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Meta-Analysis
. 2017 Mar 6;3(3):CD009868.
doi: 10.1002/14651858.CD009868.pub3.

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases

Ehete Bahiru  1 , Angharad N de Cates  2 , Matthew Rb Farr  2 , Morag C Jarvis  2 , Mohan Palla  3 , Karen Rees  2 , Shah Ebrahim  4 , Mark D Huffman  5
Affiliations
Meta-Analysis

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases

Ehete Bahiru et al. Cochrane Database Syst Rev. .

Abstract

Background: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide, yet ASCVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure- and cholesterol-lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of ASCVD.

Objectives: To determine the effect of fixed-dose combination therapy on all-cause mortality, fatal and non-fatal ASCVD events, and adverse events. We also sought to determine the effect of fixed-dose combination therapy on blood pressure, lipids, adherence, discontinuation rates, health-related quality of life, and costs.

Search methods: We updated our previous searches in September 2016 of CENTRAL, MEDLINE, Embase, ISI Web of Science, and DARE, HTA, and HEED. We also searched two clinical trials registers in September 2016. We used no language restrictions.

Selection criteria: We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure-lowering and one lipid-lowering component versus usual care, placebo, or an active drug comparator for any treatment duration in adults 18 years old or older, with no restrictions on presence or absence of pre-existing ASCVD.

Data collection and analysis: Three review authors independently selected studies for inclusion and extracted the data for this update. We evaluated risk of bias using the Cochrane 'Risk of bias' assessment tool. We calculated risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI) using fixed-effect models when heterogeneity was low (I2 < 50%) and random-effects models when heterogeneity was high (I2 ≥ 50%). We used the GRADE approach to evaluate the quality of evidence.

Main results: In the initial review, we identified nine randomised controlled trials with a total of 7047 participants and four additional trials (n = 2012 participants; mean age range 62 to 63 years; 30% to 37% women) were included in this update. Eight of the 13 trials evaluated the effects of fixed-dose combination (FDC) therapy in populations without prevalent ASCVD, and the median follow-up ranged from six weeks to 23 months. More recent trials were generally larger with longer follow-up and lower risk of bias. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Compared with the comparator groups (placebo, usual care, or active drug comparator), the effects of the fixed-dose combination treatment on mortality (FDC = 1.0% versus control = 1.0%, RR 1.10, 95% CI 0.64 to 1.89, I2 = 0%, 5 studies, N = 5300) and fatal and non-fatal ASCVD events (FDC = 4.7% versus control = 3.7%, RR 1.26, 95% CI 0.95 to 1.66, I2 = 0%, 6 studies, N = 4517) were uncertain (low-quality evidence). The low event rates for these outcomes and indirectness of evidence for comparing fixed-dose combination to usual care versus individual drugs suggest that these results should be viewed with caution. Adverse events were common in both the intervention (32%) and comparator (27%) groups, with participants randomised to fixed-dose combination therapy being 16% (RR 1.16, 95% CI 1.09 to 1.25, 11 studies, 6906 participants, moderate-quality evidence) more likely to report an adverse event . The mean differences in systolic blood pressure between the intervention and control arms was -6.34 mmHg (95% CI -9.03 to -3.64, 13 trials, 7638 participants, moderate-quality evidence). The mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were -0.61 mmol/L (95% CI -0.88 to -0.35, 11 trials, 6565 participants, low-quality evidence) and -0.70 mmol/L (95% CI -0.98 to -0.41, 12 trials, 7153 participants, moderate-quality evidence), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I2 ≥ 80% for all) that could not be explained, so these results should be viewed with caution. Fixed-dose combination therapy improved adherence to a multidrug strategy by 44% (26% to 65%) compared with usual care (4 trials, 3835 participants, moderate-quality evidence).

Authors' conclusions: The effects of fixed-dose combination therapy on all-cause mortality or ASCVD events are uncertain. A limited number of trials reported these outcomes, and the included trials were primarily designed to observe changes in ASCVD risk factor levels rather than clinical events, which may partially explain the observed differences in risk factors that were not translated into differences in clinical outcomes among the included trials. Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo, active comparator, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing, longer-term trials of fixed-dose combination therapy will help demonstrate whether short-term changes in risk factors might be maintained and lead to expected differences in clinical events based on these changes.

PubMed Disclaimer

Conflict of interest statement

Mark Huffman has received grant support from Cochrane to support the production of this update. Dr. Huffman also receives grant support from World Heart Federation to serve as senior program advisor for its Emerging Leaders program, which is supported by Boehringer Ingelheim and Novartis and has been supported by AstraZeneca and Bupa. Dr. Huffman has also received travel support from the World Heart Federation for its polypill satellite meeting at the World Congress of Cardiology and Cardiovascular Health in 2016.

