and cardiovascular death in secondary prevention. It was pro-
posed that a combination of these 4 drugs could reduce the
risk of cardiovascular disease (CVD) by 75%5 in secondary
prevention, and that a combination of 6 drugs (3 blood pres-
sure [BP] lowering drugs at half doses, aspirin, a statin, and
folic acid) could reduce CVD in all individuals older than 55
years by 80%.6 This hypothesis became popularly known as
the polypill concept. Of these components, folic acid does not
reduce CVD,7 and so current research has focused on the other
spirin,1 β-blockers,2 statins,3 and angiotensin-converting
enzyme inhibitors4 reduce myocardial infarction, stroke,
The advantages of such a fixed dose combination include
improved compliance,3 reduced side effects, and cost savings.8
In the first major clinical trial of the polypill reported in 2009,
the Indian Polycap Study (TIPS)9 demonstrated that a combina-
tion of 5 drugs at low doses (aspirin, 100 mg; atenolol, 50 mg;
ramipril, 5 mg; thiazide, 12.5 mg; simvastatin, 20 mg) was well
tolerated and reduced risk factors so that about a halving of
CVD was projected. This is substantially lower than previous
theoretical estimates.6 Similar results have also been reported
with another polypill preparation.10 However, if a higher
strength of the polypill is more effective in lowering risk fac-
tors, or has benefits through additional mechanisms, then larger
© 2012 American Heart Association, Inc.
Circ Cardiovasc Qual Outcomes is available at http://circoutcomes.ahajournals.org
Received August 22, 2011; accepted April 26, 2012.
From the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Canada (S.Y., R.A., P.G., K.K.T.); and
St. John’s Medical College and Research Institute, Bangalore, India (P.P., A.S., D.X.).
The online-only Data Supplement is available at http://circoutcomes.ahajournals.org/lookup/suppl/doi:10.1161/CIRCOUTCOMES.111.963637/-/DC1.
Correspondence to Salim Yusuf, MBBS, DPhil, Population Health Research Institute, DBCVSRI, Hamilton General Hospital, 237 Barton Street East,
Hamilton, ON, Canada L8L 2X2. E-mail firstname.lastname@example.org
Background—A daily single capsule (polycap) of 3 blood pressure (BP) lowering drugs (hydrochlorthiazide, 12.5 mg;
atenolol, 50 mg; ramipril, 5 mg) at low doses, simvastatin (20 mg), and aspirin (100 mg) has been demonstrated to be well
tolerated and to reduce BP and low-density lipoprotein cholesterol. We examined the incremental effects of 2 (full dose)
plus K+ supplementation versus single polycap (low dose) on risk factors and tolerability.
Methods and Results—After a run-in period, 518 individuals with previous vascular disease or diabetes mellitus from 27
centers in India were randomly assigned to a single-dose polycap or to 2 capsules of the polycap plus K+ supplementation
for 8 weeks. The effects on BP, heart rate (HR), serum lipids, serum and urinary K+, and tolerability were assessed using
an intention-to-treat analysis. The full-dose polycap (plus K+ supplementation) reduced BP by a further 2.8 mm Hg
systolic and 1.7 mm Hg diastolic, compared with that observed with the low-dose polycap (P=0.003; P=0.001), but
there were no differences in HR (0.1 bpm). The differences in total and low-density lipoprotein cholesterol between
the full-dose and low-dose polycap was 7.2 mg/dL (P=0.014) and 6.6 mg/dL (P=0.006), respectively, but there were no
differences in high-density lipoprotein cholesterol or triglycerides. The rates of discontinuation of the study drug after
randomization were similar in the 2 groups (6.9% low dose versus 7.8% full dose).
Conclusion—The full-dose polycap (plus K+ supplementation) reduces BP and low-density lipoprotein cholesterol to a
greater extent compared with the low dose, with similar tolerability. Therefore, the full-dose polycap should potentially
lead to larger benefits.
Clinical Trial Registration—URL: http://www.ctri.nic.in. Unique identifier: CTRI/2010/091/000054.
(Circ Cardiovasc Qual Outcomes. 2012;5:463-471.)
