Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 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 CNIC- polypill 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.​clini​caltr​ialsr​egist​er.​eu/​ctr-​search/​search?​query=​2016-​004015-​13). *Correspondence: josemaria.mostaza@salud.madrid.org 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://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​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 which contains 100 mg of acetylsalicylic acid, two pos- According to the World Health Organization (WHO) lat- sible doses of atorvastatin (20 mg or 40 mg), and three est report on the global burden of disease, cardiovascular possible doses of ramipril (2.5 mg, 5 mg, or 10 mg), is the diseases (CVD), particularly ischemic heart disease and only CV polypill currently marketed in European coun- stroke, are the leading causes of death among subjects tries [9, 13]. In patients in secondary CVD prevention 50 years and older [1]. High systolic blood pressure (SBP) and patients at high CV risk in routine clinical practice, and high low-density lipoprotein cholesterol (LDL-c) are the CNIC-polypill has been reported to efficiently reduce the two main metabolic modifiable risk factors contribut- and control BP and LDL-c, improve the overall lipid pro- ing to CVD development [2]. Of note, the global trend for file -including markers of atherogenic dyslipidaemia-, both conditions is increasing worldwide and represents a decrease the predicted CVD risk, and reduce the inci- significant public health challenge that requires interven- dence of CV events among those with established CVD tion to promote lifestyle modifications and implement [14–19] pharmacological strategies when needed [2]. However, The only non-inferiority trial conducted to date with audits of clinical practice in Europe (EUROASPIRE a CV polypill is the phase II exploratory Indian Polycap studies) have found that the risk factor control among Study (TIPS), which compared a polypill licensed in Asia patients at high risk of CVD is inadequate, with only (consisting of low doses of thiazide, atenolol, ramipril, 28–35% and 28–37% of patients at or below the recom- simvastatin, and aspirin) vs conventional multipill treat- mended blood pressure (BP) and LDL-c target, respec- ment in subjects without CVD with one risk factor [20]. tively [3]. Overall, the Polycap was non-inferior to its individual CVD must be seen as a continuum from early to components in its effect on BP and heart rate. advanced vascular disease, end-stage heart failure, and The main objective of the present randomised clinical death that develops over decades due to a chain of events trial was to determine whether the treatment with the linked to several CV risk factors [4]. As such, subjects CNIC-polypill for 16 weeks was at least non-inferior to considered at high or very high risk are those with doc- usual care (multipill strategy) in terms of LDL-c and SBP umented CVD and those with diabetes mellitus (DM), values in subjects at high or very high risk without a pre- severe-to-moderate chronic kidney disease (CDK), or vious CV event. marked hypercholesterolaemia or hypertension (HT) as single risk factors [5]. As CV risk factors commonly clus- Methods ter and interact in individuals they should be treated as a Clinical trial design composite whole and not each factor in isolation [6, 7]. The VULCANO study was a phase III, international, Based on this notion, polypills emerged as the baseline multicentre, prospective, randomised, open-label, par- therapy to prevent CVD [8]. Different versions of multi- allel-group trial of treatment with CNIC-polypill for purpose CV polypills are currently available, in general 16 weeks compared with standard care in people at high containing one or more BP-lowering drug classes and or very high CVD risk but without established disease. one lipid-lowering drug (statin) with or without an anti- The study took place between the 5th June 2017 and the platelet agent (aspirin) [9]. 11th December 2019. Compared with usual care in primary and secondary Data in this paper were reported in compliance with prevention, the benefits of the CV polypill strategy have the Consolidated Standards of Reporting Trials (CON- been documented in several trials using polypills with a SORT) guidelines extension for randomised trials. varying number of constituents, most of them licensed in Asia [9–11]. Notably, a recent meta-analysis of three Participants large trials in patients in primary prevention taking fixed- Participants were recruited from 47 hospital clinics or dose combinations -including ≥ 2 BP-lowering drugs and primary care centres, 41 in Spain, five in Portugal, and a statin with or without aspirin- found that the rate CVD one in Mexico. events was significantly reduced compared with placebo Eligible individuals were men and women aged 18 years or minimal care irrespective of CV risk factors [12]. The or older at high or very high risk of CVD, defined as CNIC (Centro Nacional de Investigaciones Cardiovas- (a) evidence of subclinical atherosclerosis diagnosed culares, Instituto de Salud Carlos III, Madrid) polypill, through invasive or non-invasive techniques, including Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 3 of 15 aortic aneurism, significant carotid or coronary atheroma expert opinion (Additional file 1: Tables S2 and S3). In plaque (intima-media thickness [IMT] ≥ 1.5 mm), severe patients previously treated with a single-pill combina- coronary artery calcification (coronary calcium > 300 tion (SPC) of ACEi/ARB plus a diuretic or a calcium Agatston units) or ankle-brachial index [ABI] < 0.9; (b) channel blocker (CCB), the SPC was substituted by the subjects with DM with concomitant HT or albuminuria; CNIC-polypill (at equipotent doses), and they were or (c) patients with HT with the following associated con- also prescribed a diuretic or a CCB. Those allocated to ditions: left ventricular hypertrophy (LVH), albuminuria, usual care continued to receive the same separate med- or renal impairment (defined as estimated glomerular fil- ications and doses before inclusion in the study. After tration rate [eGFR] 30–60 mL/min/1.73 ­m2). randomisation, no modifications of the lipid-lowering According to the investigator’s criteria, each partici- or antihypertensive drugs, doses, or regimens were pant was required to have adequate control of BP and allowed in any treatment group for 16 weeks unless LDL-c while on stable lipid-lowering treatment (with considered essential by the investigator due to a clini- at least one statin) and BP-lowering treatment (with an cally significant increase in the patient’s BP that could angiotensin-converting-enzyme inhibitor [ACEi] or put his/her health at risk. In the case of a clinically an angiotensin II receptor blocker [ARB]) during three significant increase in BP or the need to modify