Journal of Human Hypertension (2004) 18, 781–788 & 2004 Nature Publishing Group All rights reserved 0950-9240/04 $30.00 www.nature.com/jhh ORIGINAL ARTICLE Effect of statins and ACE inhibitors alone and in combination on clinical outcome in patients with coronary heart disease VG Athyros1, DP Mikhailidis3, AA Papageorgiou2, VI Bouloukos1, AN Pehlivanidis1, AN Symeonidis4 and M Elisaf5, for the GREACE Study Collaborative Group 1Atherosclerosis Unit, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece; 2Department of Clinical Biochemistry, Royal Free Hospital, Royal Free and University College Medical School, Pond Street, London, UK; 32nd Propedeutic Department of Internal Medicine, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece; 4Greek Society of General Practitioners, Thessaloniki, Greece; 5Department of Internal Medicine, Medical School, University of Ioannina, Greece We assessed the ‘synergy’ of statins and angiotensin- point in group A was 31%, (95% CI À48 to À6%, P ¼ 0.01) converting enzyme inhibitors (ACEI) in reducing vascu- in comparison to group B, 59% (95% CI À72 to À48%, lar events in patients with coronary heart disease (CHD). Po0.0001) to group C and 63% (95% CI À74 to À51%, The GREek Atorvastatin and CHD Evaluation (GREACE) Po0.0001) to group D. There was no significant Study, suggested that aggressive reduction of low difference in RRR between groups C and D (9%, CI density lipoprotein cholesterol to 2.59 mmol/l À27–10%, P ¼ 0.1). Other factors (eg the blood pressure) (o100 mg/dl) significantly reduces morbidity and mor- that can influence clinical outcome did not differ tality in CHD patients, in comparison to undertreated significantly between the four treatment groups. In patients. In this post hoc analysis of GREACE the conclusion, the statin þ ACEI combination reduces patients (n ¼ 1600) were divided into four groups cardiovascular events more than a statin alone and according to long-term treatment: Group A (n ¼ 460 considerably more than an ACEI alone. Aggressive statin þ ACEI), B (n ¼ 420; statin, no ACEI), C (n ¼ 371;no statin use in the absence of an ACEI also substantially 371;no statin, on ACEI), and D (n ¼ 349; no statin, no reduced cardiovascular events. Treatment with an ACEI ACEI). Analysis of variance was used to assess in the absence of a statin use reduced clinical events in differences in the relative risk reduction (RRR) in ‘all comparison to patients not treated with an ACEI but not events’ (primary end point) between groups. During the significantly, at least in these small groups of patients. 3-year follow-up there were 292 cardiovascular events; Journal of Human Hypertension (2004) 18, 781–788. 45 (10% of patients) in group A, 61 (14.5%) in group B, 91 doi:10.1038/sj.jhh.1001748 in group C (24.5%) and 95 events in group D (27%). The Published online 1 July 2004 RRR (95% confidence interval (CI) in the primary end Keywords: ACE inhibitors; statins; and coronary heart disease Introduction theless, whether combination treatment with statins and ACEIs can increase clinical benefit in CHD It has been clearly demonstrated that cholesterol- patients more than each drug alone has not yet been lowering with statins reduces morbidity and mor- addressed by an end point trial. tality in patients with coronary heart disease 1–4 The GREek Atorvastatin and Coronary-heart-dis- (CHD). Recently, the EURopean trial On reduction ease Evaluation (GREACE) study6–9 was a prospec- of cardiac events with Perindopril in stable coronary tive, randomised, target based, open-label and Artery disease (EUROPA) showed that perindopril, intention-to-treat secondary CHD prevention trial. an angiotensin-converting enzyme inhibitor (ACEI), GREACE showed that the structured management of significantly improved outcome in patients with 5 dyslipidaemia with dose titration of atorvastatin can stable CHD without apparent heart failure. Never- achieve the National Cholesterol Educational Pro- gram (NCEP) low-density lipoprotein cholesterol (LDL-C) treatment goal (o2.6 mmol/l;100 mg/dl).10 Correspondence: Dr VG Athyros, Atherosclerosis Unit, This was associated with significant reductions in 15 Marmara St, Thessaloniki 551 32, Greece. E-mail: [email protected] morbidity and mortality, in comparison to usual care. Received 19 January 2004; revised 03 April 2004; accepted 14 In the present post hoc subgroup analysis of the April 2004; published online 1 July 2004 GREACE results, we report the long-term effect of Statins and ACE inhibitors VG Athyros et al 782 combined treatment with a statin plus an ACEI in Endpoint adjudication comparison to each drug alone or neither drug, There was an independent adjudication committee regardless of the initial assignment of patients in the blinded to treatment assignment. All end points structured or usual care groups. were hard end points and required hospitalisation. Total and cardiac mortality, myocardial infarction