Correspondence

ACE Inhibition in Stable Coronary Artery Disease

N Engl J Med 2005; 352:937-939March 3, 2005

Article

To the Editor:

The results of the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial1 (Nov. 11 issue)1 are probably the product of an underpowered trial. Only 8290 of a planned 14,100 patients were enrolled, and the primary outcome was changed to include revascularization — an outcome that depends on practice styles and that is therefore potentially insensitive to treatment. Two other trials, the Heart Outcomes Prevention Evaluation Study (HOPE)2 and the European Trial of Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA),3 showed significant reductions in the spontaneous and major vascular outcomes. The benefits in HOPE were consistent in patients at low risk (annual rate of death from cardiovascular causes, myocardial infarction, or stroke, 2 percent; relative risk, 0.82; 95 percent confidence interval, 0.65 to 1.04), those at medium risk (annual rate, 3.5 percent; relative risk, 0.80; 95 percent confidence interval, 0.67 to 0.97), and those at high risk (annual rate, 5 percent; relative risk, 0.76; 95 percent confidence interval, 0.66 to 0.88), in patients receiving lipid-lowering drugs (relative risk, 0.75; 95 percent confidence interval, 0.60 to 0.93), and in those who underwent revascularization (relative risk, 0.85; 95 percent confidence interval, 0.72 to 1.01). A meta-analysis of the HOPE, PEACE, and EUROPA data shows significant reductions in mortality (Table 1Table 1Meta-Analysis of Data on Mortality from the HOPE, EUROPA, and PEACE Trials.), reinfarction, and stroke (data not shown). This confirms the clear benefits of angiotensin-converting–enzyme (ACE) inhibitors in patients with vascular disease and no left ventricular dysfunction.

Salim Yusuf, D.Phil.
Janice Pogue, M.Sc.
McMaster University, Hamilton, ON L8L 2X2, Canada
yusufs@mcmaster.ca

3 References

1. 1

   The PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-2068
   Full Text | Web of Science | Medline

2. 2

   The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-153
   Full Text | Web of Science | Medline

3. 3

   Fox KM. 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
   CrossRef | Web of Science | Medline

To the Editor:

The authors of the report on the PEACE Trial conclude that trandolapril may have failed to reduce cardiovascular outcomes because the study population consisted of patients at low risk for coronary heart disease. These findings are contrary to the results of a similar study, EUROPA, in which the ACE inhibitor perindopril reduced cardiovascular events in similar patients.1

There may be another reason for the neutral results in the PEACE Trial. At year 3, only 74.5 percent of the patients randomly assigned to trandolapril were receiving either trandolapril or an open-label ACE inhibitor. If the percentage of patients receiving an open-label ACE inhibitor was similar in the active-treatment group and in the placebo group, then about 66.2 percent of the patients who were randomly assigned to receive trandolapril would have received it. Only 68.6 percent of patients assigned to trandolapril therapy actually received the 4-mg dose, so less than 50 percent of patients randomly assigned to active treatment may have received the 4-mg dose. Since several other studies2-5 have noted reduced efficacy in decreasing cardiovascular end points when lower doses of ACE inhibitors were used, suboptimal therapy with trandolapril, for whatever reason, may partly explain the absence of a significant reduction in cardiovascular events in the PEACE Trial.

Martin G. Myers, M.D.
Sunnybrook and Women's College Health Sciences Centre, Toronto, ON M4N 3M5, Canada

5 References

1. 1

   Vantrimpont P, Goedhart DM, Bertrand ME, et al. Risk assessment and risk reduction by perindopril in patients with stable coronary artery disease. Circulation 2004;110:Suppl III:III-546 abstract.
   

