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

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1 (2004) 18, & 2004 Nature Publishing Group All rights reserved /04 $ ORIGINAL ARTICLE Effect of statins and ACE inhibitors alone and in combination on clinical outcome in patients with coronary heart disease VG Athyros 1, DP Mikhailidis 3, AA Papageorgiou 2, VI Bouloukos 1, AN Pehlivanidis 1, AN Symeonidis 4 and M Elisaf 5, for the GREACE Study Collaborative Group 1 Atherosclerosis Unit, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece; 2 Department of Clinical Biochemistry, Royal Free Hospital, Royal Free and University College Medical School, Pond Street, London, UK; 3 2nd Propedeutic Department of Internal Medicine, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece; 4 Greek Society of General Practitioners, Thessaloniki, Greece; 5 Department of Internal Medicine, Medical School, University of Ioannina, Greece We assessed the synergy of statins and angiotensinconverting 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 (o100 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 ¼ 1600) were divided into four groups according to long-term treatment: Group A (n ¼ 460 statin þ ACEI), B (n ¼ 420; statin, no ACEI), C (n ¼ 371;no 371;no statin, on ACEI), and D (n ¼ 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 ¼ 0.01) in comparison to group B, 59% (95% CI 72 to 48%, Po0.0001) to group C and 63% (95% CI 74 to 51%, Po0.0001) to group D. There was no significant difference in RRR between groups C and D (9%, CI 27 10%, P ¼ 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 þ 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. (2004) 18, doi: /sj.jhh Published online 1 July 2004 Keywords: ACE inhibitors; statins; and coronary heart disease Introduction Correspondence: Dr VG Athyros, Atherosclerosis Unit, 15 Marmara St, Thessaloniki , Greece. athyros@med.auth.gr Received 19 January 2004; revised 03 April 2004; accepted 14 April 2004; published online 1 July 2004 It has been clearly demonstrated that cholesterollowering with statins reduces morbidity and mortality in patients with coronary heart disease (CHD). 1 4 Recently, the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) showed that perindopril, an angiotensin-converting enzyme inhibitor (ACEI), significantly improved outcome in patients with stable CHD without apparent heart failure. 5 Nevertheless, whether combination treatment with statins and ACEIs can increase clinical benefit in CHD patients more than each drug alone has not yet been addressed by an end point trial. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study 6 9 was a prospective, randomised, target based, open-label and intention-to-treat secondary CHD prevention trial. GREACE showed that the structured management of dyslipidaemia with dose titration of atorvastatin can achieve the National Cholesterol Educational Program (NCEP) low-density lipoprotein cholesterol (LDL-C) treatment goal (o2.6 mmol/l;100 mg/dl). 10 This was associated with significant reductions in morbidity and mortality, in comparison to usual care. In the present post hoc subgroup analysis of the GREACE results, we report the long-term effect of

2 782 combined treatment with a statin plus an ACEI in comparison to each drug alone or neither drug, regardless of the initial assignment of patients in the structured or usual care groups. Study population methods Original study Study design and patients Recruitment of patients started 6 years ago and was completed within a 2-year period. 6 9 Only patients with established CHD were included: history of prior myocardial infarction or 470% stenosis of at least one coronary artery, as documented by a coronary angiogram. Patients with recent acute coronary syndromes were not excluded. Inclusion criteria were age o75 years, LDL-C 42.6 mmol/l (100 mg/dl) and triglycerides (TG) o4.5 mmol/l (400 mg/dl). Exclusion criteria were renal or liver dysfunction, prior hypolipidaemic treatment, childbearing potential and any significant disease likely to limit life to less than the duration of the study, such as malignancies and heart failure New York Heart Association class III or IV. Patients that were scheduled for coronary revascularization were also excluded. All consecutive patients referred to our out-patient clinic were enrolled if eligible. Some of them (12%) had an MI (1 3 years previously) and some (8%) were included 7 10 days after admission of unstable angina. Most of the patients were recently diagnosed. If the patients diagnosed as having CHD more than 1 year before enrolment were excluded, the