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Polypills and cardiovascular prevention: dream wedding or ménage à trois (or quatre, cinq, six…)?

Comment by Giuseppe Biondi-Zoccai, Population Science and Public Health Section member, et al.

"Seek not the favor of the multitude; it is seldom got by honest and lawful means. But seek the testimony of few; and number not voices, but weigh them." Immanuel Kant

Preventive Cardiology
Pharmacology and Pharmacotherapy

Cardiovascular prevention entails several subtleties, spanning from the precise definition of cardiovascular risk factors and disease, to different level of preventive strategies, which can range from education and lifestyle recommendations (e.g. smoking cessation) to dietary, pharmacologic and more invasive interventions.(1,2) A key dimension of cardiovascular health maintenance and thus prevention is when preventive interventions are applied during the natural history of cardiovascular disease. Focusing indeed on specific timeframes, we can typically distinguish primordial, primary, secondary and tertiary preventative efforts (Table 1).(3) Clearly, there is typically a strong association between the phase in the natural history of a disease and the number needed to intervene to prevent one event, such that number-needed-to-treat (NNT). Another crucial aspect is the individualized risk-benefit assessment, possibly quantifiable with the NNT/number-needed-to-harm (NNH) ratio.(4) Such risk-benefit profile is impactful also to maximize long-term compliance.

While Professor Sir Nicholas Wald is unlikely to be awarded a Nobel prize, we should clearly bear in mind his seminal contributions to prevention at large, including cardiovascular prevention.(5) Most poignantly for cardiovascular practitioners, we must thank him for his ingenuity in applying the concept of the triple test (later quad test) proven effective for neural tube defect diagnosis to pharmacologic prevention.(6) Indeed, in 2003 Wald and Law proposed an apparently banal but actually genial idea: the combination of several effective and tolerated drugs into a single pill, the polypill, as a tool to maximize preventive effectiveness and adherence.(7) The polypill concept has been expanded over the years to many other clinical areas, including secondary cardiovascular prevention.(8) While each individual with established cardiovascular disease might warrant individualized diagnostic, prognostic and management strategies, several cardiovascular patients are more alike than different and thus suitable for being prescribed secondary prevention polypills.

The meta-analysis conducted by Rivera and colleagues and published recently in the European Journal of Preventive Cardiology is a perfect useful summary of the favourable effects of polypills designed for secondary cardiovascular prevention.(9) Indeed, in a pooled analysis including 8 randomized trials enrolling as many as 6541 patients, followed for a period of time ranging between 6 and 60 months, a polypill could significantly reduce cardiovascular mortality, even if all-cause mortality was relatively similar. Notwithstanding the limitations in the primary studies, including heterogeneity of treatments and variable/short follow-up, this review confirms the safety and promising impact of a polypill approach in cardiovascular prevention. A key caveat remains how to pick the most appropriate polypill for each patient of interest, in light of the individual features, the phase of cardiovascular disease, and the goal of prevention. Furthermore, it should be borne in mind that the more the agents included in a polypill, the more the potential combinations (Figure 1), and these figures underestimate the role of dosage of each agent.(10)

In conclusion, without viewing polypills as the Holy Grail of cardiovascular prevention, it is clear that their role is confirmed and will progressively grow even more, helping societies as well as individuals to reach their prevention goals. 

Table 1. Stages of cardiovascular prevention

Stage Aim
Primordial Avoiding the development of risk factors
Primary Avoiding the development of disease
Secondary Reducing the severity of the clinical manifestation of disease or reducing the risk of recurrence
Tertiary Avoiding the functional impact of disease
Quaternary Avoiding overmedicalization and unethical interventions


Figure 1. Possible combinations of polypill as a function of drugs available and chosen sample of polypill (computations performed with


Note: The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.


