Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Effect of statins and ACE inhibitors alone and in combination on clinical outcome in patients with coronary heart disease

Journal of Human Hypertension volume 18, pages 781–788 (2004)Cite this article

Abstract

We assessed the ‘synergy’ of statins and angiotensin-converting enzyme inhibitors (ACEI) in reducing vascular events in patients with coronary heart disease (CHD). The GREek Atorvastatin and CHD Evaluation (GREACE) Study, suggested that aggressive reduction of low density lipoprotein cholesterol to 2.59 mmol/l (<100 mg/dl) significantly reduces morbidity and mortality in CHD patients, in comparison to undertreated patients. In this post hoc analysis of GREACE the patients (n=1600) were divided into four groups according to long-term treatment: Group A (n=460 statin+ACEI), B (n=420; statin, no ACEI), C (n=371;no statin, on ACEI), and D (n=349; no statin, no ACEI). Analysis of variance was used to assess differences in the relative risk reduction (RRR) in ‘all events’ (primary end point) between groups. During the 3-year follow-up there were 292 cardiovascular events; 45 (10% of patients) in group A, 61 (14.5%) in group B, 91 in group C (24.5%) and 95 events in group D (27%). The RRR (95% confidence interval (CI) in the primary end point in group A was 31%, (95% CI −48 to −6%, P=0.01) in comparison to group B, 59% (95% CI −72 to −48%, P<0.0001) to group C and 63% (95% CI −74 to −51%, P<0.0001) to group D. There was no significant difference in RRR between groups C and D (9%, CI −27–10%, P=0.1). Other factors (eg the blood pressure) that can influence clinical outcome did not differ significantly between the four treatment groups. In conclusion, the statin+ACEI combination reduces cardiovascular events more than a statin alone and considerably more than an ACEI alone. Aggressive statin use in the absence of an ACEI also substantially reduced cardiovascular events. Treatment with an ACEI in the absence of a statin use reduced clinical events in comparison to patients not treated with an ACEI but not significantly, at least in these small groups of patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Scandinavian Simvastatin Survival Study (4S) Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet 1994; 344: 1383–1389.

  2. Sacks FM, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–1009.

    Article  CAS  Google Scholar 

  3. Long-term Intervention with Pravastatin Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349–1357.

  4. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002; 360: 7–22.

  5. Fox KM, and The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. 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: 782–788.

    Article  CAS  Google Scholar 

  6. Athyros VG et al. Treatment with atorvastatin to the National Cholesterol Educational Program goals 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: 220–228.

    Article  Google Scholar 

  7. Athyros VG et al. Early benefit from structured care with atorvastatin in patients with coronary heart disease and diabetes mellitus: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) Study. Angiology 2003; 54: 679–690.

    Article  Google Scholar 

  8. Athyros VG et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) Study. J Clin Pathol 2004 (in press).

  9. Athyros VG et al. The effect of statins versus untreated dyslipidaemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) Study. Am J Kidney Dis 2004; 43: 589–599.

    Article  CAS  Google Scholar 

  10. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP). Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–2497.

  11. Cockroft DW, Gault MH . Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41.

    Article  Google Scholar 

  12. Kaplan RC, Heckbert SR, Furberg CD, Psaty BM . Predictors of subsequent coronary events, stroke, and death among survivors of first hospitalized myocardial infarction. J Clin Epidemiol 2002; 55: 654–664.

    Article  Google Scholar 

  13. Bickel C et al. Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol 2002; 89: 12–17.

    Article  CAS  Google Scholar 

  14. Fang J, Alderman MH . Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey. JAMA 2000; 283: 2404–2410.

    Article  CAS  Google Scholar 

  15. Elisaf M, Mikhailidis DP . Statins and renal function. Angiology 2002; 53: 493–502.

    Article  Google Scholar 

  16. Youssef F et al. The early effect of lipid-lowering treatment on carotid and femoral intima media thickness (IMT). Eur J Vasc Endovasc Surg 2002; 23: 358–364.

    Article  CAS  Google Scholar 

  17. Youssef F et al. The effect of short-term treatment with simvastatin on renal function in patients with peripheral arterial disease. Angiology 2004; 55: 53–62.

    Article  Google Scholar 

  18. Sinzinger H, Kritz H, Furberg CD . Atorvastatin reduces microalbuminuria in patients with familial hypercholesterolemia and normal glucose tolerance. Med Sci Monit 2003; 9: 88–92.

    Google Scholar 

  19. Heart Protection Study Collaborative Group . MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361: 2005–2016.

    Article  Google Scholar 

  20. Lonn EM et al. Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection. Circulation 1994; 90: 2056–2069.

    Article  CAS  Google Scholar 

  21. Dzau VJ . Mechanism of protective effects of ACE inhibition on coronary artery disease. Eur Heart J 1998; 19(Suppl J): J2–J6.

    CAS  PubMed  Google Scholar 

  22. Yusuf S et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992; 340: 1173–1178.

    Article  CAS  Google Scholar 

  23. Pfeffer MA et al; The SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1992; 327: 669–677.

    Article  CAS  Google Scholar 

  24. The Heart Outcomes Prevention Evaluation Study (HOPE) Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145–153.

  25. Kober L 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: 1670–1676.

    Article  CAS  Google Scholar 

  26. Mancini GB et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation 1996; 94: 258–265.

    Article  CAS  Google Scholar 

  27. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358: 1033–1041.

  28. Teo KK 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: 1748–1754.

    Article  CAS  Google Scholar 

  29. Schoenhagen P, White RD, Nissen SE, Tuzcu EM . Coronary imaging: angiography shows the stenosis, but IVUS, CT, and MRI show the plaque. Cleve Clin J Med 2003; 70: 713–719.