Key Words: risk factors ■ blood pressure ■ lipids ■ cardiovascular disease
Comparison of Risk Factor Reduction and Tolerability
of a Full-Dose Polypill (With Potassium) Versus
Low-Dose Polypill (Polycap) in Individuals at High Risk
of Cardiovascular Diseases
The Second Indian Polycap Study (TIPS-2) Investigators
Salim Yusuf, MBBS, DPhil; Prem Pais, MD; Alben Sigamani, MD; Denis Xavier, MD, MSc;
Rizwan Afzal, MSc; Peggy Gao, MSc; Koon K. Teo, MD, PhD
by guest on December 27, 2015 by guest on December 27, 2015 by guest on December 27, 2015 by guest on December 27, 2015 by guest on December 27, 2015http://circoutcomes.ahajournals.org/ http://circoutcomes.ahajournals.org/http://circoutcomes.ahajournals.org/http://circoutcomes.ahajournals.org/http://circoutcomes.ahajournals.org/Downloaded from Downloaded from Downloaded from Downloaded from Downloaded from
464 Circ Cardiovasc Qual Outcomes July 2012
clinical benefits (eg, two third relative reduction in CVD risk)
may be expected. This potential difference in lowering the risk
of CVD is important, as long as the higher daily dose is well
tolerated. Furthermore, target doses of each of the drugs recom-
mended for use in secondary prevention are higher than those
used in the low-dose polycap and are approximately twice the
dose used in the polycap tested in TIPS-1. Therefore, there is a
need to evaluate the relative efficacy and tolerability of the full-
dose polycap compared with the low-dose preparation.
Observational studies and post hoc analysis of data from
the Ongoing Telmisartan Alone and in Combination With
Ramipril Global Endpoint Trial (ONTARGET) trial11 have
shown an association between the higher levels of urinary
potassium (a marker of K+ intake) and lower rates of stroke
independent of BP. Further, as the dose of thiazide is increased
in the polycap, there may be greater K+ loss (although higher
doses of ramipril and β-blockers might counteract this) and,
therefore, K+ supplementation, if well tolerated, may be useful.
Therefore, the TIPS-2 study tested a single dose of low-
strength polycap (plus an equivalent placebo) versus 2 doses
of the low strength of polycap and potassium tablets in indi-
viduals with multiple risk factors or stable CVD. The study
evaluated the incremental reductions in risk factors and tolera-
bility of 2 doses of low-strength polycap (hereafter termed full
dose) and the tolerance/safety of potassium supplementation.
Study Design and Population
Between April 1, 2010, and September 18, 2010, 725 patients, who
were 40 years or older with a seated BP≥130/80 mm Hg on 2 con-
secutive occasions (or BP≥120/80 mm Hg on antihypertensive drugs)
and vascular disease or high-risk diabetes mellitus (HbA1c<7.5%,
with microalbuminuria or BP>140/90 mm Hg), were eligible.
Patients with known intolerance to, or a clear indication for any of the
study drugs, planned or recent coronary intervention or surgery, re-
nal dysfunction (serum creatinine>2 mg/dL [176.8 µmol/L] or serum
K>5.0 mEq/L or estimated glomerular filtration rate<45 mL/min/1.73
m2), or inability to attend follow-up visits were excluded. All indi-
viduals provided written informed consent and then entered a run-in
phase where they initially received 1 capsule of the low-dose polycap
(acetylsalicylic acid or aspirin, 100 mg; simvastatin, 20 mg; atenolol,
50 mg; ramipril, 5 mg; hydrochlorothiazide, 12.5 mg) for 10 days, fol-
lowed by 2 capsules of the polycap (full strength) for another 10 days
(n=645). Of these 645 individuals, 518 entered the randomized phase
of the trial comparing low-dose polycap versus full-dose polycap plus
potassium (Figure 1).
Patients were recruited from 27 clinical centers in India. The co-
ordinating centers were located at the Division of Clinical Trials, St.
John’s Research Institute, Bangalore, India, and at the Population
Health Research Institute, Hamilton Health Sciences and McMaster
University, Canada. The protocol was approved by the respective eth-
ics committee or research ethics boards and regulatory authorities.
A total of 518 patients were randomized (using a central computer-
ized system) to receive 2 capsules (full dose) of the low-dose polycap,
each containing simvastatin 20 mg, ramipril 5 mg, atenolol 50 mg, hy-
drochlorthiazide 12.5 mg, and aspirin 100 mg, or one polycap plus
equivalent placebo. Patients were instructed to take both capsules
together and at the same time every day. Those allocated to potas-
sium received 30 mEq/L once daily supplements in an open fashion;
the original design was to randomize patients using a 2 × 2 factorial
design. However, because of an error in programming, all partici-
pants randomized to the full-dose polycap also received K+, whereas
nobody in the low-dose polycap group received K+ (see online-only
Data Supplement). This error in programming in randomization was
discovered only at the end of the study, and so all investigators at the
sites or the coordinating centers were unaware of this during the con-
duct of the study, thereby maintaining the study blind. Given that the
polycap dose comparisons were placebo controlled and double blind,
whereas the K+ supplementation was open, investigators ascribed ad-
verse events to each component separately based on their judgment.