mean time from diagnosis to enrolment was 26 days. All patients attended the Hipocration Hospital. Equal numbers of patients were then randomly allocated to atorvastatin treatment based in our outpatient clinic or to usual care outside the hospital. Randomisation of patients was carried out in cooperation with the Greek Society of General Practitioners, which also carried out the follow-up of the usual care patients, while the University Clinic was responsible for the atorvastatin-treated patients. Cardiologists or general practitioners of the patients choice treated those on usual care according to their own standards of secondary CHD prevention. There were no limitations in the treatment of usual care patients. This could include life style changes, such as hypolipidaemic diet, weight loss, exercise plus all necessary drug treatment, including lipid-lowering agents. Atorvastatin was not excluded from the usual care group. One of the objectives of the study was to estimate the 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 care outside the hospital. In this way, we tried to point out the benefit of reaching this specific treatment target in CHD patients. The study received ethical approval and informed consent was obtained from all patients before enrolment. Endpoint adjudication There was an independent adjudication committee blinded to treatment assignment. All end points were hard end points and required hospitalisation. Total and cardiac mortality, myocardial infarction and stroke had to be diagnosed by a cardiology clinic to be considered as end points. Death certificates, discharge summaries, ECG, CT Scan or MRI were used to validate an end point. Patients with an end point were considered only once; even if they had several CHD events. Protocol All patients with a LDL-C 42.6 mmol/l (100 mg/dl) were enrolled into the study. In the atorvastatin group, the starting dose was 10 mg/day. If the NCEP LDL-C goal of o2.6 mmol/l was not reached within 6 weeks, the dose of atorvastatin was increased to 20 mg/day. With evaluations every 6 weeks the dose of atorvastatin was titrated up to 80 mg/day for patients not reaching the LDL-C goal with lower dosages. The patients on usual care received whatever drug treatment was prescribed by their physician. The study was powered based on a comparison of the estimated proportion of patients that would experience a cardiovascular event in the atorvastatin and usual care groups. Data from a large-scale epidemiologic study involving an adult Greek population (unpublished) provided the estimate that Greek CHD patients under usual care have an all-cause event rate of 24% over a 3-year period. We considered that our findings would be significant if treatment with atorvastatin to NCEP LDL-C goal produced a relative 30% reduction in all cause events. Using this hypothesis, we performed the two-sample z-test for comparing two binomial parameters. This suggested that 800 patients per group would provide a 90% power, with a type I error rate of 5%. No reduction in sample size due to patients not completing the study for personal or medical reasons was calculated because this was an intention-to-treat study. GREACE demonstrated significant reductions in morbidity and mortality associated with structured management of dyslipidaemia with dose titration of atorvastatin (10 80 mg/day, mean dose 24 mg/day). In the structured care arm, 98% of patients were on long-term treatment with atorvastatin and 95% reached the NCEP LDL-C treatment target o2.6 mmol/l; 100 mg/dl). In the usual care arm, only 12% of patients were on statins and 3% reached the NCEP LDL-C treatment target. Post-hoc analysis In the present post hoc subgroup analysis, we assessed the effect of the combination of a statin plus an ACEI, in comparison to each drug alone or neither drug in four groups of patients, regardless of

3 their assignment to structured or usual care in the original study. Group A included patients on a statin and ACEI, group B included patients on a statin but not an ACEI, group C patients were taking an ACEI but not a statin, and group D patients were neither on a statin or an ACEI. The demographic characteristics and baseline CHD risk factors of the four groups are shown in Table 1 and the baseline lipid values in Table 2. The study population had a high risk of events because they all had CHD. Furthermore, the baseline LDL-C level (4.6 mmol/l; 178 mg/dl) was elevated, 20% of patients had diabetes mellitus, 43% were hypertensive and 35% had a revascularization prior to entry into the study. Lipoproteins, serum creatinine (SCr), creatinine clearance (CrCl), and serum uric acid (SUA) were assessed at baseline, at the 6th treatment week and every 6 months thereafter. Biochemical measurements were made on each serum sample using an Olympus AU 560 autoanalyser and appropriate reagents (Olympus GmbH, Clare, Ireland). LDL-C was calculated using the Friedewald formula (applicable in all patients, since they had serum triglyceride levels o4.5 mmol/l (400 mg/dl). SCr was measured using the Jaffe method (reference range: mmol/l; mg/dl). CrCl was estimated from SCr using the Cockroft Gault formula, which corrects for age, weight and gender. 