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Primary prevention using a polypill

Protection against myocardial infarction?


Summary

The polypill, a combination therapy to prevent cardiovascular diseases like myocardial infarction, does not yet appear to be a wonder drug. Research into primary prevention using a polypill for patients at low risk of cardiovascular diseases has not unequivocally shown a positive effect. The adverse effects have not been sufficiently documented, so it is as yet impossible to conclude that the potential favourable effect of such a polypill balances out the adverse consequences for patients.


What is Ge-Bu’s opinion?
  • The primary focus in the prevention of cardiovascular diseases remains the reduction of risk factors, for instance by giving up smoking, or reducing body weight in case of overweight.
  • The concept of polypills involves the preventive treatment of all people aged 55 years or over who have no other risk of cardiovascular disease, using a polypill containing a statin and an antihypertensive agent, and sometimes an antiplatelet agent.
  • The question whether a polypill is effective for the primary prevention of myocardial infarction can not yet be answered, as research has not unequivocally shown a positive effect.
  • A polypill does have adverse effects, and it is as yet unclear whether the favourable effects balance out the discomfort patients experience from the adverse effects. 
  • There is no reason to recommend the use of a polypill for the primary prevention of cardiovascular diseases in individuals who may or may not be at elevated cardiovascular risk.

In 2003, Wald and Law coined the term ‘polypill’ for a strategy to prevent cardiovascular diseases. They proposed a pill combining a statin, three antihypertensive agents, folic acid and acetylsalicylic acid in a fixed dosage. Wald and Law assumed that age was the main risk factor for cardiovascular events, so this combination of drugs could be used for any individual aged 55 years or over, regardless of their blood pressure or their cholesterol level.1 

The polypill was not only intended as secondary prevention for patients who had had a myocardial infarction, a stroke or a TIA, but also as primary prevention for patients with diabetes mellitus without cardiovascular comorbidity, and even for healthy people. Folic acid was added at the time, based on the idea that this would lower the concentration of the risk marker homocysteine. It was later found that folic acid had no effect on cardiovascular disease.2 The use of acetylsalicylic acid for primary prevention is also controversial because of the risk of haemorrhage.3
In later years, more evidence was found for the effectiveness of a combination of a beta blocker, a renin-angiotensin-aldosterone system (RAAS) inhibitor, a cholesterol lowering agent and an antiplatelet agent, for the secondary prevention of myocardial infarction.4 The evidence for an effect in cases of transient ischaemic attack (TIA) and stroke is less robust.5,6,7 Starting from Wald and Law’s theory, the question is whether a polypill could also be effective at an earlier stage, as a primary prevention of cardiovascular disease. The present Ge-Bu article uses myocardial infarction as the clinical endpoint, in view of the definition used in the studies and the relative robustness of the diagnosis (compared to, e.g., a stroke diagnosis).


A recently published study, the TIPS-3 trial, investigated the efficacy of a polypill containing a cholesterol lowering agent and an antihypertensive agent for primary prevention of cardiovascular diseases.8 In addition, some randomized studies into the effectiveness of a polypill has previously been published.9,10,11

Like the TIPS-3 study, the PolyIran and HOPE-3 studies included participants over the age of 50, some of whom had an elevated cardiovascular risk profile. Two smaller studies were included in a Cochrane review, but these were too small for evaluation, and offer no clear answers.11 More information about the Cochrane meta-analysis can be found in the Background Information below.

The present article discusses the TIPS-3 study, the HOPE-3 study and the PolyIran study. The discussion is based on the concept proposed by Wald and Law, the starting question being how effective a polypill is for the primary prevention of myocardial infarction. However, these studies included patients with a higher baseline risk than those in Wald and Law’s proposal.

The TIPS-3 study

The randomised, double-blind TIPS-3 trial investigated the efficacy of a polypill compared with that of a placebo, for primary prevention in patients with a moderately elevated cardiovascular risk profile.8 The main research question was subdivided into three subsidiary questions:

  • What is the efficacy of a polypill relative to placebo?
  • What is the efficacy of acetylsalicylic acid relative to placebo?
  • What is the efficacy of a polypill with acetylsalicylic acid relative to (dual) placebo?

