Content uploaded by Neal M Davies
Author content
All content in this area was uploaded by Neal M Davies on Nov 05, 2020
Content may be subject to copyright.
OPEN
© 2020 Joule Inc. or its licensors CMAJ OPEN, 8(1) E75
Acetylsalicylic acid (ASA) is a potent inhibitor of
platelet aggregation and clotting. Nitroglycerin is a
vasodilatory drug used to alleviate cardiac chest pain
due to inadequate blood supply to the myocardium. The
American College of Cardiology Foundation/American
Heart Association guideline on management of ST-elevation
myocardial infarction recommends1 that patients with coro-
nary artery disease (CAD) carry and use both ASA and nitro-
glycerin at the onset of chest pain. Specically, patients with
known or suspected CAD who experience chest pain should
immediately chew and swallow ASA tablets at dosages from
162 mg to 325 mg and take the rst of up to 3 doses of a
nitroglycerin preparation.1 If pain is not relieved, emergency
medical services should be activated.
Early administration of ASA and nitroglycerin is benecial
in acute coronary syndromes. Immediate ASA administration
lowers mortality from myocardial infarction, with a clear
association between the onset of myocardial infarction symp-
toms and time to ASA administration.2 In observational stud-
ies, prehospital sublingual administration of nitroglycerin
reduced chest pain signicantly3 and was safe, with the only
adverse effect noted being nonclinically signicant hypoten-
sion (0.7%–3.2% of patients).3,4 Prehospital administration of
nitroglycerin by emergency response teams is associated with
improved survival,5 and a Cochrane meta-analysis of in-
hospital nitrate therapy in acute coronary syndromes showed
an improvement in survival when administered within the
rst 24hours.6
Development and validation of a compact on-person storage
device (SMHeartCard) for emergency access
to acetylsalicylic acid and nitroglycerin
Tyson Le MSc, D. Ian Paterson MD, Neal M. Davies PhD, John R. Mackey MD
Competing interests: John Mackey holds shares in the SMHeartCard.
No other competing interests were declared.
This article has been peer reviewed.
Correspondence to: John Mackey, john.mackey@
albertahealthservices.ca
CMAJ Open 2020. DOI:10.9778/cmajo.20190147
Background: Guidelines recommend that patients with coronary artery disease (CAD) carry and immediately use acetylsalicylic acid
(ASA) and sublingually administered nitroglycerin at the onset of chest pain; however, compliance with these recommendations is
poor. We designed and tested a compact on-person storage device for these medications.
Methods: We designed an airtight, light-proof and chemically inert holder to carry four 81-mg ASA tablets and three 0.3-mg
Nitrostat (nitroglycerin, Pfizer) tablets. After establishing the temperatures ranges in wallets and pockets, we tested nitroglycerin
dissolution and release of the stored Nitrostat tablets across a range of relevant temperatures and a variety of tablet enclosure
systems.
Results: Microcalorimeter thermal conduction studies as well as dissolution and release testing showed that nitroglycerin tablets
were stable at temperatures ranging from –20°C to 60°C for 1week. In testing up to 24weeks, 0.3-mg Nitrostat tablets enclosed
completely in polytetrafluoroethylene (PTFE) performed similarly to those stored in the manufacturer’s borosilicate glass packaging
across a wide range of temperatures relevant to on-person carriage. Real-world on-person testing for 24 weeks confirmed these
results. Non-PTFE enclosures performed poorly.
Interpretation: The PTFE enclosure with a PTFE-coated cap liner maintained long-term performance of 0.3-mg Nitrostat tablets
under laboratory and real-world conditions. This storage device is now commercially available as the SMHeartCard to improve com-
pliance and provide immediate access to emergency cardiac medications.
Abstract
Research
E76 CMAJ OPEN, 8(1)
OPEN
Research
An audit of a Canadian hospital showed that, among
patients presenting with acute coronary syndromes (myo-
cardial infarction or unstable angina), the median time to
ASA and nitroglycerin administration was more than
90 minutes after arrival at the emergency department.7
About 30% of people with myocardial infarction do not sur-
vive long enough to reach medical care,8 and this is more
frequent in people who live and work in geographically iso-
lated areas.