11 SUA was assessed with an enzymatic colorimetric test (uricase); reference range: mmol/l ( mg/dl). All the patients participating in the original study were included in the present post hoc subanalysis. 783 Table 1 Baseline characteristics and coronary heart disease risk factors in the four treatment groups Group A Group B Group C Group D P-value n ¼ 460 n ¼ 420 n ¼ 371 n ¼ 349 Men/women 79/21% 78/22% 77/23% 80/20% NS Age (years) NS Body mass index (kg/m 2 ) NS Myocardial infarction 82% 81% 82% 80% NS Diabetes mellitus 21% 20% 19% 20% NS Arterial hypertension 43% 41% 45% 43% NS PTCA/CABG 34% 36% 36% 35% NS Recent unstable angina 8% 9% 8% 7% NS Age and body mass index are expressed as mean values 7 1 s.d. and the rest as percentage of patients. PTCA ¼ percutaneous transluminal coronary angioplasty, CABG ¼ coronary artery bypass grafting. Table 2 Lipid profile: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), systolic blood pressure (SBP), diastolic blood pressure (DBP), creatinine clearance (CrCl), and serum uric acid (SUA) (mean values 7 1 s.d.) of the four treatment groups at baseline and during treatment Group A Group B Group C Group D ANOVA n ¼ 460 n ¼ 420 n ¼ 371 n ¼ 349 Baseline LDL-C (mmol/l) NS On-study LDL-C (mmol/l) o P-value o o NS NS Baseline HDL-C (mmol/l) NS On-study HDL-C (mmol/l) ¼ 0.02 P-value ¼ ¼ NS NS Baseline TG (mmol/l) NS On-study TG (mmol/l) o P-value o o NS NS Baseline SBP (mmhg) NS On-study SBP (mmhg) NS P-value NS NS NS NS Baseline DBP (mmhg) NS On-study DBP (mmhg) NS P-value NS NS NS NS Baseline CrCl (ml/min) NS On-study CrCl (ml/min) o P-value o o Baseline SUA (mmol/l) NS On-study SUA (mmol/l) o P-value o o To convert data from mmol/l to mg/dl multiply LDL and HDL cholesterol values by 38.7 and TG by For SUA to convert data from mmol/l to mg/dl divide by

4 784 Table 3 Medical therapy for at least 6 months at any point during the study or until the time of their death in cases of patients that died before the 6th treatment month in the four treatment groups Group A Group B Group C Group D P-values n ¼ 460 n ¼ 420 n ¼ 371 n ¼ 349 Aspirin or other antiplatelet agents 89% 90% 87% 86% NS Beta-blockers 85% 87% 85% 84% NS Nitrates 14% 15% 15% 16% NS Calcium channel blockers 26% 25% 27% 28% NS Diuretics 12% 11% 12% 13% NS Hypolipidaemic drugs 100% 100% 0% 0% o ACE inhibitors 100% 0% 100% 0% o ACE ¼ angiotensin-converting enzyme. Medical therapy The long-term medical treatment (drug treatment for at least 6 months at any point of the study) is shown in Table 3. For patients who died before the completion of 6 months of the study, their drug treatment until the time of their death was recorded. This procedure was also used for patients that died before the completion of the 3-year follow-up. No patient was excluded from the final analysis. End points In this post hoc analysis of the GREACE Study, we used the composite end point all events comprising all primary end points of the original study: allcause and coronary mortality, coronary morbidity (nonfatal myocardial infarction, revascularization, unstable angina and congestive heart failure) and stroke. No end point included in the original study was left out and no new end point was included. Statistical analyses Analysis of variance (ANOVA) was used to assess differences in lipid, SCr, CrCl and SUA values within and between treatment groups as well as primary end point rates between the four treatment groups. The Mantel Haenszel method was used to calculate relative risk reductions (RRR) between treatment groups. A two-tailed value of Po0.05 was considered statistically significant. The Statgraphics Plus (Statgraphics, Rockville, MD, USA) program was used for all statistical analyses. Results There were no significant differences between the four treatment groups in demographic characteristics and in baseline CHD risk factors (Table 1) or biochemical parameters (Table 2). There were also no significant differences in drug treatment during the study, except for the use of statins or ACEIs (Table 3). From the entire study population (n ¼ 1600), 880 patients (55%) were on statins and 720 (45%) were not, while 831 (52%) were on ACEI and 769 (48%) were not. From those on statins, 807 were on atorvastatin (783 from the structured care group, mean dose 24 mg/day and 24 from the usual care group, mean dose 15 mg/day). The remaining patients (n ¼ 73) were on various statins: 40 were on simvastatin, mean dose 20 mg/day, 25 on pravastatin, mean dose 24 mg/day and eight were on fluvastatin, mean dose 40 mg/day (all in the usual care group). From those on an ACEI, 328 (40%) were on enalapril (mean dose 11 mg/day), 293 (35%) were on quinapril (mean dose 12 mg/day), and 210 (25%) were on perindopril (4 mg/day). The GREACE study was initiated 6 years ago and that is why newer ACEI and angiotensin receptor blockers were not prescribed. From the 880 patients on statins, 460 were on various ACEIs (Group A) and 420 were not (Group B). From the 720 patients that were not on statins, 371 were on various ACEIs (Group C) and 349 were not (Group D). Lipid values Lipid values at baseline and on-study as well as their changes are shown in Table 2. As expected, Groups A and B had significant changes in lipid values, especially in LDL-C (Table 2). In contrast, patients from Groups C and D who were not on statins did not show significant changes in lipid values during study (Table 2). Blood pressure There were no significant differences in systolic or diastolic blood pressure between the four treatment groups either at baseline or during the study (Table 2). Renal function There were no significant differences in baseline CrCl between the four treatment groups (Table 2). During the study, CrCl in Groups A and B (on statins) was significantly increased (Table 2), while it was reduced in Groups C and D (not on statins) (Table 2). There were no significant differences in

5 Table 4 Comparisons of the percent relative risk reductions (RRR) and 95% confidence intervals (CI) for the primary end point and its individual components in the four treatment groups 785 Cardiovascular death + nonfatal MI Cardiovascular death + nonfatal MI + revascularization All events RRR (95% CI) RRR (95% CI) RRR (95% CI) P-value P-value P-value Group A vs B 34% ( 62 14%) 38% ( 61 3%) 31 % ( 48 6%) Group A vs C 63% ( 78 38%) 63% ( 76 44%) 59% ( 72 48%) o po o Group A vs D 71% ( 82 54%) 70% ( 82 57%) 63% ( 74 51%) o po o Group B vs C 44% ( 65 10%) 40% ( 59 13%) 42% ( 48 19%) Group B vs D 57% ( 73 32%) 55% ( 68 35%) 50% ( 65 36%) o o o Group C vs D 23% ( 48 12%) 22% ( 38 6%) 9% ( 27 10%) MI ¼ myocardial infarction, ACEI ¼ angiotensin-converting enzyme inhibitor, Group A ¼ Statin + ACEI, Group B ¼ Statin no ACEI, Group C ¼ ACEI no statins, Group D ¼ no ACEI no statins. SUA levels at baseline between the four treatment groups (Table 2). However, the mean on treatment values were significantly different: a reduction in Groups A and B and increase in Groups C and D (Table 2). End points During the 3-year follow-up there were 292 cardiovascular events (primary end point). There were 45 (10% of patients) in group A, 61 (14.5%) in group B, 91 in Group C (24.5%), and 95 events in the Group D (27% of patients). Relative risk reductions (RRR-and 95% confidence interval (CI) in the primary end point between Group A and all the rest was significant (Table 4). The RRR in Group A (statin plus ACEI) vs group C (no statin, on ACEI) was 59% (95% CI 72 to 48%, Po0.0001) and 63% (95% CI 74 to 51%, Po0.0001) vs group D (no statin, no ACEI). The RRR in Group A (statin plus ACEI) vs Group B (statin, no ACEI) was 31% (95% CI 48 to 6%, P ¼ 0.01). The RRR in Group B vs Group C was 42% (95% CI 48 to 19%, P ¼ ) and vs Group D it was 50% (95% CI 65 to 36%, Po0.0001). There was no significant difference in RRR between Groups C and D ( 9%, 95% CI 27 10%, P ¼ 0.1) (Table 4). In order to provide an idea of the contribution of the components of the primary end point to event rate reduction, we also provide (Table 4) the percent RRRs (and 95% CI) for cardiovascular death þ nonfatal MI, cardiovascular death þ nonfatal MI þ revascularization (widely used composite primary end points in other studies). Numbers needed to treat (NNT) In Group A, 17 patients needed to be treated with a statin þ ACEI combination for a period of 3 years to avoid one cardiovascular event, in comparison with Group B (on statin, no ACEI), 7.1 patients in comparison to Group C (no statin, on ACEI), and 5.4. in comparison to Group D (no statin, no ACEI). In Group B, 7.4 patients needed to be treated with a statin to avoid one cardiovascular event, in comparison to