treat- months before randomisation. Finally, according to the ments because of uncontrolled HT or lipid parameters, investigator’s view, it should not be expected that partici- the patient was withdrawn from the study. pants would need to change their lipid-lowering and BP- lowering treatments for 16 weeks after randomisation. Exclusion criteria were contraindications to the CNIC- Trial procedures polypill monocomponents (i.e., atorvastatin, ramipril, or After randomisation, a first visit took place to obtain aspirin) to control LDL-c and BP levels. These included baseline data and a second visit was scheduled after patients with recurrent peptic ulcer and/or gastric intes- 16 weeks of treatment. During the visits, SBP, DBP, and tinal bleeding, cerebrovascular haemorrhage, history heart rate were measured, and a fasting blood sample of dyspepsia, and worsening of haemoglobin levels or was obtained to assess the lipid profile and other routine anaemia that suggested active bleeding according to the haematology and biochemical parameters. Safety was investigator’s view. Moreover, we excluded subjects with evaluated at Week 8 (via telephone), Week 16, and Week a history of prior CV events (e.g., myocardial infarction, 20 (via telephone) to allow for the reporting of adverse revascularisation procedures; ischaemic or haemorrhagic events (AEs). Moreover, the use of concomitant medi- stroke or peripheral artery disease); grade 3 hyperten- cation was assessed at baseline, Week 8, and Week 16 sion (i.e., systolic BP [SBP] > 180 mm Hg and diastolic BP to discard the usage of the following concomitant drugs [DBP] > 110 mm Hg); familiar hypercholesterolemia; tri- during the trial: triple antihypertensive fix-dose combina- glycerides level ≥ 400 mg/dL; or congestive heart failure tion, oral anticoagulants or antiaggregants (except aspi- functional class III-IV (New York Heart Association clas- rin), non-steroidal anti-inflammatory drugs (NSAIDs), sification [NYHA]). gemfibrozil, rifampicin, cyclosporine, aliskiren, metho- trexate, telaprevir, tipranavir/ritonavir, oral fusidic acid, Randomisation and treatment or drugs able to modify the lipid profile (e.g., antidepres- After obtaining written informed consent, individuals sants, antipsychotics, corticoids, or thyroid hormones). entered a 10-days screening phase during which eligi- Participants were followed until the end of the follow- bility for the study was assessed. If eligible, a central up, unacceptable toxicity, or premature withdrawal. randomisation website randomly assigned (1:1) partici- pants to the CNIC-polypill treatment or conventional Outcome measures treatment (usual care). The two primary efficacy outcomes were absolute val- ues of plasma LDL-c level (Friedewald formula) and SBP nium/Trinomia®) arm received one of the six avail- Participants assigned to the CNIC-polypill (Sincro- after 16 weeks of treatment. Secondary outcomes were able formulations, namely 100 mg of aspirin with differences in SBP and DBP values, plasma levels of total either 20 or 40 mg atorvastatin and either 2.5, 5.0, or cholesterol, high-density lipoprotein cholesterol (HDL- 10 mg ramipril (Additional file 1: Table S1) on a daily c), LDL-c, and non-HDL-c. Finally, baseline and Week- regimen for 16 consecutive weeks. The investigators 16 10-year predicted CVD risk was estimated using the selected the dose based on the prior doses of statins US-derived Pooled Cohort Risk Equations (PCE) and the and ACEi/ARB medications taken by the patients and European Systematic Coronary Risk Evaluation (SCORE) according to equipotency tables provided to the clini- [5]. Incidence of AEs up to 20 weeks of follow-up was cians built according to comparative clinical trials and also assessed. Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 4 of 15 Statistical analysis deviations (N = 403). A secondary sensitivity analysis Calculation of sample size was conducted in the ITT population, defined as all We estimated the power for the trial based on assump- randomised subjects who received at least one dose of tions about differences between the baseline and Week medication (N = 492). The last observation carried for- 16 for the two primary outcomes, plasma LDL-c level ward (LOCF) rule was used to impute missing efficacy and SBP values. The required sample size was deter- data at Week 16. mined using the confidence interval approach, consider- For secondary efficacy endpoints (absolute values and ing where the confidence interval for the treatment effect LSM differences with respect to baseline in vital signs and lies with respect to the margin of non-inferiority and lipid profile), the same analysis of covariance (ANCOVA) assuming a null effect (treatments are equal). was performed to calculate the two-sided 95% CIs using In terms of LDL-c, the enrolment of 250 patients (125 baseline values as covariates. Intergroup differences per treatment group) provided > 90% power (α = 0.025) between treatments were assessed using Fisher’s exact to detect non-inferiority, defined as an absolute between- test for categorical variables and the Mann–Whitney U group difference of 10 mg/dL (SD = 30 mg/dL). In terms test for continuous variables. of SBP, we determined that a recruitment target of 424 The proportion of patients with adequate LDL-c and patients (212 per treatment group) provided 80% power BP control, based on target values from the 2016 Euro- (α = 0.025) to detect absolute between-group differences pean Society of Cardiology (ESC) guidelines [23, 24], was of 3 mm Hg (standard deviation [SD] = 11 mm Hg). provided by descriptive statistics and the comparison Accounting for a maximum of 15% loss to follow-up, between treatments at 16 weeks by the exact Fisher test. approximately 250 participants per group were necessary SCORE and PCE scores were analysed as continuous to claim for non-inferiority of the polypill. Based on these variables (risk percentage), by the corresponding risk calculations, the recruitment target was revised to up to categories, and as the reduction in the risk category at 500 randomised participants (250 per treatment group). 