HR, sitting BP in the right arm (using an automated instrument
with an average of 2 readings after 5 minutes and 7 minutes of rest),
tolerability, and compliance were assessed at each visit (screening,
first post–run-in visit, second run-in visit, at the randomization visit;
2 weeks ± 6 days, 4 weeks ± 6 days, 8 weeks ± 6 days postrandom-
ization, and after 4 weeks ± 6 days of washout). Advice on healthy
lifestyles was provided at each visit, and the quality of diet was as-
sessed at randomization and at 8 weeks. Lipid levels, serum creati-
nine, potassium, and liver function tests were done at the initial visit,
randomization, and at 8 weeks postrandomization. Serum creatinine
was also assessed at 2 weeks postrandomization. Fasting blood glu-
cose, urinary microalbuminuria, urinary, and serum K+ were obtained
at screening and at 8 weeks postrandomization.
Lipids were measured in a central laboratory on fasting blood
samples. Low-density lipoprotein (LDL)-cholesterol was measured
with a direct enzymatic photocolorimetric assay (Roche Hitachi
912 analyzer with LDL cholesterol second-generation kits; Roche
Diagnostics, Mannheim, Germany). The coefficient of variation of
the assay was <4% with a measurement range of 0.1 to 14.5 mmol/L
(3–561 mg/dL) and an analytic sensitivity of 0.08 mmol/L (3 mg/dL).
Sample Size, Power, and Statistical Analyses
Using information from the TIPS-1 study, we estimated that 500 pa-
tients randomized equally to 2 groups would provide 90% power to
detect differences of 2.4 mm Hg in diastolic BP, 3.4 mm Hg in sys-
tolic BP, and 9.7 mg/dL in LDL cholesterol.
Comparisons of the impact on BP, HR, and lipids were based on an
intention-to-treat approach using the randomization values (at which
time participants were on full-dose polycap) as the baseline measure
(as the most sensitive analysis of the subsequent differences between
the 2 doses). A repeated measures model (incorporating the BP values
by guest on December 27, 2015http://circoutcomes.ahajournals.org/
WHAT IS KNOWN?
•? Reducing cardiovascular risk factors, including
blood pressure and cholesterol, remains a critically
important strategy for reducing the global burden of
•? A polypill combining generic hydrochlorothiazide
(12.5 mg), atenolol (50 mg), ramipril (5 mg), simvas-
tatin (20 mg), and aspirin (100 mg) has been shown
to reduce blood pressure and cholesterol in patients
with vascular disease.
WHAT THIS ARTICLE ADDS
•? A randomized trial of providing 2 polypills to 257 sub-
jects, along with potassium supplementation (30 mEq),
resulted in further blood pressure reduction (mean sys-
tolic reduction of 2.8 mm Hg and diastolic reduction
of 1.7 mm Hg; 95% CI, –0.17 to –2.8 mm Hg) and
low-density lipoprotein cholesterol (adjusted differ-
ence, –7.2 mg/dL; 95% CI, –1.5 to –12.9 mg/dL), com-
pared with a single polypill provided to 261 subjects.
•? No significant difference in heart rate, high-density
lipoprotein, or triglycerides was observed.
•? The polypill regimens were similarly tolerated with
11.9% and 14% of the low- and high-dose groups
stopping the study medication for some period dur-
ing the 8 weeks of medication exposure.
1. Randomization schedules for factorial designs are generated and tested at the level of the
factorial cells, not at the margin.
2. The check list for review of all randomization schedules instructs the reviewer to ensure that
all random keys used are unique.
3. Requirement for mandatory and early checks of the implementation of the randomization
schedules for all trials, even if no DSMB exists for that study. All trials will have the randomized
allocations examined early in the trial and throughout its recruitment phase.
These processes and checks will ensure that the randomization schedule is being followed as
planned and that the appropriate allocation ratio is being implemented in the study. We are
committed to learning from our errors and improving our processes to consistently achieve high
quality randomized controlled trials. Hopefully, others can learn from our failings and adopt
similar quality assurance procedures in producing randomization schedules for their trials.
Salim Yusuf, Prem Pais, Alben Sigamani, Denis Xavier, Rizwan Afzal, Peggy Gao and Koon K.
Cardiovascular Diseases: The Second Indian Polycap Study (TIPS-2) Investigators
Potassium) Versus Low-Dose Polypill (Polycap) in Individuals at High Risk of
Comparison of Risk Factor Reduction and Tolerability of a Full-Dose Polypill (With
Print ISSN: 1941-7705. Online ISSN: 1941-7713
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2012;5:463-471; originally published online July 10, 2012;
Circ Cardiovasc Qual Outcomes.
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