Strengths and Limitations of Using the Polypill in Cardiovascular Prevention
Curr Cardiol Rep
Strengths and Limitations of Using the Polypill in Cardiovascular Prevention
Ambuj Roy 0 1
Nitish Naik 0 1
K. Srinath Reddy 0 1
0 Public Health Foundation of India, Delhi National Capital Region , Plot No. 47, Sector 44, Institutional Area, Gurugram 122002 , India
1 President, Public Health Foundation of India , New Delhi , India
Purpose of Review Polypill and its role in cardiovascular disease (CVD) prevention has been extensively discussed and debated since the inception of the concept in 2003. This article reviews the subsequent accumulated research in this area. Recent Findings Several short and intermediate to long-term studies with different brands of polypills have analysed the impact of polypill in phase II and III trials. The strengths of polypill that have emerged include better adherence, equivalent or better risk factor control and quality of life among polypill users as compared to usual care. The lurking limitations include difficulty with dose adjustment to targets, fear of mass medicalisation and low acceptability among physicians. Summary The current literature supports polypill use in reducing blood pressure and cholesterol levels for CVD prevention with improvement in adherence to medication. However, the long-term outcome of polypill on CVD events and mortality are unavailable and are currently being studied in clinical trials.
Polypill; Fixed dose combination; Cardiovascular diseases; Adherence; Secondary prevention; Primary prevention
The concept of polypill or a fixed drug combination (FDC)
was proposed, to reduce cardiovascular burden, rather
dramatically in a much cited paper by Wald and Law in the year 2003
. They proposed that this polypill comprising of six drugs
(aspirin, statin, beta-blocker, angiotensin converting enzyme
(ACE) inhibitor, diuretic and folic acid) could reduce burden
of cardiovascular disease (CVD) by 80% when taken by all
above the age of 55 years and those with CVD. The concept
was based on research accumulated over years on the benefit
of blood pressure lowering, cholesterol lowering and
antiplatelet drugs in reducing CVD morbidity and mortality.
Over the last decade or so the story of the polypill has
progressed with both successes and disappointments [2 ].
This review discusses the potential role of polypharmacy,
the current state of research, strengths and limitations and
the future directions that we foresee for the polypill.
Importance of Polypharmacy in CVD Prevention
CVD is the leading cause of mortality worldwide . This is
true of both the developed world and most of the developing
countries. While CVD burden is declining in the developed
countries, it is on the rise in developing countries with 80% of
the burden projected to be in the lower and middle income
countries (LMIC) by 2020 .
All current guidelines recommend aspirin and high dose
statins for patients with established cardiovascular disease
[5, 6]. In addition most patients with CVD are advised beta
blockers and ACE inhibitors as class I or IIA indication unless
specifically contraindicated . Modelling and nested case
control studies have shown that this combination
pharmacotherapy leads to a 75% reduction in mortality in
patients with established CAD .
In patients without CVD, the strength of evidence for
polypharmacy is not well established. While the benefits of
management of individual risks like hypertension,
dyslipidemia are well documented general use of aspirin, and statins
remains controversial. Aspirin trials for primary prevention
reduce non-fatal MI but have little impact on mortality, while
consistently causing increase in risk of bleeding . Similarly,
the utility/efficacy of statin for primary prevention is not well
established. Two large primary prevention trials did show
benefit of use of rosuvastatin in reducing cardiovascular outcomes
in individuals without CVD [9, 10]. However, they used a
biomarker or clinical risk identifier to include at risk
individuals to administer statin. Similarly, appropriate risk
stratification strategy to identify high risk individuals for primary
prevention with polypill needs to be tested before adopting it.
This could be based on clinical scores  or novel
investigations like calcium score, which has been claimed by authors
in a modelling paper, to substantially bring down the number
to treat (NNT)  as compared to basing it only on age as
proposed by Wald and Law.
