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

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 ).

Keywords: Cardiovascular disease; Cardiovascular risk factors; Fixed-dose combination; Non-inferiority trial; Polypill; Primary prevention.

Fig. 1

CONSORT diagram of the flow of participants through the trial. LDL-c low-density lipoprotein cholesterol; mITT modified intent-to-treat population; SBP systolic blood pressure

Fig. 2

Graphs with the change from baseline and after 16 weeks of treatment with the CNIC-polypill strategy or usual care for LDL-c (A) and systolic blood pressure (C) and estimated mean difference between treatments for LDL-c (B) and systolic blood pressure and (D). LDL-c low-density lipoprotein; LSM least square mean; SBP systolic blood pressure

Fig. 3

Graphs with the percentage change from baseline for each group and mean change difference between the CNIC-polypill strategy and usual care after 16 weeks for LDL-cholesterol (a), systolic blood pressure (b), total cholesterol (c), non-HDL cholesterol (d), HDL-cholesterol (e), triglycerides (f), and diastolic blood pressure (g). DBP diastolic blood pressure; HDL high-density lipoprotein cholesterol; LDL-c low-density lipoprotein cholesterol; SBP systolic blood pressure; TC total cholesterol; TG triglycerides

Fig. 4

Graphs with the percentage of patients achieving target LDL-c levels* (a) or BP values** (b) at baseline and after 16 weeks or treatment with the CNIC-polypill strategy or usual care. BP blood pressure; LDL-c low-density lipoprotein colesterol. *LDL-c controlled if < 100 mg/dL (or < 70 mg/dL in subjects with diabetes mellitus and subclinical atherosclerosis). **BP controlled if < 140/90 mm Hg (< 130/80 mmHg in subjects with diabetes mellitus)

Fig. 5

Plot with the mean change from baseline in the SCORE and PCE 10-year estimated CV risk after 16 weeks or treatment with the CNIC-polypill strategy and usual care. SD standard deviation, PCE US-derived Pooled Cohort Risk Equations; SCORE European Systematic Coronary Risk Evaluation