sess its effect on major adverse cardiac events.1 Rates of
any cardiac hospitalization were 5% in the intervention
group vs 16% in the usual care group. The approximately 70% relative risk reduction and 11% absolute risk
reduction in hospitalization for major adverse cardiac
events or heart failure are much higher than would be
expected for even the most potent intervention or treatment in this setting. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL)
study, for example, 3086 almost exclusively statinnaı¨ve patients were randomized to receive high-dose atorvastatin (80 mg/d) or placebo.8 Even one of the most impressive treatments in our therapeutic armamentarium,
which, in the MIRACL study, lowered low-density lipoprotein cholesterol level by 40%, led to far more modest
risk reductions in cardiac events requiring hospitalization than the reductions reported for enhanced depression care in the COPES trial. Indeed, most of the effect
of high-dose statin treatment in the MIRACL study was
due to a 26% relative risk reduction and 2% absolute risk
reduction in hospitalization for myocardial ischemia.
Thus, while the results of the COPES trial are provocative and exciting, they must be replicated in larger, appropriately powered trials before the promising reduction in hospitalizations can be used to calculate potential
cost savings.
Ladapo et al2 should be congratulated for addressing the
economic impact of their findings and for conducting a randomized controlled trial in patients with ACS, a difficult
enough task in and of itself. However, the task before medical professionals when interpreting studies like this is also
challenging. Coping with rising health care costs requires
us to carefully examine all the resources that would be involved in implementing “more health care” and then,
equally, to carefully determine whether this would actually lead to “better health” by evaluating the net gain to patients and society. Whether the COPES trial is good value
for the money remains unclear.
Roy C. Ziegelstein, MD
Brett D. Thombs, PhD
Published Online: October 15, 2012. doi:10.1001/2013
.jamainternmed.114
Author Affiliations: Department of Medicine, The Johns
Hopkins University School of Medicine, Baltimore, Maryland (Dr Ziegelstein); Departments of Psychiatry, Counseling and Educational Psychology, Epidemiology, Biostatistics, and Occupational Health, and Medicine and
School of Nursing, McGill University, and Lady Davis Institute for Medical Research, Jewish General Hospital (Dr
Thombs), Montreal, Quebec, Canada.
Correspondence: Dr Ziegelstein, Department of Medicine, The Johns Hopkins Bayview Center, Mason F. Lord
Building, Center Tower, 5200 Eastern Ave, Third Floor,
Room 320, Baltimore, MD 21224 (rziegel2@jhmi.edu).
Financial Disclosure: None reported.
Funding/Support: Dr Ziegelstein is supported by the
Miller Family Scholar Program of the Johns Hopkins Center for Innovative Medicine. Dr Thombs is supported by
a New Investigator Award from the Canadian Institutes
of Health Research.

1. Davidson KW, Rieckmann N, Clemow L, et al. Enhanced depression care for
patients with acute coronary syndrome and persistent depressive symptoms:
coronary psychosocial evaluation studies randomized controlled trial. Arch
Intern Med. 2010;170(7):600-608.
2. Ladapo JA, Shaffer JA, Fang Y, Ye S, Davidson KW. Cost-effectiveness of enhanced depression care after acute coronary syndrome: results from the Coronary Psychosocial Evaluation Studies randomized controlled trial [published online October 15, 2012]. Arch Intern Med. 2012;172(21):1682-1684.
3. Frasure-Smith N, Lespe´ rance F, Talajic M. Depression following myocardial
infarction: impact on 6-month survival. JAMA. 1993;270(15):1819-1825.
4. Czarny MJ, Arthurs E, Coffie DF, et al. Prevalence of antidepressant prescription or use in patients with acute coronary syndrome: a systematic review.
PLoS One. 2011;6(11):e27671.
5. Cassel CK, Guest JA. Choosing wisely: helping physicians and patients make
smart decisions about their care. JAMA. 2012;307(17):1801-1802.
6. Grady D, Redberg RF. Less is more: how less health care can result in better
health. Arch Intern Med. 2010;170(9):749-750.
7. Unu¨ tzer J, Katon W, Callahan CM, et al; IMPACT Investigators. Collaborative care management of late-life depression in the primary care setting: a randomized controlled trial. JAMA. 2002;288(22):2836-2845.
8. Schwartz GG, Olsson AG, Ezekowitz MD, et al; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators.
Effects of atorvastatin on early recurrent ischemic events in acute coronary
syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;
285(13):1711-1718.

