1

Helping to achieve safe 

medication use

ISSUE 2 VOLUME 3 FEBRUARY 2013

 MEDICATION SAFETY NEWS 

FROM THE VA NATIONAL

PHARMACY BENEFITS 

MANAGEMENT SERVICES 

[PBM] AND THE FOOD AND

DRUG ADMINISTRATION

[FDA]........................ 1,2

 VA PBM WARFARIN INR

REPORTS .................. 3

Medication

The clinical benefit of combination therapy with an angiotensin –

converting enzyme inhibitor (ACEI) and an angiotensin receptor 

blocker (ARB) compared to monotherapy in patients with chronic 

kidney disease remains controversial.1-5 A recent National PBM Bulletin described the considerations of risks versus benefits of dual therapy with agents that block the renin-angiotensin aldosterone system, 

especially for patients prescribed combination therapy for a potential 

benefit on kidney outcomes, referencing evidence in the literature 

(specifically the Ongoing Telmisartan Alone and in Combination with 

Ramipril Global Endpoint Trial [ONTARGET] trial6-7; and the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints 

[ALTITUDE] trial8-9) . These clinical trials demonstrated an increase 

in adverse events (including, but not limited to, impaired kidney function and hyperkalemia) with combination therapy compared to monotherapy, without a benefit in long-term outcomes.6-9 Pertinent VA 

PBM recommendations included:

Because of the potential for harm and the lack of proven 

long-term outcome benefits, combination therapy with an 

ACEI and ARB should not be initiated in patients with: diabetic nephropathy; diabetes and CKD; or nondiabetic kidney 

disease, if being used for kidney outcomes. Similarly, an 

ACEI or ARB should not be used concomitantly with aliskiren. 

For patients already taking an ACEI and an ARB for the 

potential benefit on kidney outcomes, providers should review treatment for potential discontinuation of either ACEI 

or ARB, as applicable. If combination therapy is continued, 

it should be documented that the patient has benefited from 

combination therapy and that there are no current safety 

concerns. 

For patients who are receiving combination ACEI and ARB 

for management of systolic heart failure, combination therapy with an ACEI and ARB may be considered in patients 

with persistent symptoms despite maximized standard therapy (if it is determined that the benefit outweighs the potential risk for adverse events); however, use of combination 

(continued on page 2) 

EDITOR-IN-CHIEF | Marie Sales, Pharm.D.

VA Pharmacy Benefits Management Services [PBM] & Center for Medication Safety [VA MedSAFE]

1st Avenue—1 Block North of Cermak Road | Building 37; Room 139 | Hines, Illinois | 60141

www.pbm.va.gov

safety in seconds

A M ONT H L Y P U B LI C AT IO N FRO M V A M E D S AF E: 

V A ’S CO M P R EH E N SI V E P H A R M ACO V IG IL A NC E C E NT E R

NEWS YOU CAN USE

FROM THE VA NATIONAL PBM: BULLETINS, COMMUNICATIONS, & RECALLS 

Zolpidem and FDA-Proposed Lower Doses Due to Impaired Mental Alertness – 01-16-2013 - National PBM Communication 

Rugby Ferrous Sulfate Recall Due to Bottle Improperly Containing Meclizine HCL 25 mg Tablets – 01-13-2013 - National PBM Communication 

 USE OF COMBINATION

RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM

BLOCKADE ............... 1-4

USE OF COMBINATION RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM BLOCKADE
2

(continued on page 3)

NEWS YOU CAN USE

FROM THE FOOD AND DRUG ADMINISTRATION (FDA)

CENTRAL NERVOUS SYSTEM 

Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem 

(Ambien, Ambien CR, Edluar, and Zolpimist)

01/10/2013

FDA mandates making label changes to lower doses of immediate and extended-release zolpidem products (Ambien®, Ambien CR®, Edluar®, Zolpimist®) at bedtime due to impaired mental alertness the following morning. Pharmacokinetic and driving simulation studies 

show that blood levels of zolpidem above 50ng/mL may cause impairment while operating a vehicle and increase the risk of accidents. Extended-release formulations impart greater next-morning impairment than immediate-release formulations. Women are more susceptible to 

next-morning impairment due to a slower rate of elimination for zolpidem than men. Studies have detected blood levels of zolpidem over 

50ng/mL as much as 8 hours post-dose. Trials involving 10 mg Ambien (or bioequivalent zolpidem products) resulted in 15% of women and 

3% of men with zolpidem concentrations that exceeded 50 ng/mL approximately 8 hours post-dosing. Trials of zolpidem extended-release 

12.5 mg resulted in approximately 33% of women and 25% of men with zolpidem blood concentrations exceeding 50 ng/mL approximately 8 

hours post-dosing. FDA recommends that healthcare practitioners should: 1) Prescribe the lowest dose capable of treating patients’ insomnia 

symptoms; and 2) Caution patients regarding possible impairment in driving and activities that require alertness the next morning, despite 

feeling fully awake. 