Group C, and 10.8 patients in comparison to Group D. Other factors that may have influenced clinical outcomes In this open label study compliance to all drugs was evaluated by recording the frequency of prescribing in a personal health book. We report on-study treatment in Table 3 according to this information. There were no significant differences between the four treatment groups in demographic characteristics and CHD factors at baseline (Table 1), in baseline lipid values and renal function (Table 2), in concomitant drug treatment during the study (Table 3), and level of glycemic control 6 9 or in blood pressure during the study (Table 2). Both at entry and during the study, smokers were similarly distributed in the four treatment groups. 6 9 All patients in the four treatment groups received advice on life-style changes and the body mass index (an approximate index of compliance) at baseline and during the study was similar in all groups. Thus, the beneficial effect on clinical outcomes should mainly be attributed to statin or ACEI treatment or both. Discussion In the present analysis involving high-risk dyslipidaemic CHD patients, treatment with a statin plus an ACEI significantly reduced cardiovascular events more than each drug alone or neither drug (Table 4). The RRR of the primary end point in patients on statin treatment (Groups A and B) in comparison to

6 786 those not treated for their dyslipidaemia (Groups C and D) was expected. However, the RRR in the primary end point in patients on the statin þ ACEI combination (Group A) in comparison to patients on a statin alone (Group B) also showed a significant benefit (Table 4), suggesting a synergistic effect of the two drug classes. This has not been previously shown in an end point study. In contrast, treatment with an ACEI but no statin (Group C) compared with those not taking either of these drugs (Group D) did not produce a significant benefit in clinical outcome (Table 4). The EUROPA Trial 5 showed a substantial benefit with a high dose of perindopril (8 mg/day) in 6110 patients vs 6108 patients on placebo (a total of patients in two groups). Our analysis included 1600 patients and only half of them (about 400 patients on ACEI þ statin and another 400 on ACEI alone) were on low doses of various ACEIs. Despite these small numbers there was an event rate reduction when comparing the ACEI alone vs the no ACEI þ no Statin group. This difference (eg 24% in cardiovascular death þ nonfatal MI) may have been statistically significant if the study had included more patients. As expected, the Groups on statins (A and B) had significant reductions in LDL-C levels, a major modulator of clinical benefit in CHD patients, while ACEI use had a neutral effect on lipid values (Table 2). In statin-treated patients there was a significant improvement in renal function and a reduction in SUA levels (Table 2), which are considered to be CHD risk factors, even within the upper limits of the reference range There are now several reports on the effects of statins (mainly atorvastatin and simvastatin) on renal function and SUA levels as well as their contribution to CHD risk reduction. 8,9,15 19 ACEIs (Group A and C) had a neutral effect on renal function and SUA levels (Table 2). These differences in renal function may have influenced the RRRs. Clinical benefit could not be attributed to a reduction in blood pressure because ACEI-treated patients (Groups A and C) had a similar systolic and diastolic blood pressure as the non-acei-treated patients (Groups B and D). This could be attributed to several reasons. ACEI were administered at low doses and patients in the non-acei groups were on higher doses of beta-blockers, CCBs or diuretics. ACEIs were prescribed not only for hypertension but also for secondary CHD prevention, mostly in patients with an anterior wall MI (this is the main reason for the low doses of ACEI) and after an MI (especially of the anterior wall) blood pressure is usually lower than before the MI. We also did not find any additive effect of statins in reducing blood pressure (Group A). This may be because all patients were on treatment for secondary CHD prevention with several antihypertensives, thus blunting any hypotensive effect of statins. Other risk factors that could influence outcome were similar in all four groups (Tables 1 and 3). Various mechanisms 20,21 have been proposed to explain the decrease in ischemic events seen with ACEIs in heart failure patients with or without CHD 22,23 or those with preserved left ventricular function. 