Cardiopulse 561 doi:10.1093/eurheartj/ehaa1064 Weekly Journal Scan

A one-size-fits-all polypill strategy for primary prevention in the era of precision medicine?

Comment on “Polypill with or without in Persons without ” which was published in the New Engl J Med (doi: 10.1056/NEJMoa2028220). Downloaded from https://academic.oup.com/eurheartj/article/42/6/561/6104708 by guest on 04 October 2021

Key Points

• The International Study 3 (TIPS-3),1 was a double-blind, randomized, placebo-controlled trial enrolling a primary-prevention popu- lation at intermediate or high risk of cardiovascular disease (CVD). Using a 2-by-2-by-2 factorial design, 5713 participants were randomly assigned to receive: (i) a fixed-dose combination of three blood pressure (BP)-lowering ( 100 mg, ramipril 10 mg, and 25 mg) and 40 mg in a single polypill taken once daily or placebo; (ii) enteric-coated aspirin 75 mg daily or placebo; and (iii) vitamin D or placebo monthly. • After a mean follow-up of 4.6 years, the primary endpoint [a composite of CV death, , myocardial infarction (MI), heart failure, resus- citated cardiac arrest, or revascularization] occurred in 4.4% of patients treated with the polypill vs. 5.5% among those treated with placebo [hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.63–1.00]. • TIPS-3 participants who received aspirin had a non-significantly lower rate of CV death, MI, or stroke vs. placebo (4.1% vs. 4.7%; HR 0.86, 95% CI 0.67-1.10). • Combined treatment with the polypill plus aspirin led to a lower incidence of the primary endpoint than double placebo (4.1% vs. 5.8%; HR 0.69, 95% CI 0.50–0.97) with a similar reduction in CV death, MI, or stroke (secondary outcome). • The incidence of hypotension or dizziness was higher in groups that received the polypill than in their respective placebo groups. There was no excess of bleeding events in participants receiving aspirin and no serious adverse events.

Comment dose adjustment to targets, and the concern for unnecessary medica- tion use. A polypill strategy to control the growing public health challenge of Results from the low-dose aspirin comparisons in TIPS-3 support CVD has been extensively debated since its first proposal two decades aspirin as part of a polypill strategy for primary prevention, despite the ago. Clinical studies enrolling participants from low-middle-income disappointing results reported by the ARRIVE,5 and ASPREE6 trials. countries (LMICs) and from the underserved population of a high- Could TIPS-3 represent the tiebreaker for aspirin use in primary pre- income country2 measured adherence rates, adverse events, and risk vention? The trial was not powered to detect a moderate treatment factor control with promising results. However, these studies did not effect, i.e., a 12% reduction in serious vascular events (SVE), as previ- have adequate statistical power to test the efficacy of a polypill strategy ously reported by a meta-analysis of six primary prevention trials in in reducing CV outcomes, with the exception of HOPE-3,3 PolyIran,4 about 90 000 low-risk subjects,7 and by the more recent, adequately and TIPS-3.1 powered, ASCEND trial8 in approximately 15 000 persons with diabe- Although there was a borderline statistically significant reduction in tes. However, the statistically uncertain 14% reduction in SVE the risk of the primary composite endpoint in individuals treated with recorded in the present study is compatible with the previously dem- the polypill when compared with placebo-treated subjects, the direc- onstrated effect size, despite marked differences in the ethnic origin of tion and magnitude of this effect in TIPS-3, especially in combination study participants. The additive benefit of low-dose aspirin combined with aspirin, were comparable to the results of HOPE-33 and with the BP- and lipid-lowering drugs contained in the polypill is also PolyIran.4 The observed benefits on CV events were consistent with consistent with the additive benefit of aspirin on top of similar CV what would be expected from the modest reductions in the LDL- treatments used by the vast majority of ASCEND participants.8 The cholesterol level (19 mg/dL) and systolic BP (5.8 mmHg), with added apparent lack of an excess of bleeding complications in aspirin-treated benefits from aspirin. Exploratory analyses suggested that the group of participants in TIPS-3 should be viewed within the context of a much centres that had the greatest differences in risk factor levels had the lower incidence of major bleeding in the placebo arm (0.7% during 4.5- greatest differences in the incidence of CV events with the polypill plus year follow-up) as compared to ASCEND (3.2% over 7.5-year follow- aspirin. Major issues for this strategy are related to the medications up), and inadequate statistical power of TIPS-3 to detect a 30% in- chosen, the high fixed dose of the polypill components, preventing crease in major bleeding, as recorded in the ASCEND trial.8 562 Cardiopulse