Summary of Current Research
The last decade has witnessed development of multiple
polypills, with varying constituents, which have been tested
in different trials. The polypills considered here for CVD
prevention are those with at least one anti-hypertensive in
addition to aspirin and statin. A list of these polypills studied or
marketed is documented in Table 1.
List of currently available polypills for research and clinical use
These polypills have been studied in numerous research
trials in comparison to placebo or usual care. These clinical
trials have measured adherence rates, adverse events and risk
factor control. None of these trials have enough power to test
the impact of polypill on clinical outcomes. These are
summarised in Table 2, and the different aspects of the trial
are discussed below.
One of the formidable challenges in management of CVD is
the requirement of adherence to medications over a long
duration, sometimes life-long, in individuals who may be
asymptomatic and thus the immediate benefits of therapy
may not be perceived by them. The polypill is conceptualised
to reduce pill burden and thus improve adherence. This was
confirmed both in the short-term and intermediate to
longterm studies done so far. Two short-term studies of 12 weeks
comparing polypill to placebo revealed high adherence rates
to polypill which was equivalent to placebo suggesting that
adherence, at least in the short term, seems related to the pill
count and not the constituents of the polypill [13, 14]. The
three intermediate to long term studies of over 12 months:
UMPIRE Trial , Kanyini GAP  and IMPACT 
clearly demonstrated higher adherence in the polypill arm. A
meta-analysis of four studies in patients with CVD or at
highrisk for CVD demonstrated 44% higher adherence rates
among polypill users as compared to usual care [22 ]
(Fig. 1). The individual participant data analyses from
Ferrer Internacional, Spain
Ferrer Internacional, Spain
Cadila Pharmaceuticals Ltd., India
Dr. Reddy’s Laboratories,India
Dr. Reddy’s Laboratories, India
a In Germany, named Sincronium® and manufactured by Hexal
b No brand name given
Adapted from [2 ]
SPACE suggested that participants with low adherence at
baseline had the highest improvement in adherence (17% at
baseline to 74%at trial end (relative risk [RR] = 4.46 [95% CI:
3.72 to 5.36]), compared with participants who were already
adherent at baseline (86 to 90%; RR = 1.04[95% CI; 1.01 to
1.07] . Interestingly, the individuals without clinical CVD
had a better risk ratio of adherence on polypill than usual care
(2.12 vs. 1.4, p < 0.001) as compared to those with CVD in the
SPACE study [20 ]. The adherence rates also seem to be
better with polypill with time as seen in the FOCUS trial
. The adherence rates in the usual care and polypill arm
at 1 month being 54.8 and 59%, respectively, with the
difference increasing to 55.7 and 65.7%, respectively, at 9 months.
Thus from available data, it seems that the polypill improves
adherence rates, more so in otherwise poorly compliant
groups like those with poor baseline compliance, high risk
cases on primary prevention and in subjects on long term
Quality of Life
The UMPIRE study showed that EQ-5D visual analog scale
score was significantly higher in the polypill group (2.43; 95%
CI, 0.87–3.99; p = .002) as compared to the usual care group
indicating better patient perceived health on polypill .
However, the same test was not different in Kanyini-GAP
study which could be due to the small sample size of this study
. Similarly, the third study with the Red Heart Pill, the
IMPACT trial, did not reveal any difference in the QOL
between groups but it did reveal that the polypill patients found
their medication regime ‘very easy’ (53% of polypill patients
compared to 46% of usual therapy patients) . This was
also supported in the short-term Red Heart Pill study, where
the polypill was preferred over usual care in 92% of patients in
the TEMPUS trial .
Fig. 1 Percentage of adherent
patients to the polypill and the
comparator group in the various
trials and the overall group. The
relative risk and the 95%
confidence interval of each
comparison is mentioned above
the bars [22 ]
Cardiovascular Risk Factor Control
Polypill combines multiple drugs within one tablet/capsule.