Storing ASA requires a low-humidity environment. In con-
trast, nitroglycerin in its pure form is volatile, reacts with oxy-
gen and degrades with light exposure. Furthermore, nitro-
glycerin adsorbs to plastics and desiccants used to store and
distribute tablets.9 Although nitroglycerin sprays are the pri-
mary way to carry and administer nitroglycerin in Canada,
these are inconvenient and and should not be stored at tem-
peratures lower than 15°C.10
The published literature shows poor compliance with on-
person carriage of nitroglycerin and ASA. In a prospective
Canadian case series conducted in a primary care clinic,
38 consecutive patients with CAD were asked to produce
their prescribed nitroglycerin and recommended ASA to a
nurse.11 Only 7 (18%) of the 38 carried their nitroglycerin;
among men, the rate was 12% (2/17). The most frequent
explanation for lack of compliance was the inconvenience of
carrying nitroglycerin spray. No patient carried ASA.
Although self-reported rates of nitroglycerin carriage appear
to be higher,12,13 self-reported compliance rates generally
exceed objectively measured compliance.14,15
Improved tablet manufacturing processes now permit
long-term storage of nitroglycerin tablets when carried in
pant pockets or purses, particularly when headspace (space left
at the top of a container to allow for expansion of contents) is
minimized.9 To improve compliance and provide immediate
access to ASA and nitroglycerin, we designed a small, conve-
nient pill holder to t in wallets, pockets and purses, with
clear instructions for its use.
In the current study, we evaluated this holder with a series
of nitroglycerin enclosures under a range of laboratory condi-
tions simulating on-person carriage, as well as a 24-week
“real-world” evaluation of on-person carriage. We hypothe-
sized that 0.3-mg Nitrostat (nitroglycerin, Pfizer) tablets
stored within the medication holder would not differ on in
vitro release testing from those stored in the original borosili-
cate glass packaging at room temperature.
Methods
We sought to optimize the stability and performance of
NitroStat tablets across a variety of physical enclosure sys-
tems, under different temperatures, and with and without
nitrogen gas packaging. We used thermal degradation test-
ing to evaluate pill stability, and in vitro nitroglycerin
release testing simulated sublingual dissolution. The tech-
nologist performing the tests was aware whether the pills
were being tested under real-world conditions or were con-
trol tablets.
Materials
We purchased 0.3-mg and 0.6-mg Nitrostat tablets from
McKesson Canada. We obtained hydrophobic polyvinylidene
difluoride Durapore membrane filters (pore size 0.45 µm,
13-mm membrane) from Millipore Sigma. We purchased
high-performance liquid chromatography (HPLC)-grade
methanol and octanol from Fischer Scientic. Water used for
release tests and HPLC analysis was puried with Elgastat
Maxima UF and an Elgastat Option 3B water purifier by
ELGA LabWater.
Product design and user testing
We designed a product made of polypropylene that is small and
thin enough to t in a wallet, holds four 81-mg acetylsalicylic
acid tablets, cradles a chemically inert insert to hold 3 nitro-
glycerin tablets, permits a cap system to completely enclose the
tablets in a chemically inert chamber without exposure to air,
moisture or light, and has clear directions for medication use.
The disassembled system is shown schematically in Figure 1A.
The back surface of the holder carries a label with instructions
for use and expiration date. The assembled product is shown in
Figure 1B and Figure 2. The nal design was tested in 5older
cognitively intact people; each was able to read the directions,
and understand and manage the device and medications.
Temperature excursions with on-body carriage
To determine on-body temperature ranges typical for Cana-
dians, we measured minimum and maximum pocket tempera-
tures at 10-second intervals with a ThermPro TP50 digital
LCD indoor hygrometer thermometer humidity meter.
Fivemen and 2women in Alberta carried this instrument in
shirt or pants pockets continuously over 24-hour periods in
spring and summer, or fall and winter conditions.