The polypill used in this study contained 40 mg simvastatin, 100 mg atenolol, 25 mg hydrochlorothiazide and 10 mg ramipril. Acetylsalicylic acid was administered at a dose of 75 mg. The primary outcome measure was the incidence of cardiovascular events.

The trial included 5,713 participants from nine middle- and low-income countries. Most of the participants were from India and the Philippines. Potential participants were men aged 50 years or over and women aged 55 years or over. The participants had a slightly elevated cardiovascular risk profile, as indicated by an ‘Interheart Risk Score’[ A validated score (0–48) based on, e.g., age, sex, body weight, physical activity, medical history, etc. A higher score means a higher cardiovascular risk. ] above ‘intermediate’ (usually based on mild hypertension, smoking or diabetes).12 Persons with stomach complaints were excluded.
The trial started with a 4-week run-in period, in which all participants received a low-dose version of a polypill (half doses except for the simvastatin), combined with acetylsalicylic acid. Almost a quarter of the participants dropped out prematurely, mostly because of adverse effects (especially hypotension with dizziness and fainting) and lack of compliance compliance. The remaining 5,713 patients (average age 63.9 years, 53% women) had an average BMI of 26 kg/m2 and an average blood pressure of 145/84 mm Hg. These participants were randomised to four treatment regimens: 1,432 participants received a polypill and a placebo, 1,429 participants received a polypill and acetylsalicylic acid, 1,431 participants received acetylsalicylic acid and a placebo, and 1,421 participants received two placebos. Each participant was also given advice about healthy behaviour, and was monitored for adverse effects and serious cardiovascular incidents, like death, stroke, heart failure and myocardial infarction, until the end of the study. The average follow-up duration was 4.6 years.8

Results regarding myocardial infarction 

The efficacy of the polypill relative to placebo was assessed by combining the group receiving the polypill and the group receiving the polypill together with acetylsalicylic acid. This combined group was compared with the group receiving acetylsalicylic acid together with the group receiving only placebo.

The number of myocardial infarctions in the polypill/polypill-acetylsalicylic acid group was 17, versus 26 in the acetylsalicylic acid/placebo group (HR 0.66 [95% confidence interval (CI) 0.36 to 1.22]), a non-significant difference.
The efficacy of acetylsalicylic acid relative to placebo was assessed by combining the group of polypill/acetylsalicylic acid users and the group of acetylsalicylic acid/placebo users and comparing them with the group using the polypill combined with the placebo group. The number of myocardial infarctions was the same in both groups, viz. 22 (HR 1.04 [0.57 to 1.89]).
The efficacy of the combination of polypill and acetylsalicylic acid relative to placebo was assessed by comparing the group receiving the polypill and acetylsalicylic acid with the placebo group. The number of myocardial infarctions did not differ significantly: 10 in the combination group versus 14 in the placebo group (HR 0.69 [0.31 to 1.56]).8

Adverse effects

The table below summarises the most common adverse effects found in the TIPS-3 study. Dizziness and hypotension were major reasons to stop, while the main reasons for users of acetylsalicylic acid were stomach complaints or a major haemorrhage, but these were also frequent in the placebo group. The results underestimate the true number of adverse effects, as patients with unacceptable adverse effects in the run-in period were excluded from the randomisation.8

Table 1. Adverse effects reported in the TIPS-3 study8

 

 

Polypill

Placebo

 

Acetylsalicylic acid

Placebo

Number randomised

 

2,861

2,852

 

2,860

2,853

Hospitalisation due to serious adverse effect

 

23

33

 

29

27

Stopped or suspended participation

 

1,775

1,690

 

1,681

1,692

 

reason:

 

 

reason:

 

 

 

dizziness

28

17

gastritis

35

46

 

hypotension

51

14

dyspepsia

5

4

 

cough

31

17

gastric ulcer

5

5

 

myalgia

9

11

gastric haemorrhage

5

1

 

weakness

5

4

 

 

 

 

 

 

 

 

 

 

Stopped permanently

 

1,221

1,190

 

1,117

1,153

 

reason:

 

 

reason:

 

 

 

dizziness/hypotension

45

25

major haemorrhage

21

19

 

muscle problems

13

10

gastritis

26

33

 

Cough

13

5

dyspepsia

3

2

 

 

 

 

gastric ulcer

5

4

 

 

 

 

gastric haemorrhage

3

0

 

The HOPE-3 study

The randomised double-blind HOPE-3 study examined the effect of a polypill relative to placebo for prevention in people who do not have cardiovascular disease but have a moderately elevated cardiovascular risk profile.9 
The polypill they investigated combined 10 mg rosuvastatin, 12.5 mg hydrochlorothiazide and 16 mg candesartan per daily dose. Participants were randomised to four groups. Group 1 received a combination of candesartan, hydrochlorothiazide and rosuvastatin, group 2 received candesartan and hydrochlorothiazide and placebo, group 3 received rosuvastatin and placebo and group 4 received dual placebo. The publication discussed here only reported on the findings regarding the comparison between the combination therapy and dual placebo.

There were two primary outcome measures. The first combined the number of deaths from cardiovascular causes, non-fatal myocardial infarctions and non-fatal strokes. The second also included the number of resuscitated patients with cardiac arrest, heart failure and revascularisation surgery. The results focus on the incidence of myocardial infarction.

Potential participants were men aged 55 years or over and women aged 65 years or over, with at least one cardiovascular risk factor. They were at intermediate risk (approx. 1%) of serious cardiovascular events. The study started with a run-in period of 4 weeks, in which all participants were given the combination therapy. Patients with unacceptable adverse effects or patients with insufficient compliance were excluded from further participation.

Results regarding myocardial infarction

The study included a total of 12,705 participants, 3,180 of whom were randomised to treatment with the combination of rosuvastatin, candesartan and hydrochlorothiazide, and 3,168 to (dual) placebo. The median follow-up was 5.6 years.
Fatal or non-fatal myocardial infarctions occurred in 21 of the 3,180 participants in the polypill group and in 28 of the 3,168 participants in the placebo group (HR 0.55 [95% CI 0.32 to 0.93], NNT 185).9

Adverse effects

The table below summarises the most common adverse effects found in the HOPE-3 study. Dizziness and hypotension were a major reason to stop. Reasons to discontinue acetylsalicylic acid included stomach complaints or major haemorrhage, but these were also frequent in the placebo group. The results underestimate the true number of adverse effects, as patients with unacceptable adverse effects during the run-in period were excluded from randomisation.9

Table 2. Adverse effects reported in the HOPE-3 study9

 

 

Rosuvastatin/candesartan/HCT

Candesartan/HCT

Rosuvastatin

Placebo

Number randomised

 

3,180

3,176

3,181

3,168

Stopped temporarily*

 

768

729

693

731

 

reason:

 

 

 

 

 

dizziness, hypotension

47

43

28

20

 

gastro-intestinal

32

21

33

23

 

 

 

 

 

 

Stopped permanently

 

697

697

718

757

 

reason:

 

 

 

 

 

dizziness/hypotension

48

42

28

40

 

rhabdomyolysis or myopathy

0

0

0

0

 

renal dysfunction

6

7

8

3

HCT: hydrochlorothiazide. *This study did not report combined figures

The PolyIran study

The PolyIran study was based on an Iranian pilot study from 2010.10,13 The first results of this randomised open-label study into the long-term effects of a polypill containing 81 mg acetylsalicylic acid, 20 mg atorvastatin, 12.5 mg hydrochlorothiazide and 5 mg enalapril were published in 2019. Enalapril was replaced by 40 mg valsartan if patients were troubled by cough. The study included almost 7,000 Iranians aged 50 to 75 years. Half of them were women, 11% had a history of cardiovascular disease, 49% had high blood pressure and 15% had diabetes mellitus. The primary endpoint was the occurrence of a serious cardiovascular event during a 60-months period. A serious cardiovascular event was defined as hospitalisation for a non-fatal myocardial infarction or unstable angina pectoris, fatal myocardial infarction, sudden death, heart failure, a coronary artery revascularization procedure or a fatal or non-fatal stroke.

Results concerning ischaemic heart disease

Fatal ischaemic heart disease (with myocardial infarction not reported separately) occurred in 21 of the 3,421 patients in the polypill group and 41 of the 3,417 patients in the placebo group (RR 0.50 [95% CI 0.29 to 0.85]). Non-fatal ischaemic heart disease occurred in 127 of the 3,421 patients in the polypill group and 169 of the 3,417 patients in the placebo group (RR 0.75 [0.59 to 0.96]). The absolute risk reduction for both fatal and non-fatal ischaemic heart disease was 1.82%, and the corresponding NNT was 55. The relative risk did not depend on prior cardiovascular incidents. Twenty-one intracranial haemorrhages were reported, 10 of which occurred in the polypill group (which included acetylsalicylic acid).10


Why use myocardial infarction as an endpoint?

The composite endpoint used in the three studies discussed here was not unequivocally defined, whereas myocardial infarction was clearly defined and comparable in all three studies. Two of the three studies did not distinguish between ischaemic and haemorrhagic stroke, whereas both diagnoses were included in the composite endpoint.8,9 Haemorrhagic stroke can also be an adverse effect of the medication used. 

Effectiveness

Both the HOPE-3 and PolyIran studies found a reduced risk of myocardial infarction, but with a large difference in NNT: 54 vs. 185 (table 3). The TIPS-3 study found no significant reduction of the number of myocardial infarctions. These differences are probably caused by the heterogeneity of the studies, which differed, among other things, in the type of polypill investigated, the baseline risk of cardiovascular disorders and the age of the participants. This makes it impossible to draw a definitive conclusion about the effectiveness of a polypill in the primary prevention of myocardial infarction.

Both the TIPS-3 and HOPE-3 studies used a run-in period. Participants who showed insufficient compliance with the regimen in this run-in period were excluded from further participation. As a result the compliance among the remaining participants was probably higher than in the general population, possibly leading to an overestimation of the effectiveness. Furthermore, the effectiveness is overestimated in all three studies since they did not include only participants without cardiovascular risk. This means that the effectiveness in relatively healthy individuals aged 55 and over (as proposed by Wald and Law) has not been proven by these studies. In the Netherlands, patients with an elevated cardiovascular risk are already treated in accordance with guidelines for cardiovascular risk management (see Background Information).14

Table 3. Summary of the results of TIPS-3, HOPE-3 and PolyIran

Study

Average follow-up (months)

Average age (years)

cardiovascular diseases

BMI (kg/m2)

Percentage patients with diabetes

Av. LDL

Active medication

Control

RR myocardial infarction (95% CI)

NNT

TIPS-3 8

55

63.9

No known

25.8

37%

3.1

Polypill 1

placebo

0.66 (0.36–1.22) NS

-

 

 

 

 

 

 

 

Polypill 1 + ASA

placebo

0.69 (0.31–1.56) NS

-

HOPE-3 9

67

65.7

No known

27

6%

3,3

Polypill 2

placebo

0.55 (0.32–0.93)

185

PolyIran 10

60

59.5

11% of participants

26.5

15%

3

Polypill 3

 

0.70 (0.57–0.86)*

54

Composition of polypill 1: simvastatin, atenolol, hydrochlorothiazide, ramipril
Composition of polypill 2: rosuvastatin, candesartan, hydrochlorothiazide
Composition of polypill 3: acetylsalicylic acid, atorvastatin, hydrochlorothiazide, enalapril (or valsartan)
* This study did not report myocardial infarctions separately; the results regard ischaemic heart disease.
ASA: acetylsalicylic acid, BI: confidence interval, BMI: body mass index, Av.: average, NNT: number needed to treat, NS: non-significant, RR: relative risk