NOTE: The VA Psychopharmacology Field Advisory Committee recommends zolpidem doses should not exceed FDA dosing recommendations in new patients. 

Helping to achieve safe medication use

USE OF COMBINATION RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM BLOCKADE

(continued from page 1)

with an aldosterone antagonist and conventional therapy 

for heart failure that includes an ACEI may be preferable 

to an ACEI and ARB. Combination therapy in patients 

with heart failure/evidence of systolic dysfunction after 

acute MI is not routinely recommended due to an increased risk for adverse events without a survival benefit. 

A brief assessment of combined therapy in fiscal year 

2012 showed that a large number of patients in the VA 

system-wide were receiving a combination of an ACEI 

and ARB. Based on the aforementioned safety considerations, VISN PBM(s)/P&T Committee(s) should discuss 

these recommendations for considering discontinuation of 

either an ACEI or ARB in patients with chronic kidney 

disease who are receiving combination therapy with both 

agents, with facilities implementing them upon direction 

from their VISN Chief Medical Officer and VISN Pharmacist Executive. Additionally, VA Patient and Provider Letters are available on the PBM INTRAnet at: https://

vaww.cmopnational.va.gov/cmop/PBM/default.aspx.

With respect to use in heart failure, combination therapy with an 

ARB and an ACEI may be considered to decrease heart failure hospitalizations.10-13 The results of the Candesartan in Heart failure 

Assessment of Reduction in Mortality and morbidity (CHARM)-

Added trial11 support the recommendation that the combination of 

an ARB with an ACEI may reduce cardiovascular death and heart 

failure hospitalizations. Candesartan received FDA approval for the 

treatment of New York Heart Association (NYHA) class II to IV 

heart failure and LVEF < 40% to reduce the risk of death from cardiovascular causes and to reduce heart failure hospitalizations. Candesartan is also approved for use in combination with an ACEI. 

FDA approval for valsartan is for treatment of NYHA class II to IV 

heart failure, and valsartan significantly reduced hospitalizations for 

heart failure; however, the product information also includes a statement that there is no evidence that valsartan provides added benefits 

when it is used with an adequate dose of an ACEI. In the Valsartan 

Heart Failure Treatment (Val-HeFT)12 trial, valsartan reduced the 

combined primary endpoint of mortality and morbidity compared to 

placebo in patients with NYHA class II to IV heart failure on standard therapy. According to a subgroup analysis, there was an increased risk of mortality and a trend toward an increased risk of 

combined morbidity and mortality in patients receiving valsartan in 

conjunction with an ACEI and beta-adrenergic blocker.12

Two meta-analyses comparing data with an ARB in combination 

with an ACEI versus an ACEI alone in patients with heart failure 

reported that there was not a statistically significant difference in all

-cause mortality between the two treatment groups, but there was a 

statistically significant reduction in heart failure hospitalizations.14,15 

According to a more recent meta-analysis evaluating the use of dual 

blockade of the renin-angiotensin aldosterone system with an ACEI, 

ARB, or direct renin inhibitor, compared to monotherapy on longterm efficacy or safety, there was no significant difference in allcause or cardiovascular mortality with combination therapy compared to monotherapy. There was, however, an increase in the 

ATTENTION HEALTHCARE PROFESSIONALS!

As a patient safety measure, USP has changed the labeling standard for Heparin Sodium Injection USP and Heparin Lock Flush Solution 

USP. As manufacturers transition labels to the new USP standard, products with both the old and new labels will be available for use. This 

transition period presents potential for confusion and errors. To assist in communicating this change to pertinent staff, USP is in the process 

of conducting a number of WebEx meetings to explain the change more fully, discuss ways to help mitigate the potential for errors until the 

label transition is completed, and answer questions you might have. The remaining session is scheduled for:

Thursday, February 28, 2013 4:00 – 5:00 p.m. EST
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Getting the most from our safety surveillance

VA PBM WARFARIN INR REPORTS

VA PBM developed Warfarin INR reports to assist facilities in 

monitoring Warfarin management practices and to identify areas for 

improvements. These reports, updated by VA PBM on a monthly 

basis, rely on prescription and INR data extracted from sites and 

generated by VA PBM. Prior to this, no national INR reports existed since some sites had the ability to conduct INR monitoring 

while others did not. The standardized approach to tracking and 

trending anticoagulation management based on prescription and 

INR data provides consistent reports for all facilities. Facilities may 

use these reports to review data across the nation and identify a 

strong practice for networking, review trends over time to quickly 

identify a negative trend, and to identify a starting point for drilling 

down to patient level data.