Giuseppe Biondi-Zoccai et al. commented on:

9. Rivera A, Campos B, Ceolin S, Godoi A, Castanha E, Campello Jorge CA, Cardoso R. Polypill-Based Strategy versus Usual Care for Secondary Prevention of Cardiovascular Disease: A Meta-Analysis of Randomised Controlled Trials. Eur J Prev Cardiol. 2023 Jul 25:zwad245. doi: 10.1093/eurjpc/zwad245. Epub ahead of print. PMID: 37490769.

Additional references:

1. Aggarwal R, Yeh RW, Joynt Maddox KE, Wadhera RK. Cardiovascular Risk Factor Prevalence, Treatment, and Control in US Adults Aged 20 to 44 Years, 2009 to March 2020. JAMA. 2023 Mar 21;329(11):899-909. doi: 10.1001/jama.2023.2307. PMID: 36871237; PMCID: PMC9986841.
2. Versaci F, Sciarretta S, Scappaticci M, Di Pietro R, Calcagno S, Del Prete A, Gaspardone C, Biondi Zoccai G. Renal arteries denervation: from the treatment of resistant hypertension to the treatment of atrial fibrillation. Eur Heart J Suppl. 2021 Oct 8;23(Suppl E):E177-E183. doi: 10.1093/eurheartj/suab117. PMID: 34650381; PMCID: PMC8503489.
3. Gillman MW. Primordial prevention of cardiovascular disease. Circulation. 2015 Feb 17;131(7):599-601. doi: 10.1161/CIRCULATIONAHA.115.014849. Epub 2015 Jan 20. PMID: 25605661; PMCID: PMC4349501.
4. Ageno W. Rivaroxaban: An Evaluation of its Cardiovascular Benefit-Risk Profile Across Indications Based on Numbers Needed to Treat or Harm, and on Clinically Meaningful Endpoint Comparisons. Drugs R D. 2015 Dec;15(4):295-306. doi: 10.1007/s40268-015-0105-9. PMID: 26416655; PMCID: PMC4662944.
5. Wikipedia, The Free Encyclopedia: Nicholas Wald. Available at: (last accessed on August 26, 2023). 
6. Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Royston P, Chard T, Haddow JE, Knight GJ, Palomaki GE, Canick JA. Maternal serum screening for Down's syndrome in early pregnancy. BMJ. 1988 Oct 8;297(6653):883-7. doi: 10.1136/bmj.297.6653.883. Erratum in: BMJ 1988 Oct 22;297(6655):1029. PMID: 2460174; PMCID: PMC1834444.
7. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003 Jun 28;326(7404):1419. doi: 10.1136/bmj.326.7404.1419. Erratum in: BMJ. 2003 Sep 13;327(7415):586. Erratum in: BMJ. 2006 Sep;60(9):823. PMID: 12829553; PMCID: PMC162259.
8. Hashmani S, Madhyastha R, El Nekidy W, Atallah B, Bader F, Attallah N. Polypharmacy in cardiorenal syndrome patients. Clin Nephrol. 2023 Mar;99(3):141-148. doi: 10.5414/CN110989. PMID: 36633378.
10. Wang A, Veasaw K, Subhan S, Patel J, Frishman WH. Examining the Use of a Polypill in Cardiovascular Disease Prevention. Cardiol Rev. 2023 Jul 4. doi: 10.1097/CRD.0000000000000574. Epub ahead of print. PMID: 37401822.

Notes to editor


Giuseppe Biondi-Zoccai,1,2 Anastasia Mihailidou,3,4 Vassilios S. Vassiliou,5,6 Elena Cavarretta1,2
1 - Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
2 – Mediterranea Cardiocentro, Napoli, Italy
3 - Department of Cardiology and Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia
4 - Macquarie University, Sydney, New South Wales, Australia
5 - Department of Cardiology, Norfolk and Norwich University Hospital, Norwich, UK
6 - Norwich Medical School, University of East Anglia, Norwich, UK

Corresponding author: Prof. Giuseppe Biondi-Zoccai, Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy. Email