Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 1/2024

Open Access 04-10-2022 | Stroke | Original Article

The Effects of a Perindopril-Based Regimen in Relation to Statin Use on the Outcomes of Patients with Vascular Disease: a Combined Analysis of the ADVANCE, EUROPA, and PROGRESS Trials

Authors: S. P. Radhoe, E. Boersma, M. Bertrand, W. Remme, R. Ferrari, K. Fox, S. MacMahon, J. Chalmers, M. L. Simoons, J. J. Brugts

Published in: Cardiovascular Drugs and Therapy | Issue 1/2024

Login to get access

Abstract

Purpose

To study the effects of a perindopril-based regimen on cardiovascular (CV) outcomes in patients with vascular disease in relation to background statin therapy.

Methods

A pooled analysis of the randomized ADVANCE, EUROPA, and PROGRESS trials was performed to evaluate CV outcomes in 29,463 patients with vascular disease treated with perindopril-based regimens versus placebo. The primary endpoint was a composite of CV mortality, nonfatal myocardial infarction, and stroke. Multivariable Cox regression analyses were performed to assess the effects of a perindopril-based regimen versus placebo in relation to statin use.

Results

At randomization, 39.5% of the overall combined study population used statins. After a mean follow-up of 4.0 years (SD 1.0), the cumulative event-free survival was highest in the statin/perindopril group and lowest in the no statin/placebo group (91.2% vs. 85.6%, respectively, log-rank p < 0.001). In statin users (adjusted hazard ratio [aHR] 0.87, 95% confidence interval [CI] 0.77–0.98) and non-statin users (aHR 0.80, 95% CI 0.74–0.87), a perindopril-based regimen was associated with a significantly lower risk of the primary endpoint when compared to placebo. The additional treatment effect appeared numerically greater in non-statin users, but the observed difference was statistically nonsignificant.