16 weeks compared to baseline as binary variable. The comparison between treatments after 16 weeks (abso- Analysis of efficacy variables lute values and differences with respect to baseline) was All randomised participants who received at least one assessed by ANCOVA using the Mann–Whitney U test dose of medication and had available measures for the or the exact Fisher test. main covariables at baseline and Week 16 were included Two-sided p values of less than 0.05 were considered in the analysis (N = 439; modified intent-to-treat popula- to indicate statistical significance. All statistical analyses tion [mITT]). were performed using SAS 9.4 software (SAS Institute, Univariate descriptive statistics and frequency dis- Inc., Cary, NC). tributions were calculated at baseline for all biologi- cal variables in each treatment group. For the primary efficacy endpoint (comparison of absolute LDL-c and Analysis of safety variables SBP values at Week 16), we used analysis of covariance The number of patients who experienced one or more (ANCOVA) to calculate adjusted means and two-sided AEs was analysed using descriptive statistics and 95% CIs, with treatment as fixed explanatory variable reported as the percentage of the subjects enrolled in the and baseline values as covariates. Noninferiority of the trial who received at least one dose of the study treat- CNIC-polypill to usual care could be claimed if the ments (N = 492). upper 95% CI limit for the difference in LDL-c and SBP after 16-week treatment, calculated in terms of base- Results line-adjusted means (least-squares mean, LSM), was Trial structure and baseline characteristics of trial entirely below the prespecified non-inferiority margin participants of 10 mg/dL for LDL-c and 3 mmHg for SBP [21, 22]. If Between June 2017 and July 2019, 534 subjects from the 95% CI for the treatment benefit excluded not only 47 centres were potentially eligible, of whom 499 were the non-inferiority margin but also zero, the P-value enrolled and underwent randomisation, namely 251 to prove the superiority of the CNIC-polypill was cal- to the polypill strategy and 248 to continue with their culated. As a sensitivity analysis, non-inferiority of the usual care (Fig. 1). After treatment initiation, a total of CNIC-polypill was also evaluated in the per-protocol 33 (6.7%) patients were prematurely withdrawn from the population (PP), defined as all randomised patients study, 24 (9.7%) in the CNIC-polypill group and 9 (3.7%) who complied with at least one dose of the assigned in the usual care group. The most frequent reason for treatment, had baseline and Week 16 data on LDL-c discontinuation was the occurrence of adverse events, and SBP measures, and had no significant protocol Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 5 of 15 experienced by 15 (6.1%) and 3 (1.2%) patients in the Finally, and based on their prior therapy, 32 patients CNIC-polypill and usual care group, respectively. (14.7%) received at least one additional medication to the The median duration of follow-up was 141 days (inter- polypill to control dyslipidaemia (mainly with ezetimibe quartile range, 140–146 days) for both groups, and the or fibrates), and 118 (54.1%) to control hypertension follow-up concluded in December 2019. (mainly with hydrochlorothiazide or amlodipine). The mean age of the overall population was 64.6 ± 8.9 years, and there was a higher proportion of Effects on primary efficacy outcomes, systolic BP and LDL‑c males (60%). There were no substantial differences in At baseline, the LDL-c levels were similar between arms the baseline clinical characteristics between the polypill (95.6 mg/dL and 95.8 mg/dL in the CNIC-polypill and strategy and the usual care groups (Table 1). The most usual care groups, respectively) (Figs. 2a and 3a). LSM frequent CV risk factors, present in almost all patients, reductions were observed for both treatment groups after were HT, hypercholesterolaemia, and type 2 diabetes 16 weeks of treatment (11.5 mg/dL and 3.01 mg/dL in the mellitus (T2DM). At study entry, all patients were being CNIC-polypill and the usual care groups, respectively). treated for hyperlipidaemia with a statin (atorvastatin The difference between the two treatments was signifi- and simvastatin as the most frequent ones) and an ACEi/ cant and favoured the CNIC-polypill (−8.48 mg/dL). The ARB (mainly enalapril) for hypertension (Additional upper bound of the two-sided 95% CI was entirely below file 1: Fig. S1). About three-quarters of participants were the 10 mg/dL prespecified non-inferiority margin and on glucose-lowering treatment (mainly with metformin), below zero, demonstrating both non-inferiority and supe- and around half were receiving antiplatelet therapy. riority of the CNIC-polypill (p = 0.0001) (Figs. 2b and3b). 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 Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 6 of 15 Table 1 Baseline clinic characteristics of study participants (mITT analyses with both the per-protocol and the ITT popula- Population) tion (Additional file 1: Table S4). Characteristic CNIC-Polypill Usual care (N = 218) (N = 221) Effects on secondary efficacy outcomes Age (years), mean (SD) 65.4 (8.6) 64.1 (9.2) Lipid profile and diastolic BP Sex (male), n (%) 124 (56.9) 138 (62.4) The total cholesterol values slightly increased (+ 0.7%) 2 BMI (kg/m ), mean (SD) 30.8 (5.1) 30.5 (4.6) in the usual care group, while they decreased (−7.0%) Medical history with the CNIC-polypill (Fig. 3c and Additional file 1: Current smoker, n (%) 26 (11.9) 33 (14.9) Table S5). The LSM for the change between treat- Years of smoking, mean (SD) 36.7 (15,3) 41.0 (12.3) ments was significantly different, favouring the polyp- Cigarettes per day, mean (SD) 13.0 (9.2) 19.3 (39.6) ill (p = 0.0004). A significant advantage with the Hypertension, n (%) 216 (99.1) 221 (100.0) CNIC-polypill was also observed for non-HDL levels, Diabetes Mellitus, n (%) 170 (78.0) 170 (76.9) with a mean decrease that was greater than among those on usual care (8.9% vs 1.8% reduction; Fig. 3d and Addi- Type 1 3 (1.8) 0 (0.0) tional file 1: Table S5), with treatment difference between Type 2 167 (98.2) 170 (100.0) groups favouring the CNIC-polypill (p = 0.0017). The Diabetes Mellitus + hypertension 170 (78.0) 169 (76.5) mean levels of HDL-c decreased to a greater extent Hypercholesterolaemia*, n (%) 212 (97.2) 213 (96.4) with the CNIC-polypill than with usual care (−2.0% vs Hypertriglyceridaemia**, n (%) 38 (17.4) 48 (21.7) −0.5%), but the mean difference between the changes Chronic kidney disease, n (%) 30 (13.8) 21 (9.5) with each treatment was not significant (Fig. 3e and Stage of kidney damage, eGFR (mL/min/1,73m2), n (%) Additional file 1: Table S5). Finally, although the CNIC- Stage I: > 90 0 (0.0) 1 (4.8) polypill decreased triglyceride levels by 3.5% while they Stage II: 60–89 1 (3.3) 0 (0.0) increased by 1.5% with usual care, the adjusted mean Stage III: 45–59 29 (96.7) 20 (95.2) difference for the change between treatments did not Evidence of TOD, n (%) reach statistical significance (Fig. 3f and Additional file 1: Subclinical atherosclerosis 48 (22.0) 50 (22.6) Table S5). Diabetes Mellitus + albuminuria 60 (27.5) 55 (24.9) There was a slight increase in the mean DBP values HT + LVH/albuminuria/CKD 107 (49.1) 113 (51.1) at Week 16 with respect to baseline in both the CNIC- Current medication, n (%) polypill and the usual care groups (0.3% and 0.4%, respec- Taking statins 218 (100.0) 221 (100.0) tively), but the mean difference for the LSM change from Taking ACEi/ARB 218 (100.0) 221 (100.0) baseline between treatments was not significant (Fig. 3g Taking aspirin 115 (52.8) 118 (53.4) and Additional