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
Authors: Mostaza José M. , Suárez-Fernández Carmen , Cosín-Sales Juan , Gómez-Huelgas Ricardo , Brotons Carlos , Araujo Francisco Pestana , Borrayo Gabriela , Ruiz Emilio ,   VULCANO investigators, Pérez Pablo , Espinosa Jacinto , Sobrino Javier , Posé Antonio , Arroyo Díaz Juan Antonio , García Vallejo Olga , Cubo Romano Maria Pilar , Jansen Chaparro Sergio , Cabezón Mariscal Jesús , Rico Corral Miguel Angel , Abellán Alemán José , Orozco Beltrán Domingo , Escobar Jimenez Luis , Valdivieso Felices Pedro , Pedro-Botet Montoya Juan Carlos , Masana Marín Luis , Guijarro Carlos , Díaz Rodríguez Ángel , Díaz Díaz José Luis , De la Peña Fernández Andrés , Coloma Bazán Emmanuel , Cuenca Acevedo Rafael , Suárez Fernández Carmen , Civeira Fernando , Castellano Vázquez José María , Mostaza Prieto José María , Suárez Tembra Manuel , Alfonso Megido Joaquín , Castiella Herrero Jesús , Tamarit Juan José , Martínez-Hervás Alonso Miguel Ángel , Carrasco Franco Francisco Javier , Álvarez Sala Luis , Calderón Sandubete Enrique , Rovira Daudi Eduardo , Bonilla Rovira Fernando , Murcia Zaragoza Juan Manuel , Cuixart Costa Lluís , Bianchi Llave José Luis , Álvarez Sánchez Carmen , Marqués Da Silva Pedro , Cunha Vitória , Santos Catarina , Araujo Francisco , Moura José , Rosas Peralta Martín 
Published: December 2022

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, atorvastatin, 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 CNIC-polypill arm.

Conclusion
The switch from conventional treatment to the CNIC-polypill approach was safe and appears a reasonable 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).