While it is one thing to know the right pharmacological agents
for primary and secondary prevention of CVD, it is important to
be sure of the physico-chemical compatibilities of these agents
within a combination pill. It is very important to conserve the
biopharmaceutical and pharmacokinetic properties of every one
of its components to have the desired pharmacodynamic effects
needed for control of the targeted risk factor. In this context
again there have been several studies both short-term phase II
studies and clinical trials in real world settings. The
meticulously designed TIPS-1 study was a phase II study to assess the
effect of five drug polypill (Aspirin 100 mg, simvastatin 20 mg,
ramipril 5 mg, hydrochlorthiazide 12.5 mg and atenolol 50 mg)
against eight groups comprising of aspirin alone, simvastatin
alone, hydrochlorthiazide alone, three combinations of the two
blood-pressure-lowering drugs, three blood-pressure-lowering
drugs alone or three blood-pressure-lowering drugs plus aspirin
. The study revealed that at the end of 12 weeks, the blood
pressure effect and the change in11-dehydrothromboxane B2, a
surrogate for aspirin effect, were similar in polypill and other
groups. The blood pressure lowering effect increased as the
number of drugs increased being 2.2/1·3 mm Hg with one
drug, 4.7/3·6 mmHg with two drugs and 6.3/4·5 mmHg with
three drugs and 7.4/5.5 mmHg with the polypill. The reduction
in 11-dehydrothromboxane B2 were similar with the polypill
(283·1 ng/mmol creatinine, 95% CI 229·1–337·0) compared
with the three blood-pressure-lowering drugs plus aspirin
(350·0 ng/mmol creatinine, 294·6–404·0), and aspirin alone
(348·8 ng/mmol creatinine, 277·6–419·9). However, the
reduction in LDL cholesterol was lower with polypill; 0·70 mmol/L
(95% CI 0·62–0·78) vs. 0·83 mmol/L (0·72–0·93; p = 0·04)
seen with simvastatin alone; with both reductions being greater
than for groups without simvastatin (p < 0·0001). The drug
discontinuity rate of polypill was similar to that of other
treatments, with no evidence of increasing intolerance with
increasing number of active components in one pill .
Another randomised double-blind placebo-controlled
crossover trial conducted by Wald et al. revealed higher blood
pressure reduction and LDL cholesterol reduction which was
closer to the predicted changes suggested in the early papers
on polypill. This polypill comprised of amlodipine 2.5 mg,
losartan 25 mg, hydrochlorothiazide 25 mg and simvastatin
40 mg and led to a reduction in systolic blood pressure of
17.9 mmHg (95% CI, 15.7–20.1); diastolic blood pressure
of 9.8 mmHg (95% CI, 8.1–11.5) and LDL cholesterol of
54.1 mg/dl (95% CI, 46.4 mg/dl −61.9 mg/dl) as compared
to placebo. The larger effect was probably due to choice and
dose of anti-hypertensives, higher dose of simvastatin and
cross-over design of the trial .
Early polypill trials in clinical settings comparing polypill
to usual care like IMPACT , TEMPUS  and
KanyiniGAP  did not observe any significant difference between
the two groups in terms of BP and LDL cholesterol reduction
despite reduced pill counts and improvement in adherence.
However, most of these were small studies without sufficient
statistical power to detect this benefit. The larger UMPIRE
Trial demonstrated better blood pressure and cholesterol
lowering throughout the study with end of study SBP and
LDLC being 2.6 mmHg and 4.2 mg/dl, respectively, lower in the
polypill arm . These findings were corroborated by
SPACE meta-analysis which revealed 2.5 mmHg lower
SBP and 3.5 mg/dl lower LDL-cholesterol in polypill
arm [20 ].
Thus, the polypill seems to be working better than usual
care for risk factor control. Further refinement in the choice of
anti-hypertensives and use of more potent statins in the future
iterations would lead to even better results.