Thermal chemical degradation and high-
temperature testing
Given the possibility of short-term high-temperature expo-
sure, we evaluated the thermal chemical degradation of 0.3-mg
Nitrostat tablets at elevated temperatures. Six 0.3-mg Nitro-
stat tablets were placed inside a stainless steel microcalorimeter
ampoule and monitored for thermal degradation with a
TAMIII thermal activity monitor (TA Instruments) at various
conditions (45°C with nitrogen gas packaging to determine
whether nitrogen would help prevent nitroglycerin degrada-
tion, and 45°C, 50°C and 60°C in atmospheric oxygen) for
1week. Performance of these pills was then assessed by means
of nitroglycerin release testing as described below.
Storage conditions
We sought to identify the appropriate materials in which to
enclose nitroglycerin tablets and to establish whether nitrogen
packaging improved stability. As a control for all packaging
experiments, Nitrostat tablets were stored at room tempera-
ture (21°C ± 2°C) in their original borosilicate glass screw-top
vial with a plastic-lined metal screw cap. The SMHeartCard
case was tested with inserts made from polytetrauoroethyl-
ene (PTFE) (a synthetic uoropolymer) or borosilicate glass,
OPEN
CMAJ OPEN, 8(1) E77
Research
and with PTFE-coated or polyethylene cap liners. Tablets
were also stored with and without nitrogen in PTFE inserts
and glass inserts with PTFE-coated cap liners. The tablets
were stored for 1, 2, 4, 8, 12 and 24 weeks at 4°C, room tem-
perature and 35°C before release testing to evaluate perfor-
mance. We performed additional studies at –20°C at 4weeks.
We performed a conrmatory 24-week “real-world” evalu-
ation with 0.3-mg and 0.6-mg Nitrostat tablets. These tablets
were stored in their original borosilicate glass packaging at
room temperature (control) or within a SMHeartCard case
containing PTFE inserts and cap, and were kept on person
within wallets, pockets, backpacks and purses.
In vitro release test
We used in vitro release testing to simulate Nitrostat exposure
to saliva and diffusion into systemic circulation. These studies
used Franz glass diffusion cells to determine the cumulative
percent drug release. The receptor medium was double-
distilled water, 12–13 mL in the receptor chamber of each
cell. Receptor chambers were maintained at 37.4°C ± 0.5°C by
means of a Haake D8 circulating water bath. A magnetic stir-
ring bar (Ikaon, IKA) was used to stir the receptor medium
in each diffusion cell at 600 rpm. A 0.45-µm synthetic hydro-
phobic (polyvinylidene difluoride) membrane was briefly
soaked in octanol to create a partition replicating a mucosal
membrane. The membrane was assembled between the donor
and receptor compartments of the Franz cell. A Nitrostat tab-
let was added on top of the membrane, and 1mL of double-
distilled water was added to dissolve the sample. Then, 100-µL
samples were collected through a sampling port with a needle
at 2, 5, 10, 20, 30 and 60 minutes. The same volume with-
drawn was replaced with double-distilled water.
Figure 1: Diagram of the disassembled (A) and assembled (B) cardiac medication holder showing 1)nitroglycerin cap, 2) nitro-
glycerin polytetrafluoroethylene (PFTE) cap liner, 3) 3 nitroglycerin tablets, 4)PTFE nitroglycerin insert, 5)base 6)grooves,
7)instructions, 8) nitroglycerin insert holder, 9)acetylsalicylic acid (ASA) well, 10)ASA tablets, 11)ASA cap liner, 12)ASA cap
and 13)cap bridge.
E78 CMAJ OPEN, 8(1)
OPEN
Research
We analyzed the samples using HPLC to assess nitroglyc-
erin release. We adapted HPLC methods from the United
States Pharmacopoeia standard16 using slight modications.
We carried out the analysis using a system equipped with
2 LC-10ADVP pumps, an SIL-HTc auto sampler and an
SPD-10AV UV/VIS detector (Shimadzu Corporation). Chro-
matographic separation was achieved with a Finesse Genesis
C18 column (100 × 3.00mm, 4µm) (Chromatographic Spe-
cialties) at room temperature. The isocratic mobile phase of
methanol in water was 45:55 with a ow rate of 0.75 mL/min.