Polypill or precision medicine for primary prevention? The use of a cular disease prevention in an underserved population. N Engl J Med polypill strategy has been claimed as an effective solution for those 2019;381:1114–1123. 3. Lonn EM, Bosch J, Lopez-Jaramillo P, Zhu J, Liu L, Pais P, Diaz R, Xavier D, Sliwa who have poor access to care and budget limitations while simplifying K, Dans A, Avezum A, Piegas LS, Keltai K, Keltai M, Chazova I, Peters RJG, Held healthcare delivery, improving cost-effectiveness, and promoting C, Yusoff K, Lewis BS, Jansky P, Parkhomenko A, Khunti K, Toff WD, Reid CM, evidence-based therapy.1–4 In countries with limited resources, the Varigos J, Leiter LA, Molina DI, McKelvie R, Pogue J, Wilkinson J, Jung H, Dagenais G, Yusuf S; HOPE-3 Investigators. Blood-pressure lowering in polypill may provide better protection than inadequate care. On the intermediate-risk persons without cardiovascular disease. N Engl J Med other hand, a trial comparing the polypill vs. a precision medicine strat- 2016;374:2009–2020. egy in high-income countries may help determine whether an ap- 4. Roshandel G, Khoshnia M, Poustchi H, Hemming K, Kamangar F, Gharavi A, Ostovaneh MR, Nateghi A, Majed M, Navabakhsh B, Merat S, Pourshams A, Nalini proach involving simplicity vs. complexity will be more effective in the M, Malekzadeh F, Sadeghi M, Mohammadifard N, Sarrafzadegan N, Naemi-Tabiei M, ongoing challenge of CVD prevention. Fazel A, Brennan P, Etemadi A, Boffetta P, Thomas N, Marshall T, Cheng KK, Malekzadeh R. Effectiveness of polypill for primary and secondary prevention of car- Conflict of interest: G.L. received grant support (to the Institution) diovascular diseases (PolyIran): a pragmatic, cluster-randomised trial. Lancet 2019;394:672–683.. for investigator-initiated research from American Heart Association, Downloaded from https://academic.oup.com/eurheartj/article/42/6/561/6104708 by guest on 04 October 2021 5. Gaziano JM, Brotons C, Coppolecchia R, Cricelli C, Darius H, Gorelick PB, Howard Italian National Health Service and Italian Minister of Education, G, Pearson TA, Rothwell PM, Ruilope LM, Tendera M, Tognoni G; ARRIVE University and Research. She is currently involved in the Research Executive Committee. Use of aspirin to reduce risk of initial vascular events in Programs of the Italian Cardiovascular Network. C.P. received consul- patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet 2018;392:1036–1046. tant and speaker fees from Acticor Biotech, Amgen, Bayer, 6. McNeil JJ, Wolfe R, Woods RL, Tonkin AM, Donnan GA, Nelson MR, Reid CM, GlaxoSmithKline, Tremeau, Zambon, and grant support (to the Lockery JE, Kirpach B, Storey E, Shah RC, Williamson JD, Margolis KL, Ernst ME, Abhayaratna WP, Stocks N, Fitzgerald SM, Orchard SG, Trevaks RE, Beilin LJ, Institution) for investigator-initiated research from AIFA (Italian Drug Johnston CI, Ryan J, Radziszewska B, Jelinek M, Malik M, Eaton CB, Brauer D, Cloud Agency), Bayer, Cancer Research UK and European Commission; he G, Wood EM, Mahady SE, Satterfield S, Grimm R, Murray AM; ASPREE Investigator chairs the Scientific Advisory Board of the International Aspirin Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018;379:1509–1518. Foundation. 7. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A; References Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant 1. Yusuf S, Joseph P, Dans A, Gao P, Teo K, Xavier D, Lopez-Jaramillo Yusoff K, data from randomised trials. Lancet 2009;373:1849–1860. Santoso A, Gamra H, Talukder S, Christou C, Girish P, Yeates K, Xavier F, Dagenais 8. Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, G, Rocha C, McCready T, Tyrwhitt J, Bosch J, Pais P; International Polycap Study 3 Aung T, Haynes R, Cox J, Murawska A, Young A, Lay M, Chen F, Sammons E, Investigators. Polypill with or without aspirin in persons without cardiovascular dis- Waters E, Adler A, Bodansky J, Farmer A, McPherson R, Neil A, Simpson D, Peto ease. N Engl J Med 2020; doi: 10.1056/NEJMoa2028220. R, Baigent C, Collins R, Parish S, Armitage J; ASCEND Study Collaborative Group. 2. Munoz~ D, Uzoije P, Reynolds C, Miller R, Walkley D, Pappalardo S, Tousey P, Effects of aspirin for primary prevention in persons with mellitus. N Engl J Munro H, Gonzales H, Song W, White C, Blot WJ, Wang TJ. Polypill for cardiovas- Med 2018;379:1529–1539.

Carlo Patrono MD, FESC Giovanna Liuzzo MD, PhD, FESC Adjunct Professor of Pharmacology, Associate Professor of Cardiology, Catholic University, School of Medicine, Catholic University, Italy and Perelman School of Medicine, Largo A. Gemelli, Rome, Italy University of Pennsylvania, Email: [email protected] Philadelphia, USA