Titration of Doses
Clinicians by training are taught to titrate dosages to ‘treat to
target’ various risk factors. The key worry for most
practitioners has been the inconvenience of dose adjustments with
a polypill. The lack of ability to fine tune one component of
the polypill if the therapeutic goals are not reached is a
constant concern. However, the more recent guidelines have
shifted to risk-based treatment for lipids irrespective of
baseline cholesterol levels , and others have advocated the
same for blood pressure . This approach was tested for
intermediate risk individuals without CVD in the HOPE-3
trial. The study included men above 55 years and women
above 65 years with one additional cardiovascular risk factor.
In a 2 × 2 factorial design individuals received rosuvastatin
10 mg/day or placebo and fixed combination of candesartan
(16 mg per day) and hydrochlorothiazide (12.5 mg per day) or
placebo. The trial demonstrated that individuals on dual
therapy versus those on dual placebo had a 29% reduction (hazard
ratio, 0.71; 95% confidence interval [CI], 0.56 to 0.90;
p = 0.005) in death from cardiovascular causes, non-fatal MI
and non-fatal stroke. While the lipid lowering arm had 24%
reduction (hazard ratio, 0.76; 95% confidence interval [CI],
0.64 to 0.91; p = 0.002) in the combined end point, the benefit
in the blood pressure lowering arm was restricted to the top
tertile with SBP above 143.5 mmHg .
Impact of Drug Intolerance
The other concern with polypill has been that a side-effect of
any one of the components can lead to discontinuation of all
drugs. A Cochrane review revealed that discontinuation rates
were 26% (95% CI 1.02 to 1.55) higher in participants who
were randomised to polypill  but comparator groups
included participants receiving usual care and placebo.
However, the long-term studies showing better risk factor
control suggests that this increased discontinuation was offset
by other advantages of polypill including better adherence.
Low Acceptability among Physicians
The buzz over polypill has now been around for several years.
The studies with polypill have also been published, and in
some countries like India it has been available in store;
however, its use has not picked up. Polypills with more than two
drugs have not picked up commercially, and the reasons for
this need to be explored.
The other concern of polypill, since the first paper by Wald
and Law on treating everyone above 50 years of age, was the
mass medicalisation of the population. This would lead to
rapid escalation in numbers qualifying to receive polypill.
Another feared fallout of this approach is the poor compliance
and non-adherence to life-style advice among polypill users.
However, this is not borne out in the available clinical trials. In
the UMPIRE Trial, the lifestyle changes were similar in the
polypill group and the usual care group and showed
improvement from baseline .
The polypill has been an area of active research over the last
decade as was discussed above. However, none of the studies
performed so far were powered to detect the impact of polypill
on cardiovascular events and mortality. The meta-analysis by
SPACE collaborators revealed similar fatal and non-fatal
cardiovascular outcomes during follow-up (5.9% in polypill and
4.8% usual care arm, p = 0.18). The all cause (1.6 vs. 1.8%,
p = 0.59) and cardiovascular mortality (1.1 vs. 0.8%, p = 0.27)
in the polypill and usual care arm, respectively, were also
similar [20 ]. Ongoing studies with larger patient population
and longer follow-up like TIPS-3 , SECURE trial  and
PolyIran trial  may be able to address this question and
tease out the difference between these two approaches in the
future. Importantly, the TIPS-3 trial is a purely primary
prevention trial in medium to high risk individuals and thus will
help understand the role of polypill in subjects without CVD.
The study employs a 2 × 2 × 2 factorial design testing whether
polypill compared to placebo leads to prevention of
cardiovascular death, stroke and MI in male participants aged over
55 years and female participants over 60 years and
INTERHEAT risk score above 10. The study would recruit
5000 subjects from ten different countries and follow up for
about 5 years . The SECURE trial on the other hand is a
secondary prevention trial and will assess the potential of the
polypill to prevent major cardiovascular events in 3206
elderly patients (aged >65 years) with recent MI, stroke or coronary
revascularisation over a minimum period of 2 years . The
third large trial is the PolyIran trial being conducted
exclusively in a developing country to assess the role of polypill in
primary and secondary prevention. The study is expected to
enrol 7000 participants over 50 years of age and follow them
up over 5 years to document time elapsed before the first
cardiovascular event .