file 1: Table S5). Taking glucose-lowering drugs 166 (75.1) 166 (75.1) ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blocker; CDK, chronic kidney disease; DM, diabetes mellitus; HT, hypertension; Rate of LDL‑c and BP control LVH, left ventricular hypertrophy; TOD, target organ damage As for LDL-c levels, which were above the target in more *Hipercholesterolemia was defined as total cholesterol ≥ 200 mg/dL than 75% of patients in each group, both treatments **Hypertrygliceridemia was defined as triglycerides ≥ 150 mg/dL increased the rates of patients with adequate control at Week 16, with a trend toward a higher percentage of controlled subjects among those on the CNIC-polypill The mean SBP at baseline was 134.4 mm Hg in the strategy (14.2% vs 5.4% increase; p = 0.054; Fig. 4a). At CNIC-polypill group and 133.2 mm Hg in the usual baseline, BP was above the target in more than 62% of the care group (Fig. 2c). The values remained stable during patients in both treatment groups. The rate of BP con- the trial in both treatment groups, with a slight increase trol increased by approximately 4% after 16 weeks of (+ 1.14 mm Hg) in the CNIC-polypill group and a slight treatment in the overall population, with no significant decrease (−0.3 mm Hg) in the usual care group at Week differences between the CNIC-polypill and the usual care 16. The difference in the LSM reductions between treat- arms (p = 0.206; Fig. 4b). ments was not significant (1.43 mm Hg; p = 0.2099), and Among those with LDL-c, BP values or both well con- the upper bound of the two-sided 95% CI was 3.69, thus trolled at baseline, more than half of them were still at extending above the 3 mm Hg prespecified non-inferior- target levels at the end of the study (Week 16), with no ity margin (Fig. 2d). Therefore, the results were inconclu- significant differences between those treated with the sive, and non-inferiority was not proven. CNIC-polypill and those who continued with their usual The results of the analyses with the mITT population care in any case (Additional file 1: Fig. S2). were consistent with those obtained in the sensitivity Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 7 of 15 a b c d 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 Change in cardiovascular risk CV risk, and the distribution across categories was simi- The mean baseline 10-year CVD risk estimated using the lar between treatment arms. After 16 weeks of treatment, SCORE chart was close to 6% in both the CNIC-polypill there was a reduction in the predicted CV risk compared and the usual care groups, which corresponds to a high with baseline in the CNIC-polypill group, while there (See figure on next page.) 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 Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 8 of 15 a b c d e f g Fig. 3 (See legend on previous page.) Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 9 of 15 a b 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) was an increase in the usual care group. However, the group, although the difference between groups was not adjusted mean for the change between groups was not statistically significant (p = 0.168; Fig. 5). significant (p = 0.089; Fig. 5). The mean estimated US-derived PCE CV risk Safety was ≥ 20% in both treatment groups, corresponding to During the trial, 120 subjects (24.4%) reported AEs a very high risk, with a similar proportion of patients (Table 2); nine of them were considered serious (six in in each category. At Week 16, the risk had decreased in the CNIC-polypill and three in the usual care group). the CNIC-polypill group and increased in the usual care Although the frequency of gastrointestinal disorders was Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 10 of 15 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 more frequent in the CNIC-polypill arm (5.3% vs 1.6%; Discussion p = 0.044), there were no serious gastrointestinal disor- In this randomised trial in patients at high or very high ders in any of the treatment arms. CV risk without established CVD, the CNIC-polypill was Treatment-related AEs were more frequent in the non-inferior (and even superior) to the multipill strategy CNIC-polypill treatment than in the usual care group regarding LDL-c reduction. As for SBP reduction, con- (21 AEs in 17 subjects; 6.9% vs 2 AEs in 2 subjects; clusions could not be drawn because the results were 0.8%; Additional file 1: Table S6). The most frequent clinically inconclusive. However, there was a significantly system-organ class affected by treatment-related AEs larger improvement in lipid parameters with the CNIC- was respiratory, thoracic, and mediastinal disorders, polypill strategy, and both treatments increased the rate namely cough in three subjects who were not taking of BP and LDL-c control at the end of the study. ACEi at baseline. Only one subject in the CNIC-polypill The results of the non-inferiority outcomes in our group reported a treatment-related AE (elevated liver study are not comparable with the only available phase enzymes) considered of severe intensity and serious. II, exploratory, non-inferiority trial conducted to date The remaining treatment-related AEs were of mild to with the Polycap CV polypill licensed in India, namely moderate intensity. the TIPS study, because of methodological differences Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 11 of 15 Table 2 Summary of adverse events (AEs) reported during the with established CVD showed an improvement in the trial (safety population) overall lipid profile, including markers indicative of ath- CNIC-Polypill Usual care erogenic dyslipidaemia [14]. These improved outcomes (N = 247) (N = 245) have been partially attributed to the reported enhanced adherence and persistence in patients who were treated Any AE, n (%) 70 (28.3) 50 (20.4) with the CNIC-polypill compared with those on the Severe 7 (2.8) 3 (1.2) identical loose combination or conventional treatment Leading to temporary treatment discontinu- 3 (1.2) 1 (0.4) ation [17, 18, 25]. In our study, we must take account of the Leading to permanent treatment discontinu- 15 (6.1) 3 (1.2) possible greater reduction in LDL-c levels among sub- ation jects who were treated with less potent statins (e.g., ator- Leading to trial discontinuation 18 (3.7) 3 (1.2) vastatin 10 mg, simvastatin 10 or 20 mg, fluvastatin 40 Serious AEs*, n (%) 6 (2.3) 3 (1.2) or 80 mg) before study entry. Along this line, a post-hoc Leading to death 0 (0.0) 0 (0.0) analysis of the randomised UMPIRE study compared the Deaths, n (%) 0 (0.0) 0 (0.0) impact of switching to a polypill-based strategy across Treatment-related AEs, n (%) 17 (6.9) 2 (0.8) different usual care patterns of prior medication regi- Leading to permanent treatment discontinu- 10 (4.1) 0 (0.0) men in patients with established CVD [26]. The results ation showed that, although there were benefits in LDL-c and Serious 1 (0.4) 