Conclusion

Our data suggest that the treatment benefits of a perindopril-based regimen in patients with vascular disease are independent of statin use.
Appendix
Available only for authorised users
Literature
1.
Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med. 2015;372(14):1333–41.PubMedPubMedCentralCrossRef
2.
Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459–72.PubMedPubMedCentralCrossRef
3.
Collaborators GBDRF. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1923–94.CrossRef
4.
Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2224–60.PubMedPubMedCentralCrossRef
5.
Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Back M, et al. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42(34):3227–337.PubMedCrossRef
6.
McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–726.PubMedCrossRef
7.
Collet JP, Thiele H, Barbato E, Barthelemy O, Bauersachs J, Bhatt DL, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021;42(14):1289–367.PubMedCrossRef
8.
Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41(3):407–77.PubMedCrossRef
9.
Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–88.PubMedCrossRef
10.
Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255–323.PubMedCrossRef
11.
Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–77.PubMedCrossRef
12.
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–104.PubMedCrossRef
13.
Fox KM, Investigators EUtOrocewPiscAd. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362(9386):782–8.PubMedCrossRef
14.
Group PC. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358(9287):1033–41.CrossRef
15.
Patel A, Group AC, MacMahon S, Chalmers J, Neal B, Woodward M, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370(9590):829–40.PubMedCrossRef
16.
Brugts JJ, Ninomiya T, Boersma E, Remme WJ, Bertrand M, Ferrari R, et al. The consistency of the treatment effect of an ACE-inhibitor based treatment regimen in patients with vascular disease or high risk of vascular disease: a combined analysis of individual data of ADVANCE, EUROPA, and PROGRESS trials. Eur Heart J. 2009;30(11):1385–94.PubMedCrossRef
17.
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267–78.PubMedCrossRef
18.
Cholesterol Treatment Trialists C, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117–25.CrossRef
19.
Cholesterol Treatment Trialists C, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–81.CrossRef
20.
Cholesterol Treatment Trialists C, Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581–90.CrossRef
21.
Cholesterol Treatment Trialists C, Fulcher J, O’Connell R, Voysey M, Emberson J, Blackwell L, et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015;385(9976):1397–405.CrossRef
22.
Brugts JJ, Bertrand M, Remme W, Ferrari R, Fox K, MacMahon S, et al. The treatment effect of an ACE-inhibitor based regimen with perindopril in relation to beta-blocker use in 29,463 patients with vascular disease: a combined analysis of individual data of ADVANCE, EUROPA and PROGRESS trials. Cardiovasc Drugs Ther. 2017;31(4):391–400.PubMedPubMedCentralCrossRef
23.
Athyros VG, Mikhailidis DP, Papageorgiou AA, Bouloukos VI, Pehlivanidis AN, Symeonidis AN, et al. Effect of statins and ACE inhibitors alone and in combination on clinical outcome in patients with coronary heart disease. J Hum Hypertens. 2004;18(11):781–8.PubMedCrossRef
24.
Sundstrom J, Gulliksson G, Wiren M. Synergistic effects of blood pressure-lowering drugs and statins: systematic review and meta-analysis. BMJ Evid Based Med. 2018;23(2):64–9.PubMedPubMedCentralCrossRef
25.
Kanukula R, Esam H, Sundstrom J, Rodgers A, Salam A. Does co-administration of antihypertensive drugs and statins alter their efficacy and safety? A systematic review and meta-analysis of randomized controlled trials. J Cardiovasc Pharmacol. 2019;73(6):352–8.PubMedCrossRef
26.
Sever P, Dahlof B, Poulter N, Wedel H, Beevers G, Caulfield M, et al. Potential synergy between lipid-lowering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac outcomes Trial. Eur Heart J. 2006;27(24):2982–8.PubMedCrossRef
27.
Bertrand ME, Vlachopoulos C, Mourad JJ. Triple combination therapy for global cardiovascular risk: atorvastatin, perindopril, and amlodipine. Am J Cardiovasc Drugs. 2016;16(4):241–53.PubMedCrossRef
28.
Wang N, Harris K, Chalmers J, Harrap S, Mancia G, Marre M, et al. Combination blood pressure lowering in the presence or absence of background statin and aspirin therapy: a combined analysis of PROGRESS and ADVANCE Trials. J Hypertens. 2021;39(8):1689–96.PubMedCrossRef
29.
Investigators S, Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325(5):293–302.CrossRef
30.
Konstam MA, Rousseau MF, Kronenberg MW, Udelson JE, Melin J, Stewart D, et al. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. SOLVD Investigators. Circulation. 1992;86(2):431–8.PubMedCrossRef
31.
Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327(10):669–77.PubMedCrossRef
32.
The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342(8875):821–8.
33.
Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med. 1995;333(25):1670–6.PubMedCrossRef
34.
Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366(9489):895–906.PubMedCrossRef
35.
Heart Outcomes Prevention Evaluation Study I, Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342(3):145–53.CrossRef
36.
van Vark LC, Bertrand M, Akkerhuis KM, Brugts JJ, Fox K, Mourad JJ, et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients. Eur Heart J. 2012;33(16):2088–97.PubMedPubMedCentralCrossRef
37.
Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med. 1998;339(18):1285–92.PubMedCrossRef
38.
Murphey LJ, Malave HA, Petro J, Biaggioni I, Byrne DW, Vaughan DE, et al. Bradykinin and its metabolite bradykinin 1–5 inhibit thrombin-induced platelet aggregation in humans. J Pharmacol Exp Ther. 2006;318(3):1287–92.PubMedCrossRef
39.
Ceconi C, Fox KM, Remme WJ, Simoons ML, Bertrand M, Parrinello G, et al. ACE inhibition with perindopril and endothelial function. Results of a substudy of the EUROPA study: PERTINENT. Cardiovasc Res. 2007;73(1):237–46.PubMedCrossRef
40.
Borghi C, Levy BI. Synergistic actions between angiotensin-converting enzyme inhibitors and statins in atherosclerosis. Nutr Metab Cardiovasc Dis. 2022;32(4):815–26.PubMedCrossRef
41.
Fujita M, Yamazaki T, Hayashi D, Kohro T, Okada Y, Nagai R, et al. Comparison of cardiovascular events in patients with angiographically documented coronary narrowing with combined renin-angiotensin system inhibitor plus statin versus renin-angiotensin system inhibitor alone versus statin alone (from the Japanese Coronary Artery Disease Study). Am J Cardiol. 2007;100(12):1750–3.PubMedCrossRef
42.
Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis AN, Basayannis EO, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus “usual” care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin. 2002;18(4):220–8.PubMedCrossRef
43.
Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA, et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation. 2004;110(18):2809–16.PubMedCrossRef
44.
Teo KK, Burton JR, Buller CE, Plante S, Catellier D, Tymchak W, et al. Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation. 2000;102(15):1748–54.PubMedCrossRef
45.
White CM. Pharmacologic, pharmacokinetic, and therapeutic differences among ACE inhibitors. Pharmacotherapy. 1998;18(3):588–99.PubMedCrossRef
46.
Reid JL. From kinetics to dynamics: are there differences between ACE inhibitors? Eur Heart J. 1997;18 Suppl E:E14-8.PubMedCrossRef
47.
48.
Ferrari R, Pasanisi G, Notarstefano P, Campo G, Gardini E, Ceconi C. Specific properties and effect of perindopril in controlling the renin-angiotensin system. Am J Hypertens. 2005;18(9 Pt 2):142S-S154.PubMedCrossRef
49.
Belsey JD. Optimizing adherence in hypertension: a comparison of outcomes and costs using single tablet regimens vs individual component regimens. J Med Econ. 2012;15(5):897–905.PubMedCrossRef
50.
Egan BM, Bandyopadhyay D, Shaftman SR, Wagner CS, Zhao Y, Yu-Isenberg KS. Initial monotherapy and combination therapy and hypertension control the first year. Hypertension. 2012;59(6):1124–31.PubMedCrossRef
51.
52.
Munoz D, Uzoije P, Reynolds C, Miller R, Walkley D, Pappalardo S, et al. Polypill for cardiovascular disease prevention in an underserved population. N Engl J Med. 2019;381(12):1114–23.PubMedPubMedCentralCrossRef
53.
Roshandel G, Khoshnia M, Poustchi H, Hemming K, Kamangar F, Gharavi A, et al. Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial. Lancet. 2019;394(10199):672–83.PubMedCrossRef
Metadata
Title
The Effects of a Perindopril-Based Regimen in Relation to Statin Use on the Outcomes of Patients with Vascular Disease: a Combined Analysis of the ADVANCE, EUROPA, and PROGRESS Trials
Authors
S. P. Radhoe
E. Boersma
M. Bertrand
W. Remme
R. Ferrari
K. Fox
S. MacMahon
J. Chalmers
M. L. Simoons
J. J. Brugts
Publication date
04-10-2022
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 1/2024
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-022-07384-2

Other articles of this Issue 1/2024

Cardiovascular Drugs and Therapy 1/2024 Go to the issue

Letter to the Editor

The Effect of Colchicine in Acute Myocardial Infarction

Original Article

Sulfated Galactofucan from Sargassum Thunbergii Attenuates Atherosclerosis by Suppressing Inflammation Via the TLR4/MyD88/NF-κB Signaling Pathway

Review Article

Shedding Light on Treatment Options for Coronary Vasomotor Disorders: A Systematic Review

Original Article

Effect of Dapagliflozin on the Outcome of Radiofrequency Catheter Ablation in Patients with Type 2 Diabetes Mellitus and Atrial Fibrillation

Original Article

Comparing the Clinical Outcomes Observed with Rivaroxaban Versus Warfarin for the Management of Obese Patients with Non-valvular Atrial Fibrillation: a Systematic Review and Meta-analysis

Original Article

Novel Insights into the Management of Patients with Very High Cardiovascular Risk Eligible for PCSK9 Inhibitor Treatment: Baseline Findings from the PERI-DYS Study