and stroke had to be diagnosed by a cardiology Study population—methods clinic to be considered as end points. Death Original study certificates, discharge summaries, ECG, CT Scan or MRI were used to validate an end point. Patients Study design and patients with an end point were considered only once; even Recruitment of patients started 6 years ago and was if they had several CHD events. completed within a 2-year period.6–9 Only patients with established CHD were included: history of Protocol prior myocardial infarction or 470% stenosis of at All patients with a LDL-C 42.6 mmol/l (100 mg/dl) least one coronary artery, as documented by a were enrolled into the study. In the atorvastatin coronary angiogram. Patients with recent acute group, the starting dose was 10 mg/day. If the NCEP coronary syndromes were not excluded. Inclusion LDL-C goal of o2.6 mmol/l was not reached within criteria were age o75 years, LDL-C 42.6 mmol/l 6 weeks, the dose of atorvastatin was increased to (100 mg/dl) and triglycerides (TG) o4.5 mmol/l 20 mg/day. With evaluations every 6 weeks the dose (400 mg/dl). Exclusion criteria were renal or liver of atorvastatin was titrated up to 80 mg/day for dysfunction, prior hypolipidaemic treatment, child- patients not reaching the LDL-C goal with lower bearing potential and any significant disease likely dosages. The patients on usual care received to limit life to less than the duration of the study, whatever drug treatment was prescribed by their such as malignancies and heart failure New York physician. Heart Association class III or IV. Patients that were The study was powered based on a comparison of scheduled for coronary revascularization were also the estimated proportion of patients that would excluded. All consecutive patients referred to our experience a cardiovascular event in the atorvastatin out-patient clinic were enrolled if eligible. Some of and usual care groups. Data from a large-scale them (12%) had an MI (1–3 years previously) and epidemiologic study involving an adult Greek some (8%) were included 7–10 days after admission population (unpublished) provided the estimate of unstable angina. Most of the patients were that Greek CHD patients under usual care have an recently diagnosed. If the patients diagnosed as all-cause event rate of 24% over a 3-year period. We having CHD more than 1 year before enrolment were considered that our findings would be significant if excluded, the mean time from diagnosis to enrol- treatment with atorvastatin to NCEP LDL-C goal ment was 26 days. All patients attended the produced a relative 30% reduction in all cause Hipocration Hospital. Equal numbers of patients events. Using this hypothesis, we performed the were then randomly allocated to atorvastatin treat- two-sample z-test for comparing two binomial ment based in our outpatient clinic or to usual care parameters. This suggested that 800 patients per outside the hospital. Randomisation of patients was group would provide a 90% power, with a type I carried out in cooperation with the Greek Society of error rate of 5%. No reduction in sample size due to General Practitioners, which also carried out the patients not completing the study for personal or follow-up of the usual care patients, while the medical reasons was calculated because this was an University Clinic was responsible for the atorvasta- intention-to-treat study. tin-treated patients. Cardiologists or general practi- GREACE demonstrated significant reductions in tioners of the patients’ choice treated those on usual morbidity and mortality associated with structured care according to their own standards of secondary management of dyslipidaemia with dose titration of CHD prevention. There were no limitations in the atorvastatin (10–80 mg/day, mean dose 24 mg/day). treatment of usual care patients. This could include In the structured care arm, 98% of patients were on life style changes, such as hypolipidaemic diet, long-term treatment with atorvastatin and 95% weight loss, exercise plus all necessary drug treat- reached the NCEP LDL-C treatment target ment, including lipid-lowering agents. Atorvastatin o2.6 mmol/l; 100 mg/dl). In the usual care arm, was not excluded from the usual care group. One of only 12% of patients were on statins and 3% the objectives of the study was to estimate the reached the NCEP LDL-C treatment target. difference in lipid lowering treatment within two settings: a specialist unit with a strict protocol dictating to treat to the NCEP LDL-C target and usual Post-hoc analysis care outside the hospital. In this way, we tried to point out the benefit of reaching this specific In the present post hoc subgroup analysis, we treatment target in CHD patients. The study received assessed the effect of the combination of a statin ethical approval and informed consent was obtained plus an ACEI, in comparison to each drug alone or from all patients before enrolment.