    Article  Google Scholar 

  30. Esper RJ et al. Endothelium-dependent responses in patients with hypercholesterolemic coronary artery disease under the effects of simvastatin and enalapril, either separately or combined. Am Heart J 2000; 140: 684–689.

    Article  CAS  Google Scholar 

  31. Gryglewski RJ et al. Comparison of endothelial pleiotropic actions of angiotensin converting enzyme inhibitors and statins. Ann N Y Acad Sci 2001; 947: 229–245.

    Article  CAS  Google Scholar 

  32. Nazzaro P et al. Distinct and combined vascular effects of ACE blockade and HMG-CoA reductase inhibition in hypertensive subjects. Hypertension 1999; 33: 719–725.

    Article  CAS  Google Scholar 

  33. Papadakis JA et al. Effect of hypertension, and its treatment, on lipid, lipoprotein (a), fibrinogen and bilirubin levels in patients referred for dyslipidaemia. Am J Hypertens 1999; 12: 673–681.

    Article  CAS  Google Scholar 

  34. Milionis HJ, Elisaf MS, Mikhailidis DP . The effects of lipid-regulating therapy on haemostatic parameters. Curr Pharm Des 2003; 9: 2425–2443.

    Article  CAS  Google Scholar 

  35. Tsiara S, Elisaf M, Mikhailidis DP . Early vascular benefits of statin therapy. Curr Med Res Opin 2003; 19: 540–556.

    Article  CAS  Google Scholar 

  36. Ganotakis ES, Papadakis JA, Vrentzos GE, Mikhailidis DP . The effects of antihypertensive therapy on haemostatic parameters. Curr Pharm Des 2003; 9: 2445–2464.

    Article  CAS  Google Scholar 

  37. Virdis A et al. Presence of cardiovascular structural changes in essential hypertensive patients with coronary microvascular disease and effects of long-term therapy. Am J Hypertens 1996; 9: 361–369.

    Article  CAS  Google Scholar 

  38. Novo S, Abrignani MG, Corda M, Strano A . Cardiovascular structural changes in hypertension: possible regression during long-term antihypertensive treatment. Eur Heart J 1991; 12(Suppl G): 47G–53G.

    Google Scholar 

  39. Eichstadt HW et al. Improvement of myocardial perfusion by short-term fluvastatin therapy in coronary artery disease. Am J Cardiol 1995; 76(Suppl A): 122A–125A.

    Article  CAS  Google Scholar 

  40. Cheng KS, Mikhailidis DP, Hamilton G, Seifalian AM . A review of the carotid and femoral intima-media thickness as an indicator of the presence of peripheral vascular disease and cardiovascular risk factors. Cardiovasc Res 2002; 54: 528–538.

    Article  CAS  Google Scholar 

  41. Kontopoulos AG, Athyros VG, Papageorgiou AA, Boudoulas H . Effect of quinapril or metoprolol on circadian sympathetic and parasympathetic modulation after acute myocardial infarction. Am J Cardiol 1999; 84: 1164–1169.

    Article  CAS  Google Scholar 

  42. Pehlivanidis AN et al. Heart rate variability after long-term treatment with atorvastatin in hypercholesterolaemic patients with or without coronary artery disease. Atherosclerosis 2001; 157: 463–469.

    Article  CAS  Google Scholar 

  43. Kontopoulos AG et al. Long-term treatment effect of atorvastatin on aortic stiffness in hypercholesterolaemic patients. Curr Med Res Opin 2003; 19: 22–27.

    Article  CAS  Google Scholar 

  44. Mitchell LB et al; AVID Investigators. Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the Antiarrhythmics versus Implantable Defibrillators (AVID) trial. J Am Coll Cardiol 2003; 42: 81–87.

    Article  CAS  Google Scholar 

  45. Quintana M et al. Heart rate variability as a means of assessing prognosis after acute myocardial infarction. Eur Heart J 1997; 18: 789–797.

    Article  CAS  Google Scholar 

  46. van Boven AJ et al. Depressed heart rate variability is associated with events in patients with stable coronary artery disease and preserved left ventricular function. REGRESS Study Group. Am Heart J 1998; 135: 571–576.

    Article  CAS  Google Scholar 

  47. Stefanadis C et al. Aortic stiffness as a risk factor for recurrent acute coronary events in patients with ischaemic heart disease. Eur Heart J 2000; 21: 390–396.

    Article  CAS  Google Scholar 

  48. Benetos A et al. Pulse pressure: a predictor of long-term cardiovascular mortality in a French male population. Hypertension 1997; 30: 1410–1415.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Atherosclerosis Unit, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece

    V G Athyros, V I Bouloukos & A N Pehlivanidis

  2. Department of Clinical Biochemistry, Royal Free Hospital, Royal Free and University College Medical School, Pond Street, London, UK

    A A Papageorgiou

  3. 2nd Propedeutic Department of Internal Medicine, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece

    D P Mikhailidis

  4. Greek Society of General Practitioners, Thessaloniki, Greece

    A N Symeonidis

  5. Department of Internal Medicine, Medical School, University of Ioannina, Greece

    M Elisaf

Authors
  1. V G Athyros
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D P Mikhailidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A A Papageorgiou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V I Bouloukos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A N Pehlivanidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A N Symeonidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Elisaf
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the GREACE Study Collaborative Group

Corresponding author

Correspondence to V G Athyros.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Athyros, V., Mikhailidis, D., Papageorgiou, A. et al. Effect of statins and ACE inhibitors alone and in combination on clinical outcome in patients with coronary heart disease. J Hum Hypertens 18, 781–788 (2004). https://doi.org/10.1038/sj.jhh.1001748

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.jhh.1001748

Keywords

This article is cited by

Search

Advanced search

Quick links