2. 2

   Pitt B, O'Neill B, Feldman R, et al. The Quinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol 2001;87:1058-1063
   CrossRef | Web of Science | Medline

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   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[Erratum, Lancet 2001;358:1556, 2002;359:2120.]
   CrossRef | Web of Science | Medline

4. 4

   Lonn EM, Yusuf S, Dzavik V, et al. Effects of ramipril and vitamin E on atherosclerosis -- The Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE). Circulation 2001;103:919-925
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   Marre M, Lievre M, Chatellier G, Mann JFE, Passa P, Menard J. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study). BMJ 2004;328:495-495[Erratum, BMJ 2004;328:686.]
   CrossRef | Web of Science | Medline

To the Editor:

The PEACE Trial reports an absence of improvement in cardiovascular outcome among patients with stable coronary artery disease that was treated with trandolapril. Reference is made to the HOPE, EUROPA, and Studies of Left Ventricular Dysfunction trials that showed mortality reduction in populations with somewhat different patient characteristics. An obvious alternate interpretation of the data is that trandolapril is an inferior ACE inhibitor. This study would have been more illuminating had it used an ACE inhibitor that had previously been shown to reduce mortality in sicker patients.

Craig McCullough, M.D.
Venice Internal Medicine, Venice, FL 34285

Author/Editor Response

In response to Dr. McCullough, the ACE inhibitor trandolapril was chosen on the basis of its demonstrated survival benefit in patients with reduced left ventricular function after acute myocardial infarction in the Trandolapril Cardiac Evaluation (TRACE) trial.1 This choice also provided the effective target dose (4 mg daily). In response to Dr. Myers, of the patients assigned to trandolapril, 68.6 percent, 64.0 percent, and 57.8 percent were taking 4 mg daily at one, two, and three years, respectively.2 An additional approximately 10 percent of patients received lower doses because of tolerability issues. It is likely that higher doses would have had the result of offsetting further reductions in tolerability and compliance. The regimen of trandolapril used in the PEACE Trial resulted in consistently lower blood pressure, and among patients randomly assigned to receive the ACE inhibitor fewer were hospitalized for heart failure or had diabetes develop than among those who did not receive the ACE inhibitor.2 These findings support the activity of trandolapril as used in the PEACE Trial.

The PEACE Trial was well powered to report its primary composite end point of death from cardiovascular causes, nonfatal myocardial infarction, or coronary revascularization. With the elimination of revascularization procedures from the composite end point, as suggested by Drs. Yusuf and Pogue, we still found no reductions or even favorable trends in the other components of the end point.2 The low event rate in the PEACE Trial (a 1.6 percent annualized rate of death, which is similar to that in the general population matched for age and sex), in concert with other baseline differences between patients in the PEACE Trial and those enrolled in HOPE and EUROPA, complicates the interpretation of the pooled analysis and underscores the importance of further clarification of the differences among these populations. We also cannot assume that the patients in the HOPE trial with lower event rates were sufficiently similar to the PEACE patients. The PEACE Trial underscores the importance of addressing modifiable risk factors and incorporating an assessment of individual risks and benefits as well as of cost-effectiveness3 in making decisions regarding the long-term use of ACE inhibitors in low-risk patients with coronary artery disease and a left ventricular ejection fraction above 40 percent.

Marc A. Pfeffer, M.D., Ph.D.
Brigham and Women's Hospital, Boston, MA 02115

Michael J. Domanski, M.D.
National Heart, Lung, and Blood Institute, Bethesda, MD 20824

Eugene Braunwald, M.D.
Brigham and Women's Hospital, Boston, MA 02115

3 References

1. 1

   Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333:1670-1676
   Full Text | Web of Science | Medline

2. 2

   Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-2068
   Full Text | Web of Science | Medline

3. 3

   Pitt B. ACE inhibitors for patients with vascular disease without left ventricular dysfunction -- may they rest in PEACE? N Engl J Med 2004;351:2115-2117
   Full Text | Web of Science | Medline

Citing Articles (16)