RESEARCH LETTERS

Stability of Active Ingredients
in Long-Expired Prescription Medications

D

ebate exists regarding the relative potency of
medications beyond their labeled expiration
dates. Expired medications have not necessarily lost potency, since the expiration date is only an assurance that the labeled potency will last at least until
that time.1 Clinical situations may arise in which expired drugs might be considered owing to lack of viable
alternatives2 or financial concerns.3 Ongoing studies show
that many medications retain their potency years after
their initially labeled expiration dates.4 We sought to characterize the potency of some prescription medications that
had expired decades ago.
Methods. Eight long-expired medications with 15 different active ingredients were discovered in a retail pharmacy in their original, unopened containers. All had expired 28 to 40 years prior to analysis. Three tablets or
capsules of each medication were analyzed, with each
sample tested 3 times for each labeled active ingredient.
No analytical standard for homatropine could be found,
so that ingredient was not tested.
Tablets or capsule contents were dissolved and sonicated in methanol, reconstituted in analysis buffer (10%
methanol) and analyzed with Liquid Chromatograph (Agilent Technologies) Time-of-Flight Mass Spectrometer
(Agilent) using electrospray ionization in negative and
positive polarities. Chromatography was run with gradient elution using Eclipse Plus C18 column (Agilent).
Data analysis was performed using Mass Hunter Qualitative and Quantitative Analysis (Agilent). Quantification was performed by isotope dilution method with a
6-point calibration curve.

ARCH INTERN MED/ VOL 172 (NO. 21), NOV 26, 2012
1685

WWW.ARCHINTERNMED.COM

©2012 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/intemed/26027/ by Marshall Allen on 03/13/2017

 Table. Declared and Measured Amounts in Drugs
Drug Trade Name
With Active
Ingredients
Somnafac
Methaqualone
Fiorinal with codeine No. 1
Codeine
Butalbital
Aspirin
Phenacetin
Caffeine
Codempiral No. 3
Codeine
Phenobarbital
Aspirin
Phenacetin
Bamadex
Meprobamate
Amphetamine
Obocell
Amphetamine
Nebralin
Pentobarbital
Seconal
Secobarbital
Hycomine
Hydrocodone
Homatropine
Chlorpheniramine
Acetaminophen
Caffeine

Declared
Amount, mg

Measured
Amount,
Mean (SD), mg

200.0

240.3 (20.6)

7.5
50.0
200.0
130.0
40.0

7.4 (0.3)
51.1 (1.6)
2.28 (0.10)
142.8 (7.1)
51.2 (4.8)

32.4
16.2
226.8
162.0

29.3 (2.6)
15.2 (0.2)
1.53 (0.04)
87.8 (2.7)

300.0
15.0

390.8 (44.9)
8.1 (0.9)

5.0

2.2 (0.1)

90.0

105.1 (7.4)

100.0

90.5 (7.1)

5.0
1.5
2.0
250.0
30.0

5.2 (0.4)
Not tested
6.1 (0.2)
249.2 (38.3)
30.3 (1.8)

Results. Twelve of the 14 drug compounds tested (86%)
were present in concentrations at least 90% of the labeled amounts, the generally recognized minimum acceptable potency. Three of these compounds were present
at greater than 110% of the labeled content. Two compounds (aspirin and amphetamine) were present in
amounts of less than 90% of labeled content. One compound (phenacetin) was present at greater than 90% of
labeled amounts from 1 medication tested, but less than
90% in another medication that contained that drug
(Table).
Comment. The US Food and Drug Administration (FDA)
permits “reasonable variation,” such that most medications marketed in the United States contain 90% to 110%
of the amount of the active ingredient claimed on the label.5 Drug expiration dates typically range from 12 to 60
months after their production.4 However, FDA regulations do not require determination of how long medications remain potent after that, allowing manufacturers
to arbitrarily establish expiration dates without determining actual long-term drug stability.
The Shelf-Life Extension Program (SLEP) checks longterm stability of federal drug stockpiles. Eighty-eight percent of 122 different drugs stored under ideal environmental conditions had their expiration dates extended
more than 1 year, with an average extension of 66 months
and a maximum extension of 278 months.4 In our data
set, 12 of 14 medications retained full potency for at least
336 months, and 8 of these for at least 480 months. Given