Figures

1
1
Flow diagram
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
4
4
Funnel plot of comparison: 3 Cholesterol, outcome: 3.1 Total cholesterol.
1.1
1.1. Analysis
Comparison 1 Mortality and cardiovascular events, Outcome 1 All‐cause mortality.
1.2
1.2. Analysis
Comparison 1 Mortality and cardiovascular events, Outcome 2 All‐cause mortality: comparator as usual care.
1.3
1.3. Analysis
Comparison 1 Mortality and cardiovascular events, Outcome 3 All‐cause mortality: comparator provision of individual drugs.
1.4
1.4. Analysis
Comparison 1 Mortality and cardiovascular events, Outcome 4 All‐cause mortality: 3+ drugs.
1.5
1.5. Analysis
Comparison 1 Mortality and cardiovascular events, Outcome 5 All‐cause mortality: 2+ drugs.
1.6
1.6. Analysis
Comparison 1 Mortality and cardiovascular events, Outcome 6 Fatal or non‐fatal ASCVD events.
1.7
1.7. Analysis
Comparison 1 Mortality and cardiovascular events, Outcome 7 Fatal and non‐fatal ASCVD events: primary prevention trials.
1.8
1.8. Analysis
Comparison 1 Mortality and cardiovascular events, Outcome 8 Fatal and non‐fatal ASCVD events: secondary prevention trials.
1.9
1.9. Analysis
Comparison 1 Mortality and cardiovascular events, Outcome 9 Fatal and non‐fatal ASCVD events: comparator provision of individual drugs.
1.10
1.10. Analysis
Comparison 1 Mortality and cardiovascular events, Outcome 10 Fatal and non‐fatal ASCVD events: comparator as usual care.
1.11
1.11. Analysis
Comparison 1 Mortality and cardiovascular events, Outcome 11 Fatal and non‐fatal ASCVD events: 3+ drugs.
1.12
1.12. Analysis
Comparison 1 Mortality and cardiovascular events, Outcome 12 Fatal and non‐fatal ASCVD events: 2 drugs.
2.1
2.1. Analysis
Comparison 2 Adverse events, Outcome 1 Any adverse event.
2.2
2.2. Analysis
Comparison 2 Adverse events, Outcome 2 Any adverse event: primary prevention trials.
2.3
2.3. Analysis
Comparison 2 Adverse events, Outcome 3 Any adverse event: secondary prevention trial.
2.4
2.4. Analysis
Comparison 2 Adverse events, Outcome 4 Any adverse event: comparator as usual care.
2.5
2.5. Analysis
Comparison 2 Adverse events, Outcome 5 Adverse event: comparator as placebo or inactive control.
2.6
2.6. Analysis
Comparison 2 Adverse events, Outcome 6 Adverse event: 3+ drugs only.
2.7
2.7. Analysis
Comparison 2 Adverse events, Outcome 7 Adverse events: 2 drugs.
2.8
2.8. Analysis
Comparison 2 Adverse events, Outcome 8 Myalgias.
2.9
2.9. Analysis
Comparison 2 Adverse events, Outcome 9 Increased liver enzymes.
2.10
2.10. Analysis
Comparison 2 Adverse events, Outcome 10 Cough.
2.11
2.11. Analysis
Comparison 2 Adverse events, Outcome 11 Dyspepsia/gastrointestinal irritation.
2.12
2.12. Analysis
Comparison 2 Adverse events, Outcome 12 Bleeding.
3.1
3.1. Analysis
Comparison 3 Blood pressure, Outcome 1 Systolic blood pressure.
3.2
3.2. Analysis
Comparison 3 Blood pressure, Outcome 2 Diastolic blood pressure.
3.3
3.3. Analysis
Comparison 3 Blood pressure, Outcome 3 Systolic blood pressure: primary prevention trials.
3.4
3.4. Analysis
Comparison 3 Blood pressure, Outcome 4 Systolic blood pressure: secondary prevention trial.
3.5
3.5. Analysis
Comparison 3 Blood pressure, Outcome 5 Systolic blood pressure: comparator as usual care.
3.6
3.6. Analysis
Comparison 3 Blood pressure, Outcome 6 Systolic blood pressure: placebo or inactive control.
3.7
3.7. Analysis
Comparison 3 Blood pressure, Outcome 7 Systolic blood pressure: 3+ drugs only.
3.8
3.8. Analysis
Comparison 3 Blood pressure, Outcome 8 Systolic blood pressure: 2 drugs.
4.1
4.1. Analysis
Comparison 4 Lipids, Outcome 1 Total cholesterol.
4.2
4.2. Analysis
Comparison 4 Lipids, Outcome 2 LDL cholesterol.
4.3
4.3. Analysis
Comparison 4 Lipids, Outcome 3 Total cholesterol: primary prevention trials.
4.4
4.4. Analysis