Four distinct metrics for INR values are stratified at the National, 

VISN, and Facility level to provide twelve reports.

COMMON QUESTIONS:

Are non-VA labs captured in the lab review?

No. Non-VA labs are not captured with the exception of non-VA 

labs that have been transcribed into the VA lab package. Lab values contained in external systems or progress notes are not able to 

be queried for these reports.

My facility has developed local reports with similar metrics for 

evaluating anticoagulation. Which report should be used?

Locally and/or regionally developed reports may be used instead of 

the VA PBM Warfarin INR Reports. The reports may differ as 

locally or regionally developed reports may not use the same parameters or criteria when evaluating patients receiving anticoagulation. Facilities without a local report may utilize the VA PBM Warfarin INR Reports. The VA PBM Warfarin INR Reports were developed so all facilities would have access to a monitoring report 

and be able to monitor trends and benchmark their data.

Who can access the VA PBM Warfarin INR Reports? 

Access is granted to individuals who have received approval from 

the local facility Chief of Pharmacy or if working in a network position the approval may be granted by the VISN Pharmacist Executive (VPE). Individuals with approval from the respective Chief of 

Pharmacy or VPE will be granted access to the reports. Send an 

Outlook e-mail message containing the approval to Anthony.Au@va.gov and Von.Moore@va.gov to be granted access.

Helping to achieve safe medication use

USE OF COMBINATION RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM BLOCKADE

(continued on page 4)

risk for hyperkalemia (RR 1.55, 95% CI 1.32 to 1.82; P<0.001), 

hypotension (RR 1.66, 95% CI 1.38 to 1.98; P<0.001), and renal 

failure (RR 1.41, 95% CI 1.09 to 1.84; P=0.01) with combination 

therapy compared to monotherapy in the overall patient population 

that was also significantly increased in the subgroup of patients 

with heart failure. In the trials that reported heart failure hospitalizations, there was a reduction in heart failure hospitalizations (RR 

0.82, 95% CI 0.74 to 0.92; P=0.0003) in patients receiving combination therapy compared to monotherapy. Heart failure hospitalizations were also reduced when the groups were analyzed according 

to patients with heart failure (RR 0.77 95% CI 0.68 to 0.99; 

P<0.001); although, the difference was not significant in the subgroup of patients without heart failure. There was no significant 

difference in all-cause or cardiovascular mortality with dual therapy 

versus monotherapy in the subgroup of patients with heart failure.13

Patients with NYHA class II to IV heart failure who are on standard 

therapy for heart failure should be considered as a candidate for an 

aldosterone antagonist (provided the patient has preserved kidney 

function and normal potassium levels), as treatment with an aldosterone antagonist was shown to improve symptoms, decrease hospitalizations for worsening heart failure, and decrease mortality in 

this patient population.16,17 In a meta-analysis evaluating the addition of an ARB, direct renin inhibitor, or aldosterone antagonist in 

patients receiving standard therapy for heart failure that included an 

ACEI, addition of an aldosterone antagonist decreased the rate of 

death, cardiovascular death, heart failure hospitalizations, and the 

composite cardiovascular death or heart failure hospitalizations. 

There was no difference in these outcomes when either an ARB or 

direct renin inhibitor was added to standard therapy. Regarding 

safety, addition of an aldosterone antagonist increased the risk for 

hyperkalemia by 110%; whereas the addition of an ARB increased 

the risk of hyperkalemia by 138%, renal failure by 126%, and hypotension by 63%, and addition of a direct renin inhibitor increased 

the risk for hypotension by 98%.18

Guidelines recommend that combination therapy with an ACEI and 

ARB may be considered in patients with systolic heart failure and 

persistent symptoms despite maximized standard therapy (i.e., an 

ACEI and beta-blocker, with diuretics as indicated);10,11 however, 

*Each available 

at the Facility, 

VISN, and National level.

Contributed by:

Von Moore, Pharm.D., Anthony Au, Pharm.D., and 

Lisa Longo, Pharm.D., BCPS

Figure 1: Trend-Decreasing percent of patients with no INR in 6 weeks.

(continued from page 2)
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Helping to achieve safe medication use

USE OF COMBINATION RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM BLOCKADE

(continued from page 3)

use of combination with an aldosterone antagonist and conventional 

therapy for heart failure that includes an ACEI may be preferable to 

an ACEI and ARB.18,19 Combination therapy in patients with heart 

failure/evidence of systolic dysfunction after acute MI is not routinely recommended due to an increased risk for adverse events 

without a survival benefit.20

REFERENCES 

1. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. 