24 The Trandolapril Cardiac Evaluation (TRACE) Study 25 reported that long-term treatment with trandolapril in patients with reduced left ventricular function soon after MI significantly reduced the risk of overall mortality, mortality from cardiovascular causes, sudden death and the development of severe heart failure. The Trial on Reversing ENdothelial Dysfunction (TREND) 26 showed that the ACEI quinapril improved endothelial dysfunction in patients who were normotensive and who did not have severe hyperlipidaemia or evidence of heart failure. The Heart Outcomes Prevention Evaluation (HOPE) study 24 confirmed the benefits of ramipril in patients aged 55 years or older, with normal left ventricular function, at high risk of cardiovascular complications (high prevalence of diabetes, hypertension, stroke, and obstructive peripheral vascular disease). In this high-risk cohort, ramipril reduced the risk of MI, worsening and new angina, and the occurrence of coronary revascularization. In the HOPE Trial, only 28% of patients were on lipid lowering treatment. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) 27 provided definitive evidence that blood pressure lowering in patients with previous stroke or transient ischaemic attack significantly reduces the incidence of secondary stroke and major vascular events. There was no report on how many patients were on statins in the PRO- GRESS trial. The EUROPA Trial showed that 8 mg/ day of perindopril can significantly improve outcome in patients with stable CHD without apparent heart failure. 5 The benefits reported for perindopril were in addition to other preventive measures, including aspirin, beta-blockers, and lipid-lowering drugs, and were consistent for all patients. Interestingly, 58% of patients in the EUROPA Trial patients were on statins, in both treatment groups. Therefore, it would be useful to carry out a subgroup analysis of EUROPA. The benefit of the statin þ ACEI combination was assessed in the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). 28 This was an angiographic study (2 2 factorial design). The main finding was that lipid-lowering therapy for 3 5 years with simvastatin resulted in significant slowing of coronary atherosclerosis in normolipidaemic CHD patients. Enalapril (an ACEI) had a neutral effect on CHD. Adding enalapril to simvastatin did not result in an incremental angiographic benefit. However, coronary angiography has its limitations 29 and the participants were low risk CHD patients. Furthermore, SCAT was not an end point study and it only included 460 patients. In contrast to SCAT, another study showed a synergistic effect of simvastatin and enalapril in increasing the response to postischaemic vasodilatation in hypercholesterolaemic patients. 30

7 It is likely that the synergistic/additive effect of statins and ACEI we found could be attributed to the complementary pleiotropic effects of these drugs. 31,32 For example, ACEIs and statins can have beneficial effects on haemostatic and other factors Moreover, it has been shown that treatment with ACEIs 37,38 and statins 39,40 improved vasodilatation and decreased vascular damage. A significant additive effect on structural vascular damage, blood pressure, and vascular resistance was also shown during combination treatment of simvastatin and enalapril in hypertensive subjects. 30,32 We reported that quinapril 41 and atorvastatin 42,43 have a beneficial effect on heart rate variability and aortic elasticity, left ventricular ejection fraction and left ventricular mass index. 43 All these factors could account for an increased event rate Study limitations This post hoc analysis was not double-blind and placebo-controlled, because of ethical and practical restrictions. The main goal was to assess the clinical benefit from NCEP guideline implementation in comparison to that seen with real-life treatment patterns. GREACE was an unsponsored target-based study. Conclusions In dyslipidaemic CHD patients the combination of a statin plus an ACEI reduces cardiovascular events more than a statin alone and substantially more than an ACEI alone. Such a combination should be considered when treating high-risk CHD patients. Treatment with an ACEI but not a statin in comparison to patients not treated with either drug did not significantly reduce clinical events, at least in these small groups of patients. These relationships need to be assessed in the trials already published and should be considered when designing future trials. Declaration of interest The GREACE study was conducted independently; no Company or Institution has supported it financially. 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