Adverse effects

The adverse effects were incompletely examined in these studies. Although they were recorded, no quantitative analysis was undertaken. Hence, the question whether the effectiveness found is balanced out by the adverse effects arising while using the polypill cannot be answered. In both the TIPS-3 and HOPE-3 studies, participants who experienced unacceptable adverse effects during the run-in period were excluded from further participation. As a result, the number of recorded adverse effects probably underestimates the number that can be expected to occur in practice. One striking aspect is that the TIPS-3 study does not mention angioedema as an adverse effect, even though this is a well-known adverse effect of ramipril.15

Polypill vs. lifestyle

The effectiveness of the polypill has not been compared with that of individual lifestyle advice. Risk can also be reduced by reducing risk factors, for instance by giving up smoking or losing weight. There is a danger that the polypill will be seen as a ‘quick fix’, whereas a healthy lifestyle may produce greater health gains in the longer term.16


Cardiovascular risk management in the Netherlands

The polypill strategy contrasts with the current Dutch strategy for the treatment of at-risk groups, which involves recommending drug treatment to patients at high risk of cardiovascular events, based on an assessment of risk factors.

Dutch health care uses an extensive and widely supported guideline for cardiovascular risk management14, which mentions the situations in which primary prevention by means of a cholesterol lowering agent or an antihypertensive agent is indicated. This is the case if certain comorbidities (including diabetes mellitus and chronic kidney disfunction) or risk factors (e.g. smoking or obesity) are present which increase the patient’s risk of developing a cardiovascular disorder. Treatment with a cholesterol lowering drug is indicated to keep the LDL-cholesterol concentration below 2.6 mmol/L and the blood pressure below 140 to 150 mm Hg. In the case of cholesterol lowering agents, the choice of a specific drug depends, among other things, on the intended reduction of the LDL-cholesterol level, while in the case of antihypertensive agents it depends on comorbidity.14 Thrombosis prophylaxis is not recommended in primary prevention. Based on the current Dutch guidelines, a polypill for primary prevention would therefore only contain an antihypertensive agent and a cholesterol lowering agent.

Advantages and disadvantages of polypill therapy

In view of its ease of administration, a polypill might improve therapy compliance compared to the individual drugs.17 A meta-analysis using individual data of 3,140 patients examined whether the cholesterol and blood pressure lowering objectives were more likely to be attained with a polypill than with usual care.18 This meta-analysis did not define usual care. As regards the use of an antiplatelet agent, the attainment of the objective was determined using patient-reported compliance. After 12 months, small but significant differences in favour of the polypill were found regarding blood pressure reduction and LDL-cholesterol lowering. The relative risk for blood pressure was found to be 1.08 (95% CI 1.02 to 1.15, NNT 25), while that for LDL-cholesterol concentration was 1.13 (1.02 to 1.25, NNT 20). Compliance regarding the use of acetylsalicylic acid did not differ significantly (RR 1.00 [0.98 to 1.01]).18

A previous Ge-Bu article listed the possible disadvantages of a combination pill:16

  • A combination pill aims at primary prevention in the entire population and is not tailored to individual patients (in terms of dosage, adverse effects, comorbidity or interactions with other drugs).
  • There is a risk of overtreatment or undertreatment.
  • The absolute risk reduction for patients is often disappointing, especially in patients with a low-risk profile.
  • Patients may experience adverse effects, especially with a combination of multiple drugs.

The Cochrane review

A Cochrane systematic review from 2017 examined the efficacy of the polypill and used the number of myocardial infarctions as the primary outcome measure.11 This systematic review included two randomised studies that both used the reduction of LDL-cholesterol and lowering of diastolic blood pressure as an outcome measure.13,19 Both studies were too short (8 weeks and 1 year) to yield enough endpoints for the meta-analysis, so the meta-analysis found no difference between the intervention and control groups.11 Conclusions were further hampered by the large differences between the studies, including the difference in control groups and the difference in the participants’ health status.

