USP

5 New Best Practices for Medication Safety All Hospital Pharmacists Should Know

Treatment of Acute Venous Thromboembolism in Obese Patients

Use of Neprilysin Inhibitors in Chronic Heart Failure

Acute Pain: Considerations in Geriatric Patients

Venothromboembolism: Treatment Recommendations and Therapeutic Options

4 Ways Hospital Pharmacists Can Help Improve Post-Acute Care Coordination

How Health-System Pharmacists Can Improve Adherence in Patients with Acute Coronary Syndrome

The Importance of Advocacy