0 (0.0) BP reduction when switching from equipotent regimens, *A serious AE was defined as any untoward medical occurrence that: 1) results in the benefits were greatest among patients stepped up death; 2) is life-threatening; 3) requires inpatient hospitalisation or prolongation from partial or less potent treatments [26]. Besides, a of existing hospitalization; 4) results in persistent or significant disability/ incapacity; 5) leads to a congenital anomaly/birth defect in the offspring of a potential synergy between atorvastatin and BP-lowering subject; 6) is an important medical event that may expose the subject to danger, drugs in the prevention of coronary heart disease (CHD) even though the event is not immediately life threatening or fatal or does not result in hospitalization in hypertensive patients was initially hypothesised in the ASCOT trial [27]. Moreover, the GREACE study found that treatment with a statin plus an ACEi significantly and substantial disparities in the recruited populations reduced CV events more than each drug alone or neither [20]. Firstly, it was conducted in Indian population, and drug in high-risk dyslipidemic CHD patients [28]. In this the mean age of the TIPS population was nearly 10 years vein, a recent open-label, parallel-group trial compar- younger than that in our study. While the TIPs trial ing the effect of the CNIC polypill vs atorvastatin alone enrolled patients with one risk factor, we included a pri- found that the reductions in LDL-c were greater in the mary prevention population where most of the patients polypill group, thus supporting the notion of a synergistic had several concomitant risk factors and evidence of effect between components [29]. target organ damage. Secondly, the TIPS trial excluded Significant BP reduction has been reported in sub- patients taking two or more antihypertensives, while we jects in primary prevention from real-life clinical settings switched patients to the CNIC-polypill strategy based switched for one year to the CNIC-polypill strategy in on the prior treatment and added other medications the SORS study [16]. Regarding non-inferiority in SBP (antihypertensive or lipid-lowering drugs) when the ini- reduction in our study, the results were inconclusive tial regimen was a combination. Finally, the TIPS trial because the CNIC-polypill was neither clearly inferior assessed non-inferiority to the individual components nor clearly non-inferior to standard treatment. This could of the polypill, while we evaluated the non-inferiority be explained by several methodological issues inherent to the multipill strategy, and thus to all the components to the study design that, for unclear reasons, might have simultaneously. impacted BP management to a larger extent than LDL-c Our findings showed that the effects of the CNIC- control. Firstly, therapeutic intensification through dose polypill regarding LDL-c reduction were non-inferior escalation or additional drug classes to the baseline med- and even superior to conventional treatment. In addi- ication to further control BP or LDL-c was not allowed tion, we observed benefits in lipid parameters other after randomisation. Of note, 65% of the overall popula- than LDL-c, with significantly larger decreases in total tion had uncontrolled BP at baseline (without significant and non-HDL cholesterol among those on the polyp- differences between treatment arms), suggesting sub- ill strategy than with usual care. A significant improve- optimal doses of antihypertensive medication before ment in LDL-c values in patients with or at high risk of a study entry (therapeutic inertia). Similar rates of poor CV event treated for 1 year with the CNIC-polypill was BP control have been reported in the cross-sectional reported in the real-world, phase IV SORS study [16]. EUROASPIRE studies, with only 53% of patients at high Moreover, a post-hoc analysis in the cohort of subjects CVD risk who received BP-lowering medication being Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 12 of 15 controlled [3]. In Spain, poor BP control in primary care been associated with an increased risk of total bleeding was reported in 71% of hypertensive patients, 42% of without a clear reduction in the risk of major CV events whom were not intensified (therapeutic inertia) despite (MACE) [32–34]. Thus, in general, clinical guidelines being at high CV risk [30]. Therefore, we cannot rule out recommend its use in selected patients, such as those that intensifying the baseline treatment in some patients younger than 70 years, with DM and at very high CV at the physicians’ discretion in our study would have risk, at low risk of bleeding, or with difficulties in con- shown differences between groups. Secondly, although trolling modifiable CV risk factors [35–37]. In our study, patients were switched to a CNIC-polypill version with patients were at very high CV risk and those at elevated components equally potent to the patient’s prior treat- risk or with a medical history of bleeding episodes were ment, we cannot discard non-adequate dose equivalences excluded from the trial because this was considered a in some cases. Thirdly, the follow-up period of the study contraindication for the polypill. Different trials using the was 16 weeks, which could be relatively short to observe CV polypill strategy containing low-dose aspirin, one of a difference between groups and probably minimised them with the CNIC-polypill, have shown greater reduc- problems with therapeutical control usually seen with tions in the predicted CVD risk and the incidence of CV long-term, complex treatments. For instance, patients events compared to placebo or conventional treatment were aware of being monitored, thus possibly prompting among subjects in primary prevention [16, 38–40]. A adherence, and reducing dissimilarities between different meta-analysis evaluated the benefit-risk ratio of aspirin therapies [31]. for primary CVD prevention by subgroups, namely sex, Finally, we observed a trend toward a greater increase concomitant statin treatment, DM, and smoking [32]. in the rate of patients with BP or LDL-c controlled at the The results showed that the likelihood of MACE was end of the study and a larger decrease of borderline sig- reduced by 9% in subjects with DM (who represented nificance in the SCORE and PCE predicted 10-year CV more than three quarters in our study population), which risk in patients on the polypill approach compared with is consistent with that of the general population. Most patients who continued with the multipill strategy. It is notably, there was an interaction for the aspirin effect possible that the borderline significance for the control among patients taking statins. Indeed, patients treated rates and predicted CV risk outcomes in our study was with aspirin and also statins had a 12% reduction in the related to the small sample size, which was calculated