December 2016 Newsletter

The Georgia Board of Pharmacy has begun the online renewal process for active pharmacist and nuclear pharmacist licenses. Licensees interested in license renewal should consult the Board's website at All pharmacist and nuclear pharmacist licenses expire on December31,2016.
If a licensee has submitted a timely and complete renewal application on or before December31,2016, the licensee's license status online will change from "active"to"active-renewal pending"after submission of the renewal application."Active-Renewal Pending"does not mean that the license has lapsed, is inactive, is deficient,or invalid in anyway. Rather, "Active-Renewal Pending" status merely reflects that the licensee has submitted a timely renewal application. A licensee should save the receipt generated after submission of a timely and complete application as additional proof of renewal during the period in which the application is reviewed.
Please be reminded that licensees will not receive pocket license cards in the mail. Pocket license cards may now be printed, free of charge,on the Georgia Board of Pharmacy website: PocketCards/ . Pocket license cards may be also ordered using the" Duplicate Pharmacy License-License Verification Order Form" that appears under "Applications and Forms" on the website of the Georgia Board of Pharmacy :
Illuminated waterfront Savannah Historic District at night
Save the Date

GSHP Spring Meeting

March 24-26, 2017
Marriott Riverfront
Savannah, GA

A wall calendar with tear-away pages, and words that read Save the Date
Call for Resolutions for the
2017 ASHP House of Delegates
The Call for Resolutions for the 2017 House of Delegates Session is open. Deadline for submissions is March 6, 2017.
The ASHP policy development process allows professional policies to originate in three ways:
  • from ASHP councils, which meet in July, September and February;
  • from executive committees of sections and forums; and
  • directly from ASHP members via Resolutions.
ASHP's Resolution process offers a mechanism for ASHP members to have input into the House of Delegates. Resolutions require sponsorship by two active members, who need not be delegates. All Resolutions must be submitted 90 days in advance of the House session, which is March 6, 2017. Resolutions must be submitted via the online Resolutions Submission Form.
Before submitting a Resolution, members are encouraged to familiarize themselves with the Guidelines for Submitting Resolutions and existing ASHP policy on the proposed topic. New policy recommendations that resulted from September's ASHP Policy Week and are currently under Board consideration are available on the ASHP Connect House of Delegates Community site.
We appreciate your interest and participation in the policymaking process of ASHP. If you have any questions about the process for submitting a Resolution, you are encouraged to contact the Chair of the House of Delegates at .