our inability to confirm ideal storage conditions for our
samples, our results support the effectiveness of broadly
extending expiration dates for many drugs, the efficacy
of which has been demonstrated by SLEP in a more controlled fashion.
The 3 drugs found with less than 90% of their labeled potency were amphetamine and aspirin in both
samples tested and phenacetin in 1 of 2 samples tested.
Aspirin is known to degrade in vitro,6 but there are no
such published data regarding amphetamine. For phenacetin, the difference in recovery between the 2 samples
could be due to differences in packaging or storage of the
containers. Aside from aspirin, all drugs in Fiorinal (butalbital, aspirin, caffeine, and codeine phosphate) had almost 100% of labeled concentrations, while those of Codempiral No. 3 (phenacetin with codeine phosphate) were
all less than 95%. Since the codeine measured in Codempiral No. 3 was also lower than that of Fiorinal (90% vs
99%), this suggests that Codempiral’s packaging was less
intact, allowing moisture to penetrate, which can promote hydrolysis. Because phenacetin has an amide functional group, it is more prone to this type of degradation
than codeine.
Three drugs were unexpectedly found in our samples
at potencies greater than 110% of the labeled amounts.
Some samples may have been produced prior to 1963,
when FDA-mandated quality control measures were instituted (Paula R. Katz, Regulatory Counsel, FDA, Center for Drug Evaluation and Research, Division of Manufacturing and Product Quality, Guidance and Policy;
e-mail communication, May 23, 2011); however, exact
dating of all our samples was not possible. Alternately,
these drugs could have come from lots untested by the
manufacturer, or the accuracy between analytical methods used in this study compared with those used decades ago could be questioned.
The most important implication of our study involves
the potential cost savings resulting from lengthier product expiration dating. Each dollar spent on SLEP to demonstrate longer than labeled drug stability results in $13
to $94 saved on reacquisition costs.4 Given that Americans currently spend more than $300 billion annually on
prescription medications,7 extending drug expiration dates
could yield enormous health care expenditure savings.
In conclusion, this study provides additional evidence that many prescription pharmaceuticals retain their
full potency for decades beyond their manufacturerascribed expiration dates. Given the potential costsavings, we suggest the current practices of drug expiration dating be reconsidered.
Lee Cantrell, PharmD
Jeffrey R. Suchard, MD
Alan Wu, PhD
Roy R. Gerona, PhD
Published Online: October 8, 2012. doi:10.1001
/archinternmed.2012.4501
Author Affiliations: California Poison Control System,
San Diego Division, University of California San Francisco School of Pharmacy, San Diego (Dr Cantrell); Department of Emergency Medicine, University of Califor-

ARCH INTERN MED/ VOL 172 (NO. 21), NOV 26, 2012
1686

WWW.ARCHINTERNMED.COM

©2012 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/intemed/26027/ by Marshall Allen on 03/13/2017

 nia, Irvine Medical Center, Orange (Dr Suchard); and
Department of Laboratory Medicine, San Francisco General Hospital/University of California San Francisco, San
Francisco (Drs Wu and Gerona).
Correspondence: Dr Cantrell, California Poison Control System, San Diego Division, University of California San Francisco School of Pharmacy, 200 W Arbor Dr,
San Diego, CA 92103-8925 (lcantrell@calpoison.org).
Author Contributions: Study concept and design: Cantrell,
Suchard, Wu, and Gerona. Acquisition of data: Gerona.
Analysis and interpretation of data: Cantrell, Wu, and
Gerona. Drafting of the manuscript: Cantrell, Suchard, Wu,
and Gerona. Critical revision of the manuscript for important intellectual content: Cantrell, Suchard, Wu, and
Gerona. Statistical analysis: Gerona. Obtained funding: Wu.
Administrative, technical, and material support: Cantrell
and Wu. Study supervision: Cantrell and Wu.
Financial Disclosure: None reported.
Previous Presentation: This study was an oral presentation at the 2011 North American Congress of Clinical
Toxicology; September 23, 2011; Washington, DC.
1. Title 21 CFR 211.166(a) and (b). Current good manufacturing practice in
manufacturing for finished pharmaceuticals and expiration dating (2012).
2. Sandford-Smith J. Outdated drugs may be useful. BMJ. 2003;326(7379):51.
3. Consumer Reports. Risky prescription drug practices are on the rise in a grim
economy. http://news.consumerreports.org/health/2011/09/risky
-prescription-drug-practices-are-on-the-rise-in-a-grim-economy.html. Accessed
October 11, 2011.
4. Courtney B, Easton J, Inglesby TV, SooHoo C. Maximizing state and local medical countermeasure stockpile investments through the Shelf-Life Extension
Program. Biosecur Bioterror. 2009;7(1):101-107.
5. US Food and Drug Administration. Questions and answers on levothyroxine
sodium products. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrug
SafetyInformationforPatientsandProviders/ucm161266.htm?utm_source
=fdaSearch&utm_medium=website&utm_term=. Accessed April 18, 2012.
6. Martin BK. The formulation of aspirin. Adv Pharm Sci. 1971;3:107-171.
7. The White House. We can’t wait: Obama administration takes action to reduce prescription drug shortages, fight price gouging. http://www.whitehouse
.gov/the-press-office/2011/10/31/we-can-t-wait-obama-administration
-takes-action-reduce-prescription-drug. Accessed January 18, 2012.

Persistence With Therapy
Among Patients Treated With Warfarin
for Atrial Fibrillation

T

he major challenges of warfarin therapy relate
to poor adherence and persistence, the need for
regular monitoring, and the risk of hemorrhage. In clinical trials, persistence with warfarin treatment ranges from 75% to 79% at 1 year,1,2 but persistence in clinical practice is thought to be poorer. Small
observational studies suggest that approximately onequarter of patients cease warfarin treatment within a year
of initiation.3,4 To our knowledge, there are currently no
large studies offering real-world estimates of persistence among warfarin users.

See Invited Commentary
at end of letter
The objective of this study was to examine persistence
with warfarin therapy in a large population-based cohort
of newly treated patients with atrial fibrillation (AF).

Methods. We conducted a population-based cohort study
among residents of Ontario, Canada, 66 years and older,
who commenced treatment with warfarin between April
1, 1997, and March 31, 2008. We used multiple linked
administrative data sets from Ontario, the most populous province in Canada, to identify outpatient prescription records, hospitalizations, emergency department visits, physician services, patient demographics, and
comorbidities. Details of these databases are given in the
eAppendix (http://www.archinternmed.com). The data
were held securely in a linked, deidentified form and analyzed at the Institute for Clinical Evaluative Sciences.
For each study subject, we identified a period of continuous warfarin use beginning with the first prescription dispensed after their 66th birthday and defined by
successive prescription refills within 180 days, thereby
allowing for periodic dose adjustments, brief lapses in
adherence, and variable timing of prescription refills. To
create an inception cohort of patients with AF, patients
with any prescription for warfarin in the preceding year
were excluded, and the analysis was restricted to patients who had a physician visit, emergency department
assessment, or hospital admission for AF or flutter in the
100 days preceding the first prescription for warfarin. We
followed patients from their cohort entry date until the
first instance of discontinuation of warfarin therapy, death,
or the end of the study period (March 31, 2010), with a
maximum follow-up of 5 years.
We constructed Kaplan-Meier curves to characterize
drug therapy discontinuation. Secondary analyses described persistence with warfarin therapy according to
age (66 to 75 years, 76 to 85 years, and Ն86 years), sex,
CHADS2 (congestive heart failure, hypertension, age Ն75
years, diabetes mellitus, and prior stroke or transient ischemic attack) score,5 and date of warfarin therapy initiation (before or after April 1, 2003; presuming progressive improvements in anticoagulation management over
time).6,7 The log-rank test was used to examine differences in persistence among patient subgroups. This research was approved by the research ethics board of Sunnybrook Health Sciences Centre, Toronto, Ontario.
Results. Over the 13-year study period, we identified
125 195 new users of warfarin in Ontario 66 years or older
with a recent diagnosis of AF. Of these, 86 432 (69.0%)
had a CHADS2 score of 2 or higher at the outset of therapy,
and 62 851 (50.2%) initiated treatment within a week of
their AF diagnosis.
Of 125 195 patients who started warfarin therapy for
AF, 8.9% did not fill a second warfarin prescription during follow-up, 31.8% discontinued therapy within 1 year,
43.2% discontinued therapy within 2 years, and 61.3%
discontinued therapy within 5 years (Figure). The median time to discontinuation (MTD) was 2.9 years. Men
discontinued warfarin therapy earlier than women (MTD,
2.6 years vs 3.2 years, respectively; PϽ .001), while patients aged 66 to 75 years were more likely to discontinue therapy compared with older patient groups (MTD,
2.7 years vs 3.1 years for patients Ͼ85 years; P Ͻ.001).
Persistence with warfarin therapy increased with stroke
risk, as reflected by the CHADS2 score (MTD, 2.3 years,
2.9 years, and 3.3 years among people with a CHADS2

ARCH INTERN MED/ VOL 172 (NO. 21), NOV 26, 2012
1687

WWW.ARCHINTERNMED.COM

©2012 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/intemed/26027/ by Marshall Allen on 03/13/2017