relative risk of MACE compared with controls, while this based on the non-inferiority hypothesis and thus poten- reduction was not observed among subjects on aspirin tially underpowered for the proposed secondary efficacy without statin co-treatment [32]. The authors postulated analyses. However, the results of the present study are in that this could be related to either an increased benefit line with those of the real-life SORS study [14–16]. In the among those with hyperlipidaemia because of an a priori original report of this trial, one year of treatment with increased CV risk or a direct plaque-stabilising effect of the CNIC-polypill led to a significant decrease in the statins. Lastly, a recent meta-analysis of three large trials 10-year Framingham CVD risk from baseline in patients including patients in primary prevention taking fixed- at high- and intermediate CV risk [16]. Moreover, in the dose combinations found that the rate of fatal and non- post-hoc analysis of the subcohort of subjects with CVD, fatal CVD events was significantly reduced compared the proportion of patients who achieved adequate BP with placebo or minimal care [12]. The largest reduc- control increased significantly compared to baseline [15]. tions were observed for fixed-dose combinations con- Yet another post-hoc analysis of the overall SORS popu- taining aspirin and, although gastrointestinal bleeding lation (with either established CVD or intermediate- or was slightly more frequent than in control groups, it was high CV risk) reported that the likelihood that patients uncommon and the frequency of fatal bleeding or haem- attained their corresponding target LDL-c and triglycer- orrhagic stroke was not significantly higher [12] ides levels was almost three-fold and seven-fold higher, The findings of this study must be interpreted with respectively, than before switching to the CNIC-polypill caution, and some limitations should be borne in mind. strategy [14]. Firstly, and as previously mentioned, the timeframe of the The incidence of AEs was higher in the CNIC-polypill study was short (16 weeks), possibly reducing the possi- arm, but the treatment was well tolerated, and there were bility of observing differences between groups for some of no safety concerns compared with conventional treat- the studied outcomes. Moreover, this was an open-label ment. Of note, there were no reports of serious gastro- trial, and thus subject to bias because of knowledge of intestinal disorders. Approximately half of the patients in treatment allocation on outcomes reporting. However, the our study were already on aspirin at study entry, which is response criteria were not subjective, and the pragmatic significant considering that the use of antiplatelet therapy design has the advantage of making the trial closer to the in primary prevention is a matter of debate because it has real-world approach as opposed to double-blinded trials Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 13 of 15 where an artificial environment that does not reflect true VULCANO investigators Pablo Pérez, Jacinto Espinosa, Javier Sobrino, Antonio Posé, Juan Antonio clinical practice is created. Finally, the sample size was Arroyo Díaz, Olga García Vallejo, María Pilar Cubo Romano, Carlos Brotons, calculated to evaluate non-inferiority comparisons, which Sergio Jansen Chaparro, Jesús Cabezón Mariscal, Miguel Ángel Rico Corral, could have resulted in an insufficient number of subjects José Abellán Alemán, Domingo Orozco Beltrán, Luis Escobar Jimenez, Pedro Valdivielso Felices, Joan Carles Pedro-Botet Montoya, Luis Masana Marín, to assess differences in the secondary efficacy variables. Carlos Guijarro, Ángel Díaz Rodríguez, José Luis Díaz Díaz, Andrés De la Peña Fernández, Emmanuel Coloma Bazán, Rafael Cuenca Acevedo, Carmen Suárez Fernández, Fernando Civeira, José María Castellano Vázquez, José Conclusion María Mostaza Prieto, Manuel Suárez Tembra, Joaquín Alfonso Megido, Jesús The results of the VULCANO study showed that Castiella Herrero, Juan José Tamarit, Miguel Angel Martínez-Hervás Alonso, Francisco Javier Carrasco Franco, Luis Álvarez Sala, Enrique Calderón Sandu‑ switching from conventional treatment to the CNIC- bete, Eduardo Rovira Daudi, Fernando Bonilla Rovira, José Manuel Murcia polypill approach in patients at high CV risk without a pre- Zaragoza, Lluis Cuixart Costa, José Luis Bianchi Llave, Carmen Álvarez Sánchez, vious event was safe and it was associated with a significant Pedro Marqués Da Silva, Vitória Cunha, Catarina Santos, Francisco Araujo, José Moura, Martín Rosas Peralta. improvement in LDL-c and other lipid parameters, no clin- ically meaningful changes in BP levels throughout the study Author contributions follow-up, and there was a trend to improve the overall All authors contributed to the design and conception of this study. JMM was the study coordinator. All the Vulcano investigators (listed in the Supplemen‑ patient’s predicted CV risk. In the context of the additional tary Material) contributed to the acquisition of data. JMM, CS-F, JC-S, RG-H, advantages provided by polypills (i.e., baseline treatment, CB, FPA, GB, and ER contributed to the analysis and interpretation of data for increased adherence, and cost-effectiveness), the CNIC- the work. All authors have critically revised the manuscript. All authors gave final approval and agreed to be accountable for all aspects of work ensuring polypill approach appears to be a reasonable strategy to integrity and accuracy. All authors read and approved the final manuscript. control risk factors simultaneously to prevent CVD. Funding Ferrer Internacional SA, the sponsor of the study, was part of the steering com‑ Abbreviations mittee that designed the trial, but had no role in data collection, data analysis, ABI: Ankle-brachial index; ACEi: Angiotensin-converting-enzyme inhibitor; data interpretation, or writing the report. AE: Adverse event; ARB: Angiotensin II receptor blocker; BP: Blood pressure; CCB: Calcium channel blocker; CDK: Chronic kidney disease; CHD: Coronary Availability of data and materials heart disease; CV: Cardiovascular; CVD: Cardiovascular disease; DBP: Diastolic The datasets used and/or analysed during the study are available from the blood pressure; DM: Diabetes mellitus; eGFR: Estimated glomerular filtration corresponding author upon reasonable request. rate; ESC: European Society of Cardiology; HDL-c: High-density lipoprotein cholesterol; HT: Hypertension; IMT: Intima-media thickness; LDL-c: Low-density Declarations lipoprotein cholesterol; LVH: Left ventricular hypertrophia; LSM: Least-squares mean; MACE: Major CV events; mITT: Modified intent-to-treat population; Ethics approval and consent to participate NYHA: New York Heart Association; NSAID: Non-steroidal anti-inflammatory The protocol was approved by the research Ethics Committee of the coordi‑ drug; PCE: Pooled Cohort Risk Equation; PP: Per protocol population; SCOREW: nating centre, Hospital Universitario La Paz (code HULP 4756). The study was European Systematic Coronary Risk Evaluation; SBP: Systolic blood pressure; conducted in accordance with the Declaration of Helsinki (Tokyo, 2004). All SPC: Single-pill combination. participants provided written informed consent before participating in the trial. Supplementary Information Consent for publication The online version contains supplementary material available at https://​doi.