Clinical Articles
The Role of Zinc in the Management of Hepatic Encephalopathy
Yelena Lugin, PharmD candidate 20181
Leah Pendleton, PharmD candidate 20181
Nicole Spivey, PharmD candidate 20181
Valana Vannoy, PharmD, PGY-1 Pharmacy Practice Resident1,2
Anthony Hawkins, PharmD, BCCCP, Clinical Assistant Professor1
1 University of Georgia College of Pharmacy, Athens, Georgia
2 Phoebe Putney Memorial Hospital, Albany, Georgia
Hepatic encephalopathy (HE) affects up to 30% of patients living with cirrhosis. This complication reduces health-related quality of life and causes a reversible decline in cognitive function.1Encephalopathy is likely caused by the accumulation of toxic byproducts of endogenous substances, notably ammonia, that are typically cleared by healthy hepatocytes, but rather damage the nervous system, causing a loss of brain function. In the brain, astrocytes are the only cells that metabolize ammonia by the enzyme glutamine synthetase, converting glutamate and ammonia into glutamine. Elevated ammonia levels saturate the astrocytes and subsequently lead to glutamine accumulation, resulting in astrocyte swelling.2 In a systematic review, a general correlation was seen between higher levels of ammonia and more severe encephalopathy in cirrhosis was observed.3
The first-line treatment for HE is lactulose, which can be used in the acute setting or chronically to prevent recurrence.4 Orally administered lactulose is poorly absorbed from the gastrointestinal tract, and thus reaches the colon primarily unchanged. In the colon, lactulose is broken down into acidic byproducts, inhibiting ammonia absorption by converting it to ammonium and excreted.  This is the rationale for titration of lactulose to two to four loose stools per day.
Rifaximin, a semisynthetic nonsystemic antibiotic, can be used in combination with lactulose in the management of HE. Rifaximin works by stopping the growth of bacteria that are responsible for toxin production from digested food.  Rifaximin, at a dose of 550mg twice daily, has been effective in improving behavioral, laboratory and neurologic abnormalities in patients with hepatic encephalopathy.5 Other antibiotics, including neomycin and metronidazole, have been used but have less clinical utility due to side effect profile and concern for bacterial resistance.
Another option included in the armamentarium for the management of HE is elemental zinc. Cirrhotic patients, notably those with HE, have been shown to be zinc deficient. Zinc deficiency is associated with disturbances in learning, memory, emotional stability, and is accompanied by hyperammonemia. There is evidence which suggests that zinc helps treat HE due to its role in ammonia elimination. Some studies have also shown zinc to be important in maintaining the blood brain barrier's integrity.4 This suggests that a zinc deficiency along with oxidative stress causes a predisposition for damage to the brain.
Zinc is thought to exert its effect based on the metabolic pathways of ammonia.  Ammonia is converted to urea by ornithine transcarbamylase, which is then combined with glutamate by glutamine synthetase in the skeletal muscle to form glutamine. Both of these ammonia reduction pathways rely on zinc as an important cofactor.1
Zinc comes in a variety of forms such as zinc gluconate, zinc sulfate, and zinc acetate. It can also come in a variety of formulations ranging from oral tablets to sublingual and topical. In clinical trials, both zinc sulfate and zinc acetate have been used at a dose of 600 mg orally every day.6 In patients with a normal zinc level, using a dose of zinc sulfate 220mg twice dailyas a chronic maintenance medication is beneficial in those suffering with HE. A dose 220mg equates to approximately 50mg of elemental zinc.7 Generally, toxicities such as nausea and vomiting are seen after ingesting high doses of elemental zinc upwards of 570mg. Chronic intake of zinc at doses such as 70mg per day for 10 days can lead to a copper deficiency.6
If a patient is treated with appropriate doses of lactulose and/or rifaximin, however the ammonia concentrations are not decreasing, there may be issues in the patient's metabolic pathways responsible for ammonia elimination. In this case, zinc may be effective in helping to eliminate the ammonia by facilitating its metabolism.
Zinc is typically well tolerated. Therefore, it is relatively safe to give to patients with a zinc deficiency and HE, however, there is no clear evidence that supplementation improves encephalopathy or encephalopathy-related quality of life. More trials are needed to evaluate the use of oral zinc supplementation in patients with liver cirrhosis and hepatic encephalopathy. In cases where other drug treatments are not effective in lowering a patient's ammonia levels or the patient is zinc deficient, then zinc should be added to the patient's treatment plan. The length of therapy has not been studied long-term, but a 3 month double-blind randomized controlled trial shows that zinc replacement can be useful for reducing ammonia levels in patients with liver cirrhosis and zinc deficiency.8
  1. Chavez-Tapia, N.C., Cesar-Arce, A., Barrientos-Gutierrez, T., Villegas-Lopez, F.A., Mendez-Sanchez,N., & Uribe, M (2013). A systematic review and meta-analysis of the use of oral zinc in the treatment of hepatic encephalopathy. Nutrition Journal, 12, 74.
  2. Romero-Gómez M. Role of phosphate-activated glutaminase in the path-ogenesis of hepatic encephalopathy. Metab Brain Dis 2005;20:319-325.
  3. OldeDamink SW, Deutz NE, Dejong CH, Soeters PB, Jalan R. Interorgan ammonia metabolism in liver failure. Neurochem Int 2002;41:177-188.
  4. Mina Shaker, W. D. (2014). Hepatic Encephalopathy. Retrieved 2016, from Cleveland Clinic:
  5. Schiano TD. Treatment options for hepatic encephalopathy. Pharmacotherapy. 2010;30(5):16S-21S.[PubMed]
  6. Health, N. I. (2016, February 11). Zinc. Retrieved June 23, 2016, from U.S. Department of Health & Human Services:
  7. Blei, Andres T., and Juan Córdoba. "Hepatic encephalopathy." The American journal of gastroenterology 96.7 (2001): 1968.
  8. Katayama, K., Saito, M., Kawaguchi, T., Endo, R., Sawara, K., Nishiguchi, S., . . . Suzuki, K. (2014). Effect of zinc on liver cirrhosis with hyperammonemia: A preliminary randomized, placebo-controlled double-blind trial. Nutrition,30(11-12), 1409-1414. doi:10.1016/j.nut.2014.04.018

What`s New With the 2016 AHA/ACCF/HFSA Heart Failure Guideline?