The polypill, especially in primary prevention, also needs
to be tested against a multi-component life-style intervention
(Poly-lifestyle) like regular physical activity, healthy diet and
optimum body weight to see their respective roles in
preventing cardiovascular events. While the two approaches
may not be mutually exclusive, it may be worthwhile testing
the benefits of the two interventions in isolation and
Customisation of the Polypill
The lack of enthusiasm after the initial hype for the
prescription of the polypill even in countries where it is widely
available, like India, could be due to lack of customisation of the
CVD drugs for individual patients. A common polypill for all
CVD prevention subsets is probably viewed as a shotgun
approach by practitioners. There may thus be a need for
customisation of the polypill into broad categories like those
for CHD, stroke and high risk primary prevention. The
polypill for secondary prevention among stroke patients has
little basis for beta-blocker as one of the constituents. The
polypill in this case should have aspirin, statin with diuretic
or ACE inhibitors or both depending on the baseline blood
pressure level . The polypill for CAD could include
aspirin, high dose potent statin, ACE inhibitors and beta-blockers.
The polypill should be customised for high risk primary
prevention based on baseline blood pressure levels in the light of
the HOPE-3 blood pressure lowering trial, which showed
benefit of blood pressure reduction only in the individuals in the
highest tertile with high blood pressure . Similarly, in
these patients polypill with and without aspirin should be
available to guide therapy based on individual risk of patients.
In summary, a choice of four to six polypills instead of one, for
different subsets of patients, may improve uptake of polypill
prescription among physicians.
Incorporation in the Health System
World Health Organisation has outlined nine targets for
reducing premature mortality from non-communicable diseases by
25% by 2025. Two of these directly relate to pharmacotherapy
in (i) ensuring at least 50% of eligible people receive drug
therapy to prevent heart attack and stroke and (ii) 80%
availability of the affordable essential medicines, including
generics, required to treat major NCDs in both public and private
facilities . However, the PURE study revealed that less
than 50% of patients with CVD in high income countries
and less than 10% of patients in low income countries
received the three or more proven effective drugs for secondary
prevention . The reasons for this poor rates of therapy was
both non-availability and unaffordability of these medicines in
upper middle-income, lower middle-income and low-income
countries . The polypill is thus well suited to fill this void
and provide alternative cardiovascular preventive therapeutic
strategy as the current mode of administering secondary
prevention does not seem to be working. The affordability and
availability of these medicines could be improved by
providing them through a publically financed or subsidised universal
health coverage programme. Large scale-pooled public
procurement of the drug could help substantially drive down the
In its journey of the past decade, the polypill has travelled
from a hyped concept to attaining acceptability in the
competitive world of pharmacotherapeutics. The available studies do
seem to favour the polypill in terms of improving adherence
and reducing the cardiovascular risk burden of high blood
pressure and dyslipidemia. The extent of its impact on major
cardiovascular events would become evident in the near future
through large trials with outcome endpoints. If positive, this
would probably increase its acceptability among physicians
and health administrators to unreservedly accept it in their
armamentarium to fight the mounting burden of CVD. In the
meanwhile, strategies to prevent CVD through improved
behaviours and judicious use of available drugs must be
implemented effectively through an efficient health system. The
polypill can fit well in to such a system but cannot substitute
Compliance with Ethics Guidelines
Conflict of Interest Ambuj Roy, Nitish Naik, and K. Srinath Reddy
declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Open Access This article is distributed under the terms of the Creative
C o m m o n s A t t r i b u t i o n 4 . 0 I n t e r n a t i o n a l L i c e n s e ( h t t p : / /
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
Papers of particular interest, published recently, have been
Of major importance
1. Wald NJ , Law MR . A strategy to reduce cardiovascular disease by more than 80% . BMJ. 2003 Jun 28 ; 326 ( 7404 ): 1419 .