​ Not applicable. org/​10.​1186/​s12872-​022-​03013-w. Competing interests Additional file 1: Table S1. The available versions of the CNIC-polypill E.R. is an employee in the Medical Department in Ferrer Internacional SA. The given to patients. Table S2. The dose equivalence between ACEi and remaining authors received consultant honoraria and research support from ARB and the available ramipril options of the polypill. Table S3. The Ferrer Internacional SA. dose equivalence of statins and the available atorvastatin options of the CNIC-polypill. Table S4. The summary results of the change in primary Author details 1 outcomes (LDL-c and SBP) and superiority tests in the per-protocol popu‑ Internal Medicine Service, Hospital Carlos III, Madrid, Spain. 2 Internal Medicine lation and ITT population. Table S5. Summarises the results of the change Department Hospital de la Princesa, Madrid, Spain. 3 Fundación Investigación in secondary outcomes from baseline to Week 16 after treatment with the Biomédica del Hospital de la Princesa, Madrid, Spain. 4 Universidad Autónoma CNIC-polypill or usual care (mITT population). Table S6. lists treatment- de Madrid (UAM), Madrid, Spain. 5 Cardiology Service, Hospital Arnau de related adverse events by system organ class (SOC) and preferred Vilanova, Valencia, Spain. 6 Medicine Department, Facultad de Ciencias de la term. Fig. S1. the percentage of patients receiving lipid-lowering (A) or Salud, Universidad UCH-CEU, Alfara del Patriarca, Valencia, Spain. 7 Internal BP-lowering drugs, in particular an ACEI (B) or an ARB (C), at baseline by Medicine Department, Regional University Hospital of Málaga, Malaga, Spain. treatment group. Fig. S2. The percentage of subjects who had their LDL-c 8 Biomedical Research Institute of Málaga (IBIMA), University of Málaga (UMA), levels (A), BP values (B), and both LDL-c levels and BP values (C) controlled Malaga, Spain. 9 Sardenya Primary Health Care Center, Barcelona, Spain. 10 Bio‑ at baseline and were still at target after 16 weeks of treatment with the medical Research Institute Sant Pau, Barcelona, Spain. 11 Hospital dos Lusíadas, CNIC-polypill or usual care. Lisbon, Portugal. 12 Instituto Mexicano del Seguro Social (IMSS), Ciudad de Mexico, Mexico. 13 Corporate Medical Affairs Department, Ferrer Internacional, Barcelona, Spain. Acknowledgements Medical writing and editorial support were provided by Mònica Gratacòs funded by Ferrer Internacional SA. Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 14 of 15 Received: 3 November 2021 Accepted: 14 December 2022 Dyslipidemia and Secondary Cardiovascular Prevention: The START-Study. Integr Blood Press Control. 2022;15:11–21. https://​doi.​org/​10.​2147/​ibpc.​ S3363​24. 19. Gonzalez-Juanatey JR, Cordero A, Castellano JM, et al. The CNIC-Polypill reduces recurrent major cardiovascular events in real-life secondary pre‑ References vention patients in Spain: The NEPTUNO study. Int J Cardiol. 2022. https://​ 1. Vos T, Lim SS, Abbafati C, et al. Global burden of 369 diseases and injuries doi.​org/​10.​1016/j.​ijcard.​2022.​05.​015. in 204 countries and territories, 1990–2019: a systematic analysis for the 20. Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in Global Burden of Disease Study 2019. Lancet. 2020;396:1204–22. https://​ middle-aged individuals without cardiovascular disease (TIPS): a phase doi.​org/​10.​1016/​S0140-​6736(20)​30925-9. II, double-blind, randomised trial. Lancet. 2009;373:1341–51. https://​doi.​ 2. Roth GA, Mensah GA, Johnson CO, et al. Global Burden of Cardiovascular org/​10.​1016/​s0140-​6736(09)​60611-5. Diseases and Risk Factors, 1990–2019: Update From the GBD 2019 Study. 21. Gumprecht J, Gosho M, Budinski D, Hounslow N. Comparative long-term J Am Coll Cardiol. 2020;76:2982–3021. https://​doi.​org/​10.​1016/j.​jacc.​2020.​ efficacy and tolerability of pitavastatin 4 mg and atorvastatin 20–40 11.​010. mg in patients with type 2 diabetes mellitus and combined (mixed) 3. Kotseva K, Investigators E. The EUROASPIRE surveys: lessons learned in dyslipidaemia. Diabetes Obes Metab. 2011;13:1047–55. https://​doi.​org/​ cardiovascular disease prevention. Cardiovasc Diagn Ther. 2017;7:633–9. 10.​1111/j.​1463-​1326.​2011.​01477.x. https://​doi.​org/​10.​21037/​cdt.​2017.​04.​06. 22. Laurent S, Parati G, Chazova I, et al. Randomized evaluation of a novel, 4. Dzau V, Braunwald E. Resolved and unresolved issues in the preven‑ fixed-dose combination of perindopril 3.5 mg/amlodipine 2.5 mg as a tion and treatment of coronary artery disease: a workshop consensus first-step treatment in hypertension. J Hypertens. 2015;33:653–61. https://​ statement. Am Heart J. 1991;121:1244–63. https://​doi.​org/​10.​1016/​0002-​ doi.​org/​10.​1097/​HJH.​00000​00000​000440. (discussion 62). 8703(91)​90694-d. 23. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on 5. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardio‑ cardiovascular disease prevention in clinical practice: The Sixth Joint vascular disease prevention in clinical practice. Eur Heart J. 2021;42:3227– Task Force of the European Society of Cardiology and Other Societies 337. https://​doi.​org/​10.​1093/​eurhe​artj/​ehab4​84. on Cardiovascular Disease Prevention in Clinical Practice (constituted by 6. Mancia G. Total cardiovascular risk: a new treatment concept. J Hypertens representatives of 10 societies and by invited experts)Developed with Suppl. 2006;24:S17-24. https://​doi.​org/​10.​1097/​01.​hjh.​00002​20099.​12154.​ the special contribution of the European Association for Cardiovascu‑ c1. lar Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37:2315–81. 7. Williams B, Masi S, Wolf J, Schmieder RE. Facing the Challenge of Lower‑ https://​doi.​org/​10.​1093/​eurhe​artj/​ehw106. ing Blood Pressure and Cholesterol in the Same Patient: Report of a 24. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the Symposium at the European Society of Hypertension. Cardiol Ther. management of arterial hypertension: The Task Force for the manage‑ 2020;9:19–34. https://​doi.​org/​10.​1007/​s40119-​019-​00159-1. ment of arterial hypertension of the European Society of Cardiology and 8. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more the European Society of Hypertension: The Task Force for the manage‑ than 80%. BMJ. 2003;326:1419. https://​doi.​org/​10.​1136/​bmj.​326.​7404.​ ment of arterial hypertension of the European Society of Cardiology and 1419. the European Society of Hypertension. J Hypertens. 