Sara Rabie, Pharm.D. Candidate Class of 2017, and Maria Miller Thurston, Pharm.D., BCPS
Mercer University College of Pharmacy

Corresponding Author: Maria Miller Thurston, Clinical Assistant Professor, Mercer University College of Pharmacy, 3001 Mercer University Drive, Atlanta, GA 30341, T: (678) 547-6253 , F: (678) 547-6384,

"Heart failure (HF) is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood."1 Essentially, HF is a condition in which the heart will not be able to pump blood to meet the body`s need. As a result, blood may back up in the veins, fluid can build up in the body causing peripheral and pulmonary edema, and cells may not get enough oxygen and/or nutrients. The clinical manifestations of these pathophysiologic alternations that occur with HF include fatigue, shortness of breath especially when lying down, fluid retention, coughing or wheezing, and confusion.2
Classification of Heart Failure
The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) classifies HF into three different groups based on ventricular ejection fraction (VEF) percentage. The groups include: HF with reduced EF (HFrEF) also known as systolic HF with an EF ≤ 40%, HF with preserved EF (HFpEF) also known as diastolic HF with an EF ≥ 50%, and HFpEF borderline with the EF between 41%-49%. The diagnosis and evaluation of HF is based upon the presence of structural heart disease or signs and symptoms of HF (stages A to D). The New York Heart Association (NYHA) classification system also classifies HF into four classes based on the limitation of physical activity associated with the extent of HF (NYHA class I-IV). 3 These classifications, in conjunction with clinical practice guidelines, aid clinicians in diagnosis and the determination of appropriate therapy.
Heart Failure Clinical Treatment Algorithm (The 2013 ACCF/AHA Guideline for the Management of HF)
The 2013 ACCF/AHA Guideline for the Management of HF recommends focusing on the treatment of concomitant diseases (e.g., hypertension, type 2 diabetes, and dyslipidemia), according to their appropriate guidelines, for patients with stage A HF (class I recommendation). For Stage B HF, initiation of angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy as first line is recommended due to the agent's ability to improve vasodilation and EF percentage (class I recommendation). Additionally, if there is a history of pervious MI and/or EF is < 40%, adding a beta blocker (BB) to the regimen is recommended as well to reduce morbidity and mortality (class I recommendation). In Stage C HF, adding on therapy may be included for more targeted populations based on their symptoms and the NYHA class they fall in to; a loop diuretic can be added for volume overloaded patients, use of isosorbide dinitrate and hydralazine is preferred in African-American patients, and also aldosterone antagonists may be considered for some patients in NYHA class II-IV who still have symptoms with their current treatment regimen. Intravenous inotropic support, cardiac shock (class I recommendation), cardiac transplantation and palliative therapy (class IIa recommendation), and device therapy are all options for patients with stage D HF.4 Even though evidence and clinical experience indicate that current treatment options are effective at reducing morbidity and mortality in patents with HF, the condition remains a leading cause of death and disability in adults, with approximately 6 million people in the Unites States affected. Therefore, there is a clear need for novel pharmacological interventions that would offer additional treatment options for the population.5
New FDA Approved Pharmacological Interventions for Heart Failure
Sacubitril/valsartan (Entresto®)
Entresto® is a unique combination of sacubitril and valsartan, known as an angiotensin receptor neprilysin inhibitor (ARNi). Entresto® is FDA approved for patients with NYHA class II-IV chronic symptomatic HF with reduced EF to lessen the risk of cardiovascular death and hospitalization from HF. This drug can be used in place of an ACEi or ARB along with other therapies for HF.6
The dosing of this mediation is dependent upon a patient's history of use of an ACEi /ARB; the starting dose may be higher for patients who are not ACEi/ARB naïve. The target dose for all patients is 97/103 mg by mouth twice daily, and the dose can be doubled every two to four weeks to reach the target dose, as tolerated. If switching from an ACEi to an ARNi, a 36 hours washout period is required before starting Entresto®. Dose adjustment is required if there is severe hepatic impairment or renal impairment (eGFR < 30 ml/min). The most common adverse effects include hypotension (18%), hyperkalemia (12%), dizziness (6%), renal failure (5%), and angioedema (0.5%).6

Colanor (ivabradine ® )

Ivabradine is FDA approved for chronic stable symptomatic HF in patients with an EF of 35% or lower, who are in sinus rhythm with a resting heart rate of 70 beats per minute (bpm) or greater and are either on a maximized dose of a BB or have a contraindication to BB use. The recommended starting dose is 5 mg by mouth twice daily with meals. The dose can be adjusted based on the resting heart rate and tolerability. The maximum dose is 7.5 mg by mouth twice daily. Renal dose adjustment is not required in patients with renal failure, although the use of ivabradine in patients with a creatinine clearance below 15 mL/min has not been studied. Two common adverse effects of ivabradine include bradycardia (10%) and atrial fibrillation (8.3%). Ivabradine is metabolized primarily by CYP3A4 and is contraindicated with strong CYP3A4 inhibitors.7