An Iranian pilot study

The first study included in the Cochrane review was a pilot study from 2010. The primary endpoint in this study was blood pressure and LDL-cholesterol lowering after 1 year, while an important second endpoint was cardiovascular disease.13 A polypill containing 81 mg acetylsalicylic acid, 2.5 mg enalapril, 20 mg atorvastatin and 125 mg hydrochlorothiazide was compared with placebo for 12 months. The study sample consisted of participants aged 50 to 79 years, who had no cardiovascular diseases, hypertension or hyperlipidaemia. Of the 475 participants, 241 received the polypill and 234 received a placebo. Myocardial infarction occurred in none of the 165 polypill users and 1 of the 183 placebo users who completed the study. Two participants in the polypill group dropped out because of cough (a well-known adverse effect of enalapril).13

The Olsta study

The second study included in the Cochrane review, the ‘Olsta’ study from 2016, included 181 Korean patients aged 20 years or over, who had mild to moderate hypertension and dyslipidaemia.19 The primary outcome measures were diastolic blood pressure reduction and LDL-cholesterol lowering after 8 weeks. These patients were subdivided into four groups. The first group (71 patients) received a polypill containing 40 mg olmesartan and 20 mg rosuvastatin. The second and third groups (38 patients each) received 40 mg olmesartan and 20 mg rosuvastatin, respectively. The fourth group (34 patients) received a placebo. The average age was around 61 years, and about two thirds were male. Diabetes was present in 44, 39, 22 and 31% of the patients, respectively. None of the participants had a history of cardiovascular disease. After 8 weeks, a myocardial infarction occurred in one patient in the olmesartan group, and a subarachnoid haemorrhage was diagnosed in one patient in the rosuvastatin group.19

Adverse effects

The Cochrane review presented a meta-analysis including the adverse effects reported in 11 of the included studies (concerning both primary and secondary prevention) with a total of 6,905 participants. The risk of adverse effects was greater in the various intervention groups than in the control groups, with a relative risk of 1.16 (32% vs. 27%, [95% CI 1.09 to 1.25]). The relative risk of adverse effects in the primary compared to the secondary prevention studies was 1.37 (1.17 to 1.60).11

Study details

TIPS-3 study 8
Study name: The International Polycap Study-3 (TIPS-3)
Design: randomised placebo-controlled study with 2x2 factorial design[ Design for a study investigating two or more factors, interventions or treatments at once]
Inclusion criteria: women aged 55 years or over, men aged 50 years or over, without known cardiovascular diseases and a risk score not based on laboratory findings 
Intervention

1. Polypill (40 mg simvastatin, 100 mg atenolol, 25 mg hydrochlorothiazide, 10 mg ramipril) vs. placebo
2. 75 mg acetylsalicylic acid vs. placebo 
3. 75 mg acetylsalicylic acid + polypill vs. dual placebo