Comparison 4 Lipids, Outcome 4 Total cholesterol: secondary prevention trials.
4.5
4.5. Analysis
Comparison 4 Lipids, Outcome 5 Total cholesterol: comparator as usual care.
4.6
4.6. Analysis
Comparison 4 Lipids, Outcome 6 Total cholesterol: placebo or inactive control.
4.7
4.7. Analysis
Comparison 4 Lipids, Outcome 7 Total cholesterol: 3+ drugs only.
4.8
4.8. Analysis
Comparison 4 Lipids, Outcome 8 Total cholesterol: 2 drugs.
5.1
5.1. Analysis
Comparison 5 Adherence, Outcome 1 Adherence.
5.2
5.2. Analysis
Comparison 5 Adherence, Outcome 2 Adherence: usual care as comparator.
5.3
5.3. Analysis
Comparison 5 Adherence, Outcome 3 Adherence: comparator provision of individual drugs.
6.1
6.1. Analysis
Comparison 6 Discontinuation, Outcome 1 Discontinuation.
7.1
7.1. Analysis
Comparison 7 Health‐related quality of life, Outcome 1 EQ‐5D health state.
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Dresser 2013 {published data only}
    1. Dresser GK, Nelson SA, Mahon JL, Zou G, Vandervoort MK, Wong CJ, et al. Simplified therapeutic intervention to control hypertension and hypercholesterolemia: a cluster randomized controlled trial (STITCH2). Journal of Hypertension 2013;31(8):1702‐13. [DOI: ] - PubMed
Elley 2012 {published data only}
    1. Elley CR, Gupta AK, Webster R, Selak V, Jun M, Patel A, et al. The efficacy and tolerability of 'polypills': meta‐analysis of randomised controlled trials. PLoS ONE 2012;7:e52145. [DOI: ] - PMC - PubMed
Fedacko 2013 {published data only}
    1. Fedacko J, Pella D, Jarcuska P, Sabol F, Kmec J, Lopuchovsky T, et al. Slovak trial on cardiovascular risk reduction following national guidelines with CaDUET (the STRONG DUET study). Advances in Therapy 2013;30(1):60‐70. [DOI: ] - PubMed
Feldman 2012 {published data only}
    1. Feldman RD, Flack J, Howes L, Jenssen T, Reeves R, Shi H, et al. Impact of age and gender on blood pressure and low‐density lipoprotein cholesterol reduction: results of a pooled analysis. Current Medical Research and Opinion 2012;28:1421‐33. - PubMed
Feldman 2014 {published data only}
    1. Feldman RD, Nattel S. Increasing appreciation for the role of single‐pill combinations for the prevention of atherosclerotic disease: a pro‐polypill polemic. Canadian Journal of Cardiology 2014;30(5):517‐9. [DOI: ] - PubMed
Feng 2012 {published data only}
    1. Feng Y, Xu H, Chen K. Natural polypill Xuezhikang: its clinical benefit and potential multicomponent synergistic mechanisms of action in cardiovascular disease and other chronic conditions. Journal of Alternative and Complementary Medicine 2012;18:318‐28. [DOI: ] - PubMed
Galindo Ocana 2012 {published data only}
    1. Galindo‐Ocana J, Bernabeu‐Wittel M, Formiga F, Fuertes‐Martin A, Baron‐Franco B, Murcia‐Zaragoza JM, et al. Effects of renin‐angiotensin blockers/inhibitors and statins on mortality and functional impairment in polypathological patients. European Journal of Internal Medicine 2012;23:179‐84. [DOI: 10.1016/j.ejim.2011.06.004] - DOI - PubMed
Gaziano 2013 {published data only}
    1. Gaziano JM. Progress with the polypill?. JAMA 2013;310(9):910‐1. [DOI: ] - PubMed
Holzgreve 2014 {published data only}
    1. Holzgreve H. Health and longevity by one tablet daily. Fiction and hard facts on the polypill. MMW Fortschritte der Medizin 2014;156(1):55‐7. - PubMed
Huang 2016 {published data only}
    1. Huang Z, Chen C, Li S, Kong F, Shan P, Huang W. Combined treatment with amlodipine and atorvastatin calcium reduces circulating levels of intercellular adhesion molecule‐1 and tumor necrosis factor‐alpha in hypertensive patients with prediabetes. Frontiers in Aging Neuroscience 2016;8:206. [DOI: ] - PMC - PubMed
Huffman 2012 {published data only}