Clinical Trials
Angiotensin-Neprilysin Inhibition Versus Enalapril in Heart Failure (PARADIGM-HF)
The objective of this study was to compare enalapril with Entresto® in reducing the morbidity and mortality related to chronic HFrEF. The study was randomized, multinational, double blinded, and parallel group. 10,521 patients older than 18 years of age with NYHA class II-IV HF and an EF < 40% (later in study changed to < 30%), who had been taking either an ACEi or ARB for at least four weeks were randomized. Almost two thirds of patients in this trial had NYHA class II HF and hypertension, and they were taking diuretics. Patients then either received enalapril 10 mg by mouth twice daily (n=4,233) or LCZ696 titrated to 200 mg by mouth twice daily (n= 4,187). The median duration of follow up was 27 months. The primary objective of the study was death from cardiovascular causes or hospitalization for worsening HF. The results indicated that death from cardiovascular causes or hospitalization for HF occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio 0.80 [95% CI 0.73-0.87]; p < 0.001). A total of 558 deaths (13.3%) in the LCZ696 group and 693 (16.5%) in the enalapril group were due to cardiovascular causes (hazard ratio 0.80 [95% CI 0.71 to 0.89]; p < 0.001), and of the patients receiving LCZ696, 537 (12.8%) were hospitalized for heart failure, as compared with 658 patients (15.6%) receiving enalapril (hazard ratio 0.79 [95% CI 0.71 to 0.89]; p < 0.001). In conclusion, the ARNi, LCZ696, was superior to enalapril in reducing the risk of death and hospitalization for patients with HF.9

Ivabradine and Outcomes in Chronic Heart Failure (SHIFT): A Randomized Placebo-Controlled Study

The objective of this study was to assess the effect of heart rate reduction by a selective sinus node inhibitor (ivabradine) in patients with systolic HF. The study was a randomized, multicenter, placebo- controlled trial, with 6,505 patients who were randomized to receive either ivabradine 5 mg by mouth twice daily or placebo. There were no significant differences at baseline in terms of demographics between the two groups. Patients were followed up every four months for a mean of approximately 23 months. Patients included were over 18 years of age, in sinus rhythm with a resting heart rate of > 70 bpm, and had stable symptomatic chronic HF (NYHA class II-IV) for more than four weeks or had a previous admission to the hospital for HF within 12 months; all patients had an EF of < 35% and were on guideline directed therapy. The primary objective of the study was to assess the composite endpoint of cardiovascular death or hospital admission for worsening HF. The results of this study demonstrated a statistically significant reduction in the primary endpoint in the ivabradine group (24% in ivabradine group vs. 29% in placebo group (hazard ratio 0.82 [95% CI 0.75-0.90]; p < 0.0001). There was also a reduction in hospitalization for worsening HF (21% in placebo group vs. 16% in ivabradine group (hazard ratio 0.74 [95% CI 0.66-0.83]; p < 0.0001). The number needed to treat was 26, meaning 26 patients need to be treated with this medication to prevent one additional negative outcome, such as cardiovascular death or hospitalization due to worsening HF. In conclusion, the results support the importance of heart rate reduction to improve the clinical outcomes in patients with HF; additionally, patients with a higher resting heart rate at baseline derived more benefit from this medication, than did those with a lower baseline heart rate.8

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

In May of 2016, an update to the 2013 ACCF/AHA guideline was released with recommendations for the incorporation of these two novel therapies for HF into clinical practice.

The 2016 ACCF/AHA/HFSA Guideline for the Management of HF now provides a class I recommendation for initiation of an ACEi or ARB (level of evidence A) or ARNi (level of evidence B-R) in conjunction with evidence-based BB and aldosterone antagonists in patients with HFrEF to reduce morbidity and mortality. ARNi therapy was added to the guideline as first line therapy instead of an ACEi or ARB based on the PARADIGM-HF trial findings, which resulted in a 20% reduction in the composite endpoint of cardiovascular death or HF hospitalization. The guideline recommends the replacement of an ACEi or an ARB with an ARNi in select patients with symptomatic HFrEF (NYHS class II/III) with controlled blood pressure, who are already tolerating ACEi or ARB therapy. For those patients with prior or current symptoms of chronic HFrEF in whom an ARNi is not appropriate, continuing the use of an ACEi is strongly advised to reduce morbidity and mortality (class I recommendation, level A). Use of an ARB is recommended in symptomatic HF patients who are intolerant to an ACEi due to cough or angioedema side effects (class I recommendation); use of an ARNi is contraindicated in patients with a history of angioedema to an ACEi (class III recommendation). The guideline also recommends against the concomitant use of an ACEi and ARNi as well as use of an ARNi within 36 hours of the last dose of an ACEi (class III recommendation).10