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   Fernando Arós, Magda Heras, Joan Vila, Héctor Sanz, Ignacio Ferreira-González, Gaietà Permanyer-Miralda, José Cuñat, Lorenzo López-Bescós, Adolfo Cabadés, Angel Loma-Osorio, Jaume Marrugat. (2011) Reducción de la mortalidad precoz y a 6 meses en pacientes con IAM en el periodo 1995-2005. Datos de los registros PRIAMHO I, II y MASCARA. Revista Española de Cardiología 64:11, 972-980
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   Fernando Arós, Magda Heras, Joan Vila, Héctor Sanz, Ignacio Ferreira-González, Gaietà Permanyer-Miralda, José Cuñat, Lorenzo López-Bescós, Adolfo Cabadés, Angel Loma-Osorio, Jaume Marrugat. (2011) Reduction in 28 Days and 6 Months of Acute Myocardial Infarction Mortality From 1995 to 2005. Data From PRIAMHO I, II and MASCARA Registries. Revista Española de Cardiología (English Edition) 64:11, 972-980
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   S. Verma, M. Gupta, D. T. Holmes, L. Xu, H. Teoh, S. Gupta, S. Yusuf, E. M. Lonn. (2011) Plasma renin activity predicts cardiovascular mortality in the Heart Outcomes Prevention Evaluation (HOPE) study. European Heart Journal 32:17, 2135-2142
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   F. Felices-Abad, J. Latour-Pérez, M.P. Fuset-Cabanes, M. Ruano-Marco, J. Cuñat-de la Hoz, F. del Nogal-Sáez. (2010) Indicadores de calidad en el síndrome coronario agudo para el análisis del proceso asistencial pre e intrahospitalario. Medicina Intensiva 34:6, 397-417
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   Roberto Ferrari, Gabriele Guardigli, Claudio Ceconi. (2010) Secondary Prevention of CAD with ACE Inhibitors: A Struggle Between Life and Death of the Endothelium. Cardiovascular Drugs and Therapy 24:4, 331-339
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   K. Fox. (2008) Benefits of perindopril all along the cardiovascular continuum: the level of evidence. European Heart Journal Supplements 10:Suppl G, G4-G12
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   J.E. Pflumm, T. Pomykaj, M.P. Heintzen. (2008) Sekundärprävention nach Myokardinfarkt. Der Internist 49:9, 1052-1060
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   Roberto Ferrari, Michel E Bertrand, Willem J Remme, Maarten L Simoons, Jaap W Deckers, Kim M Fox. (2007) Insight into ACE inhibition in the prevention of cardiac events in stable coronary artery disease: the EUROPA trial. Expert Review of Cardiovascular Therapy 5:6, 1037-1046
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   (2007) Guía de Práctica Clínica para el diagnóstico y tratamiento del síndrome coronario agudo sin elevación del segmento ST. Revista Española de Cardiología 60:10, 1070.e1-1070.e80
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    Kim M. Fox, Michel E. Bertrand, Willem J. Remme, Roberto Ferrari, Maarten L. Simoons, Jaap W. Deckers. (2007) Efficacy of perindopril in reducing risk of cardiac events in patients with revascularized coronary artery disease. American Heart Journal 153:4, 629-635
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    Nathaniel M Hawkins, Francis G Dunn. (2006) The management of hypertension in ischaemic heart disease. Current Opinion in Cardiology 21:4, 273-278
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    Fernando Arós, Ángel Loma-Osorio, Joan Vila, Lorenzo López-Bescós, José Cuñat, Emilio Rodríguez, José M. San José, Magda Heras, Jaume Marrugat. (2006) Efecto de la asociación de bloqueadores beta e inhibidores de la enzima de conversión en la supervivencia al año tras un infarto agudo de miocardio. Resultados del registro PRIAMHO II. Revista Española de Cardiología 59:4, 313-320
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    Mouaz H. Al-Mallah, Imad M. Tleyjeh, Ahmed A. Abdel-Latif, W. Douglas Weaver. (2006) Angiotensin-Converting Enzyme Inhibitors in Coronary Artery Disease and Preserved Left Ventricular Systolic Function. Journal of the American College of Cardiology 47:8, 1576-1583
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    Erik B. Friedrich, Koon K. Teo, Michael Böhm. (2006) ACE Inhibition in secondary prevention: are the results controversial?. Clinical Research in Cardiology 95:2, 61-67
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    Lionel H Opie, Patrick J Commerford, Bernard J Gersh. (2006) Controversies in stable coronary artery disease. The Lancet 367:9504, 69-78
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    Kwang Kon Koh, Seung Hwan Han, Michael J. Quon. (2005) Inflammatory Markers and the Metabolic Syndrome. Journal of the American College of Cardiology 46:11, 1978-1985
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