    1. Huffman MD, Bhatnagar D. Novel treatments for cardiovascular disease prevention. Cardiovascular Therapeutics 2012;30(5):257‐63. [DOI: 10.1111/j.1755-5922.2011.00280.x] - DOI - PMC - PubMed
Huffman 2014 {published data only}
    1. Huffman MD, Yusuf S. Polypills: essential medicines for cardiovascular disease secondary prevention?. Journal of the American College of Cardiology 2014;63(14):1368‐70. [DOI: ] - PubMed
Ito 2012 {published data only}
    1. Ito K, Shrank WH, Avorn J, Patrick AR, Brennan TA, Antman EM, et al. Comparative cost‐effectiveness of interventions to improve medication adherence after myocardial infarction. Health Services Research 2012;47:2097‐117. [DOI: ] - PMC - PubMed
Ivanovic 2013 {published data only}
    1. Ivanovic B, Tadic M. Fixed combination of amlodipine/atorvastatin: from mechanisms to trials. Journal of Cardiovascular Pharmacology and Therapeutics 2013;18(6):544‐9. [DOI: ] - PubMed
Jadhav 2014 {published data only}
    1. Jadhav U, Hiremath J, Namjoshi DJ, Gujral VK, Tripathi KK, Siraj M, et al. Blood pressure control with a single‐pill combination of indapamide sustained‐release and amlodipine in patients with hypertension: The EFFICIENT Study. PLoS One 2014;9(4):6. [DOI: 10.1371/journal.pone.0092955] - DOI - PMC - PubMed
Jang 2015 {published data only}
    1. Jang JY, Lee SH, Kim BS, Seo HS, Kim WS, Ahn Y, et al. Additive beneficial effects of valsartan combined with rosuvastatin in the treatment of hypercholesterolemic hypertensive patients. Korean Circulation Journal 2015;45(3):225‐33. [DOI: 10.4070/kcj.2015.45.3.225] - DOI - PMC - PubMed
Jaques 2011 {published data only}
    1. Jaques H. The polypill concept: the story so far. [Erratum appears in European Heart Journal 2012 Mar; 33(5):551]. European Heart Journal 2011;32:2471‐2. - PubMed
Kawashiri 2015 {published data only}
    1. Kawashiri MA, Sakata K, Gamou T, Kanaya H, Miwa K, Ueda K, et al. Impact of combined lipid lowering with blood pressure control on coronary plaque regression: rationale and design of MILLION study. Heart Vessels 2015;30(5):580‐6. [DOI: ] - PubMed
Kereiakes 2012 {published data only}
    1. Kereiakes DJ, Chrysant SG, Izzo JL, Littlejohn T, Melino M, Lee J, et al. Olmesartan/amlodipine/hydrochlorothiazide in participants with hypertension and diabetes, chronic kidney disease, or chronic cardiovascular disease: a subanalysis of the multicenter, randomized, double‐blind, parallel‐group TRINITY study. Cardiovascular Diabetology 2012;11:13. [DOI: 10.1186/1475-2840-11-134] - DOI - PMC - PubMed
Khaled 2015 {published data only}
    1. Khaled SA, Burley JC, Alexander MR, Yang J, Roberts CJ. 3D printing of five‐in‐one dose combination polypill with defined immediate and sustained release profiles. Journal of Controlled Release 2015;217:308‐14. [DOI: 10.1016/j.jconrel.2015.09.028] - DOI - PubMed
Laba 2014a {published data only}
    1. Laba TL, Howard K, Rose J, Jan S. Using DCE to assess adherence and treatment preferences for combination therapies for cardiovascular disease. Global Heart 2014;1:e44. [DOI: ]
Laba 2014b {published data only}
    1. Laba TL, Hayes A, Jan S, Rodgers A, Patel A, Cass A, et al. Can a CVD polypill save money in the 'real world'?. Value in Health 2014;17(7):A482. [DOI: ] - PubMed
Lafeber 2011 {published data only}
    1. Lafeber M, Spiering W, Bots ML, Valk V, Visseren FL, Grobbee DE. Cardiovascular polypill in high risk patients. Nederlands Tijdschrift Voor Geneeskunde 2011;155:A3070. - PubMed
Lafeber 2012 {published data only}
    1. Lafeber M, Spiering W, Singh K, Guggilla RK, Patil V, Webster R. The cardiovascular polypill in high‐risk patients. European Journal of Preventive Cardiology 2012;19:1234‐42. [DOI: ] - PubMed
Lafeber 2013a {published data only}