2018;36:1953–2041. 9. Webster R, Castellano JM, Onuma OK. Putting polypills into practice: chal‑ https://​doi.​org/​10.​1097/​HJH.​00000​00000​001940. lenges and lessons learned. Lancet. 2017;389:1066–74. https://​doi.​org/​10.​ 25. Castellano JM, Sanz G, Penalvo JL, et al. A polypill strategy to improve 1016/​S0140-​6736(17)​30558-5. adherence: results from the FOCUS project. J Am Coll Cardiol. 10. Sukonthasarn A, Chia YC, Wang JG, et al. The feasibility of polypill for 2014;64:2071–82. https://​doi.​org/​10.​1016/j.​jacc.​2014.​08.​021. cardiovascular disease prevention in Asian Population. J Clin Hypertens 26. Lafeber M, Spiering W, Visseren FL, et al. Impact of switching from dif‑ (Greenwich). 2021;23:545–55. https://​doi.​org/​10.​1111/​jch.​14075. ferent treatment regimens to a fixed-dose combination pill (polypill) 11. Webster R, Patel A, Selak V, et al. Effectiveness of fixed dose combina‑ in patients with cardiovascular disease or similarly high risk. Eur J Prev tion medication (’polypills’) compared with usual care in patients with Cardiol. 2017;24:951–61. https://​doi.​org/​10.​1177/​20474​87317​695616. cardiovascular disease or at high risk: A prospective, individual patient 27. Sever P, Dahlof B, Poulter N, et al. Potential synergy between lipid-low‑ data meta-analysis of 3140 patients in six countries. Int J Cardiol. ering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac 2016;205:147–56. https://​doi.​org/​10.​1016/j.​ijcard.​2015.​12.​015. Outcomes Trial. Eur Heart J. 2006;27:2982–8. https://​doi.​org/​10.​1093/​ 12. Joseph P, Roshandel G, Gao P, et al. Fixed-dose combination therapies eurhe​artj/​ehl403. with and without aspirin for primary prevention of cardiovascular disease: 28. Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. Effect of statins and an individual participant data meta-analysis. Lancet. 2021. https://​doi.​ ACE inhibitors alone and in combination on clinical outcome in patients org/​10.​1016/​S0140-​6736(21)​01827-4. with coronary heart disease. J Hum Hypertens. 2004;18:781–8. https://​ 13. Castellano JM, Fuster V. Polypill, el policomprimido cardiovascular: doi.​org/​10.​1038/​sj.​jhh.​10017​48. del concepto a la realidad en España. Rev Espanola de Cardiol Supl. 29. Gonzalez-Juanatey JR, Tamargo J, Torres F, Weisser B, Oudovenko N. Phar‑ 2015;15:19–24. https://​doi.​org/​10.​1016/​s1131-​3587(16)​30005-x. macodynamic study of the cardiovascular polypill. Is there any interaction 14. Gomez-Alvarez E, Verdejo J, Ocampo S, et al. The CNIC-polypill improves among the monocomponents? Rev Esp Cardiol (Engl Ed). 2021;74:51–8. atherogenic dyslipidemia markers in patients at high risk or with cardio‑ https://​doi.​org/​10.​1016/j.​rec.​2019.​11.​008. vascular disease: Results from a real-world setting in Mexico. Int J Cardiol 30. Gil-Guillen V, Orozco-Beltran D, Marquez-Contreras E, et al. Is there a Heart Vasc. 2020;29: 100545. https://​doi.​org/​10.​1016/j.​ijcha.​2020.​100545. predictive profile for clinical inertia in hypertensive patients? An observa‑ 15. Gomez-Alvarez E, Verdejo J, Ocampo S, Ruiz E, Martinez-Rios MA. Reach‑ tional, cross-sectional, multicentre study. Drugs Aging. 2011;28:981–92. ing blood pressure guideline targets with the CNIC polypill in patients https://​doi.​org/​10.​2165/​11596​640-​00000​0000-​00000. with a previous cardiovascular event in Mexico: a post hoc analysis of 31. Saturni S, Bellini F, Braido F, et al. Randomized Controlled Trials and real the SORS study. Future Cardiol. 2020;16:53–60. https://​doi.​org/​10.​2217/​ life studies. Approaches and methodologies: a clinical point of view. Pulm fca-​2019-​0075. Pharmacol Ther. 2014;27:129–38. https://​doi.​org/​10.​1016/j.​pupt.​2014.​01.​ 16. Castellano JM, Verdejo J, Ocampo S, et al. Clinical Effectiveness of the 005. Cardiovascular Polypill in a Real-Life Setting in Patients with Cardiovascu‑ 32. Gelbenegger G, Postula M, Pecen L, et al. Aspirin for primary preven‑ lar Risk: The SORS Study. Arch Med Res. 2019;50:31–40. https://​doi.​org/​10.​ tion of cardiovascular disease: a meta-analysis with a particular focus 1016/j.​arcmed.​2019.​04.​001. on subgroups. BMC Med. 2019;17:198. https://​doi.​org/​10.​1186/​ 17. Ros-Castelló V, Natera-Villalba E, Gómez-López A, et al. Use of the Cardio‑ s12916-​019-​1428-0. vascular Polypill in Secondary Prevention of Cerebrovascular Disease: A 33. Mahmoud AN, Gad MM, Elgendy AY, Elgendy IY, Bavry AA. Efficacy and Real-Life Tertiary Hospital Cohort Study of 104 Patients. Cerebrovasc Dis safety of aspirin for primary prevention of cardiovascular events: a meta- Extra. 2020;10:166–73. https://​doi.​org/​10.​1159/​00051​1064. analysis and trial sequential analysis of randomized controlled trials. Eur 18. Wilke T, Weisser B, Predel HG, et al. Effects of Single Pill Combinations Heart J. 2019;40:607–17. https://​doi.​org/​10.​1093/​eurhe​artj/​ehy813. Compared to Identical Multi Pill Therapy on Outcomes in Hypertension, Mostaza et al. BMC Cardiovascular Disorders (2022) 22:560 Page 15 of 15 34. Zheng SL, Roddick AJ. Association of Aspirin Use for Primary Prevention With Cardiovascular Events and Bleeding Events: A Systematic Review and Meta-analysis. JAMA. 2019;321:277–87. https://​doi.​org/​10.​1001/​jama.​ 2018.​20578. 35. Aimo A, De Caterina R. Aspirin for primary prevention of cardiovascular disease: advice for a decisional strategy based on risk stratification. Anatol J Cardiol. 2020;23:70–8. https://​doi.​org/​10.​14744/​Anato​lJCar​diol.​2019.​ 89916. 36. Angiolillo DJ, Capodanno D. Aspirin for primary prevention of cardiovas‑ cular disease in the 21(st) Century: a review of the evidence. Am J Cardiol. 2021;144(Suppl 1):S15–22. https://​doi.​org/​10.​1016/j.​amjca​rd.​2020.​12.​022. 37. Mogul A, Leppien EE, Laughlin E, Spinler SA. Aspirin for primary preven‑ tion of cardiovascular disease: a review of recent literature and updated guideline recommendations. Expert Opin Pharmacother. 2021;22:83–91. https://​doi.​org/​10.​1080/​14656​566.​2020.​18173​89. 38. Group PC, Rodgers A, Patel A, et al. An international randomised placebo- controlled trial of a four-component combination pill (“polypill”) in people with raised cardiovascular risk. PLoS ONE. 2011;6: e19857. https://​ doi.​org/​10.​1371/​journ​al.​pone.​00198​57. 39. Roshandel G, Khoshnia M, Poustchi H, et al. Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial. Lancet. 2019;394:672–83. https://​doi.​ org/​10.​1016/​S0140-​6736(19)​31791-X. 40. Yusuf S, Joseph P, Dans A, et al. Polypill with or without aspirin in persons without cardiovascular disease. N Engl J Med. 2021;384:216–28. https://​ doi.​org/​10.​1056/​NEJMo​a2028​220. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations. Ready to submit your research ? Choose BMC and benefit from: • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations • maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions