sess its effect on major adverse cardiac events.1 Rates of
1. Davidson KW, Rieckmann N, Clemow L, et al. Enhanced depression care for
any cardiac hospitalization were 5% in the intervention
patients with acute coronary syndrome and persistent depressive symptoms:coronary psychosocial evaluation studies randomized controlled trial. Arch
group vs 16% in the usual care group. The approxi-
Intern Med. 2010;170(7):600-608.
mately 70% relative risk reduction and 11% absolute risk
2. Ladapo JA, Shaffer JA, Fang Y, Ye S, Davidson KW. Cost-effectiveness of en-
hanced depression care after acute coronary syndrome: results from the Coro-
reduction in hospitalization for major adverse cardiac
nary Psychosocial Evaluation Studies randomized controlled trial [pub-
events or heart failure are much higher than would be
lished online October 15, 2012]. Arch Intern Med. 2012;172(21):1682-1684.
expected for even the most potent intervention or treat-
3. Frasure-Smith N, Lespe´rance F, Talajic M. Depression following myocardial
infarction: impact on 6-month survival. JAMA. 1993;270(15):1819-1825.
ment in this setting. In the Myocardial Ischemia Reduc-
4. Czarny MJ, Arthurs E, Coffie DF, et al. Prevalence of antidepressant prescrip-
tion with Aggressive Cholesterol Lowering (MIRACL)
tion or use in patients with acute coronary syndrome: a systematic review.
study, for example, 3086 almost exclusively statin-
5. Cassel CK, Guest JA. Choosing wisely: helping physicians and patients make
naı¨ve patients were randomized to receive high-dose ator-
smart decisions about their care. JAMA. 2012;307(17):1801-1802.
vastatin (80 mg/d) or placebo.8 Even one of the most im-
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.
pressive treatments in our therapeutic armamentarium,
7. Unu¨tzer J, Katon W, Callahan CM, et al; IMPACT Investigators. Collabora-
which, in the MIRACL study, lowered low-density lipo-
tive care management of late-life depression in the primary care setting: a ran-
protein cholesterol level by 40%, led to far more modest
domized controlled trial. JAMA. 2002;288(22):2836-2845.
8. Schwartz GG, Olsson AG, Ezekowitz MD, et al; Myocardial Ischemia Reduc-
risk reductions in cardiac events requiring hospitaliza-
tion with Aggressive Cholesterol Lowering (MIRACL) Study Investigators.
tion than the reductions reported for enhanced depres-
Effects of atorvastatin on early recurrent ischemic events in acute coronary
sion care in the COPES trial. Indeed, most of the effect
syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285(13):1711-1718.
of high-dose statin treatment in the MIRACL study wasdue to a 26% relative risk reduction and 2% absolute riskreduction in hospitalization for myocardial ischemia. Thus, while the results of the COPES trial are provoca-tive and exciting, they must be replicated in larger, ap-
RESEARCH LETTERS
propriately powered trials before the promising reduc-tion in hospitalizations can be used to calculate potentialcost savings.
Ladapo et al2 should be congratulated for addressing the
economic impact of their findings and for conducting a ran-
Stability of Active Ingredients
domized controlled trial in patients with ACS, a difficult
in Long-Expired Prescription Medications
enough task in and of itself. However, the task before medi-cal professionals when interpreting studies like this is alsochallenging. Coping with rising health care costs requires
D ebateexistsregardingtherelativepotencyof
medications beyond their labeled expiration
us to carefully examine all the resources that would be in-
dates. Expired medications have not necessar-
volved in implementing “more health care” and then,
ily lost potency, since the expiration date is only an as-
equally, to carefully determine whether this would actu-
surance that the labeled potency will last at least until
ally lead to “better health” by evaluating the net gain to pa-
that time.1 Clinical situations may arise in which ex-
tients and society. Whether the COPES trial is good value
pired drugs might be considered owing to lack of viable
alternatives2 or financial concerns.3 Ongoing studies showthat many medications retain their potency years after
their initially labeled expiration dates.4 We sought to char-
acterize the potency of some prescription medications thathad expired decades ago. Published Online: October 15, 2012. doi:10.1001/2013 .jamainternmed.114 Methods. Eight long-expired medications with 15 dif- Author Affiliations: Department of Medicine, The Johns
ferent active ingredients were discovered in a retail phar-
Hopkins University School of Medicine, Baltimore, Mary-
macy in their original, unopened containers. All had ex-
land (Dr Ziegelstein); Departments of Psychiatry, Coun-
pired 28 to 40 years prior to analysis. Three tablets or
seling and Educational Psychology, Epidemiology, Bio-
capsules of each medication were analyzed, with each
statistics, and Occupational Health, and Medicine and
sample tested 3 times for each labeled active ingredient.
School of Nursing, McGill University, and Lady Davis In-
No analytical standard for homatropine could be found,
stitute for Medical Research, Jewish General Hospital (Dr
Tablets or capsule contents were dissolved and soni-
Correspondence: Dr Ziegelstein, Department of Medi-
cated in methanol, reconstituted in analysis buffer (10%
cine, The Johns Hopkins Bayview Center, Mason F. Lord
methanol) and analyzed with Liquid Chromatograph (Agi-
Building, Center Tower, 5200 Eastern Ave, Third Floor,
lent Technologies) Time-of-Flight Mass Spectrometer
Room 320, Baltimore, MD 21224 ([email protected]).
(Agilent) using electrospray ionization in negative and
Financial Disclosure: None reported.
positive polarities. Chromatography was run with gra-
Funding/Support: Dr Ziegelstein is supported by the
dient elution using Eclipse Plus C18 column (Agilent).
Miller Family Scholar Program of the Johns Hopkins Cen-
Data analysis was performed using Mass Hunter Quali-
ter for Innovative Medicine. Dr Thombs is supported by
tative and Quantitative Analysis (Agilent). Quantifica-
a New Investigator Award from the Canadian Institutes
tion was performed by isotope dilution method with a
ARCH INTERN MED/ VOL 172 (NO. 21), NOV 26, 2012
2012 American Medical Association. All rights reserved. Downloaded From: http://archinte.jamanetwork.com/ by a Istanbul Üniversitesi User on 01/03/2013
our inability to confirm ideal storage conditions for our
Table. Declared and Measured Amounts in Drugs
samples, our results support the effectiveness of broadlyextending expiration dates for many drugs, the efficacy
Drug Trade Name Measured
of which has been demonstrated by SLEP in a more con-
With Active Declared Ingredients Amount, mg Mean (SD), mg
The 3 drugs found with less than 90% of their la-
beled 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 phen-
acetin, 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 (butal-
bital, aspirin, caffeine, and codeine phosphate) had al-
most 100% of labeled concentrations, while those of Co-
dempiral No. 3 (phenacetin with codeine phosphate) were
all less than 95%. Since the codeine measured in Codem-
piral 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 pro-
mote hydrolysis. Because phenacetin has an amide func-
tional group, it is more prone to this type of degradation
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 in-
stituted (Paula R. Katz, Regulatory Counsel, FDA, Cen-
ter for Drug Evaluation and Research, Division of Manu-
facturing and Product Quality, Guidance and Policy;e-mail communication, May 23, 2011); however, exactdating of all our samples was not possible. Alternately,
Results. Twelve of the 14 drug compounds tested (86%)
these drugs could have come from lots untested by the
were present in concentrations at least 90% of the la-
manufacturer, or the accuracy between analytical meth-
beled amounts, the generally recognized minimum ac-
ods used in this study compared with those used de-
ceptable potency. Three of these compounds were present
at greater than 110% of the labeled content. Two com-
The most important implication of our study involves
pounds (aspirin and amphetamine) were present in
the potential cost savings resulting from lengthier prod-
amounts of less than 90% of labeled content. One com-
uct expiration dating. Each dollar spent on SLEP to dem-
pound (phenacetin) was present at greater than 90% of
onstrate longer than labeled drug stability results in $13
labeled amounts from 1 medication tested, but less than
to $94 saved on reacquisition costs.4 Given that Ameri-
90% in another medication that contained that drug
cans currently spend more than $300 billion annually on
(Table).
prescription medications,7 extending drug expiration datescould yield enormous health care expenditure savings. Comment. The US Food and Drug Administration (FDA)
In conclusion, this study provides additional evi-
permits “reasonable variation,” such that most medica-
dence that many prescription pharmaceuticals retain their
tions marketed in the United States contain 90% to 110%
full potency for decades beyond their manufacturer-
of the amount of the active ingredient claimed on the la-
ascribed expiration dates. Given the potential cost-
bel.5 Drug expiration dates typically range from 12 to 60
savings, we suggest the current practices of drug expi-
months after their production.4 However, FDA regula-
tions do not require determination of how long medica-tions remain potent after that, allowing manufacturers
to arbitrarily establish expiration dates without deter-
mining actual long-term drug stability.
The Shelf-Life Extension Program (SLEP) checks long-
term stability of federal drug stockpiles. Eighty-eight per-cent of 122 different drugs stored under ideal environ-
Published Online: October 8, 2012. doi:10.1001
mental conditions had their expiration dates extended
more than 1 year, with an average extension of 66 months
Author Affiliations: California Poison Control System,
and a maximum extension of 278 months.4 In our data
San Diego Division, University of California San Fran-
set, 12 of 14 medications retained full potency for at least
cisco School of Pharmacy, San Diego (Dr Cantrell); De-
336 months, and 8 of these for at least 480 months. Given
partment of Emergency Medicine, University of Califor-
ARCH INTERN MED/ VOL 172 (NO. 21), NOV 26, 2012
2012 American Medical Association. All rights reserved. Downloaded From: http://archinte.jamanetwork.com/ by a Istanbul Üniversitesi User on 01/03/2013
nia, Irvine Medical Center, Orange (Dr Suchard); and
Methods. We conducted a population-based cohort study
Department of Laboratory Medicine, San Francisco Gen-
among residents of Ontario, Canada, 66 years and older,
eral Hospital/University of California San Francisco, San
who commenced treatment with warfarin between April
1, 1997, and March 31, 2008. We used multiple linked
Correspondence: Dr Cantrell, California Poison Con-
administrative data sets from Ontario, the most popu-
trol System, San Diego Division, University of Califor-
lous province in Canada, to identify outpatient prescrip-
nia San Francisco School of Pharmacy, 200 W Arbor Dr,
tion records, hospitalizations, emergency department vis-
San Diego, CA 92103-8925 ([email protected]).
its, physician services, patient demographics, and
Author Contributions: Study concept and design: Cantrell,
comorbidities. Details of these databases are given in the
Suchard, Wu, and Gerona. Acquisition of data: Gerona.
eAppendix (http://www.archinternmed.com). The data
Analysis and interpretation of data: Cantrell, Wu, and
were held securely in a linked, deidentified form and ana-
Gerona. Drafting of the manuscript: Cantrell, Suchard, Wu,
lyzed at the Institute for Clinical Evaluative Sciences.
and Gerona. Critical revision of the manuscript for impor-
For each study subject, we identified a period of con-
tant intellectual content: Cantrell, Suchard, Wu, and
tinuous warfarin use beginning with the first prescrip-
Gerona. Statistical analysis: Gerona. Obtained funding: Wu.
tion dispensed after their 66th birthday and defined by
Administrative, technical, and material support: Cantrell
successive prescription refills within 180 days, thereby
and Wu. Study supervision: Cantrell and Wu.
allowing for periodic dose adjustments, brief lapses in
Financial Disclosure: None reported.
adherence, and variable timing of prescription refills. To
Previous Presentation: This study was an oral presen-
create an inception cohort of patients with AF, patients
tation at the 2011 North American Congress of Clinical
with any prescription for warfarin in the preceding year
Toxicology; September 23, 2011; Washington, DC.
were excluded, and the analysis was restricted to pa-tients who had a physician visit, emergency department
1. Title 21 CFR 211.166(a) and (b). Current good manufacturing practice in
assessment, or hospital admission for AF or flutter in the
manufacturing for finished pharmaceuticals and expiration dating (2012).
2. Sandford-Smith J. Outdated drugs may be useful. BMJ. 2003;326(7379):51.
100 days preceding the first prescription for warfarin. We
3. Consumer Reports. Risky prescription drug practices are on the rise in a grim
followed patients from their cohort entry date until the
economy. http://news.consumerreports.org/health/2011/09/risky-prescription-drug-practices-are-on-the-rise-in-a-grim-economy.html. Accessed
first instance of discontinuation of warfarin therapy, death,
or the end of the study period (March 31, 2010), with a
4. Courtney B, Easton J, Inglesby TV, SooHoo C. Maximizing state and local medi-
cal countermeasure stockpile investments through the Shelf-Life ExtensionProgram. Biosecur Bioterror. 2009;7(1):101-107.
We constructed Kaplan-Meier curves to characterize
5. US Food and Drug Administration. Questions and answers on levothyroxine
drug therapy discontinuation. Secondary analyses de-
sodium products. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrug
scribed persistence with warfarin therapy according to
SafetyInformationforPatientsandProviders/ucm161266.htm?utm_source=fdaSearch&utm_medium=website&utm_term=. Accessed April 18, 2012.
age (66 to 75 years, 76 to 85 years, and Ն86 years), sex,
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 re-
2 (congestive heart failure, hypertension, age Ն75
duce prescription drug shortages, fight price gouging. http://www.whitehouse
years, diabetes mellitus, and prior stroke or transient is-
.gov/the-press-office/2011/10/31/we-can-t-wait-obama-administration
chemic attack) score,5 and date of warfarin therapy ini-
-takes-action-reduce-prescription-drug. Accessed January 18, 2012.
tiation (before or after April 1, 2003; presuming progres-sive improvements in anticoagulation management overtime).6,7 The log-rank test was used to examine differ-ences in persistence among patient subgroups. This re-
Persistence With Therapy
search was approved by the research ethics board of Sun-
Among Patients Treated With Warfarin
nybrook Health Sciences Centre, Toronto, Ontario. for Atrial Fibrillation Results. Over the 13-year study period, we identified T hemajorchallengesofwarfarintherapyrelate 125195newusersofwarfarininOntario66yearsorolder
to poor adherence and persistence, the need for
with a recent diagnosis of AF. Of these, 86 432 (69.0%)
regular monitoring, and the risk of hemor-
had a CHADS2 score of 2 or higher at the outset of therapy,
rhage. In clinical trials, persistence with warfarin treat-
and 62 851 (50.2%) initiated treatment within a week of
ment ranges from 75% to 79% at 1 year,1,2 but persis-
tence in clinical practice is thought to be poorer. Small
Of 125 195 patients who started warfarin therapy for
observational studies suggest that approximately one-
AF, 8.9% did not fill a second warfarin prescription dur-
quarter of patients cease warfarin treatment within a year
ing follow-up, 31.8% discontinued therapy within 1 year,
of initiation.3,4 To our knowledge, there are currently no
43.2% discontinued therapy within 2 years, and 61.3%
large studies offering real-world estimates of persis-
discontinued therapy within 5 years (Figure). The me-
dian time to discontinuation (MTD) was 2.9 years. Mendiscontinued warfarin therapy earlier than women (MTD,2.6 years vs 3.2 years, respectively; P Ͻ.001), while pa-
See Invited Commentary
tients aged 66 to 75 years were more likely to discon-
at end of letter
tinue therapy compared with older patient groups (MTD,2.7 years vs 3.1 years for patients Ͼ85 years; PϽ.001).
The objective of this study was to examine persistence
Persistence with warfarin therapy increased with stroke
with warfarin therapy in a large population-based cohort
risk, as reflected by the CHADS2 score (MTD, 2.3 years,
of newly treated patients with atrial fibrillation (AF).
2.9 years, and 3.3 years among people with a CHADS2
ARCH INTERN MED/ VOL 172 (NO. 21), NOV 26, 2012
2012 American Medical Association. All rights reserved. Downloaded From: http://archinte.jamanetwork.com/ by a Istanbul Üniversitesi User on 01/03/2013
E-14-041–ARAI (Asset) Online Auction CATALOGUE UNDER INSTRUCTIONS FROM The Automotive Research Association of India, Survey No. 102, Vetal Hill, Off Paud Road, Kothrud, Pune – 411 038 Kisan Ramchandra Auctioneers Pvt. Ltd. Deccan Towers, 5 – Mezzanine Floor, Poolgate, Pune – 411001 Tel: 26360356, 26361357, Fax: (020) 26361359 Website: www.krauct
Vetri Velamail I was born in Malaysia and came to England for further education in 1978, aged 17, with all my family back in Malaysia supporting me financially. Having successfully passed A’ levels, I then studied medicine at the University of Sheffield, qualifying in 1986. Since this time I have worked as a GP in Rotherham. I married Susan, a senior midwifery sister, and we have three won