2. Bramlage P , Sims H , Minguet J , Ferrero C. The polypill: an effective approach to increasing adherence and reducing cardiovascular event risk . Eur J Prev Cardiol . 2017 ; 24 ( 3 ): 297 - 310 . This paper provides a comprehensive review of studies on polypill and their impact on adherence . It also summarises ongoing trials of polypill
3. GBD 2015 . Mortality and causes of death collaborators . Global , regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the global burden of disease study 2015 . Lancet. 2016 ; 388 ( 10053 ): 1459 - 544 .
4. Reddy KS . Cardiovascular disease in non-western countries . N Engl J Med. 2004 Jun 10 ; 350 ( 24 ): 2438 - 40 .
5. Piepoli MF , Hoes AW , Agewall S , Albus C , Brotons C , Catapano AL , et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the European Society of Cardiology and Other Societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & rehabilitation (EACPR) . Eur Heart J . 2016 ; 37 ( 29 ): 2315 - 81 .
6. Smith SC , Benjamin EJ , Bonow RO , Braun LT , Creager MA , Franklin BA , et al. AHA/ ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update . Circulation . 2011 ; 124 ( 22 ): 2458 - 73 .
7. Hippisley-Cox J , Coupland C. Effect of combinations of drugs on all cause mortality in patients with ischaemic heart disease: nested case-control analysis . BMJ . 2005 ; 330 ( 7499 ): 1059 - 63 .
8. Østergaard L , Fosbøl EL , Roe MT . The role of antiplatelet therapy in primary prevention . A review. Curr Pharm Des . 2016 Dec 5. [Epubahead of print] doi:10.2174/1381612822666161205115540
9. Ridker PM , Danielson E , Fonseca FAH , Genest J , Gotto AM , Kastelein JJP , et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein . N Engl J Med . 2008 ; 359 ( 21 ): 2195 - 207 .
10. Yusuf S , Lonn E , Pais P , Bosch J , López-Jaramillo P , Zhu J , et al. Blood-pressure and cholesterol lowering in persons without cardiovascular disease . N Engl J Med . 2016 ; 374 ( 21 ): 2032 - 43 .
11. Bittencourt MS , Blaha MJ , Blankstein R , Budoff M , Vargas JD , Blumenthal RS , et al. Polypill therapy, subclinical atherosclerosis, and cardiovascular events-implications for the use of preventive pharmacotherapy . J Am Coll Cardiol . 2014 ; 63 ( 5 ): 434 - 43 .
12. Selak V , Elley CR , Bullen C , Crengle S , Wadham A , Rafter N , et al. Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: randomised controlled trial in primary care . BMJ . 2014 ; 348 :g 3318.
13. PILL Collaborative Group , Rodgers A , Patel A , Berwanger O , Bots M , Grimm R , et al. An international randomised placebo-controlled trial of a four-component combination pill (“polypill”) in people with raised cardiovascular risk . PLoS One . 2011 ; 6 ( 5 ): e19857 .
14. Wald DS , Morris JK , Wald NJ . Randomized polypill crossover trial in people aged 50 and over . PLoS One . 2012 ; 7 ( 7 ): e41297 .
15. Indian Polycap Study (TIPS), Yusuf S , Pais P , Afzal R , Xavier D , Teo K , et al. Effects of a polypill (polycap) on risk factors in middleaged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial . Lancet . 2009 ; 373 ( 9672 ): 1341 - 51 .
16. Yusuf S , Pais P , Sigamani A , Xavier D , Afzal R , Gao P , et al. 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 . Circ Cardiovasc Qual Outcomes . 2012 ; 5 ( 4 ): 463 - 71 .