Samples were injected at 50µL with the ultraviolet detector’s
wavelength set at 210nm.
Statistical analysis
We used DDSolver, a Microsoft Excel add-in program, to
analyze the release proles of Nitrostat tablets. As recom-
mended by the US Food and Drug Administration,17 we cal-
culated F2 statistics to compare the mean cumulative percent
release of nitroglycerin between the control sample and the
experimental storage congurations and conditions. F2 is a
similarity factor used to measure the similarity between
2 release proles and takes all points into consideration. F2
values above 50 indicate that 2release proles are statistically
similar17 and therefore meet the US Food and Drug Adminis-
tration standard of clinically acceptable performance.
Ethics approval
As the study involved laboratory testing only, ethics approval
was not required.
Results
On-person pocket temperatures ranged from 13.2°C to
32.4°C (Figure 3). We consequently tested various enclosure
systems at long-term temperatures ranging from 4°C to 35°C,
Temperat ure, °C
Season
Spring/summer Fall/winter
0
10
20
30
40
Figure 3: Minimum and maximum 24-hour pocket temperature excur-
sions in spring/summer and fall/winter conditions. Each data point
represents a single daily minimum or maximum temperature reading
from 1person.
Figure 2: SMHeartCard medication holder capped (A) and uncapped
and filled (B), and reverse view (C).
OPEN
CMAJ OPEN, 8(1) E79
Research
and short-term temperature extremes. Nitroglycerin tablets
were chemically stable for 1 week at 45°C, 50°C and 60°C;
nitrogen packaging did not improve their stability (Figure 4A).
One-week exposure to high temperatures (45°C–60°C) with
and without nitrogen packaging did not trigger nitroglycerin
degradation or impairment (Figure 4B).
On in vitro nitroglycerin release testing, 0.3-mg Nitro-
stat tablets stored in PTFE-enclosed conditions (PTFE
insert and cap) performed similarly to control samples
across a range of temperatures (–20°C, 4°C, room temper-
ature and 35°C) (Figure 5, Table 1).
Storage of 0.3-mg tablets with a PTFE insert and cap
under real-world conditions for 24 weeks produced release
profiles similar to those for the borosilicate glass control,
which indicated that these tablets maintained their stability
during on-person carriage (Figure 6).
The F2 values for comparison of the similarity in nitro-
glycerin release proles between control samples and tablets
45°C for 1 wk
45°C + nitrogen for 1 wk
50°C for 1 wk
60°C for 1 wk
–0.0006
–0.0004
–0.0002
0.0
0.0002
050 100 150
Heat flow, W
Time, h
45°C for 1 wk
45°C + nitrogen for 1 wk
50°C for 1 wk
60°C for 1 wk
0
20
40
60
80
100
120
0102030405060
Cumulative nitroglycerin release, %
Time, min
A
B
Figure 4: Mean high-temperature (45°C–60°C) tolerance of six 0.3-mg Nitrostat (nitroglycerin, Pfizer) tablets stored with or
without nitrogen packaging for 1week. (A)Tablets were continuously monitored over 1 week to detect changes in their abil-
ity to conduct heat, indicative of thermal degradation. Only small changes in heat flow were observed, even at 60ºC, indi-
cating that the tablets were stable under these conditions. (B)Cumulative nitroglycerin release profiles of tablets stored in a
microcalorimeter. Exposure to high temperatures did not trigger nitroglycerin degradation or impairment. Error bars repre-
sent standard error of the mean.
