Original article
Pharmacodynamic study of the cardiovascular polypill. Is there any interaction among the monocomponents?Estudio farmacodinámico del policomprimido cardiovascular: ¿existe algún tipo de interacción entre los monocomponentes?

https://doi.org/10.1016/j.rec.2019.11.008Get rights and content

Abstract

Introduction and objectives

To compare the pharmacodynamics of the CNIC polypill (atorvastatin 40 mg/ramipril 10 mg/aspirin 100 mg) in terms of low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP), with the corresponding reference products (atorvastatin and ramipril).

Methods

This was a multicenter, randomized, open-label, and parallel 3-arm study comparing the effect of the CNIC polypill vs ramipril 10 mg and atorvastatin 40 mg on SBP and LDL-C. The coprimary endpoints were differences in the adjusted mean 24-hour SBP (using ambulatory BP measurement) and LDL-C during the study period estimated using an ANCOVA model.

Results

Of the 241 patients included in the per protocol population, 84 received the CNIC polypill (group A), 84 atorvastatin (group B), and 73 ramipril (group C). SBP decreased from 139.3 ± 12.5 to 133.2 ± 12.9 mmHg in group A and from 138.1 ± 11.9 to 134.0 ± 12.8 mmHg in group C (baseline adjusted mean difference for the decrease in SBP was 1.77 mmHg (90%CI, −0.5 to 4.0) in favor of group A, without reaching statistical significance. LDL-C was reduced by 33.9 ± 21.6 and 29.2 ± 25.8 mg/dL in groups A and B, respectively (baseline adjusted mean difference for the decrease in LDL-C was 7.0% (90%CI, 1.5–12.4), a significantly greater decrease with the polypill). The 3 treatments were well tolerated.

Conclusions

The results of this study rule out a negative effect on blood pressure of the interaction between the components of the CNIC polypill. The reduction in LDL-C was greater in the CNIC polypill group, suggesting a synergistic effect of the components.

Resumen

Introducción y objetivos

Comparar la farmacodinámica del policomprimido CNIC (atorvastatina 40 mg, ramipril 10 mg, ácido acetilsalicílico 100 mg) sobre el colesterol unido a lipoproteínas de baja densidad (c-LDL) y presión arterial sistólica (PAS) con los productos de referencia, atorvastatina y ramipril.

Métodos

Estudio multicéntrico, aleatorizado, abierto, de 3 grupos paralelos, que comparó el efecto del policomprimido CNIC frente a ramipril 10 mg y atorvastatina 40 mg sobre la PAS y c-LDL. Los objetivos coprimarios fueron las diferencias en las medias ajustadas de PAS 24 h (mediante monitorización ambulatoria de PA) y el c-LDL durante el estudio, mediante un modelo ANCOVA.

Resultados

De los 241 pacientes en la población por protocolo, 84 recibieron policomprimido CNIC (grupo A), 84 atorvastatina (grupo B), y 73 ramipril (grupo C). La PAS se redujo de 139,3 (12,5) a 133,2 (12,9) mmHg en el grupo A y de 138,1 (11,9) a 134,0 (12,8) mmHg en el grupo C (diferencia media ajustada de PAS desde niveles basales 1,77 mmHg (IC90%, −0,5–4,0) a favor del grupo A, sin alcanzar diferencias significativas. El c-LDL se redujo en 33,9 (21,6) y 29,2 (25,8) mg/dl en los grupos A y B, respectivamente (diferencia media ajustada desde niveles basales para el descenso del c-LDL del 7,0% (IC90%, 1,5–12,4), significativamente a favor del policomprimido). Los 3 tratamientos fueron bien tolerados.

Conclusiones

Los resultados de este estudio descartan un efecto negativo de la interacción entre los componentes del policomprimido-CNIC sobre la PA. La reducción del c-LDL fue mayor con el policomprimido-CNIC, sugiriendo un efecto sinérgico de los componentes.

Section snippets

INTRODUCTION

Cardiovascular disease is the main cause of premature death worldwide in adults, accounting for more than 30% of all deaths.1 In the last few decades, reduced cardiovascular mortality has been reported in developed countries, thus highlighting the importance of secondary prevention.2 International guidelines indicate that the most effective cardioprotective drug therapy for secondary prevention includes angiotensin-converting enzyme inhibitors (ACEi), statins, and low-dose aspirin.3, 4, 5

METHODS

This was a multicenter, randomized, open-label, repeated-dose, parallel enriched 3-arm study. The main objective was to compare pharmacodynamic interactions in the CNIC polypill (effect on SBP and LDL-C) and the reference products, namely, atorvastatin and ramipril. Secondary objectives were to compare diastolic BP (DBP), high-density lipoprotein (HDL) cholesterol (HDL-C), total cholesterol, and triglycerides between the groups at the end of the study. Finally, the safety and tolerability of

RESULTS

The study flow chart is shown in figure 2. A total of 403 participants were enrolled. Of these, 321 were randomized: 105 participants to the CNIC polypill arm and 108 participants each to the atorvastatin 40 mg and ramipril 10 mg arms were included in the safety analysis. The per protocol population included 241 participants with no major protocol deviations and adherence to treatment (80%-120%), with 84 participants in the CNIC polypill arm, 84 participants in the atorvastatin arm, and 73

DISCUSSION

The results of our study suggest that a negative pharmacodynamic interaction between the components of the polypill can be ruled out (ie, a reduction in the BP-lowering effect of ramipril owing to a possible interaction with aspirin). Furthermore, no significant differences were observed in the total number of participants experiencing TEAEs in the CNIC polypill group compared with the ramipril or atorvastatin group. Therefore, the CNIC polypill should be considered at least as safe as the

CONCLUSIONS

The results of this study rule out a negative effect on BP resulting from the interaction between the components of the CNIC polypill. The reduction in LDL-C was greater in the CNIC polypill group, thus suggesting a synergistic effect of the components. This synergistic effect did not translate into more frequent adverse effects.

WHAT IS KNOWN ABOUT THE TOPIC?

  • -

    Several clinical trials have demonstrated the safety and efficacy of cardiovascular polypills in cardiovascular prevention.

  • -

    The CNIC polypill contains aspirin, ramipril

FUNDING

Writing and editorial assistance was provided by Content Ed Net (Madrid, Spain) with funding from Ferrer Internacional S.A.

CONFLICTS OF INTEREST

J.R. González-Juanatey has received speaker fees Ferrer. N. Oudovenko is a Ferrer employee. The other authors have nothing to disclose.

Acknowledgements

Authors would like to thank José Luis Lorenzo Ferrer, an employee of Ferrer, who helped to edit the manuscript.

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