17. Lafeber M , Grobbee DE , Schrover IM , Thom S , Webster R , Rodgers A , et al. Comparison of a morning polypill, evening polypill and individual pills on LDL-cholesterol, ambulatory blood pressure and adherence in high-risk patients; a randomized crossover trial . Int J Cardiol . 2015 ; 181 : 193 - 9 .
18. Thom S , Poulter N , Field J , Patel A , Prabhakaran D , Stanton A , et al. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial . JAMA . 2013 ; 310 ( 9 ): 918 - 29 .
19. Patel A , Cass A , Peiris D , Usherwood T , Brown A , Jan S , et al. A pragmatic randomized trial of a polypill-based strategy to improve use of indicated preventive treatments in people at high cardiovascular disease risk . Eur J Prev Cardiol . 2015 ; 22 ( 7 ): 920 - 30 .
20. Webster R , Patel A , Selak V , Billot L , Bots ML , Brown A , et al. Effectiveness of fixed dose combination medication ('polypills') compared with usual care in patients with cardiovascular disease or at high risk: a prospective, individual patient data meta-analysis of 3140 patients in six countries . Int J Cardiol . 2016 ; 205 : 147 - 56 . This is a recent meta-analysis encompassing data from largest number of patients from clinical trials on polypill
21. Castellano JM , Sanz G , Peñalvo JL , Bansilal S , Fernández-Ortiz A , Alvarez L , et al. A polypill strategy to improve adherence: results from the FOCUS project . J Am Coll Cardiol . 2014 ; 64 ( 20 ): 2071 - 82 .
22. Huffman MD . THe polypill: from promise to pragmatism . PLoS Med . 2015 ; 12 ( 8 ) :e1001862. A recent review on polypill that suggests steps to improve the acceptability and use of polypill .
23. Stone NJ , Robinson JG , Lichtenstein AH , Bairey Merz CN , Blum CB , Eckel RH , et al. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines . Circulation.
2014 ; 129 ( 25 Suppl 2 ): S1 - 45 .
Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data . Lancet . 2014 ; 384 ( 9943 ): 591 - 8 .
Blood-pressure lowering in intermediate-risk persons without cardiovascular disease . N Engl J Med . 2016 ; 374 ( 21 ): 2009 - 20 .
de Cates AN , Farr MRB , Wright N , Jarvis MC , Rees K , Ebrahim S , et al. Fixed-dose combination therapy for the prevention of cardiovascular disease . Cochrane Database Syst Rev . 2014 ; 4 : CD009868 .
The International Polycap Study 3 (TIPS-3) - Full Text ViewClinical Trials .gov [Internet]. 2017 [ cited 2017 Jan 19] . Available from: https://clinicaltrials.gov/ct2/show/ NCT01646437 Secondary Prevention of Cardiovascular Disease in the Elderly Trial-Full Text View-ClinicalTrials .gov [Internet]. [cited 2017 Jan 18] . Available from: https://clinicaltrials.gov/ct2/show/ NCT02596126?term= NCT02596126&rank=1 29.
Ostovaneh MR , Poustchi H , Hemming K , Marjani H , Pourshams A , Nateghi A , et al. Polypill for the prevention of cardiovascular disease (PolyIran): study design and rationale for a pragmatic cluster randomized controlled trial . Eur J Prev Cardiol . 2015 ; 22 ( 12 ): 1609 - 17 .
Kernan WN , Ovbiagele B , Black HR , Bravata DM , Chimowitz MI , Ezekowitz MD , et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack . Stroke . 2014 ; Stroke. 2014 ; 45 ( 7 ): 2160 - 236 .
WHO | About 9 voluntary global targets [Internet] . WHO. [cited 2017 Jan 19] . Available from: http://www.who.int/nmh/ncd-tools/ definition-targets/en/ Yusuf S, Islam S , Chow CK , Rangarajan S , Dagenais G , Diaz R , et al. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE study): a prospective epidemiological survey .
Lancet. 2011 ; 378 ( 9798 ): 1231 - 43 .