E80 CMAJ OPEN, 8(1)
OPEN
Research
Table 1: Performance of Nitrostat (nitroglycerin, Pfizer) tablets stored in varying packaging configurations (n = 6)
Experimental storage
condition
Week*†
1 2 4 8 12 24
F2 S/NS F2 S/NS F2 S/NS F2 S/NS F2 S/NS F2 S/NS
Control: original borosilicate
glass packaging, RT
PTFE insert, PTFE cap, RT 64.6 S69.4 S84.6 S86.6 S87.6 S52.4 S
Borosilicate glass insert,
PTFE cap, RT
46.9 NS 59.8 S 66.1 S 69.5 S 85.8 S 58.7 S
PTFE insert, PTFE cap, 4°C 68.5 S76.1 S67.4 S68.9 S80.1 S58.6 S
Borosilicate glass insert,
PTFE cap, 4°C
53.2 S 59.6 S 75.6 S 85.0 S 73.5 S 62.9 S
PTFE insert, PTFE cap, 35°C 62.3 S78.2 S71.1 S95.1 S64.8 S61.8 S
Borosilicate glass insert,
PTFE cap, 35°C
46.7 NS 71.4 S 64.1 S 82.2 S 58.1 S 26.4 NS
PTFE insert, PE cap, 35°C 77.4 S 82.3 S 44.3 NS 46.3 NS 45.0 NS 30.2 NS
PTFE insert, PTFE cap,
35°C, N2 packaging
58.8 S 78.7 S 65.1 S 75.7 S 84.2 S 37.1 NS
Borosilicate glass insert, PTFE
cap, 35°C, N2 packaging
55.0 S 61.2 S 75.8 S 62.0 S 77.1 S 31.1 NS
PTFE insert, PTFE cap, –20°C – – – – 60.1 S– – – – – –
PTFE insert, PTFE cap,
0.3-mg, RWC
– – – – – – – – – – 56.0 S
PTFE insert, PTFE cap,
0.6-mg, RWC
– – – – – – – – – – 49.9 NS
Note: N2 = nitrogen, NS = not similar, PE = polyethylene, PTFE = polytetrafluoroethylene, RT = room temperature, RWC = real-world conditions, S = similar.
*F2 values less than 50 indicate significant differences in the release profiles.
†Red letters indicate results for the marketed product components and configuration of the SMHeartCard.
0
20
40
60
80
100
120
0102030405060
Cumulative nitroglycerin release, %
Time, min
Control
PTFE insert, PTFE cap, 4°C
Glass insert, PTFE cap, 4°C
PTFE insert, PTFE cap, RT
PTFE insert, PTFE cap, 35°C
Glass insert, PTFE cap, RT
PTFE insert, PTFE cap, 35°C, + nitrogen
Glass insert, PTFE cap, 35°C, + nitrogen
PTFE insert, PE cap, 35°C
Glass insert, PTFE cap, 35°C
Figure 5: Mean cumulative nitroglycerin release profiles of six 0.3-mg Nitrostat (nitroglycerin, Pfizer) tablets stored in varying holder configura-
tions with or without nitrogen packaging for 24weeks. Note: PE = polyethylene, PTFE = polytetrafluoroethylene, RT = room temperature. Error
bars represent standard error of the mean.
OPEN
CMAJ OPEN, 8(1) E81
Research
stored under the test conditions described for all experiments
are given in Table 1. Taken together, these results showed
that 0.3-mg Nitrostat tablets were stable across a range of
temperatures (–20°C to 35°C) when enclosed in PTFE for up
to 24weeks.
Storage conditions that did not perform similarly to the
control included a borosilicate glass insert and PTFE cap;
PTFE insert and polyethylene cap; nitrogen packaging
(PTFE insert, PTFE cap and glass insert, PTFE cap) at 35°C;
and 0.6-mg Nitrostat tablets in PTFE insert with PTFE cap
under real-world conditions (Figure 5, Table 1).
Representative HPLC traces of nitroglycerin peaks
obtained after Nitrostat tablet storage can be found in Appen-
dix 1 (available at www.cmajopen.ca/content/8/1/E75/suppl/
DC1).
Based on the results of the above tests, the conguration
chosen for the commercial SMHeartCard case was a PTFE
cap liner and PTFE insert to enclose 0.3-mg NitroStat tab-
lets, without nitrogen packaging.
Interpretation
We evaluated several configurations and conditions to
optimize the stability of nitroglycerin tablets for long-
term on-person carriage. Among the experimental permu-
tations, we found that tightly enclosed 0.3-mg Nitrostat
tablets in a PTFE insert covered with a PTFE-coated cap
liner maintained long-term performance properties for
24 weeks under both laboratory and real-world condi-
tions. Nitrogen packaging provided no benefit. The com-
plete PTFE enclosure performed as well as storage in
standard borosilicate glass vials.