Primary endpoint(s) and study duration: composed of major cardiovascular diseases (stroke, myocardial infarction, mortality due to cardiovascular disease). Duration 5 years
Intended number of participants and power: 80% power 5,000 participants. The size of the study , coordinated by McMaster University in Canada, was large enough to detect differences in relative risks up to 35% 
Randomisation: in accordance with CONSORT
Population analysed: intention-to-treat
Number of patients included and patient characteristics: 5,713 in total, polypill n=1,432, polypill + acetylsalicylic acid n=1,429, acetylsalicylic acid n=1,431, dual placebo n=1,421. Average age 63.9 years, 52.9% women, from India (47.9%), the Philippines (29.3%) and other countries
Trial registration: NCT01646437
Funding: largely public, including Wellcome Trust, Canadian Institutes for Health Research
Conflicts of interest: 4 of the 16 authors
HOPE-3 study 9
Study name: Heart Outcomes Prevention Evaluation-3 (HOPE-3)
Design: randomised placebo-controlled study with 2x2 factorial design
Inclusion criteria: women aged ≥65 years, men aged ≥55 years, without known cardiovascular diseases and with at least one risk factor in addition to their age. Intermediate risk of serious cardiovascular events (approx. 1%)
Main exclusion criteria: unacceptable adverse effects or insufficient compliance during the run-in period
Intervention: 10 mg rosuvastatin, 16 mg candesartan, 12.5 mg hydrochlorothiazide vs. placebo (results of rosuvastatin vs. placebo and candesartan/hydrochlorothiazide vs. placebo are presented in another publication)
Primary endpoint(s) and study duration: composed of major cardiovascular diseases (stroke, myocardial infarction, mortality from cardiovascular disease). Median duration 5.6 years
Intended number of participants and power: 12,700 participants had to be included to be able to detect a difference in relative risk of 22.5% with 80% power
Randomisation: in accordance with CONSORT 
Population analysed: intention-to-treat
Number of patients included and patient characteristics: a total of 12,705, of whom 3180 in the combined therapy group, 3181 in the rosuvastatin group, 3176 in the candesartan/hydrochlorothiazide group and 3168 in the placebo group. Average age 65.7 years, 46.2% women, average systolic blood pressure 138.1 mm Hg, average LDL-cholesterol 3.3 mmol/L
Trial registration: ClinicalTrials.gov number, NCT00468923
Funding: AstraZeneca and Canadian Institutes for Health Research
Conflict of interests: 8 of the 32 authors
PolyIran study 10
Study name: PolyIran (WHO study)
Design: randomised open-label study, part of a larger cohort study in Golestan province, Iran (n=50,045)
Inclusion criteria: >50 jaar and living in rural areas; those eligible for the polypill who had previously used acetylsalicylic acid or statin were transferred to the defined study dose
Main exclusion criteria: use of anticoagulants, history of stroke, systolic blood pressure <90 mm Hg and diastolic blood pressure <60 mm Hg. 
Intervention: polypill (acetylsalicylic acid 81 mg, enalapril 5 mg (valsartan 40 mg in case of cough), atorvastatin 20 mg and hydrochlorothiazide 12.5 mg + usual care including prevention education
Primary endpoint(s) and study duration: e.g. fatal or non-fatal myocardial infarction, stroke
Intended number of patients and power: 3612 participants per arm, 28 participants per cluster (22 after dropout), 80% power at an alpha of 0.05
Randomisation: per village: 130 (polypill) vs. 132 (control), stratified to 3 districts in the province
Blinding: pragmatic study, so participants, researchers and staff providing the medication were not blinded, but those evaluating the results were 
Population analysed: after randomisation 6999 assigned to polypill group, 6883 to control group; after problems with some of the villages, cancellations and exclusion, 3421 participants in the polypill group and 3417 in the control group (analysis). Lost to follow-up: 5 in the polypill group and 1 in the control group 
Number of patients included and patient characteristics: 3421 participants in the polypill group and 3417 in the control group, average age 59.5 years, 50.3% women
Trial registration: clinicaltrials.gov NCT01271985.
Funding: Tehran University, Barakat Foundation (UK) and pills producer.
Conflicts of interest: not reported
Cochrane review 2017 11
Design: systematic literature review and meta-analysis
Primary endpoint(s): number of cardiovascular events and number of adverse effects
Inclusion criteria: randomised study of adults aged 18 years or over with or without atherosclerotic cardiovascular diseases, one arm using a combination therapy for cardiovascular diseases, containing at least one statin and an antihypertensive agent, control group with usual care, placebo or active control
Number of articles analysed: 36 publications on 13 studies, including two studies on primary prevention
Number of patients: 656 
Quality standards applied: GRADE
Methods to determine risk of bias: ‘Cochrane risk of bias tool’
Funding: Warwick Medical School, University of Warwick, UK, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, UK, NIHR Cochrane Programme Grant, UK, National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care West Midlands at University Hospitals Birmingham NHS Foundation Trust, UK
Conflicts of interest: 1 of the 3 authors

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Authors

  • Frans M. Helmerhorst, prof. dr
  • Anton J.F.A. Kerst, dr
  • Niels H. Schut
  • Marielle A.E. Nieuwhof, pharmacist