    1. Lafeber M, Grobbee DE, Spiering W, Graaf Y, Bots ML, Visseren FL. The combined use of aspirin, a statin, and blood pressure‐lowering agents (polypill components) in clinical practice in patients with vascular diseases or type 2 diabetes mellitus. European Journal of Preventive Cardiology 2013;20(5):771‐8. [DOI: ] - PubMed
Lafeber 2013b {published data only}
    1. Lafeber M, Spiering W, Graaf Y, Nathoe H, Bots ML, Grobbee DE, et al. The combined use of aspirin, a statin, and blood pressure‐lowering agents (polypill components) and the risk of vascular morbidity and mortality in patients with coronary artery disease. American Heart Journal 2013;166(2):282‐9.e1. [DOI: ] - PubMed
Lafeber 2014a {published data only}
    1. Lafeber M, Grobbee DE, Bots ML, Thom S, Webster R, Rodgers A, et al. The Evening versus Morning Polypill Utilization Study: The TEMPUS rationale and design. European Journal of Preventive Cardiology 2014;21(4):425‐33. [DOI: ] - PubMed
Lafeber 2014b {published data only}
    1. Lafeber M, Spiering W, Grobbee DE, Bots ML, Webster R, Thom S, et al. Impact of switching from different treatment regimens to a fixed‐dose combination pill (polypill) in patients with cardiovascular disease or similarly high risk. Circulation 2014;129:AP381. - PubMed
Lafeber 2014c {published data only}
    1. Lafeber M, Stanton A, Thom S, Hughes A, Grobbee DE, Rodgers A, et al. A randomized controlled trial of a cardiovascular fixed‐dose combination pill (polypill) treatment strategy compared with usual care on carotid intima media thickness progression in individuals at high risk of cardiovascular disease. Circulation 2014;129:AP445.
Lafeber 2014d {published data only}
    1. Lafeber M, Grobbee DE, Schrover IM, Thom S, Webster R, Rodgers A, et al. The effect of morning or evening use of a fixed‐dose combination pill (polypill) on LDL‐cholesterol, ambulatory blood pressure and adherence in patients with cardiovascular disease. European Journal of Preventive Cardiology 2014;1:S132. [DOI: ]
Lafeber 2015 {published data only}
    1. 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. International Journal of Cardiology 2015;181:193‐9. [DOI: ] - PubMed
Lafeber 2016 {published data only}
    1. Lafeber M, Spiering W, Visseren FLJ, Grobbee DE. Multifactorial prevention of cardiovascular disease in patients with hypertension: the cardiovascular polypill. Current Hypertension Reports 2016;18(5):40. [DOI: 10.1007/s11906-016-0648-3] - DOI - PMC - PubMed
Law 2006 {published data only}
    1. Law MG. Cardiovascular complications of HIV: an overview of risk and a novel approach to prevention ‐ the HIV polypill study. Current Opinion in HIV and AIDS 2006;1(6):482‐7. [DOI: 10.1097/01.coh.0000247389.08485.87] - DOI - PubMed
Liu 2014 {published data only}
    1. Liu H, Massi L, Laba T, Jan S. Understanding adherence to a cardiovascular polypill strategy‐a process evaluation of a pragmatic clinical trial. Global Heart 2014;1:e118. [DOI: ]
Liu 2015 {published data only}
    1. Liu H, Massi L, Laba TL, Peiris D, Usherwood T, Patel A, et al. Patients' and providers' perspectives of a polypill strategy to improve cardiovascular prevention in Australian Primary Health Care. Circulation: Cardiovascular Quality and Outcomes 2015;8(3):301‐8. [DOI: ] - PubMed
Marazzi 2016 {published data only}
    1. Marazzi G, Pelliccia F, Campolongo G, Cacciotti L, Poggi S, Tanzilli A, et al. Greater cardiovascular risk reduction with once‐daily fixed combination of three antihypertensive agents and statin versus free‐drug combination: The ALL‐IN‐ONE trial. International Journal of Cardiology 2016;222:885‐7. [DOI: ] - PubMed
Mishchenko 2014 {published data only}
    1. Mishchenko O, Bezditko N, Adonkina V, Tkachova O. Pharmacoeconomic grounding of using polypill amlodipine with atorvastatin versus monodrugs in patients with hypertension and dyslipidemia in Ukraine. Value in Health 2014;17(7):A475. [DOI: ] - PubMed
Mossello 2015 {published data only}
    1. Mossello E. Targeting vascular risk factors in older adults: from polypill to personalized prevention. JAMA Internal Medicine 2015;175(12):1949‐50. [DOI: ] - PubMed
Neutel 2009 {published data only}
    1. Neutel JM, Bestermann WH, Dyess EM, Graff A, Kursun A, Sutradhar S, et al. The use of a single‐pill calcium channel blocker/statin combination in the management of hypertension and dyslipidemia: a randomized, placebo‐controlled, multicenter study. Journal of Clinical Hypertension 2009;11(1):22‐30. [DOI: 10.1111/j.1751-7176.2008.00058.x] - DOI - PMC - PubMed
Nguyen 2013 {published data only}
    1. Nguyen C, Cheng‐Lai A. The polypill a potential global solution to cardiovascular disease. Cardiology in Review 2013;21:49‐54. [DOI: 10.1097/CRD.0b013e3182755429] - DOI - PubMed
OliverasVila 2014 {published data only}
    1. Oliveras Vila T, Ferrer Massot M, Curos Abadal A, Rueda Sobella F, Serra Flores J, Carrillo Suarez, et al. Real‐life use of the polypill components (ASA+ACEI+statins) after an acute coronary syndrome and long‐term mortality. International Journal of Cardiology 2014;177(1):209‐10. [DOI: ] - PubMed
Reiner 2013 {published data only}
    1. Reiner Z. Polypill is not a 'vaccine‐like' solution for primary cardiovascular disease prevention in all parts of the world. Journal of Epidemiology and Community Health 2013;67(12):981‐2. [DOI: 10.1136/jech-2013-203220] - DOI - PubMed
Selak 2013 {published data only}
    1. Selak V, Crengle S, Elley CR, Wadham A, Harwood M, Rafter N, et al. Recruiting equal numbers of indigenous and non‐indigenous participants to a 'polypill' randomized trial. International Journal for Equity in Health 2013;12:44. [DOI: ] - PMC - PubMed
Selak 2016 {published data only}
    1. Selak V, Bullen C, Stepien S, Arroll B, Bots M, Bramley D, et al. Do polypills lead to neglect of lifestyle risk factors? Findings from an individual participant data meta‐analysis among 3140 patients at high risk of cardiovascular disease. European Journal of Preventive Cardiology 2016;23(13):1393‐400. [DOI: ] - PubMed
Sepanlou 2012 {published data only}
    1. Sepanlou SG, Farzadfar F, Jafari E, Danaei G. Cardiovascular disease prevention using fixed dose pharmacotherapy in Iran: updated meta‐analyses and mortality estimation. Archives of Iranian Medicine 2012;15(9):531‐7. [DOI: ] - PubMed
Sigamani 2012 {published data only}
    1. Sigamani A, Pais P, Xavier D, Koon T, Xavier F, Girish P, et al. Comparison of risk factor reduction and tolerability of a full dose versus low dose of a polypill (polycap) in individuals at high risk of cardiovascular diseases: a phase II, double blind randomized trial. Circulation 2012;125(19):e803. [DOI: ] - PubMed
Simonyi 2016 {published data only}
    1. Simonyi G, Ferenci T. One year persistence of atorvastatin and amlodipine fixed dose combination versus atorvastatin therapy. Orvosi Hetilap 2016;157(11):425‐9. [DOI: ] - PubMed
Son 2013 {published data only}
    1. Son H, Roh H, Lee D, Chang H, Kim J, Yun C, et al. Pharmacokinetics of rosuvastatin/olmesartan fixed‐dose combination: a single‐dose, randomized, open‐label, 2‐period crossover study in healthy Korean subjects. Clinical Therapeutics 2013;35(7):915‐22. [DOI: ] - PubMed
Tanaka 2014 {published data only}
    1. Tanaka M, Nishimura R, Nishimura T, Kawai T, Meguro S, Irie J, et al. Effect of single tablet of fixed‐dose amlodipine and atorvastatin on blood pressure/lipid control, oxidative stress, and medication adherence in type 2 diabetic patients. Diabetology and Metabolic Syndrome 2014;6:8. [DOI: 10.1186/1758-5996-6-56] - DOI - PMC - PubMed
Truelove 2014 {published data only}