Our nding that the SMHeartCard holder is an effective
storage device to provide immediate access to emergency car-
diac medications for 24 weeks suggests that the product has
the potential to reduce myocardial infarction mortality by
improving access and timeliness of treatment.
The results are of potential importance to 3groups. The
rst group is the population with established CAD, whose
compliance with carrying ASA and standard nitroglycerin
spray formulations is poor.11 The second group comprises
people with risk factors for myocardial infarction but with-
out a previous cardiac ischemic event. Canadians have a
high prevalence of risk factors for CAD,18 and treatment of
modiable risk factors reduces, but does not eliminate, the
risk of myocardial infarction. In addition, although people
with cardiovascular risk factors are sometimes advised to
take daily low-dose ASA as prophylaxis, new evidence sug-
gests that, for older people, the risks of daily ASA use out-
weigh the benefits.19 Finally, first responders and those
trained in rst aid may wish to carry the SMHeartCard to
provide immediate treatment to people with heart attack
symptoms.
Limitations
Our study has several limitations. We have not tested the
SMHeartCard for periods exceeding the manufacturer’s rec-
ommended 6 months and thus recommend replacement of
NitroStat pills every 6months. The laboratory studies were
conducted by qualied technical staff, but the technicians
0
20
40
60
80
100
120
0102030405060
Cumulative nitroglycerin release, %
Time, min
Control 0.3 mg
Control 0.6 mg
PTFE insert, PTFE cap, 0.3 mg
PTFE insert, PTFE cap, 0.6 mg
Figure 6: Mean nitroglycerin release profiles of six 0.3-mg and six 0.6-mg Nitrostat (nitroglycerin, Pfizer) tablets stored at room temperature for
24weeks in original borosilicate glass packaging (controls) and enclosed with polytetrafluoroethylene (PTFE) under real-world conditions for
24weeks. Error bars represent standard error of the mean.
E82 CMAJ OPEN, 8(1)
OPEN
Research
were not blinded to the experimental storage conditions. To
demonstrate improved compliance with SMHeartCard car-
riage compared to sublingually administered nitroglycerin
spray preparations, a formal prospective clinical trial will be
required.
Conclusion
We designed and validated a medication storage device to
permit on-person carriage and immediate treatment of
symptoms of myocardial infarction and angina. Given that
time to initial treatment is an important determinant of sur-
vival in myocardial infarction and that a substantial propor-
tion of myocardial infarctions are fatal before the patient
reaches the hospital, this device has the potential to improve
outcomes in people with established and previously undiag-
nosed CAD.
Note: This product is patented (CA180764S) and trademarked as
SMHeartCard, and is now marketed in Canada (www.smheartcard.ca) for
on-person carriage of ASA and 0.3-mg Nitrostat tablets.
References
1. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for
the management of ST-elevation myocardial infarction: a report of the Ameri-
can College of Cardiology Foundation/American Heart Association Task
Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78-140.
2. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither
among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2
(Second International Study of Infarct Survival) Collaborative Group. Lancet
1988;2:349-60.
3. Clemency BM, Thompson JJ, Tundo GN, et al. Prehospital high-dose sublin-
gual nitroglycerin rarely causes hypotension. Prehosp Disaster Med 2013;28:
477-81.
4. Engelberg S, Singer AJ, Moldashel J, et al. Effects of prehospital nitroglycerin
on hemodynamics and chest pain intensity. Prehosp Emerg Care 2000;4:290-3.
5. Strandmark R, Herlitz J, Axelsson C, et al. Determinants of pre-hospital phar-
macological intervention and its association with outcome in acute myocardial
infarction. Scand J Trauma Resusc Emerg Med 2015;23:105.
6. Perez MI, Musini VM, Wright JM. Effect of early treatment with anti-
hypertensive drugs on short and long-term mortality in patients with an acute
cardiovascular event. Cochrane Database Syst Rev 2009;(4):CD006743.