The updated guideline also offers a class IIa recommendation (level of evidence B -R) for use of ivabradine to reduce HF hospitalization in patients with symptomatic (NYHA class II-III) stable chronic HFrEF (EF ≤ 35%) receiving guideline-directed therapy, such as a BB at maximum tolerated dose and who are in sinus rhythm with a resting heart rate of 70 bpm or greater.10

Summary and Clinical Implications

Overall, the 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure provides new recommendations for first line therapy in patients with chronic symptomatic HF with HFrEF (EF < 35%) and stage C (NYHA class II-IV). The guideline added ARNi as first line therapy to the previous therapy with only an ACEi or ARB due to its significant reduction in cardiovascular death and HF hospitalization in the PRADIGM-HF clinical trial. Even though this novel agent may be significantly effective in reducing mortality and morbidity associated with HF, there are still some limitations associated with its utilization in patients with HF. Almost two thirds of the patients in the PARADIGM-HF trial in which this drug was evaluated were in the NYHA class II category with stage C HF and were already on guideline directed therapy with alternate agents. This elucidates that patients need to fit the PARADIGM-HF inclusion criteria, in order to derive the expected benefits from this medication. Furthermore, according to the estimates published in the New England Journal of Medicine, Entresto® may add approximately one to two years of life, depending on the age, patients with HF.11 Considering it isthe only FDA approved ARNi drug in the market currently and the annual cost of it is roughly $5000, as compared to enalapril at an approximate $48 annual cost, using it may not be affordable for many patients. However, for an appropriate patient subgroup, using Entresto® may be a viable therapeutic option to reduce the mortality and hospitalization rate in patient with HFrEF.

Another new recommendation is the use of ivabradine to reduce HF hospitalization in patients with symptomatic (NYHA class II/III) stable chronic HFrEF (EF ≤ 35%) receiving guideline-directed evaluation and management. Recent evidence has found that use of ivabradine may be beneficial as adjunctive therapy to a maximally tolerated BB in patients who are in sinus rhythm with a heart rate of 70 bpm or greater at rest. This infers that ivabradine can be a substitute for a BB in patients with an inability to tolerate such therapy, in order to lower risk of hospitalization for worsening HF. Patients in the SHIFT trial were selected on the basis of having a high resting heart rate > 70 bpm, a normal heart beat, and reduced EF < 35%, and the proportion of elderly patients were limited. Therefore, the efficacy of this new agent may not be generalizable all patients with HF who meet the SHIFT criteria. Furthermore, the majority of the patients in the study (90%) were on BB therapy, and the trial was not designed to compare the new agent with a BB. Thus, the main conclusion that can be deduced based upon the results from SHIFT is that in chronic stable patients with HF who are already on BB therapy, if their heart rate is still elevated for any reason, use of ivabradine may be considered in addition to their current BB regimen to improve cardiovascular outcomes. The major caveat of ivabradine use is the annual cost, roughly $4000, which may not be feasible for some. Further studies are needed in order to fully determine the place of this new drug in HF therapy for special patient populations.  

  1. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371: 993-1004.
  2. What is heart failure? American heart association. Available at Accessed on July 16, 2016. 
  3. Yancy CW, Jessup M, Bozkurt B et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;128:e240-e327.
  4. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Oct 15;62(16):e147-239.
  5. Mozzafarian D, Benjamin EJ, Go AS, et al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133:e38-e360.
  6. Entresto. Martindale - The Complete Drug Reference. Micromedex 2.0 [database online]. Greenwood Village, CO; Truven Health Analytics; 2013. Accessed July 07, 2016.
  7. ivabradine. Martindale - The Complete Drug Reference. Micromedex 2.0 [database online]. Greenwood Village, CO; Truven Health Analytics; 2013. Accessed July 07, 2016.
  8. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885. doi: 10.1016/S014-6736(10)61198-1
  9. Krum H. Prospective Comparison of ARNi With ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Paragon of a Study or Further Investigation Paramount? Circulation. 2015 Jan 6;131(1):11-2.
  1. Yancy CW, Jessup M, et al. 2016 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2016;10.1169:-e435.
  2. Claggett B. Milton P. Mcmurray J, et al, Estimating the Long-Term Treatment Benefits of Sacubitril-Valsartan - N Engl J Med. 2015;373:2289-2290.

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