KDIGO clinical practice guideline for the management of blood pressure in chronic kidney 

disease. Kidney Inter Suppl 2012; 2:337-414. 

2. National Kidney Foundation. K/DOQI Clinical Practice Guidelines and Clinical Practice 

Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 2007;49

(suppl 2):S1-S180. 

3. Kunz R, Friedrich C, Wolbers M, Mann JFE. Meta-analysis: effect of monotherapy and 

combination therapy with inhibitors of the renin-angiotensin system on proteinuria in renal 

disease. Ann Intern Med 2008;148:30-48. 

4. MacKinnon M, Shurraw S, Akbari A, et al. Combination therapy with an angiotensin 

receptor blocker and an ACEI inhibitor in proteinuric renal disease: a systematic review of 

the efficacy and safety data. Am J Kidney Dis 2006;48:8-20. 

5. National Kidney Foundation. K/DOQI Clinical Practice Guideline for Diabetes and CKD: 

2012 update. Am J Kidney Dis 2012;60(5):850-86. 

6. ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or 

both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59. 

7. Mann JFE, Schmieder RE, McQueen M, et al., on behalf of the ONgoing Telmisartan 

Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) Investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the 

ONTARGET study): a multicentre, randomized, double-blind, controlled trial. Lancet 

2008;372:547-53. 

8. Direct Healthcare Professional Communication on potential risks of cardiovascular and 

renal adverse events in patients with type 2 diabetes and renal impairment and/or cardiovascular disease treated with aliskiren (Tekturna®) tablets and aliskiren-containing combination products. January 2012. Novartis Phar-ma c e u t i c a l s Co r p o r a t i o n ; Ea s t Ha n 

o v e r NJ . h t t p : / / ww w. p h a r ma . u s . n o v a r t i s . c om/ a s s e t s / p d f / T KT -

1 1 1 8 9 2 3% 20Dear_HCP_Letter_email_with%20Tek-Val%20PIs_vf.pdf 

9. Parving HH, Brenner BM, McMurray JJV, et al., for the ALTITUDE Investigators. 

Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012. DOI: 

10.1056/NEJMoa1208799. 

10. Hunt SA, Abraham WT, Chin MH, et al.; American College of Cardiology Foundation/

American Heart Association Task Force on Practice Guidelines, International Society for 

Heart and Lung Transplantation. 2009 Focused Up-date Incorporated Into the ACC/AHA 

2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. J Am Coll 

Cardiol published online Mar 26, 2009; doi:10.1016/j.jacc.2008.11.013 

11. McMurray JJV, Östergren J, Swedberg K, et al. for the CHARM Investigators and 

Committees. Effects of candesartan in patients with chronic heart failure and reduced leftventricular systolic function taking angiotensin converting-enzyme inhibitors: the CHARMAdded trial. Lancet 2003;362:767-71. 

12. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized 

trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 

2001;345:1667-75. 

13. Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual 

blockade of the renin-angiotensin system: meta-analysis of randomised trials. BMJ 

2013;346:f360 doi: 10.1136/bmj.f360 

14. Lee VC, Rhew DC, Dylan M, et al. Meta-analysis: angiotensin-receptor blockers in 

chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med 

2004;141:693-704. 

15. Shibata MC, Tsuyuki RT, Wiebe N. The effects of angiotensin-receptor blockers on 

mortality and morbidity in heart failure: a systematic review. Int J Clin Pract 2008;62:1397-

402. 

16. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and 

mortality in patients with severe heart failure: Randomized Aldactone Evaluation Study 

Investigators. N Engl J Med 1999;341:709-17. 

17. Zannad F, McMurray JJV, Krum H, et al., for the EMPHASIS-HF Study Group. 

Eplerenone in patients with systolic heart failure with mild symptoms. N Engl J Med published online Nov 14, 2010; doi:10.1056/NEJMa1009492 

18. Bangalore S, Kumar S, Messerli FH. When conventional heart failure therapy is not 

enough: angiotensin receptor blocker, direct renin inhibitor, or aldosterone antagonist? 

Congest Heart Fail 2012. Doi: 10.1111/chf.12011. 

19. Butler J, Ezekowitz JA, Collins SP et al. Update on aldosterone antagonist use in heart 

failure with reduced left ventricular ejection fraction Heart Failure Society of America 

Guidelines Committee. J Cardiac Fail 2012;18:265-81. 

20. Pfeffer MA, McMurray J, Leizorovicz A, et al., for The Valsartan in Acute Myocardial 

Infarction Trial (VALIANT) Investigators. Valsartan, captopril, or both in myocardial 

Infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 

2003;349:1893-906. 

Contributed by: Elaine Furmaga, Pharm. D.