7. Dufresne F, Blouin D, Xue X, et al. Underutilization of acetylsalicylic acid for
acute coronary syndromes in the emergency department. CJEM 2004;6:333-6.
8. Dudas K, Lappas G, Stewart S, et al. Trends in out-of-hospital deaths due to
coronary heart disease in Sweden (1991 to 2006). Circulation 2011;123:46-52.
9. Nawarskas JJ, Koury J, Lauber DA, et al. Open-label study of the stability of
sublingual nitroglycerin tablets in simulated real-life conditions. Am J Cardiol
2018;122:2151-6.
10. Product monograph: Apo-Nitroglycerin [Internet] (revised Sept. 21, 2016).
Toronto: Apotex Inc.; 2016. Available: https://pdf.hres.ca/dpd_pm/00036567.
PDF (accessed 2020 Jan. 28).
11. Horsman C, Frederick T. Poor compliance with carrying nitroglycerin and
aspirin in patients with coronary artery disease. Can J Cardiol 2018;34:945.e1.
12. Sherrard H, Duchesne L, Wells G, et al. Using interactive voice response to
improve disease management and compliance with acute coronary syndrome
best practice guidelines: a randomized controlled trial. Can J Cardiovasc Nurs
2015;25:10-5.
13. Kimble LP, Kunik CL. Knowledge and use of sublingual nitroglycerin and
cardiac-related quality of life in patients with chronic stable angina. J Pain
Symptom Manage 2000;19:109-17.
14. Daniels T, Goodacre L, Sutton C, et al. Accurate assessment of adherence:
self-report and clinician report vs electronic monitoring of nebulizers. Chest
2011;140:425-32.
15. Grymonpre RE, Didur CD, Montgomery PR, et al. Pill count, self-report, and
pharmacy claims data to measure medication adherence in the elderly. Ann
Pharmacother 1998;32:749-54.
16. United States Pharmacopeia – national formulary. 39th ed. Rockville (MD):
United States Pharmacopeial Convention; 2016:1076.
17. Shah RB, Khan MA. The science and regulatory perspectives of emerging con-
trolled release dosage forms. In: Wen H, Park K, editors. Oral controlled release
formulation design and drug delivery: theory to practice. Hoboken (NJ): John Wiley
& Sons; 2010:337-49.
18. Tanuseputro P, Manuel DG, Leung M, et al.; Canadian Cardiovascular Out-
comes Research Team. Risk factors for cardiovascular disease in Canada. Can J
Cardiol 2003;19:1249-59.
19. McNeil JJ, Woods RL, Nelson MR, et al.; ASPREE Investigator Group.
Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med
2018;379:1499-508.
Affiliations: Faculties of Pharmacy and Pharmaceutical Sciences (Le,
Davies) and of Medicine and Dentistry (Paterson), University of Alberta;
Alberta Health Services (Mackey), Cross Cancer Institute, Edmonton, Alta.
Contributors: John Mackey led the project, designed and conducted
some of the experiments and drafted the manuscript. Neal Davies
designed the performance-testing experiments and interpreted the data.
Tyson Le performed the laboratory studies and collected and analyzed
the data. Ian Paterson reviewed the manuscript critically for important
intellectual content. All of the authors approved the nal version to be
published and agreed to be accountable for all aspects of the work.
Funding: Product prototypes and supplies for this study were provided
by SMHeartCard.
Acknowledgements: The authors thank James Stewart for input on the
SMHeartCard design, Carol Paul and Suzette Cabral-Mackey for logisti-
cal support, Dr. Catherine Horsman for feedback on product design,
Edith Pituskin for advice on knowledge translation, Darrin Berlin,
Claudia Johnston and Murtaza Hassanali for advice on the needs of Cana-
dian pharmacists and Deanna Hockley for publication coordination.
Supplemental information: Copies of the data are available from the
authors on request and with the permission of SMHeartCard. For
reviewer comments and the original submission of this manuscript, please
see www.cmajopen.ca/content/8/1/E75/suppl/DC1.