    1. Truelove M, Webster R, Bompoint S, Patel A. Impact of pill burden on the effects of a polypill‐based strategy on use of indicated medications in people with or at high risk of cardiovascular disease. Global Heart 2014;1:e298. [DOI: ]
Wald 2016 {published data only}
    1. Wald NJ, Luteijn JM, Morris JK, Taylor D, Oppenheimer P. Cost‐benefit analysis of the polypill in the primary prevention of myocardial infarction and stroke. European Journal of Epidemiology 2016;31(4):415‐26. [DOI: 10.1007/s10654-016-0122-1] - DOI - PMC - PubMed
Wang 2012 {published data only}
    1. Wang YQ, Hu Z, Yang Y, Gao PJ. Effect of amlodipine and amlodipine plus atorvastatin on impaired vascular function in patients with hypertension. Journal of Hypertension 2012;30:e163. [DOI: ]
Webster 2013 {published data only}
    1. Webster R, Patel A, Billot L, Cass, A, Burch C, Neal B, et al. Prospective meta‐analysis of trials comparing fixed dose combination based care with usual care in individuals at high cardiovascular risk: the SPACE Collaboration. International Journal of Cardiology 2013;170(1):30‐5. [DOI: ] - PubMed
Webster 2014 {published data only}
    1. Webster R, Rodgers A. PREVENTION coronary artery calcium and polypill therapy. Nature Reviews Cardiology 2014;11(1):7. [DOI: 10.1038/nrcardio.2013.185] - DOI - PubMed
Webster 2015a {published data only}
    1. Webster R, Rodgers A. Polypill: progress and challenges to global use: update on the trials and policy implementation. Current Cardiology Reports 2015;17(12):121. [DOI: ] - PubMed
Webster 2015b {published data only}
    1. Webster R, Bullen C, Patel A, Rodgers A, Selak V, Thom S. Impact of cardiovascular polypill based therapy on healthy lifestyle behavior. European Journal of Preventive Cardiology 2015;1:S150. [DOI: ]
Webster 2016a {published data only}
    1. 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. International Journal of Cardiology 2016;205:147‐56. [DOI: ] - PubMed
Webster 2016b {published data only}
    1. Webster R, Rodgers A. Polypill treatments for cardiovascular diseases. Expert Opinion on Drug Delivery 2016;13(1):1‐6. [DOI: ] - PubMed
Wei 2013 {published data only}
    1. Wei XL, Zou GY, Gong WW, Yin J, Yu YX, Walley J, et al. Cardiovascular disease risk reduction in rural China: a clustered randomized controlled trial in Zhejiang. Trials 2013;14:10. [DOI: 10.1186/1745-6215-14-354] - DOI - PMC - PubMed
Wijns 2014 {published data only}
    1. Wijns W, Rusinaru D. "De‐risking" risk reduction should coronary artery calcium scoring be the gatekeeper to preventive pharmacotherapy with the polypill?. Journal of the American College of Cardiology 2014;63(5):444‐6. [DOI: 10.1016/j.jacc.2013.09.044] - DOI - PubMed
Wiley 2014 {published data only}
    1. Wiley B, Fuster V. The concept of the polypill in the prevention of cardiovascular disease. Annals of Global Health 2014;80(1):24‐34. [DOI: 10.1016/j.aogh.2013.12.008] - DOI - PubMed
Xing 2013 {published data only}
    1. Xing DM, Zhang JH, Li L, Zhu MJ, Shang HC. Intervention effects and safety of cardiovascular polypill for the relevant risk factors of coronary heart disease: a systematic review. Chinese Journal of Evidence‐Based Medicine 2013;13:446‐51. [DOI: ]
Zeng 2016 {published data only}
    1. Zeng R, Wang M, Zhang L. Is time an important problem in management of hypertension and hypercholesterolemia by using an amlodipine‐atorvastatin single pill combination?. Medical Science Monitor 2016;22:2648‐55. [DOI: 10.12659/msm.896843] - DOI - PMC - PubMed
Zomer 2013 {published data only}
    1. Zomer E, Owen A, Magliano DJ, Ademi Z, Reid CM, Liew D. Predicting the impact of polypill use in a metabolic syndrome population: an effectiveness and cost‐effectiveness analysis. American Journal of Cardiovascular Drugs 2013;13(2):121‐8. [DOI: ] - PubMed

