Safety and efficacy of a cardiovascular polypill in people at high and very high risk without a previous cardiovascular event: the international VULCANO randomised clinical trial

(2022) 22:560 Mostaza et al. BMC Cardiovascular Disorders https://doi.org/10.1186/s12872-022-03013-w RESEARCH ARTICLE Open Access Safety and efficacy of a cardiovascular polypill in people at high and very high risk without a previous cardiovascular event: the international VULCANO randomised clinical trial José M. Mostaza1* , Carmen Suárez‑Fernández2,3,4, Juan Cosín‑Sales5,6, Ricardo Gómez‑Huelgas7,8, Carlos Brotons9,10, Francisco Pestana Araujo11, Gabriela Borrayo12 and Emilio Ruiz13 on behalf of VULCANO investigators Abstract Background: Cardiovascular (CV) polypills are a useful baseline treatment to prevent CV diseases by combining different drug classes in a single pill to simultaneously target more than one risk factor. The aim of the present trial was to determine whether the treatment with the CNIC-polypill was at least non-inferior to usual care in terms of low-density lipoprotein cholesterol (LDL-c) and systolic BP (SBP) values in subjects at high or very high risk without a previous CV event. Methods: The VULCANO was an international, multicentre open-label trial involving 492 participants recruited from hospital clinics or primary care centres. Patients were randomised to the CNIC-polypill -containing aspirin, atorvas‑ tatin, and ramipril- or usual care. The primary outcome was the comparison of the mean change in LDL-c and SBP values after 16 weeks of treatment between treatment groups. Results: The upper confidence limit of the mean change in LDL-c between treatments was below the prespecified margin (10 mg/dL) and above zero, and non-inferiority and superiority of the CNIC-polypill (p = 0.0001) was reached. There were no significant differences in SBP between groups. However, the upper confidence limit crossed the prespecified non-inferiority margin of 3 mm Hg. Significant differences favoured the CNIC-polypill in reducing total cholesterol (p = 0.0004) and non-high-density lipoprotein cholesterol levels (p = 0.0017). There were no reports of major bleeding episodes. The frequency of non-serious gastrointestinal disorders was more frequent in the CNICpolypill arm. Conclusion: The switch from conventional treatment to the CNIC-polypill approach was safe and appears a reason‑ able strategy to control risk factors and prevent CVD. Trial registration This trial was registered in the EU Clinical Trials Register (EudraCT) the 20th February 2017 (register number 2016-004015-13; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2016-004015-13). *Correspondence: 1 Internal Medicine Service, Hospital Carlos III, Madrid, Spain Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 2 of 15 Keywords: Cardiovascular disease, Primary prevention, Fixed-dose combination, Polypill, Non-inferiority trial, Cardiovascular risk factors Background According to the World Health Organization (WHO) latest report on the global burden of disease, cardiovascular diseases (CVD), particularly ischemic heart disease and stroke, are the leading causes of death among subjects 50 years and older [1]. High systolic blood pressure (SBP) and high low-density lipoprotein cholesterol (LDL-c) are the two main metabolic modifiable risk factors contributing to CVD development [2]. Of note, the global trend for both conditions is increasing worldwide and represents a significant public health challenge that requires intervention to promote lifestyle modifications and implement pharmacological strategies when needed [2]. However, audits of clinical practice in Europe (EUROASPIRE studies) have found that the risk factor control among patients at high risk of CVD is inadequate, with only 28–35% and 28–37% of patients at or below the recommended blood pressure (BP) and LDL-c target, respectively [3]. CVD must be seen as a continuum from early to advanced vascular disease, end-stage heart failure, and death that develops over decades due to a chain of events linked to several CV risk factors [4]. As such, subjects considered at high or very high risk are those with documented CVD and those with diabetes mellitus (DM), severe-to-moderate chronic kidney disease (CDK), or marked hypercholesterolaemia or hypertension (HT) as single risk factors [5]. As CV risk factors commonly cluster and interact in individuals they should be treated as a composite whole and not each factor in isolation [6, 7]. Based on this notion, polypills emerged as the baseline therapy to prevent CVD [8]. Different versions of multipurpose CV polypills are currently available, in general containing one or more BP-lowering drug classes and one lipid-lowering drug (statin) with or without an antiplatelet agent (aspirin) [9]. Compared with usual care in primary and secondary prevention, the benefits of the CV polypill strategy have been documented in several trials using polypills with a varying number of constituents, most of them licensed in Asia [9–11]. Notably, a recent meta-analysis of three large trials in patients in primary prevention taking fixeddose combinations -including ≥ 2 BP-lowering drugs and a statin with or without aspirin- found that the rate CVD events was significantly reduced compared with placebo or minimal care irrespective of CV risk factors [12]. The CNIC (Centro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, Madrid) polypill, which contains 100 mg of acetylsalicylic acid, two possible doses of atorvastatin (20 mg or 40 mg), and three possible doses of ramipril (2.5 mg, 5 mg, or 10 mg), is the only CV polypill currently marketed in European countries [9, 13]. In patients in secondary CVD prevention and patients at high CV risk in routine clinical practice, the CNIC-polypill has been reported to efficiently reduce and control BP and LDL-c, improve the overall lipid profile -including markers of atherogenic dyslipid (...truncated)