References to studies awaiting assessment

Fommei 2015 {published data only}
    1. Fommei E, Ghione S, Biagini S, Corrao G, Mancia G. A proposal for the idea of a flexible‐combination polypill in arterial hypertension. Journal of Hypertension. 2015; Vol. 33:e258.
NCT00530946 {published data only}
    1. NCT00530946. A randomized study to evaluate efficacy and safety of a fixed combination therapy of amlodipine and atorvastatin [A multi‐center, randomized study to evaluate efficacy and safety of a fixed combination therapy of amlodipine and atorvastatin in the treatment of concurrent hypertension and hyper‐LDL‐cholesterolemia]. clinicaltrials.gov/ct2/show/NCT00530946 (first received 13 September 2007).
NCT01004705 {published data only}
    1. NCT01004705. Cardiovascular fixed dose combination pill: a pharmacodynamic study of a fixed dose combination of acetylsalicylic acid, simvastatin, and ramipril in subjects with elevated LDL cholesterol. clinicaltrials.gov/ct2/show/NCT01004705 (first received 23 October 2009).
NCT01005290 {published data only}
    1. NCT01005290. Cardiovascular fixed dose combination pill: a pharmacodynamic interaction study to evaluate the effect of a fixed dose combination of acetylsalicylic acid, simvastatin and ramipril (cardiovascular fixed dose combination pill) on blood pressure. clinicaltrials.gov/ct2/show/NCT01005290 (first received 22 October 2009).
NCT01362218 {published data only}
    1. NCT01362218. Cardiovascular fixed combination pill ASR: pharmacodynamic clinical trial of a fixed dose combination of acetylsalicylic acid, simvastatin, and ramipril (cardiovascular polypill) on LDL cholesterol. clinicaltrials.gov/ct2/show/NCT01362218 (first received 26 May 2011).
NCT01406431 {published data only}
    1. NCT01406431. A single dose, sequence‐randomized, open‐label, 2x2 crossover study to compare pharmacokinetics between pitavastatin and valsartan co‐administration and Livalo® fixed combination drug in healthy male subjects. clinicaltrials.gov/ct2/show/NCT01406431 (first received 26 July 2011).
NCT01764178 {published data only}
    1. NCT01764178. A single dose, sequence‐randomized, open‐label, 2x2 crossover study to compare pharmacokinetics between pitavastatn and valsartan co‐administration and Livalo complex product in healthy male subjects. clinicaltrials.gov/ct2/show/NCT01764178 (first received 1 January 2013).
NCT02075619 {published data only}
    1. NCT02075619. An open‐label, randomized, single dose, three‐way crossover, six sequence pilot study to evaluate the relative bioavailability of one amlodipine 10mg tablet and rosuvastatin 20mg tablet to two fixed dose combination tablet formulations of amlodipine (10mg) and rosuvastatin (20mg) in healthy adult male and female subjects under fasting conditions. clinicaltrials.gov/ct2/show/NCT02075619 (first received 27 February 2014).
NCT02569814 {published data only}
    1. NCT02569814. A study to compare the pharmacokinetics and safety of a fixed dose combination of fimasartan/amlodipine/rosuvastatin. clinicaltrials.gov/ct2/show/NCT02569814 (first received 5 October 2015).
NCT02662894 {published data only}
    1. NCT02662894. Efficacy of fixed‐dose combination of valsartan + rosuvastatin versus their isolated components for hypertension and dyslipidemia. clinicaltrials.gov/ct2/show/NCT02662894 (first received 23 November 2015).
NCT02791958 {published data only}
    1. NCT02791958. Pharmacodynamic equivalence study of ramipril 10 mg and atorvastatin 40 mg administered as a cardiovascular fixed dose combination pill AAR as compared to monotherapy with the reference products Altace® 10 mg and Lipitor® 40 mg. clinicaltrials.gov/ct2/show/NCT02791958 (first received 15 February 2016).
NCT02842359 {published data only}
    1. NCT02842359. Efficacy evaluation of metabolic, anti‐inflammatory, and antioxidative factors of irbesartan/atorvastatin fixed‐dose combination in type 2 diabetic patients diagnosed with hyperlipidemia and hypertension, with adequately controlled blood glucose levels. clinicaltrials.gov/ct2/show/NCT02842359 (first received 20 July 2016).

References to ongoing studies

INTEGRATE {published data only}
    1. Hayek A, Joshi R, Usherwood T, Webster R, Kaur B, Saini B, et al. An integrated general practice and pharmacy‐based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: protocol for a cluster randomized controlled trial. Implementation Science 2016;11:129. - PMC - PubMed
    1. Joshi R, Patel A, Peiris D, Saini B, Usherwood T, Armor C, et al. INTegrated Electronic General practice support tool, phaRmacy led intervention And combination Therapy Evaluation trial (INTEGRATE). Heart Lung and Circulation. 2015:S385.
NCT01646437 {published data only}
    1. NCT01646437. The International Polycap Study‐3. clinicaltrials.gov/ct2/show/NCT01646437 (first received 10 July 2012).
NCT01826019 {published data only}
    1. NCT01826019. Heart Outcomes Prevention and Evaluation 4 (HOPE‐4). clinicaltrials.gov/ct2/show/NCT01826019 (first received 31 March 2013).
NCT02278471 {published data only}
    1. NCT02278471. The SCCS polypill pilot trial. clinicaltrials.gov/ct2/show/NCT02278471 (first received 13 October 2014).
NCT02596126 {published data only}
    1. NCT02596126. SEcondary prevention of Cardiovascular disease in the Elderly trial (SECURE). clinicaltrials.gov/ct2/show/NCT02596126 (first received 5 October 2015).
PolyIran {published data only}
    1. Merat S, Poustchi H, Hemming K, Jafari E, Radmard AR, Nateghi A, et al. PolyPill for prevention of cardiovascular disease in an urban Iranian population with special focus on nonalcoholic steatohepatitis: a pragmatic randomized controlled trial within a cohort (PolyIran ‐ Liver) ‐ study protocol. Archives of Iranian Medicine 2015;18:515‐23. - PubMed
    1. NCT01271985. Prevention of cardiovascular disease in middle‐aged and elderly Iranians using a single polypill (PolyIran). clinicaltrials.gov/ct2/show/NCT01271985 (first received 14 December 2010).
    1. 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. European Journal of Preventive Cardiology 2015;22:1609‐17. - PMC - PubMed
    1. Roshandel G, Ostovaneh MR, Poustchi H, Malekzadeh F, Sepanlou SG, Honarvar MR, et al. Reliability analysis of a newly developed questionnaire for quality control of follow‐up visits in PolyIran study. Archives of Iranian Medicine 2016;19:551‐5. - PubMed

Additional references

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Armitage 2010
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Baigent 2009
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Bangalore 2007
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Berry 2012
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Colhoun 2004
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Collins 1990
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References to other published versions of this review

deCates 2014
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